Absorica LD

1 INDICATIONS AND USAGE ABSORICA and ABSORICA LD 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, ABSORICA and ABSORICA LD 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 ABSORICA/ABSORICA LD treatment is needed, it is not recommended before a 2-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) ]. ABSORICA and ABSORICA LD 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, ABSORICA and ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD: In patients who can get pregnant, only prescribe ABSORICA/ABSORICA LD after verification and documentation that they are not pregnant. See the Full Prescribing Information for the detailed requirements prior to prescribing ABSORICA/ABSORICA LD ( 2.1 , 8.3 ) Complete the following laboratory tests in all patients: fasting lipid profile and liver function tests. ( 2.1 ) ABSORICA is not substitutable with ABSORICA LD because of different bioavailability and recommended dosage. ( 2.2 , 5.3 ) Recommended dosage for (2.2 ): o ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks ( 2.1 ) o ABSORICA LD is 0.4 to 0.8 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 ABSORICA (1.6 mg/kg/day of ABSORICA LD) in divided doses. ( 2.1 ) Once daily dosing is not recommended. ( 2.1 ) If a dose of ABSORICA/ABSORICA LD is missed, just skip that dose. Do not take two doses of ABSORICA/ABSORICA LD at the same time. ( 2.1 ) 2.1 Evaluations Prior To Prescribing and Use of ABSORICA/ABSORICA LD In patients who can get pregnant, only prescribe ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD, see Use in Specific Populations (8.3). Prior to ABSORICA / ABSORICA LD use in all patients, complete the following laboratory testing: 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 )] . 2.2 Recommended Dosage ABSORICA is not substitutable with ABSORICA LD [see Warnings and Precautions ( 5.3 )]. The recommended dosage of: ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 1). ABSORICA LD is 0.4 to 0.8 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 2). 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 ABSORICA (1.6 mg/kg/day for ABSORICA LD) in divided doses, as tolerated. The safety and effectiveness of once daily dosing with ABSORICA/ABSORICA LD has not been established and is not recommended. If a dose of ABSORICA/ABSORICA LD is missed, just skip that dose. Do not take two doses of ABSORICA/ ABSORICA LD at the same time. Table 1: ABSORICA Daily Dosage by Body Weight1 Body Total Daily Dosage (mg) 1 Weight 0.5 mg/kg 1 mg/kg 2 mg/kg 40 kg 50 kg 60 kg 70 kg 80 kg 90 kg 100 kg 20 25 30 35 40 45 50 40 50 60 70 80 90 100 80 100 120 140 160 180 200 1 Administer in two divided doses with or without meals Table 2: ABSORICA LD Daily Dosage by Body Weight1 Body Total Daily Dosage (mg) 1 Weight 0.4 mg/kg 0.8 mg/kg 1.6 mg/kg 40 kg 50 kg 60 kg 70 kg 80 kg 90 kg 100 kg 16 20 24 28 32 36 40 32 40 48 56 64 72 80 64 80 96 112 128 144 160 1 Administer in two divided doses with or without meals 2.3 Recommended 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 ABSORICA/ABSORICA LD. 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 ABSORICA/ABSORICA LD …

