Prescription Drugs

Myorisan™ (isotretinoin) Capsules, USP 10 mg, 20 mg, 30 mg, 40 mg CAUSES BIRTH DEFECTS DO NOT GET PREGNANT WARNING CONTRAINDICATIONS AND WARNINGS Myorisan must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Myorisan in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects which have been documented following Myorisan exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals ); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities , cerebellar malformation, hydrocephalus , microcephaly, cranial nerve deficit); cardiovascular abnormalities ; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted. If pregnancy does occur during treatment of a female patient who is taking Myorisan, Myorisan must be discontinued immediately and she should be referred to an Obstetrician- Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Special Prescribing Requirements Because of Myorisan's teratogenicity and to minimize fetal exposure, Myorisan is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Myorisan must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Myorisan must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS). Table 1 : Monthly Required iPLEDGE Interactions Females of Reproductive Potential Male Patients, and Females of Non-Reproductive Potential PRESCRIBER Confirms patient counseling X X Enters the 2 contraception methods chosen by the patient X Enters pregnancy test results X PATIENT Answers educational questions before every prescription X Enters 2 forms of contraception X PHARMACIST Contacts system to get an authorization X X DESCRIPTION Isotretinoin, a retinoid, is available as Myorisan in 10-mg, 20-mg, 30-mg and 40-mg soft gelatin capsules for oral administration. Each capsule contains yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, tocopherol, and soybean oil. Gelatin capsules contain gelatin, glycerin and non-crystallizing sorbitol solution, with the following dye systems: 10 mg - ferric oxide (yellow) and titanium dioxide; 20 mg - titanium dioxide; 30 mg - titanium dioxide and ferric oxide (red); 40 mg - FD&C Yellow No.6 and titanium dioxide. The edible imprinting ink for all the capsules contains: shellac glaze, dehydrated alcohol, isopropyl alcohol, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide. USP Dissolution Test Pending. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

