Prescription Drugs

CLINICAL PHARMACOLOGY Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown. Nodular Acne Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Claravis, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1 Pharmacokinetics Absorption Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Claravis under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high fat meal when compared with Claravis given under fasted conditions (see Table 2 ). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Claravis capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin. Table 2: Pharmacokinetic Parameters of Is otretinoin Mean (%CV), N = 74 Claravis 2 x 40 mg Capsules AUC0-∞ (ng • hr/mL) Cmax (ng/mL) Tmax (hr) t½ (hr) Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%) Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%) *Eating a standardized high fat meal Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. Metabolism Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. Elimination Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (tmax) of isotretinoin and 4-oxo-isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne. Special Patient Populations Pediatric Patients The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. Table 3: Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38 Parameter Isotretinoin (Single Dose) Isotretinoin (Steady State) Cmax (ng/mL) 573.25 (278.79) 731.98 (361.86) AUC(0 to 12) (ng•hr/mL) 3033.37 (1394.17) 5082 (2184.23) AUC(0 to 24) (ng•hr/mL) 6003.81 (2885.67) -- Tmax (hr)† 6 (1 to 24.6) 4 (0 to 12) CSSmin (ng/mL) -- 352.32 (184.44) H ½( hr) -- 15.69 (5.12) CL/F (L/hr) -- 17.96 (6.27) *The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high fat meal that was used in the study in Table 2. †Median (range) In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxoisotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients. REFERENCES 1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

CLINICAL PHARMACOLOGY Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown. Nodular Acne Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Amnesteem, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. Pharmacokinetics Absorption Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Amnesteem under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high fat meal when compared with Amnesteem given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Amnesteem capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin. Table 2: Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N = 74 Amnesteem 2 x 40 mg Capsules AUC0 -∞ (ng•hr/mL) Cmax (ng/mL) Tmax (hr) t½ (hr) Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%) Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%) *Eating a standardized high fat meal Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. Metabolism Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. After a single 80 mg oral dose of Amnesteem to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. Elimination Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Amnesteem to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxo-isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne. Special Patient Populations Pediatric Patients The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received Amnesteem for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38* Parameter Isotretinoin (Single Dose) Isotretinoin (Steady-State) Cmax (ng/mL) 573.25 (278.79) 731.98 (361.86) AUC(0 to 12) (ng •hr/mL) 3033.37 (1394.17) 5082 (2184.23) AUC(0 to 24) (ng •hr/mL) 6003.81 (2885.67) - Tmax (hr)† 6 (1 - 24.6) 4 (0 to 12) Cssmin (ng/mL) - 352.32 (184.44) T½ (hr) - 15.69 (5.12) CL/F (L/hr) - 17.96 (6.27) *The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2. †Median (range) In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

CLINICAL PHARMACOLOGY Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown. Nodular Acne Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Accutane (isotretinoin) , and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1 Pharmacokinetics Absorption Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Accutane (isotretinoin) under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Accutane (isotretinoin) given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Accutane (isotretinoin) capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin. Table 2 : Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74 Accutane 2 x 40 mg Capsules AUC0-∞ (ng×hr/mL) Cmax (ng/mL) Tmax (hr) t½ (hr) Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%) Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%) *Eating a standardized high-fat meal Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. Metabolism Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxotretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. After a single 80 mg oral dose of Accutane (isotretinoin) to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. Elimination Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14Cactivity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Accutane (isotretinoin) to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne. Special Patient Populations Pediatric Patients The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received Accutane (isotretinoin) for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. Table 3 : Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N=38* Parameter Isotretinoin (Single Dose) Isotretinoin (Steady-State) Cmax (ng/mL) 573.25 (278.79) 731.98 (361.86) AUC(0-12) (nghr/mL) × 3033.37 (1394.17) 5082.00 (2184.23) AUC(0-24) (ng x hr/mL) 6003.81 (2885.67) – Tmax (hr)† 6.00 (1.00-24.60) 4.00 (0-12.00) Cssmin (ng/mL) – 352.32 (184.44) T½ (hr) – 15.69 (5.12) CL/F (L/hr) – 17.96 (6.27) *The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2. †Median (range) In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients. REFERENCES 1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

CLINICAL PHARMACOLOGY Mechanism Of Action ABSORICA is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of ABSORICA is unknown. Pharmacodynamics The pharmacodynamics of ABSORICA are unknown. Pharmacokinetics Absorption Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. ABSORICA is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. ABSORICA is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of ABSORICA is approximately 83% greater than that of Accutane® . ABSORICA is therefore not interchangeable with generic products of Accutane® . A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing ABSORICA 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T½) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase. Table 2: Pharmacokinetic parameters of ABSORICA mean (%CV) following administration of 40 mg strength, N=14 ABSORICA (1 x 40 mg capsules) AUC0-t (ng x hr/mL) Cmax (ng/mL) Tmax (hr) T½ (hr) Fed 6095 (26 %) 395 (39 %) 6.4 (47 %) 22 (25 %) Fasted 4055 (20 %) 314 (26 %) 2.9 (34 %) 24 (28 %) Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin. Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. Metabolism Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. After a single 40 mg oral dose of ABSORICA to 57 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. Elimination Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 40 mg (2 x 20 mg) oral dose of ABSORICA to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T½) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively. Special Patient Populations The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. Animal Toxicology In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). Clinical Studies A double-blind, randomized, parallel group trial (Study 1) was conducted in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of ABSORICA compared to a generic product of Accutane® under fed conditions. Enrolled patients had a weight of 40 to 110 kg with at least 10 nodular lesions on the face and/or trunk. A total of 925 patients were randomized 1:1 to receive ABSORICA or a generic product of Accutane® (isotretinoin). Study patients ranged from 12 to 54 years of age, were approximately 60% male, 40% female, and were 87% White, 4% Black, 6% Asian, and 3% Other. Patients were treated an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks followed by 1 mg/kg/day in two divided doses for the following 16 weeks. Change from Baseline to Week 20 in total nodular lesion count and proportion of patients with at least a 90% reduction in total nodular lesion count from Baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1. Table 3: Efficacy Results at Week 20 (Study 1) ABSORICA N=464 Isotretinoin* N=461 Nodular Lesions Mean Baseline Count 18.4 17.7 Mean Reduction -15.68 -15.62 Patients Achieving 90% Reduction 324 (70%) 344 (75%) *A generic product of Accutane® Figure 1: Total Nodular (Facial and Truncal) Lesion Count by Visit in Study 1

Find Lowest Prices on CLARAVIS (isotretinoin) Capsules USP WARNING CONTRAINDICATIONS AND WARNINGS Claravis™ must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Claravis in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects which have been documented following is otretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals ); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovas cular abnormalities ; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted. If pregnancy does occur during treatment of a female patient who is taking Claravis, Claravismust be discontinued immediately and she should be referred to an Obstetrician- Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Special Prescribing Requirements Because of is otretinoin's teratogenicity and to minimize fetal exposure, Claravis is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program.  Claravis must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS). Table 1: Monthly Required iPLEDGE Interactions Females of Reproductive Potential Male Patients, and Females of Non-Reproductive Potential PRESCRIBER Confirms patient counseling X X Enters the two contraception methods chosen by the patient X Enters pregnancy test results X PATIENT Answers educational questions before every prescription X Enters two forms of contraception X PHARMACIST Contacts system to get an authorization X X DESCRIPTION Isotretinoin, USP a retinoid, is available as Claravis™ (isotretinoin capsules USP), in 10 mg, 20 mg, 30 mg and 40 mg hard gelatin capsules for oral administration. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder. The structural formula is: C20H28O2 Molecular Weight: 300.4 4 Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, titanium dioxide, white wax (beeswax), and vitamin E. In addition, the 10 mg capsule contains black iron oxide and FD&C yellow no. 6. The 20 mg capsule contains black iron oxide, red iron oxide and yellow iron oxide. The 30 mg capsule contains red iron oxide and yellow iron oxide. The 40 mg capsule contains FD&C yellow no. 6. The edible imprinting ink contains: 10 mg strength, D&C red no. 7 calcium lake, FD&C yellow no. 6 aluminum lake, propylene glycol, shellac glaze, and titanium dioxide; 20 mg strength, ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide; 30 mg strength, D&C yellow no. 10 aluminum lake, FD&C blue no.1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide black, propylene glycol, and shellac glaze; 40 mg strength, ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze. Meets dissolution test 2.

AMNESTEEM (isotretinoin) Capsules WARNING CONTRAINDICATIONS AND WARNINGS Amnesteem must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Amnesteem in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects which have been documented following Amnesteem exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ s cores les s than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion and premature births have been reported. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals ); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities ; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted. If pregnancy does occur during treatment of a female patient who is taking Amnesteem, Amnesteem must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Special Prescribing Requirements Because of Amnesteem's teratogenicity and to minimize fetal exposure, Amnesteem is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Amnesteem must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Amnesteem must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS). Table 1: Monthly Required iPLEDGE Interactions Females of Reproductive Potential Males, and Females of Non-Reproductive Potential PRESCRIBER Confirms patient counseling X X Enters the two contraception methods chosen by the patient X Enters pregnancy test results X PATIENT Answers educational questions before every prescription X Enters two forms of contraception X PHARMACIST Contacts system to get an authorization X X DESCRIPTION Isotretinoin, USP a retinoid, is available as Amnesteem (isotretinoin capsules, USP) in 10 mg, 20 mg and 40 mg soft gelatin capsules for oral administration. Each capsule contains yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil and soybean oil. Gelatin capsules contain glycerin, with the following dye systems: 10 mg - red iron oxide paste and black ink; 20 mg - red iron oxide paste, yellow iron oxide paste, titanium dioxide and black ink; 40 mg - red iron oxide paste, yellow iron oxide paste, titanium dioxide and black ink. Meets USP Dissolution Test 4. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

ACCUTANE® (isotretinoin) Capsules CAUSES BIRTH DEFECTS DO NOT GET PREGNANT CONTRAINDICATIONS AND WARNINGS Accutane (isotretinoin) must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Accutane (isotretinoin) in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects which have been documented following Accutane (isotretinoin) exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted. If pregnancy does occur during treatment of a female patient who is taking Accutane (isotretinoin) , Accutane (isotretinoin) must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Special Prescribing Requirements Because of Accutane (isotretinoin) 's teratogenicity and to minimize fetal exposure, Accutane (isotretinoin) is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Accutane (isotretinoin) must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Accutane (isotretinoin) must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS). Table 1 : Monthly Required iPLEDGE Interactions Female Patients of Childbearing Potential Male Patients, And Female Patients Not of Childbearing Potential PRESCRIBER Confirms patient counseling X X Enters the 2 contraception methods chosen by the patient X Enters pregnancy test results X PATIENT Answers educational questions before every prescription X Enters 2 forms of contraception X PHARMACIST Contacts system to get an authorization X X DESCRIPTION Isotretinoin, a retinoid, is available as Accutane (isotretinoin) in 10-mg, 20-mg and 40-mg soft gelatin capsules for oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

Find Lowest Prices on ABSORICA® (isotretinoin) Capsules WARNING CAUSES BIRTH DEFECTS Pregnancy Category X ABSORICA must not be used by female patients who are or may become pregnant [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking ABSORICA in any amount, even for short periods of time [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]. Potentially any fetus exposed during pregnancy can be affected [see Use in Specific Populations]. There are no accurate means of determining whether an exposed fetus has been affected [see WARNING AND PRECAUTIONS and Use in Specific Populations]. Birth defects which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion and premature births have been reported [see Use in Specific Populations]. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia; facial dysmorphia; cleft palate). Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain abnormalities previously noted [see Use in Specific Populations]. If pregnancy does occur during the treatment of a female patient who is taking ABSORICA, ABSORICA must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling [see Use in Specific Populations]. Special Prescribing Requirements Because of the risk of teratogenicity and to minimize fetal exposure, ABSORICA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called iPLEDGE™. Under the ABSORICA REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program [see WARNINGS AND PRECAUTIONS]. DESCRIPTION ABSORICA (isotretinoin) Capsules contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems: 10 mg – iron oxide (yellow) and titanium dioxide; 20 mg – iron oxide (red), and titanium dioxide; 25 mg – FD&C Blue #1, FD&C Yellow #5, FD&C Yellow #6 and titanium dioxide; 30 mg – iron oxide (black, red and yellow) and titanium dioxide; 35 mg – FD&C Blue #2, iron oxide (black, red and yellow) and titanium dioxide; 40 mg – iron oxide (black, red and yellow) and titanium dioxide. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is: Meets USP Dissolution Test 3

INDICATIONS Severe Recalcitrant Nodular Acne Claravis (isotretinoin capsules USP) is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Claravis should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Claravis is indicated only for those female patients who are not pregnant, because Claravis can cause severe birth defects (see BOXED CONTRAINDICATIONS AND WARNINGS). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Claravis. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). DOSAGE AND ADMINISTRATION Claravis should be administered with a meal (see PATIENT INFORMATION). The recommended dosage range for Claravis is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects - some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Claravis with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions. The safety of once daily dosing with Claravis has not been established. Once daily dosing is not recommended. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Claravis, even in low doses, has not been studied, and is not recommended. It is important that Claravis be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Claravis on bone loss is unknown (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis and Premature Epiphyseal Closure). Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS). Table 4: Claravis Dosing by Body Weight (Based on Administration With Food) Body Weight Total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg * 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 * See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day. Information For Pharmacists Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866- 495-0654) to obtain an authorization and the “do not dis pense to patient after” date. Claravis must only be dispensed in no more than a 30 day supply. REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM. A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patient. REFERENCES 8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984. HOW SUPPLIED Claravis™ (isotretinoin capsules USP) is available as: 10 mg: Two-piece hard gelatin capsule with light gray opaque cap and light gray opaque body filled with yellow oily dispersion. Imprinted in red ink barr on one piece and 934 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1054-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1054-56). 20 mg: Two-piece hard gelatin capsule with brown opaque cap and brown opaque body filled with yellow oily dispersion. Imprinted in white ink barr on one piece and 935 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1055-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1055-56). 30 mg: Two-piece hard gelatin capsule with orange opaque cap and orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 454 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1056-86). 40 mg: Two-piece hard gelatin capsule with light orange opaque cap and light orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 936 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1057-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1057-56). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. REFERENCES 1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980. TEVA PHARMACEUTICALS USA, INC., North Wales, PA 19454. Revised: Aug 2016

INDICATIONS Severe Recalcitrant Nodular Acne Amnesteem is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Amnesteem should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Amnesteem is indicated only for those female patients who are not pregnant, because Amnesteem can cause severe birth defects (see BOXED CONTRAINDICATIONS AND WARNINGS). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Amnesteem. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). DOSAGE AND ADMINISTRATION Amnesteem should be administered with a meal (see PATIENT INFORMATION). The recommended dosage range for Amnesteem is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5 and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects - some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Amnesteem with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions. The safety of once daily dosing with Amnesteem has not been established. Once daily dosing is not recommended. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Amnesteem, even in low doses, has not been studied, and is not recommended. It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Amnesteem on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS). Table 4: Amnesteem Dosing by Body Weight (Based on Administration with Food) Body Weight Total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg * 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 *See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day. Information For Pharmacists Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495- 0654) to obtain an authorization and the “do not dispense to patient after” date. Amnesteem must only be dispensed in no more than a 30 day supply. REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM. An Amnesteem Medication Guide must be given to the patient each time Amnesteem is dispensed, as required by law. This Amnesteem Medication Guide is an important part of the risk management program for the patient. HOW SUPPLIED Amnesteem (isotretinoin capsules, USP) contain 10 mg, 20 mg or 40 mg of isotretinoin, USP. The 10 mg capsules are reddish brown and imprinted with I10. They are available as follows: NDC 0378-6611-93 Cartons of 30 containing 3 Prescription Packs of 10 capsules The 20 mg capsules are reddish brown and cream and imprinted with I20. They are available as follows: NDC 0378-6612-93 Cartons of 30 containing 3 Prescription Packs of 10 capsules The 40 mg capsules are orange-brown and imprinted with I40. They are available as follows: NDC 0378-6614-93 Cartons of 30 containing 3 Prescription Packs of 10 capsules Storage: Store at 68° to 77°F (20° to 25°C). [See USP Controlled Room Temperature.] Protect from light. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.. Manufactured by: Catalent Pharma Solutions 74 rue Principale, 67930 Beinheim, France. Revised: Mar 2015 REFERENCES 1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980. 8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.

