Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown. Pharmacokinetics Tretinoin activity is primarily due to the parent drug. In human pharmacokinetics studies, orally administered drug was well absorbed into the systemic circulation, with approximately two-thirds of the administered radiolabel recovered in the urine. The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. There is evidence that tretinoin induces its own metabolism. Plasma tretinoin concentrations decrease on average to one-third of their day 1 values during 1 week of continuous therapy. Mean ± SD peak tretinoin concentrations decreased from 394 89 to 138 ± 139 ng/mL, while area under the curve (AUC) values decreased from 537 ± 191 ng·h/mL to 249 ± 185 ng·h/mL during 45 mg/m2 daily dosing in 7 APL patients. Increasing the dose to "correct" for this change has not increased response. Absorption A single 45 mg/m2 (~80 mg) oral dose to APL patients resulted in a mean SD peak tretinoin concentration of 347 ± 266 ng/mL. Time to reach peak concentration was between 1 and 2 hours. Distribution The apparent volume of distribution of tretinoin has not been determined. Tretinoin is greater than 95% bound in plasma, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL. Metabolism Tretinoin metabolites have been identified in plasma and urine. Cytochrome P450 enzymes have been implicated in the oxidative metabolism of tretinoin. Metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. In APL patients, daily administration of a 45 mg/m2 dose of tretinoin resulted in an approximately tenfold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide after 2 to 6 weeks of continuous dosing, when compared to baseline values. Excretion Studies with radiolabeled drug have demonstrated that after the oral administration of 2.75 and 50 mg doses of tretinoin, greater than 90% of the radioactivity was recovered in the urine and feces. Based upon data from 3 subjects, approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days. Special Populations The pharmacokinetics of tretinoin have not been separately evaluated in women, in members of different ethnic groups, or in individuals with renal or hepatic insufficiency. Drug-Drug Interactions In 13 patients who had received daily doses of tretinoin for 4 consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour prior to the administration of the tretinoin dose on day 29 led to a 72% increase (218 224 vs 375 ± 285 ng·h/mL) in tretinoin mean plasma AUC. The precise cytochrome P450 enzymes involved in these interactions have not been specified; CYP 3A4, 2C8 and 2E have been implicated in various preliminary reports. Clinical Studies VESANOID (tretinoin) has been investigated in 114 previously treated APL patients and in 67 previously untreated ("de novo") patients in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). All patients received 45 mg/m2/day as a divided oral dose for up to 90 days or 30 days beyond the day that CR was reached. Results are shown in the following table: MSKCC NCI Cohort 1 NCI Cohort 2 Relapsed N=20 De Novo n=15 Relapsed* n=48 De Novo n=14 Relapsed n=46 De Novo† n=38 Complete Remission 16 (80%) 11 (73%) 24 (50%) 5 (36%) 24 (52%) 26 (68%) Median Survival (Mo) 10.8 NR 5.8 0.5 8.8 NR Median Follow-up (Mo) 9.9 42.9 5.6 1.2 8.0 13.1 RA-APL Syndrome 4 (20%) 5 (33%) 10 (21%) 6 (43%) NA NA NR = Not Reached NA = Not Available *Including 9 chemorefractory patients †Including 8 patients who received chemotherapy but failed to enter remission The median time to CR was between 40 and 50 days (range: 2 to 120 days). Most patients in these studies received cytotoxic chemotherapy during the remission phase. These results compare to the 30% to 50% CR rate and ≤ 6 month median survival reported for cytotoxic chemotherapy of APL in the treatment of relapse. Ten of 15 pediatric cases achieved CR (8 of 10 males and 2 of 5 females). There were insufficient patients of black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in each category. Responses were seen in 3 of 4 patients for whom cytogenetic analysis failed to detect the t(15;17) translocation typically seen in APL. The t(15;17) translocation results in the PML/RARα gene, which appears necessary for this disease. Molecular genetic studies were not conducted in these cases, but it is likely they represent cases with a masked translocation giving rise to PML/RARα. Responses to tretinoin have not been observed in cases in which PML/RARα fusion has been shown to be absent.

CLINICAL PHARMACOLOGY Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

CLINICAL PHARMACOLOGY Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Pharmacokinetics In vitro and in vivo pharmacokinetic studies with AVITA® Cream indicate that less than 0.3% of the topically applied dose is bioavailable. Circulating plasma levels of both tretinoin and isotretinoin are only slightly elevated above those found in healthy normal controls. Clinical Studies In one vehicle-controlled clinical trial, AVITA® (tretinoin cream) Cream 0.025%, applied once daily was more effective than vehicle in the treatment of facial acne vulgaris of mild to moderate severity. Percent reductions in lesion count after treatment for 12 weeks in this study are shown in the following table: Avita® Cream, 0.025% Vehicle Cream N = 75 N = 58 Noninflammatory Lesions 45% 27% Inflammatory Lesions 46% 32% Total Lesions 46% 28% N = Number of Subjects

