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 been studied, and is not recommended. The effect of long-term use of Amnesteem on bone loss is unknown [see Warnings and Precautions (5.11) ] .

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 )

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 Amnesteem is contraindicated in pregnancy [see Contraindications (4) ] . Based on human data, Amnesteem 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 Amnesteem 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 Amnesteem treatment, immediately discontinue Amnesteem 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 Amnesteem 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 Amnesteem 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. Amnesteem 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, Amnesteem is 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: o Assess the reproductive status of all patients prior to initiating and during treatment. o Counsel patients who cannot get pregnant on the risk and REMS requirements prior to initiating treatment. o 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. o Comply with the pregnancy testing requirements. o Assess the pregnancy status for patients who can get pregnant by reviewing pregnancy tests and documenting a negative result prior to each prescription. o 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: o Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3) ]. o Demonstrate comprehension of the risk and REMS requirements before each prescription is dispensed. o 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 Amnesteem and not donate blood. • Pharmacies that dispense Amnesteem must be certified in the REMS and must comply with the REMS requirements, including the following: o Obtain authorization to dispense and only dispense to patients who are authorized to receive Amnesteem. o Dispense a maximum of a 30-day supply with a Medication Guide. o 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 Amnesteem 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 Amnesteem 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 Amnesteem and promptly contact their health care provider. Discontinuation of Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem. 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 Amnesteem, respectively. These lipid changes were reversible upon Amnesteem cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing Amnesteem or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Perform fasting lipid tests before Amnesteem treatment and then at intervals until the lipid response to Amnesteem is known, which usually occurs within 4 weeks. Carefully consider the risk/benefit of Amnesteem 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 Amnesteem treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.14) ] . Discontinue Amnesteem if hypertriglyceridemia cannot be controlled. 5.8 Hearing Impairment Impaired hearing has been reported in patients taking Amnesteem; 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 Amnesteem 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 Amnesteem treatment. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with Amnesteem, some of which normalized with dosage reduction or continued administration of the drug. Discontinue Amnesteem 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 Amnesteem treatment has been stopped. Discontinue Amnesteem 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 Amnesteem or following cessation. Therefore, healthcare providers should use caution when prescribing Amnesteem 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 Amnesteem 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 Amnesteem. Consider discontinuing Amnesteem 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 Amnesteem 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 Amnesteem (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 Amnesteem 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 Amnesteem 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 Amnesteem. The effect of multiple courses of Amnesteem on epiphyseal closure is unknown. 5.12 Ocular Abnormalities Carefully monitor for visual problems. If visual difficulties occur, discontinue Amnesteem treatment and obtain an ophthalmological examination [see Adverse Reactions (6) ] . Corneal Opacities Corneal opacities have occurred in patients receiving Amnesteem 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 Amnesteem 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 Amnesteem 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 have been reported in patients during isotretinoin use. Patients who wear contact lenses may have trouble wearing them while on Amnesteem 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 Amnesteem 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 Amnesteem treatment and 1 month after the discontinuation of Amnesteem [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 Amnesteem is known. The incidence of hypertriglyceridemia is 25% in patients treated with Amnesteem [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 Amnesteem, perform pretreatment and follow-up liver function tests periodically until the response to Amnesteem is known [see Warnings and Precautions (5.9) ] . Additional Laboratory Abnormalities Glucose With Amnesteem use, some patients have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Amnesteem treatment. CPK Some patients undergoing vigorous physical activity while taking Amnesteem 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.

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) ] .

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 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 pruritis, 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.