3 DOSAGE FORMS AND STRENGTHS ABSORICA and ABSORICA LD have different dosage regimens [see Dosage and Administration (2.1) ] . Although ABSORICA and ABSORICA LD have a 20 mg strength, these strengths have different bioavailability and are not substitutable. ABSORICA is available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules. 10 mg: Dark yellow, opaque, capsule imprinted with black ink “ G240 ” on cap and “ 10 ” on the body 20 mg: Red, opaque, capsule imprinted with black ink “ G241 ” on cap and “ 20 ” on the body 25 mg: Green, opaque, capsule imprinted with white ink “ G342 ” on cap and “ 25 ” on the body 30 mg: Brown, opaque, capsule imprinted with white ink “ G242 ” on cap and “ 30 ” on the body 35 mg: Dark blue, opaque, capsule imprinted with white ink “ G343 ” on cap and “ 35 ” on the body 40 mg: Brown and red, capsule imprinted with white ink “ G325 ” on cap and “ 40 ” on the body ABSORICA LD is available in 8 mg, 16 mg, 20 mg, 24 mg, 28 mg and 32 mg opaque-printed, hard-gelatin capsules. 8 mg: A size 3, light green with a colorless band (the cap is printed in white with “ RL29 ” and the body is printed in white with “ RL29 ”). 16 mg: A size 2, dark blue with a colorless band (the cap is printed in white with “ RL30 ” and the body is printed in white with “ RL30 ”). 20 mg : A size 1, dark pink with a colorless band (the cap is printed in black with “ RL33 ”and the body is printed in black with “ RL33 ”). 24 mg: A size 1, yellow with a colorless band (the cap is printed in white with “ RL31 ” and the body is printed in white with “ RL31 ”). 28 mg: A size 0, light blue, with a colorless band (the cap is printed in black with “ RL34 ” and the body is printed in black with “ RL34 ”). 32 mg: A size 0, caramel with a colorless band (the cap is printed in white with “ RL32 ” and the body is printed in white with “ RL32 ”). ABSORICA Capsules: 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg (3) ABSORICA LD Capsules: 8 mg, 16 mg, 20 mg, 24 mg, 28 mg and 32 mg (3)

4 CONTRAINDICATIONS ABSORICA/ABSORICA LD 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 )] . ABSORICA/ABSORICA LD is contraindicated in: Pregnancy ( 8.1 ) Patients with hypersensitivity to isotretinoin (or Vitamin A) or any of its components ( 5.14 )

6 ADVERSE REACTIONS The following adverse reactions with ABSORICA/ABSORICA LD 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 trials 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, 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 treatment and recurred with reinstitution of treatment. Reproductive System Abnormal menses and sexual dysfunction that may continue after discontinuation of treatment (including erectile dysfunction, decreased libido, decreased vaginal lubrication, and vaginal dryness). Respiratory Epistaxis, nasal dryn …

7 DRUG INTERACTIONS Vitamin A: avoid concomitant use (7.1) Tetracyclines: avoid concomitant use (7.2) 7.1 Vitamin A Avoid concomitant use of ABSORICA/ABSORICA LD with supplements containing vitamin A. ABSORICA/ABSORICA LD is closely related to vitamin A. Therefore, concomitant use of ABSORICA/ABSORICA LD with vitamin A may lead to ABSORICA/ABSORICA LD-associated adverse reactions. 7.2 Tetracyclines Avoid concomitant use of ABSORICA/ABSORICA LD with tetracyclines 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 Oral Contraceptives Isotretinoin Capsules did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with a norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology ( 12.3 )]. It is not known if there is an interaction with the concomitant use of ABSORICA/ABSORICA LD with other oral contraceptives.

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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD are 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 ABSORICA/ABSORICA LD is used during pregnancy, or if the patient becomes pregnant while taking ABSORICA/ABSORICA LD, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking ABSORICA/ABSORICA LD, immediately discontinue ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD, and for at least 8 days after the last dose of ABSORICA/ABSORICA LD. 8.3 Females and Males of Reproductive Potential All patients who can become pregnant must comply with the iPLEDGE program requirements [see Warnings and Precautions (5.2) ]. Pregnancy Testing 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 ABSORICA/ABSORICA LD treatment. Pregnancy Testing Prior to Prescribing ABSORICA/ABSORICA LD: In patients who can get pregnant, only prescribe ABSORICA/ABSORICA LD 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 peri …