CLINICAL PHARMACOLOGY Mechanism Of Action Tretinoin is a metabolite of Vitamin A that binds with high affinity to specific retinoic acid receptors located in both the cytosol and nucleus, but cutaneous levels of tretinoin in excess of physiologic concentrations occur following application of a tretinoin-containing topical drug product. Although tretinoin activates three members of the retinoid acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms, or both. Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Pharmacokinetics In two (2) studies, the plasma levels of tretinoin and its major metabolites (13-cis-retinoic acid and 4-oxo-13-cisretinoic acid) were investigated in a total of 14 patients (age: 13 – 25 years) with severe acne, who applied 4 g ± 0.5 g (range 3.5 g – 4.5 g) of Atralin Gel once daily to face, back and chest, as compared to a mean of 0.71 g (range of 0.07 – 3.71 g) applied in the controlled clinical trials. Blood samples were taken at baseline and immediately prior to treatment on days 1, 5, 10 and 14. On Day 14, the final study day, samples also were taken 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, post-treatment. The plasma concentrations of tretinoin and its metabolites could be measured (LOQ = 0.5 ng/mL for all three analytes) in all patients at all time points. The range of plasma concentrations of tretinoin and its metabolites, 13-cisretinoic acid and all-trans-4-oxo-retinoic acid at baseline and after multiple once daily applications of Atralin Gel, 0.05% for 14 days are given in Table 2 (below). Although some patients had increased concentrations of tretinoin or its metabolites over baseline values, no consistent increase in these concentrations were observed across patients. Table 2: Concentrations of active and metabolites at Baseline and at Day 14 after exposure to Atralin Gel, 0.05% Compound Baseline Concentration Range (ng/ml) Day 14 Concentration Range (ng/ml) Tretinoin 0.68-1.62 0.69-2.88 13-cis-retinoic acid 0.67-1.79 0.51-2.26 4-oxo-13-cis-retinoic acid 0.82-5.92 0.59-6.96 Clinical Studies Clinical Trials The safety and efficacy of Atralin Gel used once daily before bedtime for the treatment of mild to moderate acne vulgaris were assessed in two 12-week prospective, multi-center, randomized, controlled trials. Subjects in these two trials ranged from 10 to 65 years of age, were approximately 52% female, 48% male, and were 74% Caucasian, 15% Black or African American, 3% Asian, and 8% Other. Efficacy results at Week 12 are presented in Table 3. Success on the 6-point Global Severity Score is defined as a score of 0 (clear) or 1 (very mild). In Trial 2, subjects were also required to have at least two grades reduction from baseline for success. 'Very mild' acne is defined as: skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules may be hyperpigmented, though not pink-red, less than 4 lesions). The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups. Table 3: Efficacy Results at Week 12 in Trials 1 and 2 Trial 1 Atralin Gel N=375 Vehicle N=185 Global Severity Score Success* 78 (21%) 23 (12%) Non-Inflammatory Facial Lesions Mean Baseline Count 50.7 52.4 Mean Absolute Reduction 21.8 10.3 Mean Percent Reduction 43% 21% Inflammatory Facial Lesions Mean Baseline Count 23.4 23.9 Mean Absolute Reduction 9.7 5.8 Mean Percent Reduction 41% 26% Total Facial Lesions Mean Baseline Count 74.1 76.3 Mean Absolute Reduction 31.4 16.1 Mean Percent Reduction 43% 22% Trial 2 Atralin Gel N=299 Vehicle N=302 Global Severity Score Success** 69 (23%) 42 (14%) Non-Inflammatory Facial Lesions Mean Baseline Count 51.9 52.7 Mean Absolute Reduction 18.7 10.8 Mean Percent Reduction 37% 20% Inflammatory Facial Lesions Mean Baseline Count 22.9 23.4 Mean Absolute Reduction 7.0 4.0 Mean Percent Reduction 30% 17% Total Facial Lesions Mean Baseline Count 74.8 76.1 Mean Absolute Reduction 25.7 14.7 Mean Percent Reduction 35% 19% * Success was defined as 0 (clear) or 1 (very mild) ** Success was defined as 0 (clear) or 1 (very mild) with at least 2 grades reduction from baseline

Find Lowest Prices on VESANOID® (tretinoin) Capsules WARNINGS 1. Experienced Physician and Institution Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to VESANOID (tretinoin). VESANOID (tretinoin) should therefore be administered only to patients with APL under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of VESANOID (tretinoin) requires that the physician concludes that the possible benefit to the patient outweighs the following known adverse effects of the therapy. 2. Retinoic Acid-APL Syndrome About 25% of patients with APL treated with VESANOID (tretinoin) have experienced a syndrome called the retinoic acid-APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have expired with multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of VESANOID (tretinoin) . The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of patients do not require termination of VESANOID (tretinoin) therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of VESANOID (tretinoin) therapy should be considered. 3. Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During VESANOID (tretinoin) Treatment During VESANOID (tretinoin) treatment about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5x109/L) have an increased risk of a further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high-dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to VESANOID (tretinoin) treatment in the case of patients presenting with a WBC count of >5x109/L or in the case of a rapid increase in WBC count for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to the VESANOID (tretinoin) therapy on day 1 or 2 for patients presenting with a WBC count of >5x109/L, or immediately, for patients presenting with a WBC count of <5x109/L, if the WBC count reaches ≥ 6x109/L by day 5, or ≥ 10x109/L by day 10, or ≥ 15x109/L by day 28. 4. Teratogenic Effects. Pregnancy Category D - see WARNINGS There is a high risk that a severely deformed infant will result if VESANOID (tretinoin) is administered during pregnancy. If, nonetheless, it is determined that VESANOID (tretinoin) represents the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the patient has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use two reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method Within 1 week prior to the institution of VESANOID (tretinoin) therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL. When possible, VESANOID (tretinoin) therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the patient should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of VESANOID (tretinoin) treatment. DESCRIPTION VESANOID (tretinoin) is a retinoid that induces maturation of acute promyelocytic leukemia (APL) cells in culture. It is available in a 10 mg soft gelatin capsule for oral administration. Each capsule also contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oils and soybean oil. The gelatin capsule shell contains glycerin, yellow iron oxide, red iron oxide, titanium dioxide, methylparaben and propylparaben. Chemically, tretinoin is all-trans retinoic acid and is related to retinol (Vitamin A). It is a yellow to light orange crystalline powder with a molecular weight of 300.44. The structural formula is as follows:

