Isotretinoin

WARNING: EMBRYO-FETAL TOXICITY - CONTRAINDICATED IN PREGNANCY Isotretinoin Capsules can cause life-threatening birth defects and is contraindicated in pregnancy . There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking any amount of Isotretinoin Capsules even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected . If pregnancy occurs, discontinue Isotretinoin Capsules immediately and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)] . Because of the risk of embryo-fetal toxicity, Isotretinoin Capsules is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS [see Warnings and Precautions (5.2)]. WARNING: EMBRYO-FETAL TOXICITY - CONTRAINDICATED IN PREGNANCY See full prescribing information for complete boxed warning. Isotretinoin Capsules can cause life-threatening birth defects and is contraindicated in pregnancy. There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking Isotretinoin Capsules 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. (4, 5.1, 8.1) Isotretinoin Capsules are available only through a restricted program called the iPLEDGE REMS. (5.2)

5 WARNINGS AND PRECAUTIONS Psychiatric Disorders (depression, psychosis, suicidal thoughts and behavior, and aggressive and/or violent behaviors): Prior to and during treatment assess for these conditions; stop if these conditions occur on treatment (5.3) Intracranial Hypertension (Pseudotumor Cerebri) : Avoid concomitant use with tetracyclines (5.4, 7.2) Serious Skin Reactions : Monitor for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions and discontinue treatment if they occur (5.5) Acute Pancreatitis : If pancreatitis symptoms occur, discontinue treatment (5.6) Lipid Abnormalities (hypertriglyceridemia, low HDL, and elevation of cholesterol): Monitor lipid levels at regular intervals; stop if hypertriglyceridemia cannot be controlled (5.7) Hearing Impairment : Discontinue and refer to specialized care (5.8) Hepatotoxicity : Monitor liver function tests prior to and during treatment (5.9, 5.14) Inflammatory Bowel Disease : Discontinue for abdominal pain, rectal bleeding, or severe diarrhea (5.10) Musculoskeletal Abnormalities : Arthralgias, back pain, decreases in bone mineral density and premature epiphyseal closure (5.11) Ocular Abnormalities e.g., corneal opacities, decreased night vision: If visual symptoms occur, discontinue, and refer for an ophthalmological exam (5.12) 5.1 Embryo-Fetal Toxicity Isotretinoin Capsules is contraindicated in pregnancy [see Contraindications (4)] . Based on human data, Isotretinoin Capsules can cause fetal harm when administered to a pregnant patient. There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking any amount of Isotretinoin Capsules even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected. Major congenital malformations, spontaneous abortions, and premature births have been documented following exposure to isotretinoin during pregnancy [see Use in Specific Populations (8.1)]. If a pregnancy occurs during Isotretinoin Capsules treatment, immediately discontinue Isotretinoin Capsules and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Immediately report any suspected fetal exposure during or 1 month after Isotretinoin Capsules treatment 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). Inform patients not to donate blood during Isotretinoin Capsules treatment and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin. Isotretinoin Capsules is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2)]. 5.2 iPLEDGE REMS Because of the risk of embryo-fetal toxicity, Isotretinoin Capsules are available only through a restricted program under a REMS called the iPLEDGE REMS [see Warnings and Precautions (5.1)] . Notable requirements of the iPLEDGE REMS include the following: Prescribers must be certified with the REMS and comply with the REMS requirements, including the following: Assess the reproductive status of all patients prior to initiating and during treatment Counsel patients who cannot get pregnant on the risk and REMS requirements prior to initiating treatment. Counsel patients who can get pregnant on: The risk and REMS requirements prior to and during treatment. Pregnancy prevention requirements prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling Comply with the pregnancy testing requirements. Assess the pregnancy status for patients who can get pregnant by reviewing pregnancy tests and documenting a negative result prior to each prescription. Report all pregnancies to the REMS. Patients who can become pregnant must be enrolled in the REMS and must comply with REMS requirements, including the following: Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3)] Demonstrate comprehension of the risk and REMS requirements before each prescription is dispensed Obtain the prescription within the 7-day prescription window (i.e., within 7 days of the pregnancy test collection) Patients who cannot become pregnant must be enrolled in the REMS and must comply with the REMS requirements, including to not share Isotretinoin Capsules and not donate blood Pharmacies that dispense Isotretinoin Capsules must be certified in the REMS and must comply with the REMS requirements, including the following: Obtain authorization to dispense and only dispense to patients who are authorized to receive Isotretinoin Capsules Dispense a maximum of a 30-day supply with a Medication Guide. Do not dispense refills. Wholesalers and distributors must be registered in the REMS and must only distribute to certified pharmacies. Further information, including a list of qualified pharmacies and distributors, is available at www.ipledgeprogram.com or 1-866-495-0654. 