INDICATIONS Severe Recalcitrant Nodular Acne Accutane (isotretinoin) is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Accutane (isotretinoin) should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Accutane (isotretinoin) is indicated only for those female patients who are not pregnant, because Accutane (isotretinoin) can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Accutane (isotretinoin) . The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). DOSAGE AND ADMINISTRATION Accutane (isotretinoin) should be administered with a meal (see PATIENT INFORMATION). The recommended dosage range for Accutane (isotretinoin) is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects — some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2.0 mg/kg/day, as tolerated. Failure to take Accutane (isotretinoin) with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions. The safety of once daily dosing with Accutane (isotretinoin) has not been established. Once daily dosing is not recommended. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Accutane (isotretinoin) , even in low doses, has not been studied, and is not recommended. It is important that Accutane (isotretinoin) be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Accutane on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS). Table 4 : Accutane (isotretinoin) Dosing by Body Weight (Based on Administration With Food) Body Weight Total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg* 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 *See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1.0 mg/kg/day. INFORMATION FOR PHARMACISTS Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866495-0654) to obtain an authorization and the “do not dispense to patient after” date. Accutane (isotretinoin) must only be dispensed in no more than a 30-day supply. REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM. An Accutane (isotretinoin) Medication Guide must be given to the patient each time Accutane (isotretinoin) is dispensed, as required by law. This Accutane (isotretinoin) Medication Guide is an important part of the risk management program for the patient. HOW SUPPLIED Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE (isotretinoin) 10 ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0155-49). Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE (isotretinoin) 20 ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0169-49). Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE (isotretinoin) 40 ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0156-49). Storage Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light. REFERENCES 1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cisretinoic acid and acne. Lancet 2:1048-1049, 1980. 8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984. Distributed by: Roche Laboratories Inc., 340 Kingsland Street, Nutley, New Jersey 07110-1199. PI Revised: January 2010.

INDICATIONS ABSORICA is a retinoid indicated for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, means “many” as opposed to “few or several” nodules. Because of significant adverse reactions associated with its use, ABSORICA should be reserved for patients with multiple severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, ABSORICA is indicated only for those female patients who are not pregnant, because ABSORICA can cause severe birth defects [see CONTRAINDICATIONS]. Limitations of Use A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience with isotretinoin has shown that patients may continue to improve following treatment with isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth [see WARNINGS AND PRECAUTIONS]. As a part of the iPLEDGE program, ABSORICA may only be administered to patients enrolled in the program [see WARNINGS AND PRECAUTIONS]. DOSAGE AND ADMINISTRATION Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA [see WARNINGS AND PRECAUTIONS]. The required laboratory testing must be completed prior to dosing ABSORICA [see Laboratory Testing below]. Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA [see Use in Specific Populations]. Recommended Dosage The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid [see PATIENT INFORMATION]. The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended. Table 1: ABSORICA Dosing by Body Weight (Based on Administration With or Without Food) Body Weight Total Daily (mg) Kilograms Pounds 0.5 mg/kg 1 mg/kg 2 mg/kg 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 Dosage Range In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Duration Of Use A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown [see WARNINGS AND PRECAUTIONS]. Laboratory Testing Pregnancy Testing [See Use in Specific Populations] Lipid Profile Perform a fasting lipid profile including triglycerides prior to use of ABSORICA [see WARNINGS AND PRECAUTIONS]. Liver Function Test Perform liver function tests prior to use of ABSORICA [see WARNINGS AND PRECAUTIONS]. HOW SUPPLIED Dosage Forms And Strengths ABSORICA is available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules. 10 mg: Dark yellow, opaque, capsule imprinted with black ink “G 240” on cap and “10” on the body 20 mg: Red, opaque, capsule imprinted with black ink “G 241” on cap and “20” on the body 25 mg: Green, opaque, capsule imprinted with white ink “G 342” on cap and “25” on the body 30 mg: Brown, opaque, capsule imprinted with white ink “G 242” on cap and “30” on the body 35 mg: Dark blue, opaque, capsule imprinted with white ink “G 343” on cap and “35” on the body 40 mg: Brown and red, capsule imprinted with white ink “G 325” on cap and “40” on the body ABSORICA (isotretinoin) Capsules are supplied as follows: 10 mg: Dark yellow, opaque, capsule imprinted with black ink “G 240” on cap and “10” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-115-31 20 mg: Red, opaque, capsule imprinted with black ink “G 241” on cap and “20” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-116-31 25 mg: Green, opaque, capsule imprinted with white ink “G 342” on cap and “25” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-133-31 30 mg: Brown, opaque, capsule imprinted with white ink “G 242” on cap and “30” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-117-31 35 mg: Dark blue, opaque, capsule imprinted with white ink “G 343” on cap and “35” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-134-31 40 mg: Brown and red, capsule imprinted with white ink “G 325” on cap and “40” on the body Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-118-31 Storage And Handling Store at 20° C -25° C (68° F -77° F), excursion permitted between 15° C 30° C (59° F -86° F) [see USP controlled room temperature]. Protect from light. Manufactured for: Ranbaxy Laboratories Inc., Jacksonville, FL 32257 USA GK-244. Revised: September 2015.