Find Lowest Prices on RETIN-A (tretinoin) Cream and Gel DESCRIPTION RETIN-A Gel, Cream and Liquid, containing tretinoin are used for the topical treatment of acne vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or 0.01% by weight, in a gel vehicle of butylated hydroxytoluene, hydroxypropyl cellulose and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid and has the following structure:

AVITA® (tretinoin) Cream DESCRIPTION AVITA® Cream, a topical retinoid, contains tretinoin 0.025% by weight in a hydrophilic cream vehicle of stearic acid, polyolprepolymer-2, isopropyl myristate, polyoxyl 40 stearate, propylene glycol, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. Chemically, tretinoin is all-transretinoic acid (C20H2802; molecular weight 300.44 vitamin A acid) and has the following structural formula:

Find Lowest Prices on ATRALIN® (tretinoin) Gel, 0.05% DESCRIPTION Atralin (tretinoin) Gel, 0.05% is a translucent to opaque, pale yellow gel containing 0.05% tretinoin, by weight for topical administration. Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds, and a metabolite of Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C20H28O2 and the following structure: Each gram of Atralin Gel, 0.05% contains 0.5 mg of tretinoin. Other components of this formulation are benzyl alcohol, butyl paraben, butylated hydroxytoluene, carbomer 940, ethyl paraben, fish collagen hydrolyzates, glycerin, iso-butyl paraben, methylparaben, octoxynol 9, phenoxyethanol, propylparaben, purified water, sodium hyaluronate, and trolamine. The contribution to efficacy of individual components of the vehicle has not been evaluated.

INDICATIONS VESANOID (tretinoin) capsules are indicated for the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated. VESANOID (tretinoin) is for the induction of remission only. The optimal consolidation or maintenance regimens have not been defined, but all patients should receive an accepted form of remission consolidation and/or maintenance therapy for APL after completion of induction therapy with VESANOID (tretinoin) . DOSAGE AND ADMINISTRATION The recommended dose is 45 mg/m2/day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. If after initiation of treatment of VESANOID (tretinoin) the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the patient has not responded to VESANOID (tretinoin) , alternative therapy appropriate for acute myelogenous leukemia should be considered. VESANOID (tretinoin) is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All patients should, therefore, receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy with VESANOID (tretinoin) , unless otherwise contraindicated. HOW SUPPLIED VESANOID (tretinoin) is supplied as 10 mg capsules, two-tone (lengthwise), orange-yellow and reddish-brown and imprinted VESANOID (tretinoin) 10 ROCHE. Supplied in high-density polyethylene, opaque bottles of 100 capsules with child-resistant closure (NDC 0004-0250-01). Store at 15° to 30°C (59° to 86°F). Protect from light. Distributed by: Pharmaceuticals Roche Laboratories Inc. 340 kingsland street, Nutley, New Jersey 07110- 1199. Revised: July 2008. FDA Rev date: 7/1/2008

INDICATIONS RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established. DOSAGE AND ADMINISTRATION RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: The liquid may be applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alterations of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See PRECAUTIONS.) HOW SUPPLIED RETIN-A (tretinoin) is supplied as: RETIN-A Cream RETIN-A Strength/ Form RETIN-A Gel RETIN-A Liquid NDC Code RETIN-A Qty. NDC Code RETIN-A Strength/ Form RETIN-A Qty. NDC Code RETIN-A Strength/ Form RETIN-A Qty. 0062-0165-01 0.025% Cream 20g 0062-0575-44 0.01% Gel 15g 0062-0075-07 0.05% Liquid 28mL 0062-0165-02 0.025% Cream 45g 0062-0575-46 0.01% Gel 45g 0062-0175-12 0.05% 20g 0062-0475-42 0.025% Gel 15g 0062-0175-13 0.05% Cream 45g 0062-0475-45 0.025% Gel 45g 0062-0275-23 0.1% Cream 20g 0062-0275-01 0.1% Cream 45g Storage Conditions RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN-A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F. Marketed by: Ortho Dermatologics™. Manufactured by: DRAXIS Specialty Pharmaceuticals, Inc., Qc, Canada H9H 4J4

INDICATIONS AVITA® Cream is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of this product in the treatment of other disorders have not been established. DOSAGE AND ADMINISTRATION AVITA® Cream should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Application may cause a transient feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alterations of dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once-daily dosing frequencies. During the early weeks of therapy, an apparent increase in number and exacerbation of inflammatory acne lesions may occur. This is due, in part, to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. Patients treated with AVITA® Cream may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied (see PRECAUTIONS). HOW SUPPLIED AVITA (tretinoin cream) Cream, 0.025% is supplied as: NDC Code Strength Quantity 0378-6141-44 0.025% 20 g 0378-6141-45 0.025% 45 g Storage Conditions: Store below 30°C (86°F). Avoid freezing. Keep this and all medications out of the reach of children. Manufactured by: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Revised: Nov 2013

INDICATIONS Atralin Gel is indicated for topical treatment of acne vulgaris. DOSAGE AND ADMINISTRATION For topical use only. Not for ophthalmic, oral, or intravaginal use. Atralin Gel should be applied once daily, before bedtime, to the skin where acne lesions appear, using a thin layer to cover the entire affected area. Atralin Gel should be kept away from the eyes, the mouth, paranasal creases, and mucous membranes. Application of excessive amounts of gel will not provide incremental efficacy. Patients treated with Atralin Gel may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied. When treating with Atralin Gel, caution should be exercised with the use of concomitant topical over-the-counter preparations, topical medications, medicated or abrasive soaps and cleansers, products that have strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime. Particular caution should be exercised with acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid. Allow the effects of such preparations to subside before use of Atralin Gel has begun. HOW SUPPLIED Dosage Forms And Strengths Gel, 0.05% Each gram of Atralin Gel contains 0.5 mg (0.05%) tretinoin in a translucent to opaque, pale yellow topical gel. Atralin (tretinoin) Gel, 0.05% is a translucent to opaque, pale yellow topical gel and available as: 45 g tubes (NDC 13548-070-45) Storage And Handling Store at controlled room temperature 20° - 25°C (68° - 77°F) with excursions permitted between 15°-30°C (59°-86°F). Protect from freezing. Keep out of reach of children. Manufactured for: Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 by: DPT Laboratories, Ltd., San Antonio, TX 78215. Revised: 08/2014

