Isotretinoin

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 69238-1254

Application: ANDA216097

Effective: 20230824

1 INDICATIONS AND USAGE Isotretinoin capsules are 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. Limitations of Use: If a second course of isotretinoin capsules therapy 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 therapy [see Dosage and Administration (2.2) ] . Isotretinoin capsules are retinoids 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 therapy 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 therapy. (1)

2 DOSAGE AND ADMINISTRATION Isotretinoin capsules are not substitutable with ABSORICA LD because of different bioavailability and recommended dosage. (2.1 , 5.3) Recommended dosage for: Isotretinoin capsules are 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (2.1) Adult patients with very severe disease (scarring, trunk involvement) may increase dosage to 2 mg/kg/day of isotretinoin capsules in divided doses. (2.1) Once daily dosing is not recommended. (2.1) If a dose of isotretinoin capsules is missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time. (2.1) Perform pregnancy tests prior to prescribing, each month during therapy, end of therapy, and one month after discontinuation. (2.3 , 8.3) Prior to prescribing, perform fasting lipid profile and liver function tests. (2.3) 2.1 Recommended Dosage Isotretinoin capsules are not substitutable with ABSORICA LD [see Warnings and Precautions (5.3) ] . The recommended dosage of: Isotretinoin capsules are 0.5 to 1 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. 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, as tolerated. 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 are missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time. Table 1: Isotretinoin Capsules Daily Dosage by Body Weight 1 Body Weight Total Daily Dosage (mg) 1 0.5 mg/kg 1 mg/kg 2 mg/kg 40 kg 20 40 80 50 kg 25 50 100 60 kg 30 60 120 70 kg 35 70 140 80 kg 40 80 160 90 kg 45 90 180 100 kg 50 100 200 1 Administer in two divided doses with or without meals 2.2 Duration of Use A normal 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 therapy, 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 therapy 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 therapy. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of isotretinoin capsules, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of isotretinoin capsules on bone loss is unknown [see Warnings and Precautions (5.12) ] . 2.3 Laboratory Testing Prior to Administration The following laboratory testing must be completed prior to isotretinoin capsules use: Pregnancy testing: Ensure patient is not pregnant prior to administering isotretinoin capsules [see Contraindications (4) and Use in Specific Populations (8.1 , 8.3) ] A fasting lipid profile including triglycerides [see Warnings and Precautions (5.8 , 5.15) ] . Liver function tests [see Warnings and Precautions (5.10 , 5.15) ] .

4 CONTRAINDICATIONS Pregnancy (4.1 , 8.1) Hypersensitivity to this product or any of its components (4.2 , 5.14) 4.1 Pregnancy Isotretinoin is 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) ] .

Not available.

6 ADVERSE REACTIONS The following adverse reactions with isotretinoin or other isotretinoin capsule products 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 (5.4) ] Intracranial Hypertension (Pseudotumor Cerebri) [see Warnings and Precautions (5.5) ] Serious Skin Reactions [see Warnings and Precautions (5.6) ] Pancreatitis [see Warnings and Precautions (5.7) ] Lipid Abnormalities [see Warnings and Precautions (5.8) ] Hearing Impairment [see Warnings and Precautions (5.9) ] Hepatotoxicity [see Warnings and Precautions (5.10) ] Inflammatory Bowel Disease [see Warnings and Precautions (5.11) ] Musculoskeletal Abnormalities [see Warnings and Precautions (5.12) ] Ocular Abnormalities [see Warnings and Precautions (5.13) ] Hypersensitivity Reactions [see Warnings and Precautions (5.14) ] The following adverse reactions 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. Dose Relationship Cheilitis and hypertriglyceridemia were dose related. Body as a Whole Fatigue, irritability, pain, allergic reactions, systemic hypersensitivity, edema, lymphadenopathy, weight loss. Cardiovascular Vascular thrombotic disease, stroke, palpitation, tachycardia. Endocrine/Metabolism and Nutritional Decreased appetite, weight fluctuation, alterations in blood sugar. Gastrointestinal Dry lips, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting, inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis, esophageal ulceration, ileitis. Hematologic Anemia and decreased RBC parameters, thrombocytopenia, increased platelet counts, decreased WBC counts, severe neutropenia, rare reports of agranulocytosis. Infections and Infestations Nasopharyngitis, hordeolum, infections (including disseminated herpes simplex and upper respiratory tract infection). Laboratory Abnormalities The following lab tests were increased: creatine phosphokinase (CPK), triglycerides, alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT), gamma-glutamyltransferase (GGTP), cholesterol, low density lipoprotein (LDL), alkaline phosphatase, bilirubin, LDH, fasting blood glucose, uric acid, and sedimentation rate. However, high density lipoprotein (HDL) was decreased. Urine findings included increased white cells, proteinuria, microscopic or gross hematuria. Musculoskeletal and Connective Tissue Decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, arthralgia, musculoskeletal pain, neck pain, extremity pain, myalgia, musculoskeletal stiffness [see Warnings and Precautions (5.12) ] , skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient chest pain, and rare reports of rhabdomyolysis. Neurological Headache, syncope, intracranial hypertension (pseudotumor cerebri), dizziness, drowsiness, lethargy, malaise, nervousness, paresthesia, seizures, stroke, weakness. Psychiatric Suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability, suicide attempts, suicide, aggression, psychosis and auditory hallucinations. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy. Reproductive System Abnormal menses and sexual dysfunction, including erectile dysfunction, decreased libido, decreased vaginal lubrication, and vaginal dryness. Respiratory Epistaxis, nasal dryness, bronchospasm (with or without a history of asthma), respiratory infection, voice alteration. Skin and Subcutaneous Tissue Dry skin, dermatitis, eczema, rash, contact dermatitis, alopecia, pruritus, sunburn, erythema, acne fulminans, alopecia (which in some cases persisted), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, skin fragility, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, increased sunburn susceptibility, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including granulomatosis with polyangiitis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting). Senses Hearing: tinnitus and hearing impairment. Ocular: dry eyes, reduced visual acuity, blurred vision, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, conjunctivitis, corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances. Renal and Urinary Glomerulonephritis. Most common adverse reactions (incidence ≥ 5%) are: dry lips, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, increased creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or iPLEDGE at (1-866-495-0654).