Absorica Ld; Absorica — Isotretinoin drug label

WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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, ABSORICA and ABSORICA LD are 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. ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ) ABSORICA/ABSORICA LD are available only through a restricted program called the iPLEDGE ® REMS. ( 5.2 )

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)

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 )

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 (5.4) Intracranial Hypertension ( Pseudotumor Cerebri ): Avoid concomitant use with tetracyclines ( 5.5 ) Serious Skin Reactions : Monitor for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions and discontinue treatment if they occur ( 5.6 ) Acute Pancreatitis : If pancreatitis symptoms occur, discontinue treatment ( 5.7 ) Lipid Abnormalities (hypertriglyceridemia, low HDL, and elevation of cholesterol): Monitor lipid levels at regular intervals; stop if hypertriglyceridemia cannot be controlled ( 5.8 ) Hearing Impairment : Discontinue and refer to specialized care ( 5.9 ) Hepatotoxicity : Monitor liver function tests prior to and during treatment ( 5.10 , 5.15 ) Inflammatory Bowel Disease : Discontinue for abdominal pain, rectal bleeding, or severe diarrhea ( 5.11 ) Musculoskeletal Abnormalities : Arthralgias, back pain, decreases in bone mineral density and premature epiphyseal closure ( 5.12 ) Ocular Abnormalities e.g., corneal opacities, decreased night vision: If visual symptoms occur, discontinue and refer for an ophthalmological exam ( 5.13 ) 5.1 Embryo-Fetal Toxicity ABSORICA/ABSORICA LD is contraindicated in pregnancy [see Contraindications (4.1) ] . Based on human data, ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD treatment, immediately discontinue ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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). Patients must be informed not to donate blood during ABSORICA/ABSORICA LD 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. ABSORICA/ABSORICA LD is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ]. 5.2 iPLEDGE REMS ABSORICA/ABSORICA LD are available only through a restricted program under a REMS called the iPLEDGE REMS because of the risk of embryo-fetal toxicity [see Warnings and Precautions (5.1) ] . Notable requirements of the iPLEDGE REMS include the following: Prescribers must be certified in the REMS and comply with the REMS requirements, including the following: Assess the reproductive status of all patients prior to initiating treatment 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. Counsel patients who can get pregnant on 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 get pregnant must be enrolled in the REMS and must comply with the 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 get pregnant must be enrolled in the REMS and must comply with the REMS requirements, including to not share isotretinoin and not donate blood. Pharmacies that dispense ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD. 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 ABSORICA and ABSORICA LD are Not Substitutable Given that the bioavailability and the recommended dosage of ABSORICA and ABSORICA LD are different, ABSORICA and ABSORICA LD are not substitutableon a mg per mg basis. For example, ABSORICA and ABSORICA LD have a 20 mg strength; however, these strengths have different bioavailability and are not substitutable. 5.4 Psychiatric Disorders ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD and promptly contact their health care provider. Discontinuation of ABSORICA/ABSORICA LD may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare professional. 5.5 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 ABSORICA/ABSORICA LD 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 for papilledema and, if present, immediately discontinue ABSORICA/ABSORICA LD and refer the patient to a neurologist for further diagnosis and care [see Adverse Reactions ( 6 )] . 5.6 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. Patients should be monitored closely for severe skin reactions, and ABSORICA/ABSORICA LD should be discontinued if they occur. 5.7 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 ABSORICA/ABSORICA LD and seek medical attention. 5.8 Lipid Abnormalities Elevations of serum triglycerides above 800 mg/dL have been reported with isotretinoin use. 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 or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Fasting lipid tests should be performed before ABSORICA/ABSORICA LD treatment and then at intervals until the lipid response to ABSORICA/ABSORICA LD is known, which usually occurs within 4 weeks. Careful consideration should be given to risk/benefit of ABSORICA/ABSORICA LD 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 ABSORICA/ABSORICA LD treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.15) ] . ABSORICA/ABSORICA LD should be stopped if hypertriglyceridemia cannot be controlled. 