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION PATIENT INSTRUCTIONS Retin-A® (tretinoin) Acne Treatment IMPORTANT Read Directions Carefully Before Using Cream Gel Liquid For Topical Use Only THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR'S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS AND PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you do become sunburned, stop your therapy with RETIN-A until your skin has recovered. Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinue the use of RETIN-A and consult your physician. There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to RETIN-A or therapy was discontinued. Use other medication only on your physician's advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician's instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using this medication. GELS ARE FLAMMABLE. Note: Keep away from heat and flame. Keep tube tightly closed. AND WHILE YOU'RE ON RETIN-A THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn't caused by dirt, so no matter how hard you scrub, you can't wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild, bland soap. Two or three times a day should be sufficient. Pat skin dry with a towel. Let the face dry 20 to 30 minutes before applying RETIN-A. Remember, excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE RETIN-A (TRETINOIN) To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS – BE PATIENT – DON'T START AND STOP THERAPY ON YOUR OWN – IF YOU HAVE QUESTIONS, ASK YOUR DOCTOR. To help you use the medication correctly, keep these simple instructions in mind Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 to 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won't give faster or better results. Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin) Cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. Liquid: RETIN-A (tretinoin) Liquid may be applied to the skin where acne lesions appear, spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into areas where treatment is not intended (such as corners of the mouth, eyes, and nose). It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using RETIN-A. If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don't be discouraged if you see no immediate improvement. Don't stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of RETIN-A until your physician instructs otherwise. IF YOU HAVE QUESTIONS All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A (tretinoin), call our tollfree number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday through Friday.

PATIENT INFORMATION AVITA® (tretinoin) Cream CREAM, 0.025% Acne Treatment IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT AVITA (TRETINOIN) CREAM ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. PRECAUTIONS The effects of the sun on your skin: As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chances of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with AVITA Cream may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings: When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in AVITA Cream, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun: When outside, even on hazy days, areas treated with AVITA Cream should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps, or artificial sunlight while you are using AVITA (tretinoin cream) Cream, 0.025%. If you do become sunburned, stop your therapy with AVITA Cream until your skin has recovered. Avoid excessive exposure to wind or cold: Extremes of climate tend to dry or burn normal skin. Skin treated with AVITA Cream may be more vulnerable to these extremes.Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems: The skin of certain sensitive individuals may become excessively red, swollen, blistered, or crusted. If you are experiencing severe or persistent irritation, discontinue the use of AVITA Cream and consult your physician. There have been reports that, in some patients, areas treated with AVITA Cream developed a temporary increase or decrease in the amount of skin pigment (color) present. Use other medication only on your physician’s advice: Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos, and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with AVITA Cream which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant, or are nursing an infant: No studies have been conducted in humans to establish the safety of AVITA Cream in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using this medication. AND WHILE YOU’RE ON AVITA THERAPY Use a mild non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse.Wash your skin gently with a mild, bland soap. Two or three times a day should be sufficient. Pat skin dry with a towel. Let the face dry 20 to 30 minutes before applying AVITA (tretinoin cream) Cream, 0.025%. Remember, excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE AVITA (TRETINOIN) CREAM To get the best results with AVITA Cream therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when AVITA Cream is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOUR DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. AVITA Cream should be applied once a day, in the evening, or as directed by your physician, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. First, wash with a mild soap and dry your skin gently.WAIT 20 to 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication, and won’t give faster or better results. Keep the medication away from the corners of the nose, mouth, eyes, and open wounds. Spread away from these areas when applying. Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have had some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with AVITA Cream by first dabbing it on your forehead, chin, and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. If needed, you may apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) in the morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT AVITA (tretinoin cream) Cream, 0.025% works deep inside your skin and this takes time. You cannot make AVITA Cream work any faster by applying more than one dose each day, but an excess amount of AVITA Cream may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to AVITA Cream and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage, it is important to continue using AVITA Cream. If AVITA Cream is going to have a beneficial effect for you, you should notice an improvement in your appearance by 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control, you should continue regular application of AVITA Cream until your physician instructs otherwise. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088.