PATIENT INFORMATION Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor. Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand. *A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent. _______________________________________________(Patient's Name) 1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin. Initial: __________ 2. I understand that I must not get pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin. Initial: __________ 3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective forms of birth control (contraception) at the s ame time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am postmenopausal. Initial: __________ 4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use two different birth control methods at the same time, starting one month before, during, and for one month after stopping therapy every time I have sexual intercourse, even if one of the methods I choose is hormonal birth control. Initial: __________ 5. I understand that the following are effective forms of birth control: Primary forms tubal sterilization (tying my tubes) partner's vasectomy intrauterine device hormonal (combination birth control pills, skin patches, shots, under-the skin implants, or vaginal ring. Secondary forms Barrier forms: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: vaginal sponge (contains spermicide) A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm. I understand that at least one of my two forms of birth control must be a primary method. Initial: __________ 6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products. Initial: __________ 7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation. Initial: __________ 8. I must begin using the birth control methods I have chosen as described above at least one month before I start taking isotretinoin. Initial: __________ 9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment or as instructed by my doctor. I will then have one pregnancy test; in a lab. every month during treatment at the end of treatment and 1 month after stopping treatment I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab. Initial:__________ 10. I have read and understand the materials my doctor has provided to me, including The iPLEDGE Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The iPLEDGE Program Patient Introductory Brochure. My doctor provided me and asked me to watch a video about birth control and a video about birth defects and isotretinoin. I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control. Initial: __________ 11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control, or have sexual intercourse without using my two birth control methods at any time. Initial: __________ 12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin, and government health regulatory authorities. Initial: __________ 13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I: have had two negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription. have chosen and agreed to use two forms of effective birth control at the same time. At least one method must be a primary form of birth control, unless I have chosen never to have sexual contact with a male (abstinence), or I have undergone a hysterectomy. I must use two forms of birth control for at least one month before I start isotretinoin therapy, during therapy, and for one month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy. have signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin. have been informed of and understand the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within 1 month of the last dose. have interacted with the iPLEDGE Program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control. Initial: ______ My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to get pregnant one month before, during isotretinoin treatment, or for one month after I stop taking is otretinoin. Initial: ______ I now authorize my doctor ________________ to begin my treatment with isotretinoin. Patient Signature:_____________________________________ Date: ______ Parent/Guardian Signature (if under age 18):________________ Date:______ Please print: Patient Name and Address_______________________________ ______________________________ Telephone _______________________ I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to females of reproductive potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability. Doctor Signature: __________________________________ Date: ______ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. Patient Information/Informed Consent (for all patients ) To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor. Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement. Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin. 1. I,___________________________________________(Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars. Initials: __________ 2. My doctor has told me about my choices for treating my acne. Initials: __________ 3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)]. Initials: __________ 4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below). Initials: __________ 5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there. Initials: __________ 6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems. Initials: __________ 7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I: Start to feel sad or have crying spells Lose interest in activities I once enjoyed Sleep too much or have trouble sleeping Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) Have a change in my appetite or body weight Have trouble concentrating Withdraw from my friends or family Feel like I have no energy Have feelings of worthlessness or guilt Start having thoughts about hurting myself or taking my own life (suicidal thoughts) Start acting on dangerous impulses Start seeing or hearing things that are not real Initials: __________ 8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects. Initials: __________ 9. Isotretinoin will be prescribed just for me - I will not share isotretinoin with other people because it may cause serious side effects, including birth defects. Initials: __________ 10. I will not give blood while taking isotretinoin or for one month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects. Initials: __________ 11. I have read the The iPLEDGE Program Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received. Initials: __________ 12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin. Initials: __________ I now allow my doctor _______________________ to begin my treatment with isotretinoin. Patient Signature:_________________________________Date:____________________ Parent/Guardian Signature (if under age 18):____________________Date: ___________ Patient Name (print)__________________________________ Patient Address___________________________________ Telephone (____-____-____) I have: fully explained to the patient, ______________________________, the nature and purpose of isotretinoin treatment, including its benefits and risks. provided the patient with the appropriate educational materials, The iPLEDGE Program Patient Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin. answered those questions to the best of my ability. Doctor Signature:_______________________________________Date:___________ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. MEDICATION GUIDE CLARAVIS (klar-uh-vis ) (isotretinoin) Capsules USP Read the Medication Guide that comes with Claravis before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Claravis ? Claravis is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics. Because Claravis can cause birth defects, Claravis is only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE Program. Claravis may cause serious mental health problems. Birth defects (deformed babies ), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. Female patients who are pregnant or who plan to become pregnant must not take Claravis. Female patients must not get pregnant: for 1 month before starting Claravis while taking Claravis for 1 month after stopping Claravis. If you get pregnant while taking Claravis, s top taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to: FDA MedWatch at 1-800-FDA-1088, and the iPLEDGE pregnancy registry at 1-866-495-0654 2. Serious mental health problems. Claravis may cause: depression psychosis (seeing or hearing things that are not real) suicide. Some patients taking Claravis have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. Stop Claravis and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis : start to feel sad or have crying spells lose interest in activities you once enjoyed sleep too much or have trouble sleeping become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) have a change in your appetite or body weight have trouble concentrating withdraw from your friends or family feel like you have no energy have feelings of worthlessness or guilt start having thoughts about hurting yourself or taking your own life (suicidal thoughts) start acting on dangerous impulses start seeing or hearing things that are not real After stopping Claravis, you may also need follow-up mental health care if you had any of these symptoms. What is Claravis ? Claravis is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Claravis can cause serious side effects (see “What is the most important information I should know about Claravis ?”). Claravis can only be: prescribed by doctors that are registered in the iPLEDGE Program dispensed by a pharmacy that is registered with the iPLEDGE Program given to patients who are registered in the iPLEDGE Program and agree to do everything required in the program What is severe nodular acne? Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars. Who should not take Claravis ? Do not take Claravis if you are pregnant, plan to become pregnant, or become pregnant during Claravis treatment. Claravis causes severe birth defects. See “What is the most important information I should know about Claravis ?” Do not take Claravis if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in Claravis. What should I tell my doctor before taking Claravis ? Tell your doctor if you or a family member has any of the following health conditions : mental problems asthma liver disease diabetes heart disease bone loss (osteoporosis) or weak bones an eating problem called anorexia nervosa (where people eat too little) food or medicine allergies Tell your doctor if you are pregnant or breastfeeding. Claravis must not be used by women who are pregnant or breastfeeding. Tell your doctor about all of the medicines you take including pres cription and nonprescription medicines, vitamins and herbal supplements. Claravis and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take: Vitamin A supplements. Vitamin A in high doses has many of the same side effects as Claravis. Taking both together may increase your chance of getting side effects. Tetracycline antibiotics. Tetracycline antibiotics taken with Claravis can increase the chances of getting increased pressure in the brain. Progestin-only birth control pills (mini-pills ). They may not work while you take Claravis. Ask your doctor or pharmacist if you are not sure what type you are using. Dilantin (phenytoin). This medicine taken with Claravis may weaken your bones. Corticosteroid medicines. These medicines taken with Claravis may weaken your bones. St. John's Wort. This herbal supplement may make birth control pills work less effectively. These medicines should not be used with Claravisunless your doctor tells you it is okay. Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor. How should I take Claravis ? You must take Claravis exactly as prescribed. You must also follow all the instructions of the iPLEDGE Program. Before prescribing Claravis, your doctor will: explain the iPLEDGE Program to you have you sign the Patient Information/Informed Consent form (for all patients). Female patients who can get pregnant must also sign another consent form. You will not be prescribed Claravis if you cannot agree to or follow all the instructions of the iPLEDGE Program. You will get no more than a 30 day supply of Claravis at a time. This is to make sure you are following the Claravis iPLEDGE Program. You should talk with your doctor each month about side effects. The amount of Claravis you take has been specially chosen for you. It is based on your body weight, and may change during treatment. Take Claravis 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your Claravis capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Claravis can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole. If you miss a dose, just skip that dose. Do not take 2 doses at the same time. If you take too much Claravis or overdose, call your doctor or poison control center right away. Your acne may get worse when you first start taking Claravis. This should last only a short while. Talk with your doctor if this is a problem for you. You must return to your doctor as directed to make sure you don't have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from Claravis. Female patients who can get pregnant will get a pregnancy test each month. Female patients who can get pregnant must agree to use two separate forms of effective birth control at the same time one month before, while taking, and for one month after taking Claravis. You must access the iPLEDGE system to answer questions about the program requirements and to enter your two chosen forms of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654. You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes Claravis. If you have sex at any time without using two forms of effective birth control, get pregnant, or miss your expected period, stop using Claravis and call your doctor right away. What should I avoid while taking Claravis ? Do not get pregnant while taking Claravis and for one month after stopping Claravis. See “What is the most important information I should know about Claravis ?” Do not breastfeed while taking Claravis and for one month after stopping Claravis. We do not know if Claravis can pass through your milk and harm the baby. Do not give blood while you take Claravis and for one month after stopping Claravis. If someone who is pregnant gets your donated blood, her baby may be exposed to Claravis and may be born with birth defects. Do not take other medicines or herbal products with Claravis unless you talk to your doctor. See “What should I tell my doctor before taking Claravis ?” Do not drive at night until you know if Claravis has affected your vision. Claravis may decrease your ability to see in the dark. Do not have cosmetic procedures to smooth your s kin, including waxing, dermabrasion, or laser procedures, while you are using Claravis and for at least 6 months after you stop. Claravis can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures. Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Claravis may make your skin more sensitive to light. Do not share Claravis with other people. It can cause birth defects and other serious health problems. What are the possible side effects of Claravis ? Claravis can cause birth defects (deformed babies ), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. See “What is the most important information I should know about Claravis ?” Claravis may cause serious mental health problems. See “What is the most important information I should know about Claravis ?” serious brain problems. Claravis can increase the pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking Claravis and call your doctor right away if you get any of these signs of increased brain pressure: bad headache blurred vision dizziness nausea or vomiting seizures (convulsions) stroke skin problems. Skin rash can occur in patients taking Claravis. In some patients a rash can be serious. Stop using Claravis and call your doctor right away if you develop conjunctivitis (red or inflamed eyes, like “pink eye”), a rash with a fever, blisters on legs, arms or face and/or sores in your mouth, throat, nose, eyes, or if your skin begins to peel. stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking Claravis. Stop taking Claravis and call your doctor if you get: severe stomach, chest or bowel pain trouble swallowing or painful swallowing new or worsening heartburn diarrhea rectal bleeding yellowing of your skin or eyes dark urine bone and muscle problems. Claravis may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with Claravis. Tell your doctor if you get: back pain joint pain broken bone. Tell all healthcare providers that you take Claravis if you break a bone. Stop Claravis and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage. Claravis may stop long bone growth in teenagers who are still growing. hearing problems. Stop using Claravis and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent. vision problems. Claravis may affect your ability to see in the dark. This condition usually clears up after you stop taking Claravis, but it may be permanent. Other serious eye effects can occur. Stop taking Claravis and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking Claravis and after treatment. lipid (fats and cholesterol in blood) problems. Claravis can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when Claravis treatment is finished. serious allergic reactions. Stop taking Claravis and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking Claravis and call your doctor if you get a fever, rash, or red patches or bruises on your legs. blood sugar problems. Claravis may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot. decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel weak. The common, less serious side effects of Claravis are dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does not go away. These are not all of the possible side effects with Claravis. Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Claravis ? Store at 20° to 25°C (68° to 77°F). Protect from light. Keep Claravis and all medicines out of the reach of children. General Information about Claravis. Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Claravis for a condition for which it was not prescribed. Do not give Claravis to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Claravis. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Claravis that is written for healthcare professionals. You can also call iPLEDGE Program at 1-866-495-0654 or visit www.ipledgeprogram.com. What are the ingredients in Claravis ? Active Ingredient: Isotretinoin Inactive Ingredients : Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, titanium dioxide, white wax (beeswax), and vitamin E. In addition, the 10 mg capsule contains black iron oxide and FD&C yellow no. 6. The 20 mg capsule contains black iron oxide, red iron oxide and yellow iron oxide. The 30 mg capsule contains red iron oxide and yellow iron oxide. The 40 mg capsule contains FD&C yellow no. 6. The edible imprinting ink contains: 10 mg strength, D&C red no. 7 calcium lake, FD&C yellow no. 6 aluminum lake, propylene glycol, shellac glaze, and titanium dioxide; 20 mg strength, ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide; 30 mg strength, D&C yellow no. 10 aluminum lake, FD&C blue no.1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide black, propylene glycol, and shellac glaze; 40 mg strength, ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze. This Medication Guide has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION PATIENT INFORMATION/INFORMED CONSENT ABOUT BIRTH DEFECTS (for female patients who can get pregnant) To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor. Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand. *A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent. ___________________________(Patient's Name) 1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin. Initial: ______ 2. I understand that I must not get pregnant one month before, during the entire time of my treatment and for one month after the end of my treatment with isotretinoin. Initial: ______ 3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective forms of birth control (contraception) at the s ame time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am post-menopausal. Initial: ______ 4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use two different birth control methods at the same time starting one month before, during, and for one month after stopping therapy every time I have sexual intercourse, even if one of the methods I choose is hormonal birth control. Initial: ______ 5. I understand that the following are effective forms of birth control: Primary forms tubal sterilization (tying my tubes) partner’s vasectomy intrauterine device hormonal (combination birth control pills, skin patches, shots, under-the-skin implants or vaginal ring) Secondary forms Barrier: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: vaginal sponge (contains spermicide) A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm I understand that at least one of my two forms of birth control must be a primary method. Initial: ______ 6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products. Initial: ______ 7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation. Initial: ______ 8. I must begin using the birth control methods I have chosen as described above at least one month before I start taking isotretinoin. Initial: ______ 9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment or as instructed by my doctor. I will then have one pregnancy test; in a lab. every month during treatment at the end of treatment and 1 month after stopping treatment I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab. Initial: ______ 10. I have read and understand the materials my doctor has provided to me, including The iPLEDGE Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The iPLEDGE Program Patient Introductory Brochure My doctor provided me and asked me to watch the DVD containing a video about birth control and a video about birth defects and isotretinoin. I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control. Initial: ______ 11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control or have sexual intercourse without using my two birth control methods at any time. Initial: ______ 12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin and government health regulatory authorities. Initial: ______ 13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I: have had two negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription. have chosen and agreed to use two forms of effective birth control at the same time. At least one method must be a primary form of birth control, unless I have chosen never to have sexual contact with a male (abstinence), or I have undergone a hysterectomy. I must use two forms of birth control for at least one month before I start isotretinoin therapy, during therapy and for one month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy. Have signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin. have been informed of and understand the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. have interacted with the iPLEDGE Program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control. Initial: ______ My doctor has answered all my questions about is otretinoin and I understand that it is my res ponsibility not to get pregnant one month before, during is otretinoin treatment, or for one month after Is top taking is otretinoin. Initial: ______ I now authorize my doctor ____________________to begin my treatment with isotretinoin. Patient Signature:________________________________________ Date: _____________ Parent/Guardian Signature (if under age 18):___________________ Date:_____________ Please print: Patient Name and Address_________________________________________ _________________________________________ Telephone ______________________ I have fully explained to the patient, ________________________________, the nature and purpose of the treatment described above and the risks to females of reproductive potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability. Doctor Signature: ________________________________________ Date: _____________ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. PATIENT INFORMATION/INFORMED CONSENT (for all patients ): To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor. Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement. Do not sign this agreement and do not take is otretinoin if there is anything that you do not understand about all the information you have received about using is otretinoin. I, ________________________________________________________________, (Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars. Initials: ______ 2. My doctor has told me about my choices for treating my acne. Initials: ______ 3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant).] Initials: ______ 4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below). Initials: ______ 5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there. Initials: ______ 6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide or had any other serious mental problems. Initials: ______ 7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I: Start to feel sad or have crying spells Lose interest in activities I once enjoyed Sleep too much or have trouble sleeping Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) Have a change in my appetite or body weight Have trouble concentrating Withdraw from my friends or family Feel like I have no energy Have feelings of worthlessness or guilt Start having thoughts about hurting myself or taking my own life (suicidal thoughts) Start acting on dangerous impulses Start seeing or hearing things that are not real Initials: ______ 8. I agree to return to see my doctor every month I take is otretinoin to get a new prescription for is otretinoin, to check my progress and to check for signs of side effects. Initials: ______ 9. Isotretinoin will be prescribed just for me - I will not share isotretinoin with other people because it may cause serious side effects, including birth defects. Initials: ______ 10. I will not give blood while taking isotretinoin or for one month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects. Initials: ______ 11. I have read The iPLEDGE Program Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received. Initials: ______ 12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin. Initials: ______ I now allow my doctor _______________________ to begin my treatment with isotretinoin. Patient Signature: ________________________________________ Date: _____________ Parent/Guardian Signature (if under age 18): ___________________ Date: _____________ Patient Name (print) _________________________________________________________ Patient Address ________________________________ Telephone (_____._____._____) I have: fully explained to the patient, _____________________________________, the nature and purpose of isotretinoin treatment, including its benefits and risks provided the patient with the appropriate educational materials, The iPLEDGE Program Patient Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin answered those questions to the best of my ability Doctor Signature: ________________________________________ Date: _____________ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. MEDICATION GUIDE AMNESTEEM (AM-NES-TEAM) (Isotretinoin Capsules ) Read the Medication Guide that comes with Amnesteem before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Amnesteem? Amnesteem® is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics. Because Amnesteem can cause birth defects, Amnesteem is only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE Program. Amnesteem may cause serious mental health problems. 1. Birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby and early (premature) births. Female patients who are pregnant or who plan to become pregnant must not take Amnesteem. Female patients must not get pregnant: for 1 month before starting Amnesteem while taking Amnesteem for 1 month after stopping Amnesteem. If you get pregnant while taking Amnesteem, stop taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to: FDA MedWatch at 1-800-FDA-1088, and the iPLEDGE pregnancy registry at 1-866-495-0654 2. Serious mental health problems. Amnesteem may cause: depression psychosis (seeing or hearing things that are not real) suicide. Some patients taking Amnesteem have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. Stop Amnesteem and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis : start to feel sad or have crying spells lose interest in activities you once enjoyed sleep too much or have trouble sleeping become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) have a change in your appetite or body weight have trouble concentrating withdraw from your friends or family feel like you have no energy have feelings of worthlessness or guilt start having thoughts about hurting yourself or taking your own life (suicidal thoughts) start acting on dangerous impulses start seeing or hearing things that are not real After stopping Amnesteem, you may also need follow-up mental health care if you had any of these symptoms. What is Amnesteem? Amnesteem is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Amnesteem can cause serious side effects (see “What is the most important information I should know about Amnesteem?”). Amnesteem can only be: prescribed by doctors that are registered in the iPLEDGE Program dispensed by a pharmacy that is registered with the iPLEDGE Program given to patients who are registered in the iPLEDGE Program and agree to do everything required in the program What is severe nodular acne? Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars. Who should not take Amnesteem? Do not take Amnesteem if you are pregnant, plan to become pregnant or become pregnant during Amnesteem treatment. Amnesteem causes severe birth defects. See “What is the most important information I should know about Amnesteem?” Do not take Amnesteem if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in Amnesteem. What should I tell my doctor before taking Amnesteem? Tell your doctor if you or a family member has any of the following health conditions : mental problems asthma liver disease diabetes heart disease bone loss (osteoporosis) or weak bones an eating problem called anorexia nervosa (where people eat too little) food or medicine allergies Tell your doctor if you are pregnant or breast-feeding. Amnesteem must not be used by women who are pregnant or breast-feeding. Tell your doctor about all of the medicines you take including pres cription and non-pres cription medicines, vitamins and herbal s upplements. Amnesteem and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take: Vitamin A supplements. Vitamin A in high doses has many of the same side effects as Amnesteem. Taking both together may increase your chance of getting side effects. Tetracycline antibiotics. Tetracycline antibiotics taken with Amnesteem can increase the chances of getting increased pressure in the brain. Proges tin-only birth control pills (mini-pills ). They may not work while you take Amnesteem. Ask your doctor or pharmacist if you are not sure what type you are using. Dilantin (phenytoin). This medicine taken with Amnesteem may weaken your bones. Corticosteroid medicines. These medicines taken with Amnesteem may weaken your bones. St. John's Wort. This herbal supplement may make birth control pills work less effectively. These medicines should not be used with Amnesteem unless your doctor tells you it is okay. Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor. How should I take Amnesteem? You must take Amnesteem exactly as prescribed. You must also follow all the instructions of the iPLEDGE Program. Before prescribing Amnesteem, your doctor will: explain the iPLEDGE Program to you have you sign the Patient Information/Informed Consent form (for all patients). Female patients who can get pregnant must also sign another consent form. You will not be prescribed Amnesteem if you cannot agree to or follow all the ins tructions of the iPLEDGE Program. You will get no more than a 30 day supply of Amnesteem at a time. This is to make sure you are following the Amnesteem iPLEDGE Program. You should talk with your doctor each month about side effects. The amount of Amnesteem you take has been specially chosen for you. It is based on your body weight, and may change during treatment. Take Amnesteem 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your Amnesteem capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Amnesteem can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole. If you miss a dose, just skip that dose. Do not take two doses at the same time. If you take too much Amnesteem or overdose, call your doctor or poison control center right away. Your acne may get worse when you first start taking Amnesteem. This should last only a short while. Talk with your doctor if this is a problem for you. You must return to your doctor as directed to make sure you don't have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from Amnesteem. Female patients who can get pregnant will get a pregnancy test each month. Female patients who can get pregnant must agree to use two separate forms of effective birth control at the same time one month before, while taking and for one month after taking Amnesteem. You must access the iPLEDGE system to answer questions about the program requirements and to enter your two chosen forms of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654. You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes Amnesteem. If you have sex at any time without using two forms of effective birth control, get pregnant or miss your expected period, stop using Amnesteem and call your doctor right away. What should I avoid while taking Amnesteem? Do not get pregnant while taking Amnesteem and for one month after stopping Amnesteem. See “What is the most important information I should know about Amnesteem?” Do not breas t-feed while taking Amnesteem and for one month after stopping Amnesteem. We do not know if Amnesteem can pass through your milk and harm the baby. Do not give blood while you take Amnesteem and for one month after stopping Amnesteem. If someone who is pregnant gets your donated blood, her baby may be exposed to Amnesteem and may be born with birth defects. Do not take other medicines or herbal products with Amnesteem unless you talk to your doctor. See “What should I tell my doctor before taking Amnesteem?” Do not drive at night until you know if Amnesteem has affected your vision. Amnesteem may decrease your ability to see in the dark. Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, while you are using Amnesteem and for at leas t 6 months after you s top. Amnesteem can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures. Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Amnesteem may make your skin more sensitive to light. Do not share Amnesteem with other people. It can cause birth defects and other serious health problems. What are the possible side effects of Amnesteem? Amnesteem can cause birth defects (deformed babies ), loss of a baby before birth (miscarriage), death of the baby and early (premature) births. See “What is the most important information I should know about Amnesteem?” Amnesteem may cause serious mental health problems. See “What is the most important information I should know about Amnesteem?” serious brain problems. Amnesteem can increase the pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking Amnesteem and call your doctor right away if you get any of these signs of increased brain pressure: bad headache blurred vision dizziness nausea or vomiting seizures (convulsions) stroke skin problems. Skin rash can occur in patients taking Amnesteem. In some patients a rash can be serious. Stop using Amnesteem and call your doctor right away if you develop conjunctivitis (red or inflamed eyes, like “pink eye”), a rash with a fever, blisters on legs, arms or face and/or sores in your mouth, throat, nose, eyes, or if your skin begins to peel. stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines) and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking Amnesteem. Stop taking Amnesteem and call your doctor if you get: severe stomach, chest or bowel pain trouble swallowing or painful swallowing new or worsening heartburn diarrhea rectal bleeding yellowing of your skin or eyes dark urine bone and muscle problems. Amnesteem may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with Amnesteem. Tell your doctor if you get: back pain joint pain broken bone. Tell all healthcare providers that you take Amnesteem if you break a bone. Stop Amnesteem and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage. Amnesteem may stop long bone growth in teenagers who are still growing. hearing problems. Stop using Amnesteem and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent. vision problems. Amnesteem may affect your ability to see in the dark. This condition usually clears up after you stop taking Amnesteem, but it may be permanent. Other serious eye effects can occur. Stop taking Amnesteem and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking Amnesteem and after treatment. lipid (fats and cholesterol in blood) problems. Amnesteem can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when Amnesteem treatment is finished. serious allergic reactions. Stop taking Amnesteem and get emergency care right away if you develop hives, a swollen face or mouth or have trouble breathing. Stop taking Amnesteem and call your doctor if you get a fever, rash or red patches or bruises on your legs. blood sugar problems. Amnesteem may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot. decreased red and white blood cells. Call your doctor if you have trouble breathing, faint or feel weak. The common, less serious side effects of Amnesteem are dry skin, chapped lips, dry eyes and dry nose that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does not go away. These are not all of the possible side effects with Amnesteem. Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088. How should I store Amnesteem? Store at 68° to 77°F (20° to 25°C). Protect from light. Keep Amnesteem and all medicines out of the reach of children. General Information about Amnesteem Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Amnesteem for a condition for which it was not prescribed. Do not give Amnesteem to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Amnesteem. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Amnesteem that is written for healthcare professionals. You can also call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX), the iPLEDGE Program at 1-866-495-0654 or visit www.ipledgeprogram.com. What are the ingredients in Amnesteem? Active Ingredient: Is otretinoin Inactive Ingredients : butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, soybean oil and yellow wax. Gelatin capsules contain glycerin, with the following dye systems: 10 mg - black ink and red iron oxide paste; 20 mg - black ink, red iron oxide paste, titanium dioxide and yellow iron oxide paste; 40 mg - black ink, red iron oxide paste, titanium dioxide and yellow iron oxide paste. This Medication Guide has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor. Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand. *A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent. ______________________________________________________________ (Patient's Name) 1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin. Initial: ______ 2. I understand that I must not get pregnant 1 month before, during the entire time of my treatment, and for 1 month after the end of my treatment with isotretinoin. Initial: ______ 3. I understand that I must avoid sexual intercourse completely, o r I must use 2 separate, effective forms of birth control (contraception) at the same time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am post-menopausal. Initial: ______ 4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use 2 different birth control methods at the same time, starting 1 month before, during, and for 1 month after stopping therapy every time I have sexual intercourse, even if 1 of the methods I choose is hormonal birth control. Initial: ______ 5. I understand that the following are effective forms of birth control: Primary forms tying my tubes (tubal sterilization) partner's vasectomy intrauterine device hormonal (combination birth control pills, skin patches, shots, under-the-skin implants, or vaginal ring) Secondary forms Barrier: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: vaginal sponge (contains spermicide) A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm I understand that at least 1 of my 2 forms of birth control must be a primary method. Initial: ______ 6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products. Initial: ______ 7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation. Initial: ______ 8. I must begin using the birth control methods I have chosen as described above at least 1 month before I start taking isotretinoin. Initial: ______ 9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have 2 negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment, or as instructed by my doctor. I will then have 1 pregnancy test; in a lab. every month during treatment at the end of treatment and 1 month after stopping treatment I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from 2 pregnancy tests, and the second test has been done in a lab. Initial: ______ 10. I have read and understand the materials my doctor has given to me, including The iPLEDGE Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The Ipledge Program Patient Introductory Brochure. My doctor gave me and asked me to watch the DVD containing a video about birth control and a video about birth defects and isotretinoin. I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control. Initial: ______ 11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control, or have sexual intercourse without using my 2 birth control methods at any time. Initial: ______ 12. My doctor gave me information about the purpose and importance of providing information to the iPLEDGE program should I become pregnant while taking isotretinoin or within 1 month of the last dose. If I become pregnant, I agree to be contacted by the iPLEDGE program and be asked questions about my pregnancy. I also understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be given to the maker of isotretinoin and government health regulatory authorities. Initial: ______ 13. I understand that being qualified to receive isotretinoin in the iPLEDGE program means that I: have had 2 negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription. have chosen and agreed to use 2 forms of effective birth control at the same time. At least 1 method must be a primary form of birth control, unless I have chosen never to have sexual contact with a male (abstinence), or I have undergone a hysterectomy. I must use 2 forms of birth control for at least 1 month before I start isotretinoin therapy, during therapy, and for 1 month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy. have signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin. have been informed of and understand the purpose and importance of providing information to the iPLEDGE program should I become pregnant while taking isotretinoin or within 1 month of the last dose. I agree to be contacted by the iPLEDGE program and be asked questions about my pregnancy. have interacted with the iPLEDGE program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control. Initial: ______ My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to get pregnant 1 month before, during isotretinoin treatment, or for 1 month after I stop taking isotretinoin. Initial: ______ I now authorize my doctor ________________ to begin my treatment with isotretinoin. Patient Signature:_____________________________________ Date: ______ Parent/Guardian Signature (if under age 18):________________ Date:______ Please print: Patient Name and Address_______________________________ ______________________________ Telephone _______________________ have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to female patients of childbearing potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability. Doctor Signature: __________________________________ Date: ______ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. Patient Information/Informed Consent (for all patients): To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor. Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement. Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin. 1. I, ______________________________________________________, (Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars. Initials: ______ 2. My doctor has told me about my choices for treating my acne. Initials: ______ 3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)]. Initials: ______ 4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below). Initials: ______ 5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there. Initials: ______ 6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems. Initials: ______ 7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I: Start to feel sad or have crying spells Lose interest in activities I once enjoyed Sleep too much or have trouble sleeping Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) Have a change in my appetite or body weight Have trouble concentrating Withdraw from my friends or family Feel like I have no energy Have feelings of worthlessness or guilt Start having thoughts about hurting myself or taking my own life (suicidal thoughts) Start acting on dangerous impulses Start seeing or hearing things that are not real Initials: ______ 8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects. Initials: ______ 9. Isotretinoin will be prescribed just for me — I will not share isotretinoin with other people because it may cause serious side effects, including birth defects. Initials: ______ 10. I will not give blood while taking isotretinoin or for 1 month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects. Initials: ______ 11. I have read The iPLEDGE Program Patient Introductory Brochure, and other materials my provider gave me containing important safety information about isotretinoin. I understand all the information I received. Initials: ______ 12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin. Initials: ______ I now allow my doctor ___________________________ to begin my treatment with isotretinoin. Patient Signature: ____________________________________ Date: ______ Parent/Guardian Signature (if under age 18): _______________ Date: ______ Patient Name (print) ___________________________________ Patient Address ___________________________ Telephone (___.___.___) ____________________________________ I have: fully explained to the patient, __________________, the nature and purpose of isotretinoin treatment, including its benefits and risks given the patient the appropriate educational materials, The iPLEDGE Program Patient Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin answered those questions to the best of my ability Doctor Signature: _________________________________ Date: ______ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. MEDICATION GUIDE ACCUTANE (ACK-U-TANE) (isotretinoin capsules) Read the Medication Guide that comes with Accutane (isotretinoin) before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Accutane (isotretinoin) ? Accutane (isotretinoin) is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics. Because Accutane (isotretinoin) can cause birth defects, Accutane (isotretinoin) is only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE program. Accutane (isotretinoin) may cause serious mental health problems. 1. Birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. Female patients who are pregnant or who plan to become pregnant must not take Accutane (isotretinoin) . Female patients must not get pregnant: for 1 month before starting Accutane (isotretinoin) while taking Accutane (isotretinoin) for 1 month after stopping Accutane (isotretinoin) . If you get pregnant while taking Accutane (isotretinoin) , stop taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to: FDA MedWatch at 1-800-FDA-1088, and the iPLEDGE pregnancy registry at 1-866-495-0654 2. Serious mental health problems. Accutane (isotretinoin) may cause: depression psychosis (seeing or hearing things that are not real) suicide. Some patients taking Accutane (isotretinoin) have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. Stop Accutane (isotretinoin) and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis: start to feel sad or have crying spells lose interest in activities you once enjoyed sleep too much or have trouble sleeping become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) have a change in your appetite or body weight have trouble concentrating withdraw from your friends or family feel like you have no energy have feelings of worthlessness or guilt start having thoughts about hurting yourself or taking your own life (suicidal thoughts) start acting on dangerous impulses start seeing or hearing things that are not real After stopping Accutane (isotretinoin) , you may also need follow-up mental health care if you had any of these symptoms. What is Accutane (isotretinoin) ? Accutane (isotretinoin) is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Accutane (isotretinoin) can cause serious side effects (see “What is the most important information I should know about Accutane (isotretinoin) ?”). Accutane (isotretinoin) can only be: prescribed by doctors that are registered in the iPLEDGE program dispensed by a pharmacy that is registered with the iPLEDGE program given to patients who are registered in the iPLEDGE program and agree to do everything required in the program What is severe nodular acne? Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars. Who should not take Accutane (isotretinoin) ? Do not take Accutane (isotretinoin) if you are pregnant, plan to become pregnant, or become pregnant during Accutane (isotretinoin) treatment. Accutane (isotretinoin) causes severe birth defects. See “What is the most important information I should know about Accutane (isotretinoin) ?” Do not take Accutane (isotretinoin) if you are allergic to anything in it. Accutane (isotretinoin) contains parabens as the preservative. See the end of this Medication Guide for a complete list of ingredients in Accutane (isotretinoin) . What should I tell my doctor before taking Accutane (isotretinoin) ? Tell your doctor if you or a family member has any of the following health conditions: mental problems asthma liver disease diabetes heart disease bone loss (osteoporosis) or weak bones an eating problem called anorexia nervosa (where people eat too little) food or medicine allergies Tell your doctor if you are pregnant or breastfeeding. Accutane (isotretinoin) must not be used by women who are pregnant or breastfeeding. Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Accutane (isotretinoin) and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take: Vitamin A supplements. Vitamin A in high doses has many of the same side effects as Accutane (isotretinoin) . Taking both together may increase your chance of getting side effects. Tetracycline antibiotics. Tetracycline antibiotics taken with Accutane (isotretinoin) can increase the chances of getting increased pressure in the brain. Progestin-only birth control pills (mini-pills). They may not work while you take Accutane (isotretinoin) . Ask your doctor or pharmacist if you are not sure what type you are using. Dilantin (phenytoin). This medicine taken with Accutane (isotretinoin) may weaken your bones. Corticosteroid medicines. These medicines taken with Accutane (isotretinoin) may weaken your bones. St. John's Wort. This herbal supplement may make birth control pills work less effectively. These medicines should not be used with Accutane (isotretinoin) unless your doctor tells you it is okay. Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor. How should I take Accutane (isotretinoin) ? You must take Accutane (isotretinoin) exactly as prescribed. You must also follow all the instructions of the iPLEDGE program. Before prescribing Accutane (isotretinoin) , your doctor will: explain the iPLEDGE program to you have you sign the Patient Information/Informed Consent (for all patients). Female patients who can get pregnant must also sign another consent form. You will not be prescribed Accutane (isotretinoin) if you cannot agree to or follow all the instructions of the iPLEDGE program. You will get no more than a 30-day supply of Accutane (isotretinoin) at a time. This is to make sure you are following the Accutane (isotretinoin) iPLEDGE program. You should talk with your doctor each month about side effects. The amount of Accutane (isotretinoin) you take has been specially chosen for you. It is based on your body weight, and may change during treatment. Take Accutane (isotretinoin) 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your Accutane (isotretinoin) capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Accutane (isotretinoin) can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole. If you miss a dose, just skip that dose. Do not take 2 doses at the same time. If you take too much Accutane (isotretinoin) or overdose, call your doctor or poison control center right away. Your acne may get worse when you first start taking Accutane (isotretinoin) . This should last only a short while. Talk with your doctor if this is a problem for you. You must return to your doctor as directed to make sure you don't have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from Accutane (isotretinoin) . Female patients who can get pregnant will get a pregnancy test each month. Female patients who can get pregnant must agree to use 2 separate forms of effective birth control at the same time 1 month before, while taking, and for 1 month after taking Accutane (isotretinoin) . You must access the iPLEDGE system to answer questions about the program requirements and to enter your 2 chosen forms of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654. You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes Accutane (isotretinoin) . If you have sex at any time without using 2 forms of effective birth control, get pregnant, or miss your expected period, stop using Accutane (isotretinoin) and call your doctor right away. What should I avoid while taking Accutane (isotretinoin) ? Do not get pregnant while taking Accutane (isotretinoin) and for 1 month after stopping Accutane (isotretinoin) . See “What is the most important information I should know about Accutane (isotretinoin) ?” Do not breast feed while taking Accutane (isotretinoin) and for 1 month after stopping Accutane (isotretinoin) . We do not know if Accutane (isotretinoin) can pass through your milk and harm the baby. Do not give blood while you take Accutane (isotretinoin) and for 1 month after stopping Accutane (isotretinoin) . If someone who is pregnant gets your donated blood, her baby may be exposed to Accutane (isotretinoin) and may be born with birth defects. Do not take other medicines or herbal products with Accutane (isotretinoin) unless you talk to your doctor. See “What should I tell my doctor before taking Accutane (isotretinoin) ?” Do not drive at night until you know if Accutane (isotretinoin) has affected your vision. Accutane (isotretinoin) may decrease your ability to see in the dark. Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, while you are using Accutane (isotretinoin) and for at least 6 months after you stop. Accutane (isotretinoin) can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures. Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Accutane (isotretinoin) may make your skin more sensitive to light. Do not share Accutane (isotretinoin) with other people. It can cause birth defects and other serious health problems. What are the possible side effects of Accutane (isotretinoin) ? Accutane (isotretinoin) can cause birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. See “What is the most important information I should know about Accutane (isotretinoin) ?” Accutane (isotretinoin) may cause serious mental health problems. See “What is the most important information I should know about Accutane (isotretinoin) ?” serious brain problems. Accutane (isotretinoin) can increase t he pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking Accutane (isotretinoin) and call your doctor right away if you get any of these signs of increased brain pressure: bad headache blurred vision dizziness nausea or vomiting seizures (convulsions) stroke stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking Accutane (isotretinoin) . Stop taking Accutane (isotretinoin) and call your doctor if you get: severe stomach, chest or bowel pain trouble swallowing or painful swallowing new or worsening heartburn diarrhea rectal bleeding yellowing of your skin or eyes dark urine bone and muscle problems. Accutane (isotretinoin) may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with Accutane (isotretinoin) . Tell your doctor if you get: back pain joint pain broken bone. Tell all healthcare providers that you take Accutane (isotretinoin) if you break a bone. Stop Accutane (isotretinoin) and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage. Accutane (isotretinoin) may stop long bone growth in teenagers who are still growing. hearing problems. Stop using Accutane (isotretinoin) and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent. vision problems. Accutane (isotretinoin) may affect your ability to see in the dark. This condition usually clears up after you stop taking Accutane (isotretinoin) , but it may be permanent. Other serious eye effects can occur. Stop taking Accutane (isotretinoin) and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking Accutane (isotretinoin) and after treatment. lipid (fats and cholesterol in blood) problems. Accutane (isotretinoin) can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when Accutane (isotretinoin) treatment is finished. serious allergic reactions. Stop taking Accutane (isotretinoin) and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking Accutane (isotretinoin) and call your doctor if you get a fever, rash, or red patches or bruises on your legs. blood sugar problems. Accutane (isotretinoin) may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot. decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel weak. The common, less serious side effects of Accutane (isotretinoin) are dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does not go away. These are not all of the possible side effects with Accutane (isotretinoin) . Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367. How should I store Accutane (isotretinoin) ? Store Accutane (isotretinoin) at room temperature, between 59° and 86°F. Protect from light. Keep Accutane (isotretinoin) and all medicines out of the reach of children. General Information about Accutane (isotretinoin) Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Accutane (isotretinoin) for a condition for which it was not prescribed. Do not give Accutane (isotretinoin) to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Accutane (isotretinoin) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Accutane (isotretinoin) that is written for health care professionals. You can also call iPLEDGE program at 1-866-495-0654 or visit www.ipledgeprogram.com. What are the ingredients in Accutane? Active Ingredient: Isotretinoin Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide. This Medication Guide has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION ABSORICA® (AB-SORE-I-KAH) (isotretinoin) Capsules Read the Medication Guide that comes with ABSORICA before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about ABSORICA? ABSORICA is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics. Because ABSORICA can cause birth defects, ABSORICA is only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE program. ABSORICA may cause serious mental health problems. 1. Birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. Females who are pregnant or who plan to become pregnant must not take ABSORICA. Females must not get pregnant: for 1 month before starting ABSORICA while taking ABSORICA for 1 month after stopping ABSORICA If you get pregnant while taking ABSORICA, stop taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to: FDA MedWatch at 1-800-FDA-1088, and the iPLEDGE pregnancy registry at 1-866-495-0654 2. Serious mental health problems. ABSORICA may cause: depression psychosis (seeing or hearing things that are not real) suicide. Some patients taking ABSORICA have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. Stop ABSORICA and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis: start to feel sad or have crying spells lose interest in activities you once enjoyed sleep too much or have trouble sleeping become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) have a change in your appetite or body weight have trouble concentrating withdraw from your friends or family feel like you have no energy have feelings of worthlessness or guilt start having thoughts about hurting yourself or taking your own life (suicidal thoughts) start acting on dangerous impulses start seeing or hearing things that are not real After stopping ABSORICA, you may also need follow-up mental health care if you had any of these symptoms. What is ABSORICA? ABSORICA is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. ABSORICA can cause serious side effects (see “What is the most important information I should know about ABSORICA?”). ABSORICA can only be: prescribed by doctors that are registered in the iPLEDGE program dispensed by a pharmacy that is registered with the iPLEDGE program given to patients who are registered in the iPLEDGE program and agree to do everything required in the program What is severe nodular acne? Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars. Who should not take ABSORICA? Do not take ABSORICA if you are pregnant, plan to become pregnant, or become pregnant during ABSORICA treatment. ABSORICA causes severe birth defects. See “What is the most important information I should know about ABSORICA?” Do not take ABSORICA if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in ABSORICA. What should I tell my doctor before taking ABSORICA? Tell your doctor if you or a family member has any of the following health conditions: mental problems asthma liver disease diabetes heart disease bone loss (osteoporosis) or weak bones an eating problem called anorexia nervosa (where people eat too little) food or medicine allergies Tell your doctor if you are pregnant or breastfeeding. ABSORICA must not be used by females who are pregnant or breastfeeding. Tell your doctor about all of the medicines you take including prescription and over-thecounter medicines, vitamins and herbal supplements. ABSORICA and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take: Vitamin A supplements. Vitamin A in high doses has many of the same side effects as ABSORICA. Taking both together may increase your chance of getting side effects. Tetracycline antibiotics. Tetracycline antibiotics taken with ABSORICA can increase the chances of getting increased pressure in the brain. Progestin-only birth control pills (mini-pills). They may not work while you take ABSORICA. Ask your doctor or pharmacist if you are not sure what type you are using. Dilantin (phenytoin). This medicine taken with ABSORICA may weaken your bones. Corticosteroid medicines. These medicines taken with ABSORICA may weaken your bones. St. John's Wort. This herbal supplement may make birth control pills work less effectively. These medicines should not be used with ABSORICA unless your doctor tells you it is okay. Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor. How should I take ABSORICA? You must take ABSORICA exactly as prescribed. You must also follow all the instructions of the iPLEDGE program. Before prescribing ABSORICA, your doctor will: explain the iPLEDGE program to you have you sign the Patient Information/Informed Consent form (for all patients). Females who can get pregnant must also sign another consent form. You will not be prescribed ABSORICA if you cannot agree to or follow all the instructions of the iPLEDGE program. You will get no more than a 30-day supply of ABSORICA at a time. This is to make sure you are following the ABSORICA iPLEDGE program. You should talk with your doctor each month about side effects. The amount of ABSORICA you take has been specially chosen for you. It is based on your body weight, and may change during treatment. Take ABSORICA 2 times a day without regard to meals, unless your doctor tells you otherwise. Swallow your ABSORICA capsules whole with a full glass of liquid. Do not chew or suck on the capsule. ABSORICA can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole. If you miss a dose, just skip that dose. Do not take two doses at the same time. If you take too much ABSORICA or overdose, call your doctor or poison control center right away. Your acne may get worse when you first start taking ABSORICA. This should last only a short while. Talk with your doctor if this is a problem for you. You must return to your doctor as directed to make sure you don't have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from ABSORICA. Females who can get pregnant will get a pregnancy test each month. Females who can get pregnant must agree to use two separate forms of effective birth control at the same time one month before, while taking, and for one month after taking ABSORICA. You must access the iPLEDGE system to answer questions about the program requirements and to enter your two chosen forms of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654. You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes ABSORICA. If you have sex at any time without using two forms of effective birth control, get pregnant, or miss your expected period, stop using ABSORICA and call your doctor right away. What should I avoid while taking ABSORICA? Do not get pregnant while taking ABSORICA and for one month after stopping ABSORICA. See “What is the most important information I should know about ABSORICA?” Do not breastfeed while taking ABSORICA and for one month after stopping ABSORICA. We do not know if ABSORICA can pass through your milk and harm the baby. Do not give blood while you take ABSORICA and for one month after stopping ABSORICA. If someone who is pregnant gets your donated blood, her baby may be exposed to ABSORICA and may be born with birth defects. Do not take other medicines or herbal products with ABSORICA unless you talk to your doctor. See “What should I tell my doctor before taking ABSORICA?” Do not drive at night until you know if ABSORICA has affected your vision. ABSORICA may decrease your ability to see in the dark. Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, while you are using ABSORICA and for at least 6 months after you stop. ABSORICA can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures. Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. ABSORICA may make your skin more sensitive to light. Do not share ABSORICA with other people. It can cause birth defects and other serious health problems. What are the possible side effects of ABSORICA? ABSORICA can cause birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. See “What is the most important information I should know about ABSORICA?” ABSORICA may cause serious mental health problems. See “What is the most important information I should know about ABSORICA?” serious brain problems. ABSORICA can increase the pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking ABSORICA and call your doctor right away if you get any of these signs of increased brain pressure: bad headache blurred vision dizziness nausea or vomiting seizures (convulsions) stroke skin problems. Skin rash can occur in patients taking ABSORICA. In some patients a rash can be serious. Stop using ABSORICA and call your doctor right away if you develop conjunctivitis (red or inflamed eyes, like “pink eye”), a rash with a fever, blisters on legs, arms or face and/or sores in your mouth, throat, nose, eyes, or if your skin begins to peel. stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking ABSORICA. Stop taking ABSORICA and call your doctor if you get: severe stomach, chest or bowel pain trouble swallowing or painful new or worsening heartburn diarrhea rectal bleeding yellowing of your skin or eyes dark urine bone and muscle problems. ABSORICA may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with ABSORICA. Tell your doctor if you get: back pain joint pain broken bone. Tell all healthcare providers that you take ABSORICA if you break a bone. Stop ABSORICA and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage. ABSORICA may stop long bone growth in teenagers who are still growing. hearing problems. Stop using ABSORICA and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent. vision problems. ABSORICA may affect your ability to see in the dark. This condition usually clears up after you stop taking ABSORICA, but it may be permanent. Other serious eye effects can occur. Stop taking ABSORICA and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking ABSORICA and after treatment. lipid (fats and cholesterol in blood) problems. ABSORICA can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when ABSORICA treatment is finished. serious allergic reactions. Stop taking ABSORICA and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking ABSORICA and call your doctor if you get a fever, rash, or red patches or bruises on your legs. blood sugar problems. ABSORICA may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot. decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel weak. The common, less serious side effects of ABSORICA are dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds. ABSORICA contains the color additive FD&C Yellow No. 5 (tartrazine) which may cause allergic type reactions, including asthma in some people. The overall occurrence of allergic reaction is low. This reaction is most often seen in people who also have an allergy to aspirin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Ranbaxy Inc., the manufacturer of ABSORICA at 1800-406-7984. How should I store ABSORICA? Store ABSORICA at room temperature, 68° to 77° F (20° to 25° C). Protect from light. Keep ABSORICA and all medicines out of the reach of children. General Information about ABSORICA Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use ABSORICA for a condition for which it was not prescribed. Do not give ABSORICA to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about ABSORICA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ABSORICA that is written for health care professionals. You can also call iPLEDGE program at 1-866-495-0654 or visit www.ipledgeprogram.com. What are the ingredients in ABSORICA? Active ingredient: Isotretinoin, USP Inactive ingredients: Propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. Gelatin capsules contain the following dye systems: 10 mg – iron oxide (yellow) and titanium dioxide; 20 mg – iron oxide (red) and titanium dioxide; 25 mg – FD&C Blue #1, FD&C Yellow #5 (tartrazine), FD&C Yellow #6 and titanium dioxide; 30 mg – iron oxide (black, red and yellow) and titanium dioxide; 35 mg – FD&C Blue #2, iron oxide (black, red and yellow) and titanium dioxide; and 40 mg – iron oxide (black, red and yellow) and titanium dioxide.