5.9 Hearing Impairment Impaired hearing has been reported in patients taking isotretinoin; 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. Patients who experience tinnitus or hearing impairment should discontinue ABSORICA/ABSORICA LD treatment and be referred for specialized care for further evaluation. 5.10 Hepatotoxicity Clinical hepatitis has been reported with isotretinoin use. 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. If normalization does not readily occur or if hepatitis is suspected during treatment, ABSORICA/ABSORICA LD should be discontinued. 5.11 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 treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue ABSORICA/ABSORICA LD immediately [see Adverse Reactions (6) ] . 5.12 Musculoskeletal Abnormalities Bone Mineral Density Changes, Osteoporosis, and Fractures Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and another isotretinoin capsule product, 27/306 (9%) of pediatric subjects 12 years of age and older had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20-week treatment period. Repeat scans conducted within 2 to 3 months after the post-treatment scan showed no recovery of BMD. Long-term data at 4 to 11 months showed that 3 out of 7 subjects had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this pediatric population. Therefore, healthcare providers should use caution when prescribing ABSORICA/ABSORICA LD 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. 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 Abnormalities Approximately 16% of subjects 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. In a trial of pediatric subjects treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female subjects than male subjects. Arthralgias were experienced in 22% (79/358) of pediatric subjects. Arthralgias were severe in 8% (6/79) of subjects. Evaluate the musculoskeletal system of patients who present with these symptoms during or after a course of ABSORICA/ABSORICA LD. Consider discontinuing ABSORICA/ABSORICA LD 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 to administer ABSORICA/ABSORICA LD at the recommended dose 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. 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 treatment courses for acne are unknown. In a clinical trial of 217 pediatric subjects 12 years of age and older 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. 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 on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 pediatric subjects 12 years of age and older on ABSORICA or another isotretinoin capsule product who had hand radiographs taken to assess bone age, a total of 9 (3%) subjects had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded. 5.13 Ocular Abnormalities Carefully monitor for visual problems. If visual difficulties occur, discontinue ABSORICA/ABSORICA LD 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 subjects 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 use 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 ABSORICA/ABSORICA LD treatment and afterwards. 5.14 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 (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No. 5) in the 25 mg ABSORICA Capsule The 25 mg ABSORICA capsule contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of tartrazine sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. The 10 mg, 20 mg, 30 mg, 35 mg, and 40 mg ABSORICA capsules do not contain FD&C Yellow No. 5 and all of the ABSORICA LD capsules do not contain FD&C Yellow No. 5. Thus, in patients with allergic reactions to tartrazine, avoid using the 25 mg ABSORICA capsules. 5.15 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 ABSORICA/ABSORICA LD treatment, and 1 month after the discontinuation of ABSORICA/ABSORICA LD (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 ABSORICA/ABSORICA LD is known. The incidence of hypertriglyceridemia is 25% in patients treated with isotretinoin capsules [see Warnings and Precautions (5.8) ] . 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 ABSORICA/ABSORICA LD is known (5.10) ]. Additional Laboratory Abnormalities Glucose: With isotretinoin use, some patients have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin use. CPK: Some patients undergoing vigorous physical activity while taking isotretinoin 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 924 subjects, marked elevations in CPK (≥350 U/L) were observed in approximately 24% of subjects treated with isotretinoin capsules. In another clinical trial of 217 pediatric subjects 12 years of age and older elevations in CPK were observed in 12% of subjects, 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 subjects, 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.