12.1 Mechanism of Action The exact mechanism of action of ABSORICA/ABSORICA LD 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. ABSORICA/ABSORICA LD is a retinoid, which 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 ABSORICA ABSORICA (isotretinoin) Capsules contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems: •10 mg – iron oxide (yellow) and titanium dioxide; •20 mg – iron oxide (red), and titanium dioxide; •25 mg – FD&C Blue #1, FD&C Yellow #5 [see Warnings and Precautions (5.14) ] , FD&C Yellow #6 and titanium dioxide; •30 mg – iron oxide (black, red and yellow) and titanium dioxide; •35 mg – FD&C Blue #2, iron oxide (black, red and yellow) and titanium dioxide; •40 mg – iron oxide (black, red and yellow) and titanium dioxide. ABSORICA LD ABSORICA LD (isotretinoin) Capsules contain 8 mg, 16 mg, 20 mg, 24 mg, 28 mg and 32 mg of micronized isotretinoin (a retinoid) in suspension filled in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, USP each capsule contains the following inactive ingredients: butylated hydroxy anisole, gelatin, hard gelatin capsule shell, polysorbate 80 and soybean oil. The gelatin capsules contain the following dye systems: •8 mg – D&C Yellow #10, FD&C Blue #1, FD&C Red #40 and titanium dioxide •16 mg – FD&C Blue #1, FD&C Red #40, and titanium dioxide •20 mg – FD&C Blue #1, FD&C Red #40, and titanium dioxide •24 mg – D&C Yellow #10, FD&C Yellow #6 and titanium dioxide •28 mg – FD&C Blue #1, FD&C Red #40, and titanium dioxide •32 mg – ferrosoferric oxide, ferric oxide (red and yellow) and titanium dioxide The imprinting ink of 8 mg, 16 mg, 24 mg and 32 mg capsules contain the following ingredients: potassium hydroxide, propylene glycol, shellac and titanium dioxide. The imprinting ink of 20 mg and 28 mg capsules contain the following ingredients: ferrosoferric oxide, propylene glycol and shellac glaze. Isotretinoin 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. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is: ABSORICA meets USP Dissolution Test 3. For ABSORICA LD, FDA approved dissolution test differs from the USP.

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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA and ABSORICA LD have different dosage regimens. Although ABSORICA and ABSORICA LD have a 20 mg strength, these strengths have different bioavailability and are not substitutable [see Dosage and Administration (2.1) ] . ABSORICA ABSORICA (isotretinoin) Capsules (opaque) are supplied as follows: • 10 mg : Dark yellow, capsule imprinted with black ink “G 240” on cap and “10” on the body • Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-115-31 • 20 mg : Red, capsule imprinted with black ink “G 241” on cap and “20” on the body • Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-116-31 • 25 mg : Green, capsule imprinted with white ink “G 342” on cap and “25” on the bodyBox of 30 capsules (3 x 10 Prescription Packs): NDC 10631-133-31 • 30 mg : Brown, capsule imprinted with white ink “G 242” on cap and “30” on the bodyBox of 30 capsules (3 x 10 Prescription Packs): NDC 10631-117-31 • 35 mg : Dark blue, capsule imprinted with white ink “G 343” on cap and “35” on the bodyBox of 30 capsules (3 x 10 Prescription Packs): NDC 10631-134-31 • 40 mg : Brown and red, capsule imprinted with white ink “G 325” on cap and “40” on the bodyBox of 30 capsules (3 x 10 Prescription Packs): NDC 10631-118-31 ABSORICA LD ABSORICA LD (isotretinoin) Capsules (opaque-printed, hard-gelatin) are supplied as follows: • 8 mg: A size 3, light green, capsules banded with a colorless band. The cap is printed in white with “RL29” and the body is printed in white with “RL29”. Box of 30 capsules (3 x 10 Prescription Packs) NDC 10631-002-31 • 16 mg: A size 2, dark blue, capsules banded with a colorless band. The cap is printed in white with “RL30” and the body is printed in white with “RL30”. Box of 30 capsules (3 x 10 Prescription Packs) NDC 10631-003-31 • 20 mg: A size 1, dark pink, capsules banded with a colorless band. The cap is printed in black with “RL33”and the body is printed in black with “RL33”. Box of 30 capsules (3 x 10 Prescription Packs) NDC 10631-004-31 • 24 mg: A size 1, yellow, capsules banded with a colorless band. The cap is printed in white with “RL31” and the body is printed in white with “RL31”. Box of 30 capsules (3 x 10 Prescription Packs) NDC 10631-005-31 • 28 mg: A size 0, light blue, capsules banded with a colorless band. The cap is printed in black with “RL34” and the body is printed in black with “RL34”. Box of 30 capsules (3 x 10 Prescription Packs) NDC 10631-006-31 • 32 mg: A size 0, caramel, capsules banded with a colorless band. The cap is printed in white with “RL32” and the body is printed in white with “RL32”. Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-007-31 Storage and Handling of ABSORICA and ABSORICA LD 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.