OVERDOSE The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects. Claravis causes serious birth defects at any dosage (see BOXED CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the BOXED CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month. CONTRAINDICATIONS Pregnancy Teratogenic Effects Category X See BOXED CONTRAINDICATIONS AND WARNINGS. Allergic Reactions Claravis is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS, Hypersensitivity).

OVERDOSE The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness and ataxia. These symptoms quickly resolve without apparent residual effects. Amnesteem causes serious birth defects at any dosage (see BOXED CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the BOXED CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month. CONTRAINDICATIONS Pregnancy Category X. See BOXED CONTRAINDICATIONS AND WARNINGS. Allergic Reactions Amnesteem is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS: Hypersensitivity).

OVERDOSE The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects. Accutane (isotretinoin) causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with isotretinoin overdose should not donate blood for at least 1 month. CONTRAINDICATIONS Pregnancy Category X. See Boxed CONTRAINDICATIONS AND WARNINGS. Allergic Reactions Accutane (isotretinoin) is contraindicated in patients who are hypersensitive to this medication or to any of its components. Accutane (isotretinoin) should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).

OVERDOSE In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects. ABSORICA causes serious birth defects at any dosage (see BOXED CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential who present with ABSORICA overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the BOXED CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in WARNINGS AND PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with ABSORICA overdose should not donate blood for at least 1 month. CONTRAINDICATIONS Pregnancy ABSORICA can cause fetal harm when administered to a pregnant woman. Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin in any amount and even for short periods of time. ABSORICA is contraindicated in females who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. Hypersensitivity Hypersensitivity to this product (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS Clinical Trials And Postmarketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of Claravis, and the postmarketing experience. The relationship of some of these events to Claravis therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Claravis are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes). Dose Relationship Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS). Body as a Whole Allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS, Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss. Cardiovascular Palpitation, tachycardia, vascular thrombotic disease, stroke. Endocrine/Metabolic Hypertriglyceridemia (see WARNINGS, Lipids), alterations in blood sugar levels (see PRECAUTIONS, Laboratory Tests). Gastrointestinal Inflammatory bowel disease (see WARNINGS, Inflammatory Bowel Disease), hepatitis (see WARNINGS, Hepatotoxicity), pancreatitis (see WARNINGS, Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms. Hematologic Allergic reactions (see PRECAUTIONS, Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS, Laboratory Tests for other hematological parameters. Musculoskeletal Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS, Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS, Laboratory Tests). Neurological Pseudotumor cerebri (see WARNINGS, Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness. Psychiatric Suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS, Psychiatric Disorders), emotional instability.  Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. Reproductive System Abnormal menses. Respiratory Bronchospasms (with or without a history of asthma), respiratory infection, voice alteration. Skin and Appendages Acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS, Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION). Special Senses : Hearing: hearing impairment (see WARNINGS, Hearing Impairment), tinnitus. Vision: corneal opacities (see WARNINGS, Corneal Opacities), decreased night vision which may persist (see WARNINGS, Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances. Urinary System: glomerulonephritis (see PRECAUTIONS, Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS, Laboratory Tests for other urological parameters). Laboratory Elevation of plasma triglycerides (see WARNINGS, Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment. Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS, Hepatotoxicity). Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS, Laboratory Tests), hyperuricemia. Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia. White cells in the urine, proteinuria, microscopic or gross hematuria. DRUG INTERACTIONS Vitamin A: Because of the relationship of Claravis to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with Claravis and tetracyclines should be avoided because Claravis use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Claravis therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Claravis. Therefore, it is critically important for females of reproductive potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS). Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Claravis at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John's Wort: Claravisuse is associated with depression in some patients (see WARNINGS, Psychiatric Disorders and ADVERSE REACTIONS, Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. Phenytoin: Claravis has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Claravis.  Therefore, caution should be exercised when using these drugs together. Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Claravis. Therefore, caution should be exercised when using these drugs together. REFERENCES 7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

SIDE EFFECTS Clinical Trials And Post-marketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of Amnesteem, and the post-marketing experience. The relationship of some of these events to Amnesteem therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Amnesteem are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage and eyes). Dose Relationship Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS). Body as a Whole: allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss Cardiovascular: palpitation, tachycardia, vascular thrombotic disease, stroke Endocrine/Metabolic: hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests) Gastrointestinal: inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms Hematologic: allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters Musculoskeletal: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests) Neurological: pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. Reproductive System: abnormal menses Respiratory: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration Skin and Appendages : acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson Syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity) abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION) Special Senses : Hearing: hearing impairment (see WARNINGS: Hearing Impairment), tinnitus Vision: corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances Urinary System: glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters) Laboratory Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity) Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia White cells in the urine, proteinuria, microscopic or gross hematuria DRUG INTERACTIONS Vitamin A: Because of the relationship of Amnesteem to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with Amnesteem and tetracyclines should be avoided because Amnesteem use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Amnesteem therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Amnesteem. Therefore, it is critically important for females of reproductive potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS). Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Amnesteem at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John's Wort: Amnesteem use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. Phenytoin: Amnesteem has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Amnesteem. Therefore, caution should be exercised when using these drugs together. Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Amnesteem. Therefore, caution should be exercised when using these drugs together. REFERENCES 7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

SIDE EFFECTS Clinical Trials and Postmarketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of Accutane (isotretinoin) , and the postmarketing experience. The relationship of some of these events to Accutane (isotretinoin) therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane (isotretinoin) are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes). Dose Relationship Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS). Body as a Whole allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss Cardiovascular palpitation, tachycardia, vascular thrombotic disease, stroke Endocrine/Metabolic hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests) Gastrointestinal inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms Hematologic allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters. Musculoskeletal skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests). Neurological pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness Psychiatric suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. Reproductive System abnormal menses Respiratory bronchospasms (with or without a history of asthma), respiratory infection, voice alteration Skin and Appendages acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION) Special Senses Hearing - hearing impairment (see WARNINGS: Hearing Impairment), tinnitus. Vision- corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances Urinary System glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters) Laboratory Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity) Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia White cells in the urine, proteinuria, microscopic or gross hematuria DRUG INTERACTIONS Vitamin A: Because of the relationship of Accutane (isotretinoin) to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with Accutane (isotretinoin) and tetracyclines should be avoided because Accutane (isotretinoin) use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Accutane (isotretinoin) therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Accutane (isotretinoin) . Therefore, it is critically important for female patients of childbearing potential to select and commit to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form (see PRECAUTIONS). Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Accutane (isotretinoin) at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John's Wort: Accutane (isotretinoin) use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. Phenytoin: Accutane (isotretinoin) has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Accutane (isotretinoin) . Therefore, caution should be exercised when using these drugs together. Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Accutane (isotretinoin) . Therefore, caution should be exercised when using these drugs together. Laboratory Tests Pregnancy Test Female patients of childbearing potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane (isotretinoin) prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane (isotretinoin) . The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Accutane (isotretinoin) therapy and after the patient has used 2 forms of contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of Accutane (isotretinoin) therapy and after the patient has used 2 forms of contraception for 1 month. Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Accutane (isotretinoin) is established. The incidence of hypertriglyceridemia is 1 patient in 4 on Accutane therapy (see WARNINGS: Lipids). Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Accutane has been established (see WARNINGS: Hepatotoxicity). Glucose: Some patients receiving Accutane (isotretinoin) have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane (isotretinoin) therapy, although no causal relationship has been established. CPK: Some patients undergoing vigorous physical activity while on Accutane (isotretinoin) therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial. REFERENCES 7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