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 in patients who have completed skeletal growth. The use of another course of ABSORICA/ABSORICA LD treatment is not recommended before a 2-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 ABSORICA/ABSORICA LD, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of ABSORICA/ABSORICA LD on bone loss is unknown [see Warnings and Precautions ( 5.12 )] .

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)

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 dryness, bronchospasm (with or without a history of asthma), respiratory infection, voice alteration. Skin and Subcutaneous Tissue Dry skin, dermatitis, eczema, rash, contact dermatitis, alopecia, pruritus, sunburn, erythema, acne fulminans, alopecia(which in some cases persisted), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, skin fragility, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, increased sunburn susceptibility, sweating, toxic epidermal necrolysis, urticaria,vasculitis (including granulomatosis with polyangiitis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting). Senses Hearing: tinnitus and hearing impairment. Ocular : dry eyes, reduced visual acuity, blurred vision, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, conjunctivitis, corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances. Renal and Urinary Glomerulonephritis. Most common adverse reactions (incidence ≥5%) are: dry lips, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, increased creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or iPLEDGE at (1-866-495-0654).

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.

8.1 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.

8.3 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 period immediately preceding the beginning of ABSORICA/ABSORICA LD 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 test is negative, OR Amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding , complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and immediately preceding the beginning of ABSORICA/ABSORICA LD 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 test is negative. If a patient who can get pregnant has had negative screening and confirmatory pregnancy tests but they missed the 7-day prescription window (the patient has not obtained their ABSORICA/ABSORICA LD prescription within 7 days of the pregnancy test collection) and has not started ABSORICA/ABSORICA LD treatment, repeat the urine or serum pregnancy test in a medical setting and verify and document that this repeat test is negative prior to prescribing ABSORICA/ABSORICA LD. The confirmatory pregnancy test must be repeated, as needed, until the patient receives ABSORICA/ABSORICA LD. Pregnancy Testing During Treatment with ABSORICA/ABSORICA LD: In patients who can get pregnant who are being treated with ABSORICA/ABSORICA LD, within 7 days before each prescription, obtain a urine or serum pregnancy test in a medical setting (e.g., prescriber’s office, laboratory, clinic) or instruct patients to use a home pregnancy test. If the patient who can get pregnant missed the 7-day prescription window (the patient has not obtained their ABSORICA/ABSORICA LD prescription within 7 days of the pregnancy test collection), repeat the urine or serum pregnancy test within 7 days before the next prescription in a medical setting or instruct patients to use a home pregnancy test. Verify and document the negative pregnancy test result prior to prescribing additional ABSORICA/ABSORICA LD treatment. Pregnancy Testing in Patients Who Have Completed ABSORICA/ABSORICA LD Treatment: In patients who can get pregnant who have completed ABSORICA/ABSORICA LD treatment, complete a urine or serum pregnancy test in a medical setting (e.g., prescriber’s office, laboratory, clinic) or instruct patients to use a home pregnancy test: At the end of the entire course of ABSORICA/ABSORICA LD treatment, and 1 month after the discontinuation of ABSORICA/ABSORICA LD. Contraception Patients who can get pregnant must use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, for at least 1 month prior to initiation of ABSORICA/ABSORICA LD treatment, during ABSORICA/ABSORICA LD treatment, and for 1 month after discontinuing ABSORICA/ABSORICA LD treatment. However, 2 forms of contraception is not required if the patient commits to continuous abstinence from not having any sexual contact with a partner which may result in pregnancy, has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate form of contraception during ABSORICA/ABSORICA LD treatment. Any birth control method can fail. There have been reports of pregnancy from patients who have used combination oral contraceptives, as well as contraceptive vaginal systems, vaginal inserts, transdermal systems, and injections; these pregnancies occurred while taking isotretinoin capsules. These reports are more frequent for patients who use only a single method of contraception. Therefore, it is critically important that patients who can get pregnant use two forms of contraception simultaneously. Primary forms Secondary forms •Tubal sterilization Barrier: •Male partner vasectomy •male latex condom with or without spermicide •Intrauterine device •diaphragm with spermicide •Hormonal (combination oral contraceptives, vaginal systems, vaginal inserts, transdermal systems, injections, or implants) •cervical cap with spermicide Other: •Vaginal sponge (contains spermicide) If the patient has unprotected sexual contact with a partner that could result in pregnancy at any time 1 month before, during, or 1 month after treatment, the patient must: Stop taking ABSORICA/ABSORICA LD immediately, if on treatment Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy Start using 2 forms of contraception simultaneously again for 1 month before resuming ABSORICA/ABSORICA LD treatment Have a second pregnancy test after using 2 forms of contraception for 1 month. Infertility In a trial of female acne patients (n = 79) receiving another isotretinoin capsule product, the mean total ovarian volume, the total antral follicle count and mean anti-Mullerian hormone decreased at the end of the treatment (6 th month). However, the values returned to normal at the 18 th month (12 months after the end of treatment). There were no statistically significant changes in terms of follicle-stimulating hormone and luteinizing hormone, both at the end of the treatment and 12 months after the end of treatment. Although the results suggest that possible deteriorative effects of isotretinoin on ovarian reserve may be reversible, the study has important methodological limitations, including a small sample size, lack of a control group, and lack of generalizability. Sperm Study: In trials of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin treatment for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

