Amnesteem

1 INDICATIONS AND USAGE Amnesteem is indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, Amnesteem is reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. Limitations of Use : If a second course of Amnesteem treatment is needed, it is not recommended before a two-month waiting period because the patient's acne may continue to improve following a 15 to 20-week course of treatment [see Dosage and Administration (2.2) ]. Amnesteem is a retinoid indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, Amnesteem is reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. ( 1 ) Limitations of Use : If a second course of Amnesteem treatment is needed, it is not recommended before a two-month waiting period because the patient's acne may continue to improve following a 15 to 20-week course of treatment. ( 1 )

2 DOSAGE AND ADMINISTRATION • Evaluations Prior to Prescribing and Use of Amnesteem: o In patients who can get pregnant, only prescribe Amnesteem after verification and documentation that they are not pregnant. See the Full Prescribing Information for the detailed requirements prior to prescribing Amnesteem ( 2.1 , 8.3 ) o Complete the following laboratory tests in all patients: fasting lipid profile and liver function tests. ( 2.1 ) • Recommended dosage is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks ( 2.2 ) • Adult patients with very severe disease (scarring, trunk involvement) may increase dosage to 2 mg/kg/day in two divided doses with food. ( 2.1 ) • Once daily dosing is not recommended. ( 2.2 ) • If a dose is missed, just skip that dose. Do not take two doses at the same time. ( 2.2 ) • See the Full Prescribing Information for the recommended duration of use ( 2.3 ) 2.1 Evaluations Prior to Prescribing and Use of Amnesteem In patients who can get pregnant, only prescribe Amnesteem after verification and documentation that they are not pregnant [see Contraindications (4) and Warnings and Precautions (5.1 , 5.2) ] . For the detailed requirements prior to prescribing Amnesteem, see Use in Specific Populations (8.3) . Prior to Amnesteem use in all patients, complete the following laboratory testing: • A fasting lipid profile including triglycerides [see Warnings and Precautions (5.7 , 5.14) ] . • Liver function tests [see Warnings and Precautions (5.9 , 5.14) ] . 2.2 Recommended Dosage The recommended dosage range for Amnesteem is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks (see Tables 1 and 2, respectively) [see Clinical Pharmacology (12.3) ] . Table 1: Amnesteem: Recommended Divided Doses (0.5 mg/kg/day dosage) Body Weight First Dose Second Dose 40 kg 10 mg 10 mg 50 kg 12.5 mg 12.5 mg 60 kg 15 mg 15 mg 70 kg 17.5 mg 17.5 mg 80 kg 20 mg 20 mg 90 kg 22.5 mg 22.5 mg 100 kg 25 mg 25 mg Table 2: Amnesteem: Recommended Divided Doses (1 mg/kg/day dosage) Body Weight First Dose Second Dose 40 kg 20 mg 20 mg 50 kg 25 mg 25 mg 60 kg 30 mg 30 mg 70 kg 35 mg 35 mg 80 kg 40 mg 40 mg 90 kg 45 mg 45 mg 100 kg 50 mg 50 mg To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. Swallow capsules whole. Do not split, crush, chew, or suck on the capsules. During treatment, the dosage may be adjusted according to response of the disease and/or adverse reactions, 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 dosage adjustments up to 2 mg/kg/day for Amnesteem in divided doses with food, as tolerated (see Table 3). Table 3: Amnesteem: Recommended Divided Doses (2 mg/kg/day dosage) Body Weight First Dose Second Dose 40 kg 40 mg 40 mg 50 kg 50 mg 50 mg 60 kg 60 mg 60 mg 70 kg 70 mg 70 mg 80 kg 80 mg 80 mg 90 kg 90 mg 90 mg 100 kg 100 mg 100 mg The safety and effectiveness of once daily dosing with Amnesteem has not been established and is not recommended. If a dose of Amnesteem is missed, just skip that dose. Do not take two doses of Amnesteem at the same time. 2.3 Recommended Duration of Use A course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue Amnesteem. After a period of 2 months or more off treatment, and if warranted by persistent or recurring severe nodular acne, may initiate a second course of Amnesteem in patients who have completed skeletal growth. The use of another course of Amnesteem treatment is not recommended before a two-month waiting period because the patient's acne may continue to improve after a 15 to 20-week course of treatment. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Amnesteem, even in low dosages, has not bee …

3 DOSAGE FORMS AND STRENGTHS Amnesteem (Isotretinoin Capsules, USP) contains 10 mg, 20 mg, 30 mg or 40 mg of isotretinoin, USP. • The 10 mg capsules are reddish brown and imprinted with I10. • The 20 mg capsules are reddish brown and cream and imprinted with I20. • The 30 mg capsules are cream opaque and imprinted with I30. • The 40 mg capsules are orange-brown and imprinted with I40. Capsules: 10 mg, 20 mg, 30 mg and 40 mg ( 3 )

