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-week 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-week 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 mg/kg/day to 1 mg/kg/day given in two divided doses with food for 15 weeks 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 isotretinoincapsules 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 mg/kg/day to 1 mg/kg/day given in two divided doses with food for 15 weeks 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 weeks to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 weeks 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 …

3 DOSAGE FORMS AND STRENGTHS Isotretinoin capsules, USP are available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules. 10 mg: Dark yellow color cap/dark yellow color body, size ‘3’ hard gelatin band sealed capsule imprinted “ISO” on body and “10” on cap with BLACK TEK ink containing light orange or yellow color medicament. 20 mg: Red color cap/red color body, size ‘1’ hard gelatin band sealed capsule imprinted “ISO” on body and “20” on cap with BLACK TEK ink containing light orange or yellow color medicament. 25 mg: Green color cap/green color body, size ‘0’ hard gelatin capsule, imprinted “ISO” on body and “25” on cap with WHITE TEK ink containing light orange or yellow color medicament. 30 mg: Brown color cap/brown color body, size ‘0EL’ hard gelatin capsule imprinted “ISO” on body and “30” on cap with WHITE TEK ink containing light orange or yellow color medicament. 35 mg: Dark blue color cap/dark blue color body, size ‘00’ hard gelatin capsule, imprinted “ISO” on body and “35” on cap with WHITE TEK ink containing light orange or yellow color medicament. 40 mg: Brown color cap/red color body, size ‘00EL’ hard gelatin capsule imprinted “ISO” on body and “40” on cap with WHITE TEK ink containing light orange or yellow color medicament. Isotretinoin Capsules USP: 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg ( 3 )

4 CONTRAINDICATIONS Pregnancy ( 4.1 , 8.1 ) Hypersensitivity to this product or any of its components ( 4.2 , 5.14 ) 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, decreas …

7 DRUG INTERACTIONS Vitamin A: may cause additive adverse reactions (7.1) Tetracyclines: avoid concomitant use (7.2) 7.1 Vitamin A Isotretinoin capsules are closely related to vitamin A. Therefore, the use of both vitamin A and isotretinoin capsules at the same time may lead to vitamin A related adverse reactions. Patients treated with isotretinoin capsules should be advised against taking supplements containing Vitamin A to avoid additive toxic effects. 7.2 Tetracyclines Concomitant treatment with isotretinoin capsules and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines [see Warnings and Precautions (5.5) ] . 7.3 Phenytoin Phenytoin is known to cause osteomalacia. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin. Therefore, caution should be exercised when using these drugs together. 7.4 Systemic Corticosteroids Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss with concomitant use of systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together. 7.5 Norethindrone and Ethinyl Estradiol In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving norethindrone and ethinyl estradiol as an oral contraceptive agent, isotretinoin capsules within the recommended dosage, 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). Although this study did not show any clinically significant interaction between isotretinoin and norethindrone, it is not known if there is an interaction between isotretinoin with other progestins.

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 isotretinoin 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 isotretinoin 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 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, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin, immediately discontinue isotretinoin 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 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: central nervous system (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 isotretinoin, and for at least 8 days after the last dose of isotretinoin. 8.3 Females and Males of Reproductive Potential All patients who can get 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 isotretinoin treatment. Pregnancy Testing Prior to Prescribing Isotretinoin : In patients who can get pregnant, only prescribe isotretinoin 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 isotretinoin 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. Verif …

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, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin, USP (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin USP, each capsule contains the following inactive ingredients: sorbitan monooleate, soybean oil, stearoyl polyoxyglycerides, and vitamin E. The capsule shells contain the following: 10 mg - FD&C Blue No. 1, gelatin, and titanium dioxide 20 mg - FD&C Blue No. 1, gelatin, iron oxide yellow, and titanium dioxide 25 mg - D&C Yellow No. 10, FD&C Blue No. 1, FD&C Green No. 3, gelatin, and titanium dioxide 30 mg - FD&C Blue No. 1, FD&C Yellow No. 6, gelatin, sodium lauryl sulfate, and titanium dioxide 35 mg - FD&C Blue No. 1, FD&C Red No. 40, gelatin, and titanium dioxide 40 mg - FD&C Blue No. 1, FD&C Yellow No. 6, gelatin, sodium lauryl sulfate, and titanium dioxide The black imprinting ink of the 10 mg and 20 mg capsules contain the following ingredients: ammonium hydroxide, iron oxide black, propylene glycol, and shellac. The black imprinting ink of the 25 mg and 35 mg capsules contain the following ingredients: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, iron oxide black, shellac and may contain propylene glycol. The black imprinting ink of the 30 mg and 40 mg capsules contain the following ingredients: iron oxide black, propylene glycol, shellac, and may contain ammonium hydroxide or potassium hydroxide and strong ammonia solution. Isotretinoin Chemically, isotretinoin, USP is 13- cis -retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is: Meets USP Dissolution Test 3. 1

10 OVERDOSAGE Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolved without apparent residual effects. 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 isotretinoin 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 isotretinoin overdose to 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 Isotretinoin capsules USP, 10 mg are orange colored mass filled into size "2" hard gelatin capsules with yellow opaque cap & body printed "1574" on cap with black ink and are supplied as follows: NDC 70710-1574-8 in cartons of 30 (3 x 10) unit-dose capsules (Unit-dose blisters are child-resistant) Isotretinoin capsules USP, 20 mg are orange colored mass filled into size "0" hard gelatin capsules with orange opaque cap & body printed "1575" on cap with black ink and are supplied as follows: NDC 70710-1575-8 in cartons of 30 (3 x 10) unit-dose capsules (Unit-dose blisters are child-resistant) Isotretinoin capsules USP, 25 mg are orange colored mass filled into size "0" hard gelatin capsules with light green opaque cap & body printed "1576" on cap with black ink and are supplied as follows: NDC 70710-1576-8 in cartons of 30 (3 x 10) unit-dose capsules (Unit-dose blisters are child-resistant) Isotretinoin capsules USP, 30 mg are orange colored mass filled into size "00" hard gelatin capsules with light brown opaque cap & body printed "1577" on cap with black ink and are supplied as follows: NDC 70710-1577-8 in cartons of 30 (3 x 10) unit-dose capsules (Unit-dose blisters are child-resistant) Isotretinoin capsules USP, 35 mg are orange colored mass filled into size "00" hard gelatin capsules with light blue opaque cap & body printed "1578" on cap with black ink and are supplied as follows: NDC 70710-1578-8 in cartons of 30 (3 x 10) unit-dose capsules (Unit-dose blisters are child-resistant) Isotretinoin capsules USP, 40 mg are orange colored mass filled into size "00" hard gelatin capsules with light pink opaque cap & body printed "1579" on cap with black ink and are supplied as follows: NDC 70710-1579-8 in cartons of 30 (3 x 10) unit-dose capsules (Unit-dose blisters are child-resistant) Storage and Handling of Isotretinoin Capsules, USP Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Protect from light.