SIDE EFFECTS The following adverse reactions with ABSORICA or other isotretinoin products are described in more detail in other sections of the labeling: Embryofetal Toxicity [see WARNINGS AND PRECAUTIONS] Psychiatric Disorders [see WARNINGS AND PRECAUTIONS] Pseudotumor Cerebri [see WARNINGS AND PRECAUTIONS] Serious Skin Reactions [see WARNINGS AND PRECAUTIONS] Pancreatitis [see WARNINGS AND PRECAUTIONS] Lipid Abnormalities [see WARNINGS AND PRECAUTIONS] Hearing Impairment [see WARNINGS AND PRECAUTIONS] Hepatotoxicity [see WARNINGS AND PRECAUTIONS] Inflammatory Bowel Disease [see WARNINGS AND PRECAUTIONS] Skeletal Abnormalities [see WARNINGS AND PRECAUTIONS] Ocular Abnormalities [see WARNINGS AND PRECAUTIONS] Hypersensitivity [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ABSORICA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reactions listed below reflect both clinical experience with ABSORICA, and consider other adverse reactions that are known from clinical trials and the post-marketing surveillance with oral isotretinoin. The relationship of some of these events to isotretinoin therapy is unknown. Many of the side effects and adverse events seen in patients receiving isotretinoin are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes). Dose Relationship Cheilitis and hypertriglyceridemia are adverse reactions that are usually dose related. Most adverse reactions reported in clinical trials with isotretinoin were reversible when therapy was discontinued; however, some persisted after cessation of therapy. Body as a Whole The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): fatigue, irritability, pain. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: allergic reactions, including vasculitis, systemic hypersensitivity, edema, lymphadenopathy, weight loss. Cardiovascular The following adverse reactions have been reported with isotretinoin: vascular thrombotic disease, stroke, palpitation, tachycardia. Endocrine/Metabolism and Nutritional The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreased appetite, weight fluctuation, hyperlipidaemia. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: hypertriglyceridemia, alterations in blood sugar. Gastrointestinal The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): lip dry, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, and other nonspecific gastrointestinal symptoms. Hematologic The following adverse reactions have been reported with isotretinoin: allergic reactions, anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis. Infections and infestations The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): nasopharyngitis, hordeolum, upper respiratory tract infection. In addition to the above adverse reactions, the following adverse reaction has been reported with isotretinoin: infections (including disseminated herpes simplex). Laboratory Abnormalities The following changes in laboratory tests have been noted in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): blood creatine phosphokinase (CPK) increased, blood triglycerides increased, alanine aminotransferase (SGPT) increased, aspartate aminotransferase (SGOT) increased, gamma-glutamyltransferase (GGTP) increased, blood cholesterol increased, low density lipoprotein (LDL) increased, white blood cell count decreased, blood alkaline phosphatase increased, blood bilirubin increased, blood glucose increased, high density lipopoprotein (HDL) decreased, bone mineral density decreased. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: increased LDH, elevation of fasting blood sugar, hyperuricemia, decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis), elevated sedimentation rates, elevated platelet counts, thrombocytopenia, white cells in the urine, proteinuria, microscopic or gross hematuria. Musculoskeletal and Connective Tissue The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, athralgia, musculoskeletal discomfort, musculoskeletal pain, neck pain, pain in extremity, myalgia, musculoskeletal stiffness [see WARNINGS AND PRECAUTIONS]. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient pain in the chest, and rare reports of rhabdomyolysis. Neurological The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): headache, syncope. In addition to the above adverse reactions, other adverse reactions reported with isotretinoin include: pseudotumor cerebri, dizziness, drowsiness, lethargy, malaise, nervousness, paresthesias, seizures, stroke, weakness. Psychiatric The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: suicide attempts, suicide, aggression, psychosis and hallucination auditory. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. Reproductive System The following adverse reaction has been reported with isotretinoin: abnormal menses. Respiratory The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): epistaxis, nasal dryness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration. Skin and Subcutaneous Tissue The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry skin, dermatitis, eczema, rash, dermatitis contact, alopecia, pruritus, sunburn, erythema. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: acne fulminans, alopecia (which in some cases persists), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting). Special Senses Hearing: The following adverse reactions have been reported with isotretinoin: tinnitus and hearing impairment. Ocular: The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry eye, visual acuity reduced, vision blurred, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, and conjunctivitis. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances. Renal and Urinary The following adverse reactions have been reported in clinical trials conducted with isotretinoin: glomerulonephritis, nonspecific urogenital findings. DRUG INTERACTIONS Vitamin A ABSORICA is closely related to vitamin A. Therefore, the use of both vitamin A and ABSORICA at the same time may lead to vitamin A side effects. Patients should be advised against taking vitamin supplements containing Vitamin A to avoid additive toxic effects. Tetracyclines Concomitant treatment with ABSORICA and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Phenytoin Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a trial in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin. Therefore, caution should be exercised when using these drugs together. St. John's Wort Isotretinoin use is associated with depression in some patients. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. Systemic Corticosteroids Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together. Norethindrone/Ethinyl Estradiol In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Norethindrone/ethinyl estradiol as an oral contraceptive agent, isotretinoin at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

WARNINGS Psychiatric Disorders Claravis may cause depression, psychos is and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS, Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Claravis therapy, patients and family members should be as ked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults ”), includes ad mood, hopelessness, feelings of guilt, worthlessness or helplessness, los s of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Claravis and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Claravis therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Claravis therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Claravis therapy. Pseudotumor Cerebri Claravis use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Claravis immediately and be referred to a neurologis t for further diagnosis and care (see ADVERSE REACTIONS, Neurological). Serious Skin Reactions There have been postmarketing reports of erythema multiforme and severe skin reactions [e.g., Stevens- Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of Claravis should be considered if warranted. Pancreatitis Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Claravis should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Lipids Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Claravis. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Claravis in clinical trials. In addition, approximately 15% developed a decrease in highdensity lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Claravis therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Claravis.5 Blood lipid determinations should be performed before Claravis is given and then at intervals until the lipid response to Claravis is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Claravis therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Claravis therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS, Laboratory Tests). The cardiovascular consequences of hypertriglyceridemia associated with Claravis are unknown. Animal Studies In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). Hearing Impairment Impaired hearing has been reported in patients taking Claravis; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Claravis treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS, Special Senses). Hepatotoxicity Clinical hepatitis considered to be possibly or probably related to Claravis therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Claravis, the drug should be discontinued and the etiology further investigated. Inflammatory Bowel Disease Claravis has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Claravis treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Claravis immediately (see ADVERSE REACTIONS, Gastrointestinal). Skeletal Bone Mineral Density Effects of multiple courses of Claravis on the developing musculoskeletal system are unknown. There is some evidence that long-term, high dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N = 217) of a single course of therapy with Claravis for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in five of eight patients (62.5%). In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Claravis 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS, Pediatric Use). Spontaneous reports of osteoporosis, osteopenia, bone fractures and delayed healing of bone fractures have been seen in the Claravis population. While causality to Claravis has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Claravis be given at the recommended doses for no longer than the recommended duration. Hyperostosis A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Claravis treatment courses for acne are unknown. In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Claravis given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Premature Epiphyseal Closure There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Claravis. The effect of multiple courses of Claravis on epiphyseal closure is unknown. Vision Impairment Visual problems should be carefully monitored. All Claravis patients experiencing visual difficulties should discontinue Claravis treatment and have an ophthalmological examination (see ADVERSE REACTIONS, Special Senses). Corneal Opacities Corneal opacities have occurred in patients receiving Claravis for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with Claravis have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS, Special Senses). Decreased Night Vision Decreased night vision has been reported during Claravis therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. PRECAUTIONS Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Claravis must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive isotretinoin only from wholesalers registered with iPLEDGE. iPLEDGE Program requirements for wholesalers, prescribers, and pharmacists are described below: Wholesalers For the purpose of the iPLEDGE Program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Claravis, wholesalers must be registered with iPLEDGE and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include: Registering prior to distributing isotretinoin and reregistering annually thereafter Distributing only FDA approved isotretinoin product Only shipping isotretinoin to wholesalers registered in the iPLEDGE Program with prior written consent from the manufacturer or pharmacies licensed in the U.S. and registered and activated in the iPLEDGE Program Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order isotretinoin Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE Program by the isotretinoin manufacturer (or delegate) Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not reregister annually Prescribers To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy. I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer. I will comply with the iPLEDGE Program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide. Before beginning treatment of females of reproductive potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence. I will not prescribe isotretinoin to any females of reproductive potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test one month later. I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or one month after the last dose to the pregnancy registry. To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to: Register each patient in the iPLEDGE Program. Confirm monthly that each patient has received counseling and education. For females of reproductive potential: Enter patient's two chosen forms of contraception each month. Enter monthly result from CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE Program. Meeting the requirements for a female of reproductive potential signifies that she: Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter. Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests should be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month. Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. Has selected and has committed to use two forms of effective contraception simultaneously, at least one of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be postmenopausal. Patients must use two forms of effective contraception for at least one month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for one month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis. If the patient has unprotected heterosexual intercourse at any time one month before, during, or one month after therapy, she must: Stop taking isotretinoin immediately, if on therapy Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse Start using two forms of effective contraception simultaneously again for one month before resuming isotretinoin therapy Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether she has regular menses or not. Effective forms of contraception include both primary and secondary forms of contraception: Primary Forms tubal sterilization partner's vasectomy intrauterine device hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring) Secondary Forms Barrier Forms male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other vaginal sponge (contains spermicide) Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking Claravis. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive potential use two effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits). Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Claravis (see DRUG INTERACTIONS). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA- 1088 and also the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). All Patients Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions: Must be registered with the iPLEDGE Program by the prescriber Must understand that severe birth defects can occur with the use of isotretinoin by female patients Must be reliable in understanding and carrying out instructions Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for females of reproductive potential Must obtain the prescription within 30 days of the office visit for male patients and females of non-reproductive potential Must not donate blood while on isotretinoin and for one month after treatment has ended Must not share isotretinoin with anyone, even someone who has similar symptoms Females Of Reproductive Potential Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential must meet the following conditions: Must NOT be pregnant or breast-feeding Must comply with the required pregnancy testing at a CLIA-certified laboratory Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse and understand behaviors associated with an increased risk of pregnancy Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1- 866-495-0654), before starting isotretinoin, on a monthly basis during therapy and one month after the last dose to answer questions on the program requirements and to enter the patient's two chosen forms of contraception Must have been informed of the purpose and importance of providing information to the iPLEDGE Program should she become pregnant while taking isotretinoin or within one month of the last Dose Pharmacists To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE. The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE Program requirements. I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE Program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program. I will obtain Claravis product only from iPLEDGE registered wholesalers. I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy. I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually. I will not fill isotretinoin for any party other than a qualified patient. To dispense isotretinoin, the pharmacist must: be trained by the Responsible Site Pharmacist concerning the iPLEDGE Program requirements. obtain authorization from the iPLEDGE Program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin. write the Risk Management Authorization (RMA) number on the prescription. Claravis must only be dispensed: in no more than a 30 day supply with a Claravis Medication Guide after authorization from the iPLEDGE Program prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and females of non-reproductive potential and within 7 days of the date of specimen collection for females of reproductive potential) with a new prescription for refills and another authorization from the iPLEDGE Program (No automatic refills are allowed) A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patients. Claravis must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used. Patients must fill isotretinoin prescriptions only at US licensed pharmacies. A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotretinoin prescription. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription. The iPLEDGE Program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE Program includes information on the risks and benefits of isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription. Females of non-reproductive potential and male patients, and females of reproductive potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides isotretinoin information in two languages. The booklet for females of non-reproductive potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share isotretinoin with others or to donate blood during isotretinoin therapy and for one month following discontinuation of isotretinoin. The booklet for females of reproductive potential, The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects. The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line. In addition, there are patient educational materials with the following videos - “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see PATIENT INFORMATION). General Although an effect of Claravis on bone loss is not established, physicians should use caution when prescribing Claravis to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Claravis or following cessation of therapy with Claravis while involved in these activities. While causality to Claravis has not been established, an effect must not be ruled out. Information For Patients See PRECAUTIONS and BOXED CONTRAINDICATIONS AND WARNINGS. Patients must be instructed to read the Medication Guide supplied as required by law when Claravis is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE Program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form. Females of reproductive potential must be instructed that they must not be pregnant when Claravis therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Claravis, while taking Claravis, and for one month after Claravis has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Claravis therapy. They should be given an opportunity to view the patient video provided by the manufacturer to the prescriber. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using two forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Claravis at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Claravis prescription is written (see BOXED CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS). Claravis is found in the semen of male patients taking Claravis, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the noeffect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of isotretinoin treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, los s of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop isotretinoin and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of isotretinoin treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether isotretinoin therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin therapy. Patients must be informed that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin. Patients must be informed that they must not share Claravis with anyone else because of the risk of birth defects and other serious adverse events. Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Claravis. Patients should be reminded to take Claravis with a meal (see DOSAGE AND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Claravis therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS, Skin and Appendages). Patients should be advised to avoid prolonged exposure to UV rays or sunlight. Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. Patients should be informed that approximately 16% of patients treated with Claravis in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Claravis, but in some cases persisted (see ADVERSE REACTIONS, Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests, CPK). Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Claravis developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Claravis. Consideration should be given to discontinuation of Claravis if any significant abnormality is found. Neutropenia and rare cases of agranulocytosis have been reported. Claravis should be discontinued if clinically significant decreases in white cell counts occur. Patients should be advised that severe skin reactions (Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported in postmarketing data. Claravis should be discontinued if clinically significant skin reactions occur. Hypersensitivity Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Laboratory Tests Pregnancy Test Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Claravis prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Claravis. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Claravis therapy and after the patient has used 2 forms of contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of Claravis therapy and after the patient has used 2 forms of contraception for 1 month. Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. Lipids Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Claravis is established. The incidence of hypertriglyceridemia is one patient in four on Claravis therapy (see WARNINGS, Lipids). Liver Function Tests Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Claravis has been established (see WARNINGS, Hepatotoxicity). Glucose Some patients receiving Claravis have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Claravis therapy, although no causal relationship has been established. CPK Some patients undergoing vigorous physical activity while on Claravis therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial. Carcinogenesis, Mutagenesis And Impairment Of Fertility In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain. The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Claravis therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. Pregnancy Teratogenic Effects Category X See BOXED CONTRAINDICATIONS AND WARNINGS. Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Claravis. Pediatric Use The use of isotretinoin in pediatric patients less than 12 years of age has not been studied. The use of isotretinoin for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS, General). Use of isotretinoin in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients ( ≥ 18 years). Results from this study demonstrated that isotretinoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. In studies with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS). In an open-label clinical trial (N = 217) of a single course of therapy with Claravis for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twentyone (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in five of eight patients (62.5%). In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS, Skeletal, Bone Mineral Density). Geriatric Use Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS). REFERENCES 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.