4 CONTRAINDICATIONS Amnesteem is contraindicated in: • Pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . • Patients with hypersensitivity to isotretinoin (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred) [see Warnings and Precautions (5.14) ] . Amnesteem is contraindicated in: • Pregnancy ( 4 , 8.1 ) • Patients with hypersensitivity to isotretinoin (or Vitamin A) or any of its components (4.2, 5.13 )

6 ADVERSE REACTIONS The following adverse reactions with Amnesteem are described in more detail in other sections of the labeling: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] • Psychiatric Disorders [see Warnings and Precautions (5.3) ] • Intracranial Hypertension (Pseudotumor Cerebri) [see Warnings and Precautions (5.4) ] • Serious Skin Reactions [see Warnings and Precautions (5.5) ] • Pancreatitis [see Warnings and Precautions (5.6) ] • Lipid Abnormalities [see Warnings and Precautions (5.7) ] • Hearing Impairment [see Warnings and Precautions (5.8) ] • Hepatotoxicity [see Warnings and Precautions (5.9) ] • Inflammatory Bowel Disease [see Warnings and Precautions (5.10) ] • Musculoskeletal Abnormalities [see Warnings and Precautions (5.11) ] • Ocular Abnormalities [see Warnings and Precautions (5.12) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.13) ] The following adverse reactions, presented alphabetically by body system, associated with the use of Amnesteem were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. Adverse Reactions with a Dose Relationship Cheilitis and hypertriglyceridemia were dose related. Body as a Whole Allergic reactions, dry mouth, edema, fatigue, irritability, lymphadenopathy, pain, systemic hypersensitivity, vasculitis, weight loss. Cardiovascular Palpitation, stroke, tachycardia, vascular thrombotic disease Endocrine/Metabolism and Nutritional Alterations in blood sugar levels, decreased appetite, hypertriglyceridemia, weight fluctuation. Gastrointestinal Abdominal pain, bleeding and inflammation of the gums, colitis, constipation, diarrhea, esophageal ulceration, esophagitis, ileitis, nausea, hepatitis, inflammatory bowel disease, other nonspecific gastrointestinal symptoms, pancreatitis, vomiting. Hematologic Anemia, neutropenia including severe neutropenia, rare reports of agranulocytosis, thrombocytopenia. Infections and Infestations Infections (including disseminated herpes simplex, hordeolum, nasopharyngitis, upper respiratory tract infections). Laboratory Abnormalities • The following lab test values were increased: alkaline phosphatase, ALT, AST, bilirubin, cholesterol, CPK, fasting blood glucose, gamma-glutamyltransferase, LDH, LDL, platelet counts, sedimentation rate, triglycerides, and uric acid (hyperuricemia). • The following lab test values were decreased: high density lipoprotein (HDL), RBC parameters, and WBC counts. • Urine findings included increased microscopic or gross hematuria, proteinuria, white cells. Musculoskeletal and Connective Tissue Arthritis, calcification of tendons and ligaments; decreases in bone mineral density; elevations of CPK/rare reports of rhabdomyolysis musculoskeletal symptoms (sometimes severe) including arthralgia, back pain, extremity pain, musculoskeletal pain or stiffness, myalgia, neck pain [see Warnings and Precautions (5.11) ] ; other types of bone abnormalities; premature epiphyseal closure; skeletal hyperostosis; tendonitis; and transient chest pain. Neurological Dizziness, drowsiness, intracranial hypertension (pseudotumor cerebri), headache, insomnia, lethargy, malaise, nervousness, paresthesia, seizures, syncope, stroke, and weakness. Psychiatric Aggression, auditory hallucinations, anger, depression, emotional instability, insomnia, irritability, panic attack, psychosis, suicidal ideation, suicide, suicide attempts, violent behaviors. In some patients who reported depression, their depression subsided with discontinuation of Amnesteem treatment but recurred with reinstitution of Amnesteem treatment. Reproductive System Abnormal menses, sexual dysfunction that may continue after discontinuation of treatment (including erectile dysfunction, decreased libido, decreased vaginal lubrication, and va …