5.3 Psychiatric Disorders Isotretinoin Capsules may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors [see Adverse Reactions (6)] . Be alert to the warning signs of psychiatric disorders to help ensure patients receive the help they need (Prescribers should read the REMS educational material on recognizing psychiatric disorders). Prior to initiation of Isotretinoin Capsules treatment, ask patients and family members about any history of psychiatric disorder, and at each visit during treatment assess patients for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation is necessary. If a patient develops depression, mood disturbance, psychosis, or aggression, instruct patients (or caregivers) to immediately stop Isotretinoin Capsules and promptly contact their health care provider. Discontinuation of Isotretinoin Capsules may be insufficient; further evaluation may be necessary such as a referral to a mental health care professional. 5.4 Intracranial Hypertension (Pseudotumor Cerebri) Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Avoid concomitant use of Isotretinoin Capsules with tetracyclines [see Drug Interactions (7.2)] . Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Screen patients with these symptoms and, if present, immediately discontinue Isotretinoin Capsules and refer the patient to a neurologist for further diagnosis and care [see Adverse Reactions (6)] . 5.5 Serious Skin Reactions There have been postmarketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Monitor patients closely for severe skin reactions, discontinue Isotretinoin Capsules if they occur. 5.6 Pancreatitis Acute pancreatitis has been reported with isotretinoin use in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. If symptoms of pancreatitis occur, discontinue Isotretinoin Capsules and instruct patients to seek medical attention. 5.7 Lipid Abnormalities Elevations of serum triglycerides above 800 mg/dL have been reported in patients treated with Isotretinoin Capsules. In clinical trials, marked elevations of serum triglycerides, decreases in high-density lipoproteins (HDL), and increases in cholesterol levels were reported in 25%, 15%, and 7% of patients treated with Isotretinoin Capsules, respectively. These lipid changes were reversible upon Isotretinoin Capsule cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing Isotretinoin Capsules or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Perform fasting lipid tests before Isotretinoin Capsules treatment and then at intervals until the lipid response to Isotretinoin Capsules is known, which usually occurs within 4 weeks. Carefully consider the risk/benefit of Isotretinoin Capsules in patients who are at higher risk of hypertriglyceridemia (e.g., patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Isotretinoin Capsules treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.14)] . Discontinue Isotretinoin Capsules if hypertriglyceridemia cannot be controlled. 5.8 Hearing Impairment Impaired hearing has been reported in patients taking Isotretinoin Capsules; in some cases, the hearing impairment has been reported to persist after treatment has been discontinued. Mechanism(s) and causality for this reaction have not been established. Discontinue Isotretinoin Capsules treatment in patients who experience tinnitus or hearing impairment and refer them for specialized care for further evaluation. 5.9 Hepatotoxicity Clinical hepatitis has been reported with Isotretinoin Capsule treatment. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with Isotretinoin Capsules, some of which normalized with dosage reduction or continued administration of the drug. Discontinue Isotretinoin Capsules if normalization does not readily occur or if hepatitis is suspected during treatment. 5.10 Inflammatory Bowel Disease Isotretinoin 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 Isotretinoin Capsules treatment has been stopped. Discontinue Isotretinoin Capsules immediately if patients experience abdominal pain, rectal bleeding or severe diarrhea [see Adverse Reactions (6)]. 5.11 Musculoskeletal Abnormalities Osteoporosis and Fractures There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients treated with Isotretinoin Capsules or following cessation. Therefore, healthcare providers should use caution when prescribing Isotretinoin Capsules to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism or patients diagnosed with anorexia nervosa [see Use in Specific Populations (8.4)] . There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients while on treatment with isotretinoin or following cessation of treatment with isotretinoin. Patients in early and late adolescence who participate in sports with repetitive impact may be at an increased risk of spondylolisthesis with and without pars fractures, and hip growth plate injuries have been reported. Musculoskeletal Symptoms Approximately 16% of patients treated with Isotretinoin Capsules in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of isotretinoin. Evaluate the musculoskeletal system in patients who present with these symptoms during or after a course of Isotretinoin Capsules. Consider discontinuing Isotretinoin Capsules if any significant abnormality is found. Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of treatment with isotretinoin have more of an effect than a single course of treatment on the musculoskeletal system. It is important that Isotretinoin Capsules be given at the recommended dosage 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 of Isotretinoin Capsules (approximately 1.1 times the maximum recommended daily dosage). Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. In a clinical trial 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 Isotretinoin Capsules given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials of nodular acne patients treated with a single course of treatment at recommended doses. The skeletal effects of multiple Isotretinoin Capsules treatment courses for acne are unknown. Premature Epiphyseal Closure There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of Isotretinoin Capsules. The effect of multiple courses of Isotretinoin Capsules on epiphyseal closure is unknown. 5.12 Ocular Abnormalities Carefully monitor for visual problems. If visual difficulties occur, discontinue Isotretinoin Capsules treatment and obtain an ophthalmological examination [see Adverse Reactions (6)] . Corneal Opacities Corneal opacities have occurred in patients receiving Isotretinoin Capsules 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 Isotretinoin Capsules have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of isotretinoin [see Adverse Reactions (6)] . Decreased Night Vision Decreased night vision has been reported during Isotretinoin Capsule treatment and in some instances the event has persisted after treatment was discontinued. Because the onset in some patients was sudden, advise patients of this potential problem and warn patients to be cautious when driving or operating any vehicle at night. Dry Eyes Dry eyes has been reported in patients during isotretinoin use. Patients who wear contact lenses may have trouble wearing them while on Isotretinoin Capsules treatment and afterwards. 5.13 Hypersensitivity Reactions Anaphylactic reactions and other allergic reactions have been reported with isotretinoin use. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura of the extremities and extracutaneous involvement (including renal) have been reported. If a severe allergic reaction occurs, discontinue Isotretinoin Capsules treatment and initiate appropriate medical management. 5.14 Laboratory Abnormalities and Laboratory Monitoring for Adverse Reactions Laboratory Monitoring Pregnancy Testing: Obtain a screening and confirmatory pregnancy test prior to treatment initiation. Repeat a pregnancy test prior to each prescription, at the end of the entire course of Isotretinoin Capsules treatment and 1 month after the discontinuation of Isotretinoin Capsules [see Use in Specific Populations (8.3)]. Lipid Tests: Obtain pretreatment and follow-up fasting lipid tests under fasting conditions. Wait 36 hours after consumption of alcohol before testing is performed. It is recommended that these tests be performed periodically until the lipid response to Isotretinoin Capsules is known. The incidence of hypertriglyceridemia is 25% in patients treated with Isotretinoin Capsules [see Warnings and Precautions (5.7)] . Liver Function Tests: As elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on Isotretinoin Capsules, perform pretreatment and follow-up liver function tests periodically until the response to Isotretinoin Capsules is known [see Warnings and Precautions (5.9)] . Additional Laboratory Abnormalities Glucose: With Isotretinoin Capsule use, some patients have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Isotretinoin Capsule treatment. CPK: Some patients undergoing vigorous physical activity while taking Isotretinoin Capsules have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis with isotretinoin use, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years old) with severe recalcitrant nodular acne, elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this clinical trial.

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, and vaginal dryness). Respiratory Bronchospasm (with or without a history of asthma), epistaxis, nasal dryness, respiratory infection, voice alteration. Skin and Subcutaneous Tissue Abnormal wound healing (delayed healing or exuberant granulation tissue with crusting), acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), contact dermatitis, dermatitis, dry mouth, dry nose, dry skin, epistaxis, erythema, eruptive xanthomas, erythema multiforme, flushing, 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), skin fragility, Stevens-Johnson syndrome, sunburn, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including granulomatosis with polyangiitis), wound healing abnormal (delayed healing or exuberant granulation tissue with crusting). Senses Hearing: hearing impairment, tinnitus. Ocular: asthenopia, blurred vision, cataracts, color vision disorder, conjunctivitis, corneal opacities, decreased night vision which may persist, dry eyes, eye irritation, eye pruritus, eyelid inflammation, increased lacrimation, keratitis, ocular hyperemia, optic neuritis, photophobia, reduced visual acuity, visual disturbances. Renal and Urinary Glomerulonephritis, nonspecific urogenital findings. Most common adverse reactions are (incidence ≥ 5%): 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 LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or iPLEDGE at (1-866-495-0654).