8.4 Pediatric Use The safety and effectiveness of ABSORICA/ABSORICA LD for the treatment of severe recalcitrant nodular acne have been established in non-pregnant pediatric 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 . Use of ABSORICA/ABSORICA LD in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use ABSORICA to another isotretinoin capsule product in 397 pediatric subjects 12 years of age and older [see Clinical Studies (14) ] and pharmacokinetic data in pediatric subjects [see Clinical Pharmacology (12.3) ] . The safety and effectiveness of ABSORICA/ABSORICA LD in pediatric patients less than 12 years of age have not been established. Adverse Reactions in Pediatric Subjects In trials with isotretinoin capsules, adverse reactions reported in pediatric subjects 12 years of age and older were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric subjects. In a trial of pediatric subjects 12 years of age and older treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female subjects than male subjects. Arthralgias were experienced in 22% (79/358) of pediatric subjects including severe arthralgias in 8% (6/79) of subjects. Evaluate the musculoskeletal system of pediatric patients who present with these symptoms during or after a course of ABSORICA/ABSORICA LD. Consider discontinuing ABSORICA/ABSORICA LD if any significant abnormality is found. Effects on Bone Mineral Density in Pediatric Subjects The effect on bone mineral density (BMD) of a 20-week course of treatment with ABSORICA or another isotretinoin capsule product was evaluated in a double-blind, randomized clinical trial involving 396 pediatric subjects with severe recalcitrant nodular acne (mean age 15.4 years old, range 12 to 17 years old, 80% males). Given that there were no statistically significant differences between the two isotretinoin capsule groups following 20 weeks of treatment, the results are presented for the pooled treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 pediatric subjects, 27 (9%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2 to 3 months after the post treatment scan showed no recovery of BMD. Long-term follow-up at 4 to 11 months showed that 3 out of 7 subjects had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see Warnings and Precautions (5.12) ] . In an open-label clinical trial (N=217) of a single course of treatment with isotretinoin capsules for pediatric subjects 12 years of age and older with severe recalcitrant nodular acne, BMD at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of subjects. One subject had a decrease in lumbar spine BMD >4% based on unadjusted data. Sixteen (8%) subjects had decreases in lumbar spine BMD >4%, and all the other subjects (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine subjects (5%) had a decrease in total hip BMD >5% based on unadjusted data. Twenty-one (11%) subjects had decreases in total hip BMD >5%, and all the other subjects (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the subjects with decreased BMD for up to 11 months thereafter demonstrated increasing BMD in 5 subjects at the lumbar spine, while the other 3 subjects had lumbar spine BMD measurements below baseline values. Total hip BMD remained below baseline (range −1.6% to −7.6%) in 5 of 8 subjects (63%). In a separate open-label extension trial of 10 pediatric subjects including those 13 years of age and older, who started a second course of isotretinoin capsules 4 months after the first course, two subjects showed a decrease in mean lumbar spine BMD up to 3.3%. Epiphyseal Closure There are reports of premature epiphyseal closure in acne patients who used isotretinoin at recommended doses. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 pediatric subjects 12 years of age and older who had hand radiographs taken to assess bone age, a total of 9 subjects had bone age changes that were clinically significant and for which an isotretinoin-related effect cannot be excluded [see Warnings and Precautions (5.12) ] .

8.5 Geriatric Use Clinical studies of ABSORICA/ABSORICA LD did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adult subjects. The effects of aging may increase some risks associated with ABSORICA/ABSORICA LD treatment.

