Claravis

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

3 DOSAGE FORMS AND STRENGTHS Capsules: 10 mg: Two-piece hard gelatin capsule with light gray opaque cap and light gray opaque body filled with yellow oily dispersion. Imprinted in red ink barr on one piece and 934 on the other piece. 20 mg: Two-piece hard gelatin capsule with brown opaque cap and brown opaque body filled with yellow oily dispersion. Imprinted in white ink barr on one piece and 935 on the other piece. 30 mg: Two-piece hard gelatin capsule with orange opaque cap and orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 454 on the other piece. 40 mg: Two-piece hard gelatin capsule with light orange opaque cap and light orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 936 on the other piece. Capsules: 10 mg, 20 mg, 30 mg, and 40 mg ( 3)

4 CONTRAINDICATIONS Claravis 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 )] . Claravis is contraindicated in: Pregnancy ( 4 , 8.1 ) Patients with hypersensitivity to isotretinoin (or Vitamin A) or any of its components ( 4.2 , 5.13 )

6 ADVERSE REACTIONS The following adverse reactions with Claravis 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 Claravis 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 Claravis treatment but recurred with reinstitution of Claravis 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). Respi …

7 DRUG INTERACTIONS Vitamin A: Avoid concomitant use ( 7.1 ) Tetracyclines: Avoid concomitant use ( 7.2 ) 7.1 Vitamin A Avoid concomitant use of Claravis with supplements containing vitamin A. Claravis is closely related to vitamin A. Therefore, concomitant use of Claravis with vitamin A may lead to Claravis-related adverse reactions. 7.2 Tetracyclines Avoid concomitant use of Claravis with tetracyclines. Claravis 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 Claravis with oral contraceptives that do not contain norethindrone and ethinyl estradiol. Claravis 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 )] .

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 Claravis 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 Claravis 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 Claravis 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 Claravis is used during pregnancy, or if the patient becomes pregnant while taking Claravis, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking Claravis, immediately discontinue Claravis 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 Claravis 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. 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 Claravis, and for at least 8 days after the last dose of Claravis. 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 In patients who can get pregnant, pregnancy testing is required prior to, during, and after Claravis treatment. Pregnancy Testing Prior to Prescribing Claravis: In patients who can get pregnant, only prescribe Claravis after verification and documentation that they are not pregnant: 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 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 Claravis 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. Verify and document that the confirmatory …

12.1 Mechanism of Action The exact mechanism of action of Claravis 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, USP a retinoid, is available as Claravis TM (isotretinoin capsules USP), in 10 mg, 20 mg, 30 mg and 40 mg hard gelatin capsules for oral administration. 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. Isotretinoin has high lipophilicity. The structural formula is: Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, titanium dioxide, white wax (beeswax), and vitamin E. In addition, the 10 mg capsule contains black iron oxide and FD&C yellow no. 6. The 20 mg capsule contains black iron oxide, red iron oxide and yellow iron oxide. The 30 mg capsule contains red iron oxide and yellow iron oxide. The 40 mg capsule contains FD&C yellow no. 6. The edible imprinting ink contains: 10 mg strength, D&C red no. 7 calcium lake, FD&C yellow no. 6 aluminum lake, propylene glycol, shellac glaze, and titanium dioxide; 20 mg strength, ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide; 30 mg strength, 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, propylene glycol, and shellac glaze; 40 mg strength, ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze. Meets dissolution test 2. structure

10 OVERDOSAGE Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. 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 Claravis 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 Claravis overdose 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 Claravis TM (isotretinoin capsules USP) is available as: 10 mg: Two-piece hard gelatin capsule with light gray opaque cap and light gray opaque body filled with yellow oily dispersion. Imprinted in red ink barr on one piece and 934 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1054-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1054-56). 20 mg: Two-piece hard gelatin capsule with brown opaque cap and brown opaque body filled with yellow oily dispersion. Imprinted in white ink barr on one piece and 935 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1055-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1055-56). 30 mg: Two-piece hard gelatin capsule with orange opaque cap and orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 454 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1056-86). 40 mg: Two-piece hard gelatin capsule with light orange opaque cap and light orange opaque body filled with yellow oily dispersion. Imprinted in black ink barr on one piece and 936 on the other piece. Available in cartons of 30 capsules containing 3 prescription blister packs of 10 capsules (NDC 0555-1057-86) and 100 capsules containing 10 prescription blister packs of 10 capsules (NDC 0555-1057-56). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Keep this and all medications out of the reach of children.