PATIENT INFORMATION Atralin® (A-truh-lin) (tretinoin) Gel, 0.05% For topical use Important information: Atralin is for use on skin only. Do not get Atralin in your mouth, eyes, vagina, or the corners of your nose. What is Atralin? Atralin is a prescription medicine used on the skin (topical) to treat acne. Acne is a condition in which the skin has blackheads, whiteheads, and other pimples. It is not known if Atralin is safe and effective in children under 10 years of age. What should I tell my healthcare provider before using Atralin? Before using Atralin, tell your healthcare provider about all of your medical conditions, including if you: are allergic to fish. Atralin contains fish proteins. Tell your healthcare provider if you get hives or itching during treatment with Atralin. have a skin condition called eczema have a sunburn x are pregnant or plan to become pregnant. It is not known if Atralin will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if Atralin passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, herbal supplements, and any skin products that you use. Especially tell your healthcare provider if you use any other medicines to treat your acne, including medicated cleansers or soaps. Using other topical acne products may increase the irritation of your skin when used with Atralin. How should I use Atralin? Use Atralin exactly as your healthcare provider tells you to use it. Before you apply Atralin, gently wash the affected skin area with a mild, non-medicated soap. Rinse and pat your skin dry. Apply Atralin 1 time a day before bedtime. Apply a thin layer of Atralin to cover the affected skin areas. Gently rub Atralin into your skin. Do not use more Atralin than you need to cover the affected area and do not apply Atralin more than 1 time a day. Using too much Atralin may irritate or increase the irritation of your skin, and will not give faster or better results. You may use moisturizers and cosmetics. What should I avoid while using Atralin? Avoid washing your skin too often and scrubbing the affected skin area. You should avoid sunlamps, tanning beds, and ultraviolet light during treatment with Atralin. Minimize exposure to sunlight. If you have to be in the sunlight or are sensitive to sunlight, use a sunscreen with a SPF (sun protection factor) of 15 or more and wear protective clothing, and a wide brimmed hat to cover the treated areas. If you do get sunburned, stop using Atralin until your skin has healed and is back to normal. Cold weather and wind may irritate skin treated with Atralin. Skin treated with Atralin may dry out or get wind burned more easily. Talk to your healthcare provider doctor about ways to manage skin irritation. Avoid contact with the peels of limes. What are the possible side effects of Atralin? Atralin may cause skin irritation, including: skin dryness, burning, redness, excessive flaking or peeling. If you develop these symptoms, your healthcare provider may tell you to stop using Atralin for a while, decrease the number of times you apply Atralin, or completely stop treatment with Atralin. It is not known if Atralin is effective when used less than 1 time a day. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the side effects possible with Atralin. 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 Atralin? Store Atralin at room temperature, 68°F to 77°F (20°C to 25°C). Protect from freezing. Keep Atralin and all medicines out of the reach of children. General information about the safe and effective use of Atralin Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Atralin for a condition for which it was not prescribed. Do not give Atralin to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Atralin that is written for health professionals. What are the ingredients of Atralin? Active ingredient: tretinoin Inactive ingredients: benzyl alcohol, butyl paraben, butylated hydroxytoluene, carbomer 940, ethyl paraben, fish collagen hydrolyzates, glycerin, iso-butyl paraben, methylparaben, octoxynol 9, phenoxyethanol, propylparaben, purified water, sodium hyaluronate, and trolamine.

OVERDOSE In case of overdose with VESANOID (tretinoin) , reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. The maximal tolerated dose in patients with myelodysplastic syndrome or solid tumors was 195 mg/m2/day. The maximal tolerated dose in pediatric patients was lower at 60 mg/m2/day. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects. There is no specific treatment in the case of an overdose; however, it is important that the patient be treated in a special hematological unit. CONTRAINDICATIONS VESANOID (tretinoin) is contraindicated in patients with a known hypersensitivity to VESANOID (tretinoin) , any of its components, or other retinoids. VESANOID (tretinoin) should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule.

OVERDOSE If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. CONTRAINDICATIONS Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted.

OVERDOSE If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of vitamin A. CONTRAINDICATIONS The product should not be used if there is hypersensitivity to any of the ingredients.

OVERDOSE No information provided. CONTRAINDICATIONS None.

SIDE EFFECTS Virtually all patients experience some drug-related toxicity, especially headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require interruption of therapy. Some of the adverse events are common in patients with APL, including hemorrhage, infections, gastrointestinal hemorrhage, disseminated intravascular coagulation, pneumonia, septicemia, and cerebral hemorrhage. The following describes the adverse events, regardless of drug relationship, that were observed in patients treated with VESANOID (tretinoin) . Typical Retinoid Toxicity The most frequently reported adverse events were similar to those described in patients taking high doses of vitamin A and included headache (86%), fever (83%), skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased sweating (20%), visual disturbances (17%), ocular disorders (17%), alopecia (14%), skin changes (14%), changed visual acuity (6%), bone inflammation (3%), visual field defects (3%). RA-APL Syndrome APL patients treated with VESANOID (tretinoin) have experienced a potentially fatal syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension and has been observed with or without concomitant leukocytosis. Some patients have expired due to progressive hypoxemia and multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of VESANOID (tretinoin) . The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first signs of the syndrome appear to reduce morbidity and mortality. Treatment with dexamethasone, 10 mg intravenously administered every 12 hours for 3 days or until resolution of symptoms, should be initiated without delay at the first suspicion of symptoms (one or more of the following: fever, dyspnea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities). Sixty percent or more of patients treated with VESANOID (tretinoin) may require high-dose steroids because of these symptoms. The majority of patients do not require termination of VESANOID (tretinoin) therapy during treatment of the syndrome. Body as a Whole General disorders related to VESANOID (tretinoin) administration and/or associated with APL included malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), myalgia (14%), flank pain (9%), cellulitis (8%), face edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), acidosis (3%), hypothermia (3%), ascites (3%). Respiratory System Disorders Respiratory system disorders were commonly reported in APL patients administered VESANOID (tretinoin) . The majority of these events are symptoms of the RA-APL syndrome (see boxed WARNINGS). Respiratory system adverse events included upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), pulmonary edema (3%), larynx edema (3%), unspecified pulmonary disease (3%). Ear Disorders Ear disorders were consistently reported, with earache or feeling of fullness in the ears reported by 23% of the patients. Hearing loss and other unspecified auricular disorders were observed in 6% of patients, with infrequent (<1%) reports of irreversible hearing loss. Gastrointestinal Disorders GI disorders included GI hemorrhage (34%), abdominal pain (31%), other gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%). Cardiovascular and Heart Rate and Rhythm Disorders Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy. Central and Peripheral Nervous System Disorders and Psychiatric Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial hypertension (9%), agitation (9%), hallucination (6%) and for 3% of patients: abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, slow speech. Urinary System Disorders Renal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%). Miscellaneous Adverse Events Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, Sweet's syndrome, organomegaly, hypercalcemia, pancreatitis and myositis have been reported. Additional Adverse Reactions Reported With VESANOID (tretinoin) Cardiovascular Cases of thrombosis (both venous and arterial) involving various sites (eg, cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS: General). Hematologic Rare cases of thrombocytosis have been reported. Skin Genital ulceration Miscellaneous Adverse Events Rare cases of vasculitis, predominantly involving the skin, have been reported. DRUG INTERACTIONS Limited clinical data on potential drug interactions are available. Drugs Metabolized By the Hepatic P450 System As VESANOID (tretinoin) is metabolized by the hepatic P450 system, there is a potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine. To date there are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of VESANOID (tretinoin) . Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension (Such as Tetracyclines) VESANOID (tretinoin) may cause pseudotumor cerebri/intracranial hypertension. Concomitant administration of VESANOID (tretinoin) and agents known to cause pseudotumor cerebri/intracranial hypertension as well might increase the risk of this condition (see WARNINGS). Vitamin A As with other retinoids, VESANOID (tretinoin) must not be administered in combination with vitamin A because symptoms of hypervitaminosis A could be aggravated. Anti-fibrinolytic Agents (Such as Tranexamic Acid, Aminocaproic Acid, or Aprotinin) Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with VESANOID (tretinoin) and anti-fibrinolytic agents. Therefore, caution should be exercised when administering VESANOID (tretinoin) concomitantly with these agents (see PRECAUTIONS: General). Effect of Food No data on the effect of food on the absorption of VESANOID (tretinoin) are available. The absorption of retinoids as a class has been shown to be enhanced when taken together with food.

