Isotretinoin

1 INDICATIONS AND USAGE Isotretinoin Capsules 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, Isotretinoin Capsules 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 Isotretinoin Capsules 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)]. Isotretinoin Capsules 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, Isotretinoin Capsules are 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 Isotretinoin Capsules 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 Isotretinoin Capsules: In patients who can get pregnant, only prescribe Isotretinoin Capsules after verification and documentation that they are not pregnant. See the Full Prescribing Information for the detailed requirements prior to prescribing Isotretinoin Capsules (2.1, 8.3) 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 Isotretinoin Capsules In patients who can get pregnant, only prescribe Isotretinoin Capsules 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 Isotretinoin Capsules, see Use in Specific Populations (8.3)]. Prior to Isotretinoin Capsules 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 Isotretinoin Capsules 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: Isotretinoin Capsules: 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: Isotretinoin Capsules: 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 Isotretinoin Capsules in divided doses with food, as tolerated (see Table 3). Table 3: Isotretinoin Capsules: 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 Isotretinoin Capsules has not been established and is not recommended. If a dose of Isotretinoin Capsules is missed, just skip that dose. Do not take two doses of Isotretinoin Capsules 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 Isotretinoin Capsules. 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 Isotretinoin Capsules in patients who have completed skeletal growth. The use of another course of Isotretinoin Capsules 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. …

3 DOSAGE FORMS AND STRENGTHS Isotretinoin capsules, USP are available in 10 mg, 20 mg and 30 mg. 10 mg: Yellow, oblong, opaque, soft gelatin capsule, containing a yellow/orange viscous liquid, imprinted "570" in black ink. 20 mg: Pink, oblong, opaque, soft gelatin capsule, containing a yellow/orange viscous liquid, imprinted "571" in black ink. 30 mg: Brown, oblong, opaque, soft gelatin capsule, containing a yellow/orange viscous liquid, imprinted "573" in black ink. Capsules: 10 mg, 20 mg and 30 mg ( 3 )

4 CONTRAINDICATIONS Pregnancy ( 4.1 , 8.1 ) Hypersensitivity to this product or any of its components ( 4.2 , 5.15 ) 4.1 Pregnancy Isotretinoin capsules are contraindicated in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . 4.2 Hypersensitivity Isotretinoin capsules are contraindicated in 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) ] .

6 ADVERSE REACTIONS The following adverse reactions with isotretinoin capsules 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 isotretinoin capsules 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 isotretinoin capsules treatment but recurred with reinstitution of isotretinoin capsules treatment Reproductive System Abnormal menses, sexual dysfunction that may continue after discontinuation of treatment (including erectile dysfunction, decreased libido, decreased vaginal lubrication, an …

Drug Interactions Vitamin A: Because of the relationship of isotretinoin capsules to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with isotretinoin capsules and tetracyclines should be avoided because isotretinoin capsules use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations ("minipills" that do not contain an estrogen) may be an inadequate method of contraception during isotretinoin capsules therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with isotretinoin capsules. Therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS ). Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum ® 7/7/7 Tablets as an oral contraceptive agent, isotretinoin capsules at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John's Wort: Isotretinoin capsules use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric ). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. Phenytoin : Isotretinoin capsules have not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin capsules. Therefore, caution should be exercised when using these drugs together. Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and isotretinoin capsules. Therefore, caution should be exercised when using these drugs together.

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after isotretinoin therapy 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 Isotretinoin 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. If isotretinoin is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin, the patient should be apprised of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin capsules, isotretinoin capsules must be discontinued immediately and the patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Data Human Data Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases, death has occurred as a result of the malformations. 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 is 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 isotretinoin, and for at least 8 days after the last dose of isotretinoin capsules. 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 Isotretinoin capsules must only be prescribed to patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Patients who can become pregnant must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin capsules prescription (the interval between the two tests must be at least 19 days). The first test (a screening test) is obtained by the prescriber when the decision is made to prescribe isotretinoin therapy. The second pregnancy test (a confirmation test) is performed after the patient has used 2 forms of contraception for 1 month and during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy (for patients with regular menstrual cycles) or immediately preceding the beginning of isotretinoin therapy (for patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding). A pregnancy test must be repeated each month, in a CLIA-certified laboratory prior to the patient receiving each prescription. A p …

12.1 Mechanism of Action The exact mechanism of action of Isotretinoin Capsules 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 Isotretinoin capsules, USP contain 10 mg, 20 mg or 30 mg of isotretinoin (a retinoid) in soft gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin USP, each capsule contains the following inactive ingredients: butylated hydroxyanisole, disodium edetate, hydrogenated vegetable oil Type I, hydrogenated vegetable oil Type II, soybean oil, vitamin E and yellow wax. The gelatin capsules contain the following: 10 mg – glycerin, iron oxide (yellow), sorbitol and titanium dioxide 20 mg – glycerin, iron oxide (red), sorbitol and titanium dioxide 30 mg – glycerin, iron oxide (red and yellow), ferrosoferric oxide, sorbitol and titanium dioxide Chemically, isotretinoin is 13- cis -retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is: Meets USP Dissolution Test 6. Chemical Structure

OVERDOSAGE The oral LD 50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and >300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects. Isotretinoin capsules cause life-threatening birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS ). Patients who can become pregnant who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS . Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS . Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.

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 0832-8301-30). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 0832-8301-01). 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 0832-8302-30). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 0832-8302-01). Soft gelatin capsules, 30 mg (pink), imprinted in black ink with "V30". Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 0832-8303-30). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 0832-8303-01). Soft gelatin capsules, 40 mg (orange), imprinted in black ink with "V40". Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 0832-8304-30). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 0832-8304-01). Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from light.