WARNINGS Psychiatric Disorders Amnesteem may cause depression, psychos is and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Amnesteem therapy, patients and family members should be as ked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults ”), include s ad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Amnesteem and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Amnesteem therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Amnesteem therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Amnesteem therapy. Pseudotumor Cerebri Amnesteem use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant us e of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Amnesteem immediately and be referred to a neurologist for further diagnos is and care (see ADVERSE REACTIONS: Neurological). Serious Skin Reactions There have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization or disability. Patients should be monitored closely for severe skin reactions and discontinuation of Amnesteem should be considered if warranted. Pancreatitis Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Amnesteem should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Lipids Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Amnesteem. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Amnesteem in clinical trials. In addition, approximately 15% developed a decrease in highdensity lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL and cholesterol were reversible upon cessation of Amnesteem therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Amnesteem.5 Blood lipid determinations should be performed before Amnesteem is given and then at intervals until the lipid response to Amnesteem is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Amnesteem therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Amnesteem therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests). The cardiovascular consequences of hypertriglyceridemia associated with Amnesteem are unknown. Animal Studies In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). Hearing Impairment Impaired hearing has been reported in patients taking Amnesteem; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Amnesteem treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses). Hepatotoxicity Clinical hepatitis considered to be possibly or probably related to Amnesteem therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Amnesteem, the drug should be discontinued and the etiology further investigated. Inflammatory Bowel Disease Amnesteem has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Amnesteem treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Amnesteem immediately (see ADVERSE REACTIONS: Gastrointestinal). Skeletal Bone Mineral Density Effects of multiple courses of Amnesteem on the developing musculoskeletal system are unknown. There is some evidence that long-term, high dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N = 217) of a single course of therapy with Amnesteem for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in five of eight patients (62.5%). In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Amnesteem 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use). Spontaneous reports of osteoporosis, osteopenia, bone fractures and delayed healing of bone fractures have been seen in the Amnesteem population. While causality to Amnesteem has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration. Hyperostosis A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Amnesteem treatment courses for acne are unknown. In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Amnesteem given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Premature Epiphyseal Closure There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Amnesteem. The effect of multiple courses of Amnesteem on epiphyseal closure is unknown. Vision Impairment Visual problems should be carefully monitored. All Amnesteem patients experiencing visual difficulties should discontinue Amnesteem treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses). Corneal Opacities Corneal opacities have occurred in patients receiving Amnesteem for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with Amnesteem have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses). Decreased Night Vision Decreased night vision has been reported during Amnesteem therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. PRECAUTIONS Amnesteem must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Amnesteem must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive Amnesteem only from wholesalers registered with iPLEDGE. iPLEDGE Program requirements for wholesalers, prescribers and pharmacists are described below: Wholesalers For the purpose of the iPLEDGE Program, the term wholesaler refers to wholesaler, distributor and/or chain pharmacy distributor. To distribute Amnesteem, wholesalers must be registered with iPLEDGE and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include: Registering prior to distributing isotretinoin and re-registering annually thereafter Distributing only FDA approved isotretinoin product Only shipping isotretinoin to wholesalers registered in the iPLEDGE Program with prior written consent from the manufacturer or pharmacies licensed in the US and registered and activated in the iPLEDGE Program Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order isotretinoin Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE Program by the isotretinoin manufacturer (or delegate) Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not reregister annually Prescribers To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy. I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer. I will comply with the iPLEDGE Program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide. Before beginning treatment of females of reproductive potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during and one month after isotretinoin therapy, unless the patient commits to continuous abstinence. I will not prescribe isotretinoin to any females of reproductive potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin capsules and another pregnancy test one month later. I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or one month after the last dose to the pregnancy registry. To prescribe isotretinoin, the Prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to: Register each patient in the iPLEDGE Program. Confirm monthly that each patient has received counseling and education. For females of reproductive potential: Enter patient's two chosen forms of contraception each month. Enter monthly result from CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE Program. Meeting the requirements for a female of reproductive potential signifies that she: Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter. Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests should be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month. For patients with amenorrhea, irregular cycles or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two forms of contraception for one month. Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. Has selected and has committed to use two forms of effective contraception simultaneously, at least one of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use two forms of effective contraception for at least one month prior to initiation of isotretinoin therapy, during isotretinoin therapy and for one month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis. If the patient has unprotected heterosexual intercourse at any time one month before, during or one month after therapy, she must: Stop taking Amnesteem immediately, if on therapy Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse Start using two forms of effective contraception simultaneously again for one month before resuming Amnesteem therapy Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether she has regular menses or not. Effective forms of contraception include both primary and secondary forms of contraception: Primary forms tubal sterilization partner’s vasectomy intrauterine device hormonal (combination oral contraceptives, transdermal patch, injectables, implantables or vaginal ring) Secondary Forms Barrier male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other vaginal sponge (contains spermicide) Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking Amnesteem. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive potential use two effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits). Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Amnesteem (see DRUG INTERACTIONS). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. If a pregnancy does occur during Amnesteem treatment, Amnesteem must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after Amnesteem therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA- 1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). All Patients Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions: Must be registered with the iPLEDGE Program by the prescriber Must understand that severe birth defects can occur with the use of isotretinoin by female patients Must be reliable in understanding and carrying out instructions Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for females of reproductive potential Must obtain the prescription within 30 days of the office visit for male patients and females of non-reproductive potential Must not donate blood while on isotretinoin and for one month after treatment has ended Must not share isotretinoin with anyone, even someone who has similar symptoms Females Of Reproductive Potential Isotretinoin is contraindicated in females who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential must meet the following conditions: Must NOT be pregnant or breast-feeding Must comply with the required pregnancy testing at a CLIA-certified laboratory Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse and understand behaviors associated with an increased risk of pregnancy Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy Must have signed an additional Patient Information/Informed Consent About Birth Defects (for females who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy and one month after the last dose to answer questions on the program requirements and to enter the patient's two chosen forms of contraception Must have been informed of the purpose and importance of providing information to the iPLEDGE Program should she become pregnant while taking isotretinoin or within one month of the last Dose Pharmacists To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE. The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE Program requirements. I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE Program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program. I will obtain Amnesteem product only from iPLEDGE registered wholesalers. I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy. I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually. I will not fill isotretinoin for any party other than a qualified patient. To dispense isotretinoin, the pharmacist must: be trained by the Responsible Site Pharmacist concerning the iPLEDGE Program requirements. obtain authorization from the iPLEDGE Program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive Amnesteem. write the Risk Management Authorization (RMA) number on the prescription. Amnesteem must only be dispensed: in no more than a 30 day supply with an Amnesteem Medication Guide after authorization from the iPLEDGE Program prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and females of non-reproductive potential and within 7 days of the date of specimen collection for females of reproductive potential) with a new prescription for refills and another authorization from the iPLEDGE Program (No automatic refills are allowed) An Amnesteem Medication Guide must be given to the patient each time Amnesteem is dispensed, as required by law. This Amnesteem Medication Guide is an important part of the risk management program for the patients. Amnesteem must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved Amnesteem products must be distributed, prescribed, dispensed and used. Patients must obtain Amnesteem prescriptions only at U.S. licensed pharmacies. A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Amnesteem prescription. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription. The iPLEDGE Program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE Program includes information on the risks and benefits of Amnesteem which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription. Females of non-reproductive potential and male patients, and females of reproductive potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form and a toll-free line which provides isotretinoin information in two languages. The booklet for females of non-reproductive potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share Amnesteem with others or to donate blood during isotretinoin therapy and for one month following discontinuation of isotretinoin. The booklet for females of reproductive potential, The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for females who can get pregnant) form concerning birth defects. The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line. In addition, there are patient educational materials with the following videos-“Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see PATIENT INFORMATION). General Although an effect of Amnesteem on bone loss is not established, physicians should use caution when prescribing Amnesteem to patients with a genetic predisposition for age related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Amnesteem or following cessation of therapy with Amnesteem while involved in these activities. While causality to Amnesteem has not been established, an effect must not be ruled out. Patient Information See PRECAUTIONS and BOXED CONTRAINDICATIONS AND WARNINGS. Patients must be instructed to read the Medication Guide supplied as required by law when Amnesteem is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE Program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form. Females of reproductive potential must be instructed that they must not be pregnant when Amnesteem therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Amnesteem, while taking Amnesteem, and for one month after Amnesteem has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Amnesteem therapy. They should be given an opportunity to view the patient video provided by the manufacturer to the prescriber. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using two forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Amnesteem at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Amnesteem prescription is written (see BOXED CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS). Amnesteem is found in the semen of male patients taking Amnesteem, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the noeffect limit for isotretinoin induced embryopathy is unknown, 20 years of post-marketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Amnesteem treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression includes admood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses and persistent physical symptoms unresponsive to treatment. Patients should stop Amnesteem and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis or aggression, without waiting until the next visit. Discontinuation of Amnesteem treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Amnesteem therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Amnesteem therapy. Patients must be informed that some patients, while taking Amnesteem or soon after stopping Amnesteem, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down or trouble concentrating. Some patients taking Amnesteem have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on Amnesteem becoming aggressive or violent. No one knows if Amnesteem caused these behaviors or if they would have happened even if the person did not take Amnesteem. Some people have had other signs of depression while taking Amnesteem. Patients must be informed that they must not share Amnesteem with anyone else because of the risk of birth defects and other serious adverse events. Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Amnesteem. Patients should be reminded to take Amnesteem with a meal (see DOSAGE AND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Amnesteem therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS: Skin and Appendages). Patients should be advised to avoid prolonged exposure to UV rays or sunlight. Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. Patients should be informed that approximately 16% of patients treated with Amnesteem in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Amnesteem, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare post-marketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests: CPK). Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Amnesteem developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Amnesteem. Consideration should be given to discontinuation of Amnesteem if any significant abnormality is found. Neutropenia and rare cases of agranulocytosis have been reported. Amnesteem should be discontinued if clinically significant decreases in white cell counts occur. Patients should be advised that severe skin reactions (Steven-Johnson Syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Amnesteem should be discontinued if clinically significant skin reactions occur. Hypersensitivity Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Laboratory Tests Pregnancy Test Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Amnesteem prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Amnesteem. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Amnesteem therapy and after the patient has used 2 forms of contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of Amnesteem therapy and after the patient has used 2 forms of contraception for 1 month. Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. Lipids Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Amnesteem is established. The incidence of hypertriglyceridemia is one patient in four on Amnesteem therapy (see WARNINGS: Lipids). Liver Function Tests Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Amnesteem has been established (see WARNINGS: Hepatotoxicity). Glucose Some patients receiving Amnesteem have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Amnesteem therapy, although no causal relationship has been established. CPK Some patients undergoing vigorous physical activity while on Amnesteem therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial. Carcinogenesis, Mutagenesis, Impairment Of Fertility In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain. The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes and unscheduled DNA synthesis assay) were all negative. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8 or 32 mg/kg/day (0.3, 1.3 or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Amnesteem (isotretinoin) therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. Pregnancy Category X See BOXED CONTRAINDICATIONS AND WARNINGS. Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Amnesteem. Pediatric Use The use of Amnesteem in pediatric patients less than 12 years of age has not been studied. The use of Amnesteem for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General). Use of Amnesteem in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients ( ≥ 18 years). Results from this study demonstrated that Amnesteem, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. In studies with Amnesteem, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS). In an open-label clinical trial (N = 217) of a single course of therapy with Amnesteem for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in five of eight patients (62.5%). In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Amnesteem 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density). Geriatric Use Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS). REFERENCES 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.