SIDE EFFECTS The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of therapy (see DOSAGE AND ADMINISTRATION Section). DRUG INTERACTIONS Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to “rest” a patient's skin until the effects of such preparations subside before use of RETIN-A is begun.

SIDE EFFECTS The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication dosing frequency should be adjusted temporarily to a level the patient can tolerate. However, efficacy has not been established for lower dosing frequencies. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of AVITA® Cream. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with AVITA® Cream. Adverse effects of AVITA® Cream have been reversible upon discontinuation of therapy (see DOSAGE AND ADMINISTRATION). DRUG INTERACTIONS Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with AVITA® Cream. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of AVITA® Cream is begun.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under prescribing conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In two randomized, controlled trials, 674 subjects received treatment for up to 12 weeks with Atralin Gel [see Clinical Trials]. In these studies, 50% of the subjects who were treated with Atralin Gel reported one or more adverse reactions; 30% of the subjects reported treatment-related adverse reactions. In the vehicle group, 29% of the 487 randomized subjects reported at least one adverse reaction; 5% of the subjects reported events that were treatment-related. There were no serious, treatment-related adverse reactions reported by subjects in any of the treatment groups. Selected adverse reactions that occurred in at least 1% of subjects in the two trials combined are shown in Table 1 (below). Most skin-related adverse reactions first appear during the first two weeks of treatment with Atralin Gel, and the incidence rate for skin-related reactions peaks around the second and third week of treatment. In some subjects the skin-related adverse reactions persists throughout the treatment period. Table 1: Number of Subjects with Selected Adverse Reactions (Occurring in At Least 1% of Subjects) Event Atralin Gel (n = 674) Vehicle Gel (n = 487) Dry Skin 109 (16%) 8 (2%) Peeling/Scaling/ Flaking Skin 78 (12%) 7 (1%) Skin Burning Sensation 53 (8%) 8 (2%) Erythema 47 (7%) 1 ( < 1%) Pruritus 11 (2%) 3 (1%) Pain of Skin 7 (1%) 0 (0%) Sunburn 7 (1%) 3 (1%) Postmarketing Experience The following adverse reactions have been identified during post-approval use of Atralin Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Temporary hyper-or hypopigmentation has been reported with repeated application of tretinoin. DRUG INTERACTIONS No information provided.