7 DRUG INTERACTIONS Vitamin A : Avoid concomitant use ( 7.1 ) Tetracyclines : Avoid concomitant use ( 7.2 ) 7.1 Vitamin A Avoid concomitant use of Amnesteem with supplements containing vitamin A. Amnesteem is closely related to vitamin A. Therefore, concomitant use of Amnesteem with vitamin A may lead to Amnesteem-related adverse reactions. 7.2 Tetracyclines Avoid concomitant use of Amnesteem with tetracyclines. Amnesteem use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use with tetracyclines [see Warnings and Precautions (5.4) ]. 7.3 Oral Contraceptives It is not known if there is an interaction between Amnesteem with oral contraceptives that do not contain norethindrone and ethinyl estradiol. Amnesteem did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended ( 8.2 ). In Patients Who Can Get Pregnant : Pregnancy testing is required prior to, during, and after Amnesteem treatment. See the Full Prescribing Information for the detailed pregnancy test and contraception requirements. ( 8.3 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that documents pregnancies in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after Amnesteem treatment immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). Risk Summary Amnesteem is contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans [see Warnings and Precautions (5.1) ]. If Amnesteem is used during pregnancy, or if the patient becomes pregnant while taking Amnesteem, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking Amnesteem, immediately discontinue Amnesteem and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Data Human Data Major congenital malformations that have been documented following Amnesteem exposure include malformations of the face, eyes, ears, skull, central nervous system (CNS), cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases, death has occurred as a result of the malformations. Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy. 8.2 Lactation Risk Summary There are no data on the presence of isotretinoin in either animal or human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with Amnesteem, and for at least 8 days after the last dose of Amnesteem. 8.3 Females and Males of Reproductive Potential All patients who can become pregnant must comply with the iPLEDGE REMS requirements [see Warnings and Precautions (5.2) ] . Pregnancy Testing In patients who can get pregnant, pregnancy testing is required prior to, during, and after Amnesteem treatment. Pregnancy Testing Prior to Prescribing Amnesteem In patients who can get pregnant, only prescribe Amnesteem after verification and documentation that they are not pregnant: (1) Complete the first urine or serum pregnancy test (screening test) in a medical setting (e.g., prescriber’s office, clinic, laboratory) and verify and document that the test is negative, AND (2) For patients with: • Regular menstrual cycles, complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and during the first five days of their menstrual period immediately preceding the beginning of Amnesteem treatment, AND (2) after the patient has used their chosen pregnancy prevention methods (i.e., two forms of contraception or committed to abstinence) for at least 30 days. Verify and document th …

12.1 Mechanism of Action The exact mechanism of action of Amnesteem in the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics is unknown. Isotretinoin, a retinoid, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.

11 DESCRIPTION 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. Isotretinoin has high lipophilicity. The structural formula is: Amnesteem contains 10 mg, 20 mg, 30 mg or 40 mg of isotretinoin (a retinoid) for oral administration. In addition to the active ingredient, isotretinoin, each 10 mg, 20 mg, 30 mg and 40 mg soft gelatin capsule contains the following inactive ingredients: butylhydroxyanisole, gelatin, glycerol, hydrogenated partially vegetable oil, medium chain triglycerides, sodium edetate, soy lecithin, soybean oil and yellow beeswax. The 10 mg, 20 mg, and 40 mg capsules also contain red iron oxide in glycerin, and the 20 mg, 30 mg and 40 mg capsules also contain titanium dioxide in glycerin and yellow iron oxide in glycerin. The black imprinting ink contains ammonium hydroxide, black iron oxide, polyethylene glycol, propylene glycol and polyvinyl acetate phthalate. Meets USP Dissolution Test 4. Isotretinoin Structural Formula

10 OVERDOSAGE Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. Evaluate patients who can become pregnant who present with an isotretinoin overdosage for pregnancy. Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, instruct male patients treated with Amnesteem to use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for 1 month after the overdose. Instruct all patients with Amnesteem overdose not donate blood for at least 1 month. If an overdose occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Amnesteem (Isotretinoin Capsules, USP) contains 10 mg, 20 mg, 30 mg or 40 mg of isotretinoin, USP. The 10 mg capsules are reddish brown and imprinted with I10. They are available as follows: NDC 0378-6611-93 cartons of 30 containing 3 prescription packs of 10 capsules The 20 mg capsules are reddish brown and cream and imprinted with I20. They are available as follows: NDC 0378-6612-93 cartons of 30 containing 3 prescription packs of 10 capsules The 30 mg capsules are cream opaque and imprinted with I30. They are available as follows: NDC 0378-6613-93 cartons of 30 containing 3 prescription packs of 10 capsules The 40 mg capsules are orange-brown and imprinted with I40. They are available as follows: NDC 0378-6614-93 cartons of 30 containing 3 prescription packs of 10 capsules Store at 68° to 77°F (20° to 25°C). [See USP Controlled Room Temperature.] Protect from light.