WARNINGS Psychiatric Disorders Accutane (isotretinoin) may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Accutane (isotretinoin) therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Accutane (isotretinoin) and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Accutane (isotretinoin) therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Accutane (isotretinoin) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Accutane (isotretinoin) therapy. Pseudotumor Cerebri Accutane (isotretinoin) use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Accutane (isotretinoin) immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological). Serious Skin Reactions There have been post-marketing reports of erythema multiforme and severe skin reactions [eg, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of Accutane (isotretinoin) should be considered if warranted. Pancreatitis Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Accutane (isotretinoin) should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Lipids Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Accutane (isotretinoin) . Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Accutane (isotretinoin) in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Accutane (isotretinoin) therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Accutane (isotretinoin) .5 Blood lipid determinations should be performed before Accutane (isotretinoin) is given and then at intervals until the lipid response to Accutane (isotretinoin) is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Accutane (isotretinoin) therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Accutane (isotretinoin) therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests). The cardiovascular consequences of hypertriglyceridemia associated with Accutane (isotretinoin) are unknown. Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). Hearing Impairment Impaired hearing has been reported in patients taking Accutane (isotretinoin) ; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Accutane (isotretinoin) treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses). Hepatotoxicity Clinical hepatitis considered to be possibly or probably related to Accutane (isotretinoin) therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Accutane (isotretinoin) , the drug should be discontinued and the etiology further investigated. Inflammatory Bowel Disease Accutane (isotretinoin) has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Accutane (isotretinoin) treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS: Gastrointestinal). Skeletal Bone Mineral Density Effects of multiple courses of Accutane (isotretinoin) on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course of therapy with Accutane (isotretinoin) for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in 5 of 8 patients (62.5%). In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course of Accutane (isotretinoin) 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use). Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the Accutane (isotretinoin) population. While causality to Accutane (isotretinoin) has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Accutane (isotretinoin) be given at the recommended doses for no longer than the recommended duration. Hyperostosis A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Accutane (isotretinoin) treatment courses for acne are unknown. In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Accutane (isotretinoin) given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Premature Epiphyseal Closure There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Accutane (isotretinoin) . The effect of multiple courses of Accutane (isotretinoin) on epiphyseal closure is unknown. Vision Impairment Visual problems should be carefully monitored. All Accutane (isotretinoin) patients experiencing visual difficulties should discontinue Accutane (isotretinoin) treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses). Corneal Opacities Corneal opacities have occurred in patients receiving Accutane (isotretinoin) for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with Accutane (isotretinoin) have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses). Decreased Night Vision Decreased night vision has been reported during Accutane (isotretinoin) therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. PRECAUTIONS Accutane (isotretinoin) must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Accutane (isotretinoin) must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive Accutane (isotretinoin) only from wholesalers registered with iPLEDGE. iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below: Wholesalers For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Accutane (isotretinoin) , wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include: Registering prior to distributing isotretinoin and re-registering annually thereafter Distributing only FDA approved isotretinoin product Only shipping isotretinoin to wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer or pharmacies licensed in the US and registered and activated in the iPLEDGE program Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or nonactivated pharmacy or unregistered wholesaler that attempts to order isotretinoin Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the isotretinoin manufacturer (or delegate) Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not re-register annually Prescribers To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy. I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer. I will comply with the iPLEDGE program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide. Before beginning treatment of female patients of childbearing potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence. I will not prescribe isotretinoin to any female patient of childbearing potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test 1 month later. I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or 1 month after the last dose to the pregnancy registry. To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to: Register each patient in the iPLEDGE program. Confirm monthly that each patient has received counseling and education. For female patients of childbearing potential: Enter patient's two chosen forms of contraception each month. Enter monthly result from CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies that she: Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter. Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the 2 tests should be at least 19 days. For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of contraception for 1 month. Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. Has selected and has committed to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for 1 month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis. If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must: Stop taking Accutane (isotretinoin) immediately, if on therapy Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse Start using 2 forms of effective contraception simultaneously again for 1 month before resuming Accutane (isotretinoin) therapy Have a second pregnancy test after using 2 forms of effective contraception for 1 month as described above depending on whether she has regular menses or not. Effective forms of contraception include both primary and secondary forms of contraception: Primary forms Secondary forms tubal sterilization partner's vasectomy intrauterine device hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring) Barrier: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: vaginal sponge (contains spermicide) Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking Accutane (isotretinoin) . These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that female patients of childbearing potential use 2 effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits). Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Accutane (see PRECAUTIONS: DRUG INTERACTIONS). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). All Patients Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions: Must be registered with the iPLEDGE program by the prescriber Must understand that severe birth defects can occur with the use of isotretinoin by female patients Must be reliable in understanding and carrying out instructions Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test for female patients of childbearing potential Must fill and pick up the prescription within 30 days of the office visit for male patients and female patients not of childbearing potential Must not donate blood while on isotretinoin and for 1 month after treatment has ended Must not share isotretinoin with anyone, even someone who has similar symptoms Female Patients of Childbearing Potential Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, female patients of childbearing potential must meet the following conditions: Must NOT be pregnant or breast-feeding Must comply with the required pregnancy testing at a CLIA-certified laboratory Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and 1 month after the last dose to answer questions on the program requirements and to enter the patient's two chosen forms of contraception Must have been informed of the purpose and importance of providing information to the iPLEDGE program should she become pregnant while taking isotretinoin or within 1 month of the last dose Pharmacists To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE. The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE program requirements. I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program. I will obtain Accutane (isotretinoin) product only from iPLEDGE registered wholesalers. I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy. I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually. I will not fill isotretinoin for any party other than a qualified patient. To dispense isotretinoin, the pharmacist must: be trained by the Responsible Site Pharmacist concerning the iPLEDGE program requirements. obtain authorization from the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin. write the Risk Management Authorization (RMA) number on the prescription. Accutane (isotretinoin) must only be dispensed: in no more than a 30-day supply with an Accutane Medication Guide after authorization from the iPLEDGE program prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and female patients not of childbearing potential and within 7 days of the date of specimen collection for female patients of childbearing potential) with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed) An Accutane Medication Guide must be given to the patient each time Accutane (isotretinoin) is dispensed, as required by law. This Accutane Medication Guide is an important part of the risk management program for the patients. Accutane (isotretinoin) must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Accutane (isotretinoin) products must be distributed, prescribed, dispensed, and used. Patients must fill Accutane (isotretinoin) prescriptions only at US licensed pharmacies. A description of the iPLEDGE program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE program requirements and to reinforce the educational messages. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotretinoin prescription. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription. The iPLEDGE program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE program includes information on the risks and benefits of isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription. Female patients not of childbearing potential and male patients, and female patients of childbearing potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides isotretinoin information in 2 languages. The booklet for female patients not of childbearing potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share isotretinoin with others or to donate blood during isotretinoin therapy and for 1 month following discontinuation of isotretinoin. The booklet for female patients of childbearing potential, The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects. The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line. In addition, there is a patient educational DVD with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see PATIENT INFORMATION ). General Although an effect of Accutane (isotretinoin) on bone loss is not established, physicians should use caution when prescribing Accutane (isotretinoin) to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Accutane (isotretinoin) or following cessation of therapy with Accutane (isotretinoin) while involved in these activities. While causality to Accutane (isotretinoin) has not been established, an effect must not be ruled out. Information for Patients See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS. Patients must be instructed to read the Medication Guide supplied as required by law when Accutane (isotretinoin) is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form. Female patients of childbearing potential must be instructed that they must not be pregnant when Accutane (isotretinoin) therapy is initiated, and that they should use 2 forms of effective contraception simultaneously for 1 month before starting Accutane (isotretinoin) , while taking Accutane (isotretinoin) , and for 1 month after Accutane (isotretinoin) has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Accutane (isotretinoin) therapy. They should be given an opportunity to view the patient DVD provided by the manufacturer to the prescriber. The DVD includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Accutane (isotretinoin) at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Accutane prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS). Accutane (isotretinoin) is found in the semen of male patients taking Accutane (isotretinoin) , but the amount delivered to a female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible with features of retinoid exposed fetuses; however 2 of these reports were incomplete, and 2 had other possible explanations for the defects observed. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Accutane (isotretinoin) treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Accutane (isotretinoin) and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Accutane (isotretinoin) treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Accutane (isotretinoin) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Accutane (isotretinoin) therapy. Patients must be informed that some patients, while taking Accutane (isotretinoin) or soon after stopping Accutane (isotretinoin) , have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking Accutane (isotretinoin) have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on Accutane (isotretinoin) becoming aggressive or violent. No one knows if Accutane (isotretinoin) caused these behaviors or if they would have happened even if the person did not take Accutane (isotretinoin) . Some people have had other signs of depression while taking Accutane (isotretinoin) . Patients must be informed that they must not share Accutane (isotretinoin) with anyone else because of the risk of birth defects and other serious adverse events. Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Accutane (isotretinoin) . Patients should be reminded to take Accutane with a meal (see DOSAGE AND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Accutane (isotretinoin) therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS: Skin and Appendages). Patients should be advised to avoid prolonged exposure to UV rays or sunlight. Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. Patients should be informed that approximately 16% of patients treated with Accutane (isotretinoin) in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Accutane (isotretinoin) , but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests: CPK). Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Accutane (isotretinoin) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Accutane (isotretinoin) . Consideration should be given to discontinuation of Accutane (isotretinoin) if any significant abnormality is found. Neutropenia and rare cases of agranulocytosis have been reported. Accutane (isotretinoin) should be discontinued if clinically significant decreases in white cell counts occur. Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Accutane (isotretinoin) should be discontinued if clinically significant skin reactions occur. Hypersensitivity Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Carcinogenesis, Mutagenesis and Impairment of Fertility In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain. The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. Pregnancy Category X. See Boxed CONTRAINDICATIONS AND WARNINGS. Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Accutane (isotretinoin) . Pediatric Use The use of Accutane (isotretinoin) in pediatric patients less than 12 years of age has not been studied. The use of Accutane (isotretinoin) for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General). Use of Accutane (isotretinoin) in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients ( ≥ 18 years). Results from this study demonstrated that Accutane (isotretinoin) , at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. In studies with Accutane (isotretinoin) , adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS). In an open-label clinical trial (N=217) of a single course of therapy with Accutane (isotretinoin) for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (62.5%). In a separate open-label extension study of 10 patients, ages 13 to 18 years, who started a second course of Accutane (isotretinoin) 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density). Geriatric Use Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS). REFERENCES 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS ABSORICA must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking ABSORICA in any amount, even for short periods of time. ABSORICA 25 mg contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Embryofetal Toxicity Teratogenicity Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin [see Use In Specific Populations]. Females of Reproductive Potential must comply with the pregnancy testing and contraception requirements described in the iPLEDGE program [see iPLEDGE Program and Use In Specific Populations]. There are no accurate means of determining whether an exposed fetus has been affected. No Blood Donation Patients must be informed not to donate blood during isotretinoin therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to isotretinoin. iPLEDGE Program Because of the risk of teratogenicity and to minimize fetal exposure, ABSORICA is available only through a restricted program under a REMS called iPLEDGE. Under the ABSORICA REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program. ABSORICA must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used. Required components of the iPLEDGE Program are: ABSORICA must only be prescribed by prescribers who are registered and activated with the iPLEDGE program and agree to comply with the REMS requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program, The iPLEDGE Program Prescriber Contraception Counseling Guide, and Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Male patients and Females of non-reproductive potential: To obtain ABSORICA, these patients must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form. Females of reproductive potential: ABSORICA is contraindicated in female patients who are or may become pregnant [see CONTRAINDICATIONS]. Females of reproductive potential who are not pregnant must understand the risks and benefits, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant and The iPLEDGE Program Birth Control Workbook (including the pregnancy testing and contraception requirements [see Use In Specific Populations and PATIENT INFORMATION]), and sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form. Additionally, the patient must answer questions about the iPLEDGE program and pregnancy prevention monthly. Pharmacies that dispense ABSORICA must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive ABSORICA, and agree to comply with the REMS requirements described in the booklet entitled The Pharmacist Guide for the iPLEDGE Program. Females of reproductive potential must obtain the prescription within 7 days of the specimen collection for the pregnancy test; male patients and females of non-reproductive potential must obtain the prescription within 30 days of the office visit. ABSORICA must only be dispensed in no more than a 30-day supply with a Medication Guide. Refills require a new prescription and a new authorization from the iPLEDGE system. Wholesalers and distributors that distribute ABSORICA must be registered with iPLEDGE and agree to comply with the REMS requirements. If a pregnancy does occur during ABSORICA treatment, ABSORICA must be discontinued immediately. The patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). Further information, including a list of qualified pharmacies, is available at www.ipledgeprogram.com or 1-866-495-0654. Unacceptable Contraception Micro-dosed Progesterone Preparations Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during ABSORICA therapy. Psychiatric Disorders Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these reactions [see ADVERSE REACTIONS]. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of ABSORICA therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (Recognizing Psychiatric Disorders in Adolescents and Young Adults), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop ABSORICA and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of ABSORICA therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy. Pseudotumor Cerebri Isotretinoin use has been associated with cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue ABSORICA immediately and be referred to a neurologist for further diagnosis and care [see ADVERSE REACTIONS]. Serious Skin Reactions There have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of ABSORICA should be considered if warranted. Pancreatitis Acute pancreatitis has been reported in isotretinoin-treated patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. ABSORICA should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Lipid Abnormalities Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects of triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in the dose while continuing isotretinoin. Blood lipid determinations should be performed before ABSORICA is given and then at intervals until the lipid response to ABSORICA is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk of triglyceridemia during ABSORICA therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If ABSORICA therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended [see Laboratory Monitoring for Adverse Reactions]. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Hearing Impairment Impaired hearing has been reported in patients taking isotretinoin; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue ABSORICA treatment and be referred for specialized care for further evaluation [see ADVERSE REACTIONS]. Hepatotoxicity Clinical hepatitis considered to be possibly or probably related to isotretinoin therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with isotretinoin, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with ABSORICA, the drug should be discontinued and the etiology further investigated. Inflammatory Bowel Disease Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue ABSORICA immediately [see ADVERSE REACTIONS]. Skeletal Abnormalities Bone Mineral Density Changes Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and a generic product of Accutane® (isotretinoin), 27/306 (8.8%) of adolescents had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20 week treatment period. Repeat scans conducted within 2-3 months after the post-treatment scan showed no recovery of BMD. Longer term data at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. Therefore, physicians should use caution when prescribing ABSORICA to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant [see Use in Specific Populations]. Musculoskeletal Abnormalities Approximately 16% of patients treated with isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found. There have been spontaneous reports of osteoporosis, osteopenia, bone fractures and/or delayed healing of bone fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. While causality to isotretinoin has not been established, an effect cannot be ruled out. Patients may be at an increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injures in early and late adolescence are known. Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. Longer term effects have not been studied. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. Hyperostosis A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day of isotretinoin. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of isotretinoin given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Premature Epiphyseal Closure There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 adolescents on ABSORICA or a generic product of Accutane® (isotretinoin) who had hand radiographs taken to assess bone age, a total of 9 (3.11%) patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded. Ocular Abnormalities Visual problems should be carefully monitored. All ABSORICA patients experiencing visual difficulties should discontinue ABSORICA treatment and have an ophthalmological examination [see ADVERSE REACTIONS]. Corneal Opacities Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug [see ADVERSE REACTIONS]. Decreased Night Vision Decreased night vision has been reported during isotretinoin therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Dry Eye Dry eye has been reported in subjects during isotretinoin therapy. Patients who wear contact lenses may have trouble wearing them while on ABSORICA treatment and afterwards. Hypersensitivity Anaphylactic reactions and other allergic reactions have been reported in isotretinoin-treated patients. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Laboratory Monitoring For Adverse Reactions Lipids Test Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to ABSORICA is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin [see Lipid Abnormalities]. Liver Function Test Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to ABSORICA has been established [see Hepatotoxicity]. Glucose Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established. CPK Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In an isotretinoin clinical trial of 924 patients, marked elevations in CPK ( ≥ 350 U/L) were observed in approximately 24% of patients. In another clinical trial of 217 pediatric patients (12 – 17 years) elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this clinical trial. Patient Counseling Information See FDA-Approved Patient Labeling (Medication Guide) Advise the patient that ABSORICA is only available through a restricted program called iPLEDGE. As a component of the iPLEDGE program, prescribers must instruct patients to read the Medication Guide, the iPLEDGE program patient educational booklets, and watch the video with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin”. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes ABSORICA at any time during pregnancy. Male patients and Females of non-reproductive potential must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form. Females of reproductive potential must be instructed that they must not be pregnant when ABSORICA therapy is initiated or plan to become pregnant while receiving ABSORICA therapy. Additionally, they must use 2 forms of effective contraception simultaneously for 1 month before starting ABSORICA, while taking ABSORICA, and for 1 month after ABSORICA has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning ABSORICA therapy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another ABSORICA prescription is written. Additionally, a pregnancy test must be completed at the end of the entire course of ABSORICA therapy and 1 month after discontinuation of therapy. Advise the patient that isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of post-marketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed. Advise the patient that ABSORICA is available only from pharmacies that are certified in the iPLEDGE program, and provide them with the telephone number (1-866-495-0654) and website (www.ipledgeprogram.com) for information on how to obtain. Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the iPLEDGE program. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of ABSORICA treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Inform patients that symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop treatment and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of ABSORICA treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy. Patients must be informed that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts), some have tried to end their own lives, and some have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. There have also been reports of psychotic symptoms, which indicate a loss of contact with reality. Psychotic symptoms include feelings of suspiciousness toward others, strange beliefs, hearing voices or other noises without an obvious source, and seeing unusual objects or people with no explanation. No one knows if isotretinoin caused these behaviors and symptoms or if they would have happened even if the person did not take isotretinoin. If any of these behaviors or symptoms occur, the patient should stop treatment and the patient or family member should contact the prescriber promptly without waiting until the next visit [see WARNINGS AND PRECAUTIONS]. Some people have had other signs of depression while taking isotretinoin. Patients must be informed that they must not share ABSORICA with anyone else because of the risk of birth defects and other serious adverse reactions. Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to ABSORICA. ABSORICA may be taken without regard to meals [see DOSAGE AND ADMINISTRATION]. To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. Patients should be informed that inflammatory bowel disease (including regional ileitis) may occur without a prior history of intestinal disorders. In rare instances, symptoms have been reported to persist after treatment has stopped. Patients should be informed that if they experience abdominal pain, rectal bleeding or severe diarrhea, they should discontinue ABSORICA immediately. Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during ABSORICA therapy and for at least 6 months thereafter due to the possibility of scarring. Patients should be advised to avoid prolonged exposure to UV rays or sunlight. Patients should be informed that they may experience dry eye, corneal opacities, and decreased night vision. Contact lens wearers may experience decreased tolerance to contact lenses during and after therapy. Patients should be informed that 16% of patients treated with isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of therapy, but in some cases persisted. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. Pediatric patients and their caregivers should be informed that approximately 17% to 29% of pediatric patients treated with isotretinoin developed back pain. In a clinical trial, back pain was severe in 13.5% of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of treatment. Consideration should be given to discontinuation of isotretinoin if any significant abnormality is found. Neutropenia and rare cases of agranulocytosis have been reported in patients treated with isotretinoin. ABSORICA should be discontinued if clinically significant decreases in white cell counts occur. Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post marketing data in patients treated with isotretinoin. Treatment with ABSORICA should be discontinued if clinically significant skin reactions occur. Adolescent patients who participate in sports with repetitive impact should be informed that isotretinoin use may increase their risk of spondylolisthesis or hip growth plate injuries. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin while involved in these activities [see WARNINGS AND PRECAUTIONS]. Nonclinical Toxicology Carcinogenesis, Mutagenesis and Impairment Of Fertility In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain. The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In trials of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. Use In Specific Populations Pregnancy Pregnancy Category X [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Risk Summary ABSORICA is contraindicated during pregnancy because isotretinoin can cause can cause fetal harm when administered to a pregnant woman. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus. Clinical Considerations If pregnancy does occur during treatment of a female patient who is taking ABSORICA, ABSORICA must be discontinued immediately and she should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Human Data Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases death has occurred as a result of the malformations. Isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown and 20 years of post-marketing reports include four reports with isolated defects compatible with features of retinoid exposed fetuses, two of these reports were incomplete and two had other possible explanations for the defects observed. Cases of IQ scores less than 85 with or without other abnormalities have been reported. An increased risk of spontaneous abortion and premature births have been documented with isotretinoin exposure during pregnancy. Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ABSORICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The use of ABSORICA in pediatric patients less than 12 years of age has not been studied. The use of ABSORICA for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists [see WARNINGS AND PRECAUTIONS]. Use of ABSORICA in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical trial of ABSORICA compared to a generic product of Accutane® (isotretinoin) in 397 pediatric patients (12 to 17 years). Results from this trial demonstrated that both ABSORICA and the other isotretinoin drug product, at a dose of 1 mg/kg/day given in two divided doses, was effective in treating severe recalcitrant nodular acne in pediatric patients. In trials with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients. In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found. The effect on bone mineral density (BMD) of a 20-week course of therapy with ABSORICA or a generic product of Accutane® (isotretinoin) was evaluated in a double-blind, randomized clinical trial involving 396 adolescents with severe recalcitrant nodular acne (mean age 15.4, range 1217, 80% males). Following 20 weeks of treatment, there were no statistically significant differences between the treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 adolescents, 27 (8.8%) had clinically significant BMD declines defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2-3 months after the post treatment scan showed no recovery of BMD. Longer-term follow up at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pretreatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see WARNINGS AND PRECAUTIONS]. In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for adolescents with severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density > 4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (62.5%). In a separate open-label extension trial of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25%. There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20week clinical trial that included 289 adolescents who had hand radiographs taken to assess bone age, a total of 9 patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded [see WARNINGS AND PRECAUTIONS]. Geriatric Use Clinical trials of ABSORICA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with ABSORICA therapy. Females Of Reproductive Potential All females of reproductive potential must comply with the iPLEDGE program requirements [see WARNINGS AND PRECAUTIONS]. Pregnancy Testing ABSORICA must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial ABSORICA prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for ABSORICA. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. For patients with regular menstrual cycles, perform the second pregnancy test during the first 5 days of the menstrual period immediately preceding the beginning of ABSORICA therapy and after the patient has used 2 forms of contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, perform the second pregnancy test immediately preceding the beginning of ABSORICA therapy and after the patient has used 2 forms of contraception for 1 month. Each month of continued ABSORICA therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. A pregnancy test must also be completed at the end of the entire course of isotretinoin therapy and 1 month after the discontinuation of isotretinoin. Contraception Females of reproductive potential must use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of ABSORICA therapy, during ABSORICA therapy, and for 1 month after discontinuing ABSORICA therapy. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during isotretinoin therapy [see WARNINGS AND PRECAUTIONS]. Effective forms of contraception include both primary and secondary forms of contraception: Primary forms Secondary forms Tubal sterilization Partner’s vasectomy Intrauterine device Hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring) Barrier: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: Vaginal sponge (contains spermicide) Any birth control method can fail. There have been reports of pregnancy from female patients who have used combination oral contraceptives, as well as transdermal patch/ injectable/ implantable/ vaginal ring hormonal birth control products; these pregnancies occurred while taking isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important for females of reproductive potential use 2 effective forms of contraception simultaneously. Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin. Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort [see DRUG INTERACTIONS]. If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must: Stop taking ABSORICA immediately, if on therapy Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse Start using 2 forms of effective contraception simultaneously again for 1 month before resuming ABSORICA therapy Have a second pregnancy test after using 2 forms of effective contraception for 1 month as described above depending on whether she has regular menses or not. If a pregnancy does occur during ABSORICA treatment, ABSORICA must be discontinued immediately. The patient should be referred to an Obstetrician- Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-4950654 or via the internet (www.ipledgeprogram.com) [see WARNINGS AND PRECAUTIONS].