WARNINGS Pregnancy Category D - See Boxed WARNINGS Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys, and may be expected to cause fetal harm when administered to a pregnant woman. Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Although experience with humans administered VESANOID (tretinoin) is extremely limited, increased spontaneous abortions and major human fetal abnormalities related to the use of other retinoids have been documented in humans. Reported defects include abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. Cases of IQ scores less than 85, with or without obvious CNS abnormalities, have also been reported. All fetuses exposed during pregnancy can be affected and at the present time there is no antepartum means of determining which fetuses are and are not affected. Effective contraception must be used by all females during VESANOID (tretinoin) therapy and for 1 month following discontinuation of therapy. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Whenever contraception is required, it is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing or terminating the pregnancy. Patients Without the t(15;17) Translocation Initiation of therapy with VESANOID (tretinoin) may be based on the morphological diagnosis of acute promyelocytic leukemia. Confirmation of the diagnosis of APL should be sought by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RARα fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to VESANOID (tretinoin) has not been demonstrated; therefore, patients who lack the genetic marker should be considered for alternative treatment. Retinoic Acid-APL (RA-APL) Syndrome In up to 25% of patients with APL treated with VESANOID (tretinoin) , a syndrome occurs which can be fatal (see boxed WARNINGS and ADVERSE REACTIONS). Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During VESANOID Treatment See boxed WARNINGS. Pseudotumor Cerebri Retinoids, including VESANOID (tretinoin) , have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in pediatric patients. The concomitant use of other agents known to cause pseudotumor cerebri/intracranial hypertension, such as tetracyclines, might increase the risk of this condition (see PRECAUTIONS: DRUG INTERACTIONS). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be evaluated for pseudotumor cerebri, and, if present, appropriate care should be instituted in concert with neurological assessment. Lipids Up to 60% of patients experienced hypercholesterolemia and/or hypertriglyceridemia, which were reversible upon completion of treatment. The clinical consequences of temporary elevation of triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Elevated Liver Function Test Results Elevated liver function test results occur in 50% to 60% of patients during treatment. Liver function test results should be carefully monitored during treatment and consideration be given to a temporary withdrawal of VESANOID (tretinoin) if test results reach >5 times the upper limit of normal values. However, the majority of these abnormalities resolve without interruption of VESANOID (tretinoin) or after completion of treatment. PRECAUTIONS General VESANOID (tretinoin) has potentially significant toxic side effects in APL patients. Patients undergoing therapy should be closely observed for signs of respiratory compromise and/or leukocytosis (see boxed WARNINGS). Supportive care appropriate for APL patients, eg, prophylaxis for bleeding, prompt therapy for infection, should be maintained during therapy with VESANOID (tretinoin) . There is a risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see ADVERSE REACTIONS). Therefore, caution should be exercised when treating patients with the combination of VESANOID (tretinoin) and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see DRUG INTERACTIONS). The ability to drive or operate machinery might be impaired in patients treated with VESANOID (tretinoin) , particularly if they are experiencing dizziness or severe headache. Microdosed progesterone preparations ("minipill") may be an inadequate method of contraception during treatment with VESANOID (tretinoin) . Laboratory Tests The patient's hematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently. Carcinogenesis, Mutagenesis and Impairment of Fertility No long-term carcinogenicity studies with tretinoin have been conducted. In short-term carcinogenicity studies, tretinoin at a dose of 30 mg/kg/day (about 2 times the human dose on a mg/m2 basis) was shown to increase the rate of diethylnitrosamine (DEN)-induced mouse liver adenomas and carcinomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A twofold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitroassay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m2 basis). In a 6-week toxicology study in dogs, minimal to marked testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m2). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from VESANOID (tretinoin) in nursing infants, mothers should discontinue nursing prior to taking this drug. Pediatric Use There are limited clinical data on the pediatric use of VESANOID (tretinoin) . Of 15 pediatric patients (age range: 1 to 16 years) treated with VESANOID (tretinoin) , the incidence of complete remission was 67%. Safety and effectiveness in pediatric patients below the age of 1 year have not been established. Some pediatric patients experience severe headache and pseudotumor cerebri, requiring analgesic treatment and lumbar puncture for relief. Increased caution is recommended in the treatment of pediatric patients. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable toxicity; however, the efficacy and safety of VESANOID (tretinoin) at doses lower than 45 mg/m2/day have not been evaluated in the pediatric population. Geriatric Use Of the total number of subjects in clinical studies of VESANOID (tretinoin) , 21.4% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS No information provided. PRECAUTIONS General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Carcinogenesis Long-term animal studies to determine the carcinogenic potential of tretinoin have not been performed. Studies in hairless albino mice suggest that tretinoin may accelerate the tumorigenic potential of weakly carcinogenic light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVB light, the incidence and rate of development of skin tumors was reduced. Due to significantly different experimental conditions, no strict comparison of these disparate data is possible. Although the significance of these studies to man is not clear, patients should avoid or minimize exposure to sun. Pregnancy Teratogenic effects - Pregnancy Category C Oral tretinoin has been shown to be teratogenic in rats when given in doses 1000 times the topical human dose. Oral tretinoin has been shown to be fetotoxic in rats when given in doses 500 times the topical human dose. Topical tretinoin has not been shown to be teratogenic in rats and rabbits when given in doses of 100 and 320 times the topical human dose, respectively (assuming a 50 kg adult applies 250 mg of 0.1% cream topically). However, at these topical doses, delayed ossification of a number of bones occurred in both species. These changes may be considered variants of normal development and are usually corrected after weaning. There are no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RETIN-A is administered to a nursing woman. GELS ARE FLAMMABLE. Note: Keep away from heat and flame. Keep tube tightly closed.