INDICATIONS Severe Recalcitrant Nodular Acne Myorisan is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Myorisan should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Myorisan is indicated only for those female patients who are not pregnant, because Myorisan can cause severe birth defects (see BOXED CONTRAINDICATIONS AND WARNINGS). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Myorisan. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, Premature Epiphyseal Closure). DOSAGE AND ADMINISTRATION Myorisan should be administered with a meal (see PATIENT INFORMATION). The recommended dosage range for Myorisan is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects - some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Myorisan with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions. The safety of once daily dosing with Myorisan has not been established. Once daily dosing is not recommended. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Myorisan, even in low doses, has not been studied, and is not recommended. It is important that Myorisan be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Myorisan on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS). Table 4 : Myorisan Dosing by Body Weight (Based on Administration With Food) Body Weight Total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg * 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 *See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day. INFORMATION FOR PHARMACISTS Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866- 495-0654) to obtain an authorization and the “do not dispens e to patient after” date. Myorisan must only be dispensed in no more than a 30-day supply. REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM. A Myorisan Medication Guide must be given to the patient each time Myorisan is dispensed, as required by law. This Myorisan Medication Guide is an important part of the risk management program for the patient. HOW SUPPLIED Soft gelatin capsules, 10 mg (pale yellow), imprinted in black ink with “V10”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-301-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-301-11). Soft gelatin capsules, 20 mg (white to slight pink), imprinted in black ink with “V20”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-302-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-302-11). Soft gelatin capsules, 30 mg (pink), imprinted in black ink with “V30”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-303-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-303-11). Soft gelatin capsules, 40 mg (orange), imprinted in black ink with “V40”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-304-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-304-11). Storage Store at 20°-25°C (68° to 77°F). [See USP controlled room temperature]. Protect from light. Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor. Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand. *A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent. ______________________________________________________________ (Patient's Name) 1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin. Initial: ______ 2. I understand that I must not get pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin. Initial: ______ 3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective forms of birth control (contraception) at the same time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am post-menopausal. Initial: ______ 4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use two different birth control methods at the same time, starting one month before, during, and for one month after stopping therapy every time I have sexual intercourse, even if one of the methods I choose is hormonal birth control. Initial: ______ 5. I understand that the following are effective forms of birth control: Primary forms tying my tubes (tubal sterilization) partner's vasectomy intrauterine device hormonal (combination birth control pills, skin patches, shots, under-the-skin implants or vaginal ring) Secondary forms Barrier: male latex condom with or without spermicide diaphragm with spermicide cervical cap with spermicide Other: vaginal sponge (contains spermicide) A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm. I understand that at least one of my two forms of birth control must be a primary method. Initial: ______ 6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products. Initial: ______ 7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation. Initial: ______ 8. I must begin using the birth control methods I have chosen as described above at least one month before I start taking isotretinoin. Initial: ______ 9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment, or as instructed by my doctor. I will then have one pregnancy test; in a lab. every month during treatment at the end of treatment and 1 month after stopping treatment I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab. Initial: ______ 10. I have read and understand the materials my doctor has provided to me, including The Ipledge Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The iPLEDGE Program Patient Introductory Brochure. My doctor provided me and asked me to watch a video about birth control and a video about birth defects and isotretinoin. I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control. Initial: ______ 11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control, or have sexual intercourse without using my two birth control methods at any time. Initial: ______ 12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin and government health regulatory authorities. Initial: ______ 13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I: have had two negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription. have chosen and agreed to use two forms of effective birth control at the same time. At least one method must be a primary form of birth control, unless I have chosen never to have sexual contact with a male (abstinence), or I have undergone a hysterectomy. I must use two forms of birth control for at least one month before I start isotretinoin therapy, during therapy, and for one month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy. have signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin. have been informed of and understand the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within 1 month of the last dose. have interacted with the iPLEDGE Program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control. Initial: ______ My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to get pregnant one month before, during isotretinoin treatment, or for one month after I s top taking isotretinoin. Initial: ______ I now authorize my doctor ________________ to begin my treatment with isotretinoin. Patient Signature:___________________________________ Date: ______ Parent/Guardian Signature (if under age 18):________________ Date:______ Please print: Patient Name and Address_______________________________ ________________________________ Telephone ______________________ I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to females of reproductive potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability. Doctor Signature: ____________________________________ Date: ______ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. Patient Information/Informed Consent (for all patients ): To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor. Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement. Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin. 1. I, ______________________________________________________________, (Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars. Initials: ______ 2. My doctor has told me about my choices for treating my acne. Initials: ______ 3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)]. Initials: ______ 4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below). Initials: ______ 5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there. Initials: ______ 6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems. Initials: ______ 7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I: Start to feel sad or have crying spells Lose interest in activities I once enjoyed Sleep too much or have trouble sleeping Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) Have a change in my appetite or body weight Have trouble concentrating Withdraw from my friends or family Feel like I have no energy Have feelings of worthlessness or guilt Start having thoughts about hurting myself or taking my own life (suicidal thoughts) Start acting on dangerous impulses Start seeing or hearing things that are not real Initials: ______ 8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects. Initials: ______ 9. Isotretinoin will be prescribed just for me - I will not share isotretinoin with other people because it may cause serious side effects, including birth defects. Initials: ______ 10. I will not give blood while taking isotretinoin or for 1 month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects. Initials: ______ 11. I have read The iPLEDGE Program Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received. Initials: ______ 12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin. Initials: ______ I now allow my doctor ___________________________ to begin my treatment with isotretinoin. Patient Signature: ____________________________________ Date: ______ Parent/Guardian Signature (if under age 18): _______________ Date: ______ Patient Name (print) ___________________________________ Patient Address ___________________________ Telephone (___.___.___) _____________________________________________________________ I have: fully explained to the patient, __________________, the nature and purpose of isotretinoin treatment, including its benefits and risks provided the patient with the appropriate educational materials, The iPLEDGE Program Patient Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin answered those questions to the best of my ability Doctor Signature: _________________________________ Date: ______ PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT. REFERENCES 1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980. 8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter doseresponse study. J Am Acad Dermatol 10:490-496, 1984. Distributed by: VersaPharm Inc. - An Akorn Company, Lake Forest, IL 60045. Revised: Sep 2015

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