WARNINGS No Information Provided. PRECAUTIONS General If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, or artificial sunlight should be minimized during the use of AVITA® Cream, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. AVITA® (tretinoin cream) Cream, 0.025% should be kept away from the eyes, the mouth, the paranasal creases, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to temporarily use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Efficacy at reduced frequencies of application has not been established. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Information For Patients See attached Patient Package Insert. Carcinogenesis, Mutagenesis And Impairment Of Fertility In a life-time dermal study in CD-1 mice with another tretinoin cream, at 100 and 200 times the average recommended human topical clinical dose, a few skin tumors in the female mice and liver tumors in male mice were observed. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when tretinoin was administered topically at a dose five times the average recommended human topical clinical dose. For purposes of comparisons of the animal exposure to human exposure, the “recommended human topical clinical dose” is defined as 1.0 g of 0.025% AVITA® Cream applied daily to a 50 kg person. In a chronic, two-year bioassay of vitamin A acid in mice performed by Tsubura and Yamamoto, generalized amyloid deposition was reported in all vitamin A treated groups in the basal layer of the skin. In CD-1 mice, a similar study reported hyalinization at the treated skin sites and the incidence of this finding was 0/50, 3/50, 3/50, and 2/50 in male mice and 1/50, 0/50, 4/50, and 2/50 in female mice from the vehicle control, 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg groups, respectively. Studies in hairless albino mice suggest that tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. In other studies, when lightly pigmented hairless mice treated with tretinoin were exposed to carcinogenic doses of UVA/UVB light, the incidence and rate of development of skin tumors were either reduced or no effect was seen. Due to significantly different experimental conditions, no strict comparison of these disparate data is possible at this time. Although the significance of these studies to humans is not clear, patients should minimize exposure to sun. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. Dermal Segment I and III studies with AVITA® Cream have not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (> 400 times the average recommended human topical clinical dose). Pregnancy Pregnancy Category C. Teratogenic Effects Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. It was teratogenic and fetotoxic in rats when given orally in doses 1000 times the average recommended human topical clinical dose. However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than other species examined, fetal malformations were reported at oral doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (1000 times the average recommended human topical clinical dose), although increased skeletal variations were observed at all doses. Dose-related increased embryolethality and abortion were reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (200 times the recommended human topical clinical dose). Anomalies (humerus: short 13%, bent 6%; os parietal incompletely ossified 14%) have also been reported in rats when 10 mg/kg/day was dermally applied. Topical tretinoin (AVITA® Cream, 0.1%) has been shown to be teratogenic in rabbits when given in doses 91 times the topical human dose for cream (assuming a 50 kg adult applies 1.0 g of 0.1% cream topically). In this study, increased incidence of cleft palate and hydrocephaly was reported in the tretinoin-treated animals. There are other reports, in New Zealand White rabbits with doses of approximately 80 times the recommended human topical clinical dose, of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. When given subcutaneously to rabbits, tretinoin was teratogenic at 2 mg/kg/day but not at 1 mg/kg/day. These doses are approximately 400 and 200 times, respectively, the human topical dose of tretinoin cream, 0.025% (assuming a 50 kg adult applies 1.0 g of 0.025% cream topically). In contrast, several well-controlled animal studies have shown that dermally applied tretinoin was not teratogenic at doses of 100 and 200 times the recommended human topical clinical dose, in rats and rabbits, respectively. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin (Retin-A). Although no definite pattern of teratogenicity and no causal association have been established from these cases, five of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic Effects Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 100 times the recommended topical human clinical dose. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 500 times the recommended topical human clinical dose. There are, however, no adequate and well-controlled studies in pregnant women. AVITA® (tretinoin cream) Cream, 0.025% should not be used during pregnancy. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AVITA® Cream is administered to a nursing woman.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Skin Irritation The skin of certain individuals may become dry, red, or exfoliated while using Atralin Gel. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. Mild to moderate skin dryness may also be experienced; if so, use of an appropriate moisturizer during the day may be helpful. Tretinoin has been reported to cause severe irritation on eczematous or sunburned skin and should be used with caution in patients with these conditions. To help limit skin irritation, patients must: wash the treated skin gently, using a mild, non-medicated soap, and pat it dry avoid washing the treated skin too often and scrubbing the affected skin area avoid contact with the peels of limes Ultraviolet Light And Environmental Exposure Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Atralin Gel. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products of at least SPF 15 and protective clothing over treated areas is recommended when exposer cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin. Fish Allergies Atralin Gel contains soluble fish proteins and should be used with caution in patients with known sensitivity or allergy to fish. Patients who develop pruritus or urticaria should contact their health care provider. Patient Counseling Information See FDA-Approved Patient Labeling (PATIENT INFORMATION) Instruct patients to clean the affected areas with an appropriate cleanser before applying Atralin Gel. Patients may use moisturizers that are non-comedogenic, and should avoid products that could be drying or irritating. Patients may also wear cosmetics while being treated with Atralin Gel; however, they should be instructed to remove the cosmetics and clean the area thoroughly before applying Atralin Gel. Warn patients of the drying and irritation effects often seen during treatment. Continue use of the medication if these effects are tolerable. Caution patients against application of Atralin Gel around the eyes, mouth, paranasal creases, and mucous membranes as the skin is especially prone to irritation. Minimize exposure to sunlight, including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility A 2-year dermal mouse carcinogenicity study was initiated with topical administration of 0.005%, 0.025% and 0.05% Atralin Gel. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results. Studies in hairless albino mice with a different formulation suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect was confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative. In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (3 mg/m², approximately 4 times the clinical dose based on body surface area comparison), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (1.5 mg/m², approximately 2 times the clinical dose based on body surface area comparison), were observed. Use In Specific Populations Pregnancy Pregnancy Category C There are no well-controlled trials in pregnant women treated with Atralin Gel. Atralin Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Atralin Gel at doses of 0.1, 0.3 and 1 g/kg/day was tested for maternal and developmental toxicity in pregnant Sprague-Dawley rats by dermal application. The dose of 1 g/kg/day was approximately 4 times the clinical dose assuming 100% absorption and based on body surface area comparison. Possible tretinoin-associated teratogenic effects (craniofacial abnormalities (hydrocephaly), asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were noted in the fetuses of Atralin Gel treated animals. These finding were not observed in control animals. Other maternal and reproductive parameters in the Atralin Gel treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the clinical dose is defined as 2 g of Atralin Gel applied daily to a 50 kg person. Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters and nonhuman primates. Tretinoin was teratogenic in Wistar rats when given orally in doses greater than 1 mg/kg/day (approximately 8 times the clinical dose based on body surface area comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day, but none were observed at 5 mg/kg/day (approximately 80 times the clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in a different formulation has generated equivocal results in animal teratogenicity tests. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (approximately 8 times the clinical dose assuming 100% absorption and based on body surface area comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 160 times the clinical dose assuming 100% absorption and based on body surface areas comparison) was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Cases of temporally associated congenital malformations have been reported with use of other topical tretinoin products. The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects on fetuses Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 20 times the clinical dose based on body surface area comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses 8 times the clinical dose based on body surface area comparison. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Atralin Gel is administered to a nursing woman. Pediatric Use Safety and effectiveness in children below the age of 10 have not been established. A total of 381 pediatric subjects (aged 10 to 16 years) treated with Atralin Gel were enrolled into the two clinical studies. Across these two studies, comparable safety and efficacy were observed between pediatric and adult subjects. Geriatric Use Safety and effectiveness in a geriatric population have not been established. Clinical studies of Atralin Gel did not include any subjects over age 65 to determine whether they respond differently from younger subjects.