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 period immediately preceding the beginning of ABSORICA/ABSORICA LD 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 test is negative, OR Amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding , complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and immediately preceding the beginning of ABSORICA/ABSORICA LD 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 test is negative. If a patient who can get pregnant has had negative screening and confirmatory pregnancy tests but they missed the 7-day prescription window (the patient has not obtained their ABSORICA/ABSORICA LD prescription within 7 days of the pregnancy test collection) and has not started ABSORICA/ABSORICA LD treatment, repeat the urine or serum pregnancy test in a medical setting and verify and document that this repeat test is negative prior to prescribing ABSORICA/ABSORICA LD. The confirmatory pregnancy test must be repeated, as needed, until the patient receives ABSORICA/ABSORICA LD. Pregnancy Testing During Treatment with ABSORICA/ABSORICA LD: In patients who can get pregnant who are being treated with ABSORICA/ABSORICA LD, within 7 days before each prescription, obtain a urine or serum pregnancy test in a medical setting (e.g., prescriber’s office, laboratory, clinic) or instruct patients to use a home pregnancy test. If the patient who can get pregnant missed the 7-day prescription window (the patient has not obtained their ABSORICA/ABSORICA LD prescription within 7 days of the pregnancy test collection), repeat the urine or serum pregnancy test within 7 days before the next prescription in a medical setting or instruct patients to use a home pregnancy test. Verify and document the negative pregnancy test result prior to prescribing additional ABSORICA/ABSORICA LD treatment. Pregnancy Testing in Patients Who Have Completed ABSORICA/ABSORICA LD Treatment: In patients who can get pregnant who have completed ABSORICA/ABSORICA LD treatment, complete a urine or serum pregnancy test in a medical setting (e.g., prescriber’s office, laboratory, clinic) or instruct patients to use a home pregnancy test: At the end of the entire course of ABSORICA/ABSORICA LD treatment, and 1 month after the discontinuation of ABSORICA/ABSORICA LD. Contraception Patients who can get pregnant must use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, for at least 1 month prior to initiation of ABSORICA/ABSORICA LD treatment, during ABSORICA/ABSORICA LD treatment, and for 1 month after discontinuing ABSORICA/ABSORICA LD treatment. However, 2 forms of contraception is not required if the patient commits to continuous abstinence from not having any sexual contact with a partner which may result in pregnancy, has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate form of contraception during ABSORICA/ABSORICA LD treatment. Any birth control method can fail. There have been reports of pregnancy from patients who have used combination oral contraceptives, as well as contraceptive vaginal systems, vaginal inserts, transdermal systems, and injections; these pregnancies occurred while taking isotretinoin capsules. These reports are more frequent for patients who use only a single method of contraception. Therefore, it is critically important that patients who can get pregnant use two forms of contraception simultaneously. Primary forms Secondary forms •Tubal sterilization Barrier: •Male partner vasectomy •male latex condom with or without spermicide •Intrauterine device •diaphragm with spermicide •Hormonal (combination oral contraceptives, vaginal systems, vaginal inserts, transdermal systems, injections, or implants) •cervical cap with spermicide Other: •Vaginal sponge (contains spermicide) If the patient has unprotected sexual contact with a partner that could result in pregnancy at any time 1 month before, during, or 1 month after treatment, the patient must: Stop taking ABSORICA/ABSORICA LD immediately, if on treatment Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy Start using 2 forms of contraception simultaneously again for 1 month before resuming ABSORICA/ABSORICA LD treatment Have a second pregnancy test after using 2 forms of contraception for 1 month. Infertility In a trial of female acne patients (n = 79) receiving another isotretinoin capsule product, the mean total ovarian volume, the total antral follicle count and mean anti-Mullerian hormone decreased at the end of the treatment (6 th month). However, the values returned to normal at the 18 th month (12 months after the end of treatment). There were no statistically significant changes in terms of follicle-stimulating hormone and luteinizing hormone, both at the end of the treatment and 12 months after the end of treatment. Although the results suggest that possible deteriorative effects of isotretinoin on ovarian reserve may be reversible, the study has important methodological limitations, including a small sample size, lack of a control group, and lack of generalizability. Sperm Study: In trials of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin treatment for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. 8.4 Pediatric Use The safety and effectiveness of ABSORICA/ABSORICA LD for the treatment of severe recalcitrant nodular acne have been established in non-pregnant pediatric 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 . Use of ABSORICA/ABSORICA LD in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use ABSORICA to another isotretinoin capsule product in 397 pediatric subjects 12 years of age and older [see Clinical Studies (14) ] and pharmacokinetic data in pediatric subjects [see Clinical Pharmacology (12.3) ] . The safety and effectiveness of ABSORICA/ABSORICA LD in pediatric patients less than 12 years of age have not been established. Adverse Reactions in Pediatric Subjects In trials with isotretinoin capsules, adverse reactions reported in pediatric subjects 12 years of age and older were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric subjects. In a trial of pediatric subjects 12 years of age and older treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female subjects than male subjects. Arthralgias were experienced in 22% (79/358) of pediatric subjects including severe arthralgias in 8% (6/79) of subjects. Evaluate the musculoskeletal system of pediatric patients who present with these symptoms during or after a course of ABSORICA/ABSORICA LD. Consider discontinuing ABSORICA/ABSORICA LD if any significant abnormality is found. Effects on Bone Mineral Density in Pediatric Subjects The effect on bone mineral density (BMD) of a 20-week course of treatment with ABSORICA or another isotretinoin capsule product was evaluated in a double-blind, randomized clinical trial involving 396 pediatric subjects with severe recalcitrant nodular acne (mean age 15.4 years old, range 12 to 17 years old, 80% males). Given that there were no statistically significant differences between the two isotretinoin capsule groups following 20 weeks of treatment, the results are presented for the pooled treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 pediatric subjects, 27 (9%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2 to 3 months after the post treatment scan showed no recovery of BMD. Long-term follow-up at 4 to 11 months showed that 3 out of 7 subjects had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see Warnings and Precautions (5.12) ] . In an open-label clinical trial (N=217) of a single course of treatment with isotretinoin capsules for pediatric subjects 12 years of age and older with severe recalcitrant nodular acne, BMD at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of subjects. One subject had a decrease in lumbar spine BMD >4% based on unadjusted data. Sixteen (8%) subjects had decreases in lumbar spine BMD >4%, and all the other subjects (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine subjects (5%) had a decrease in total hip BMD >5% based on unadjusted data. Twenty-one (11%) subjects had decreases in total hip BMD >5%, and all the other subjects (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the subjects with decreased BMD for up to 11 months thereafter demonstrated increasing BMD in 5 subjects at the lumbar spine, while the other 3 subjects had lumbar spine BMD measurements below baseline values. Total hip BMD remained below baseline (range −1.6% to −7.6%) in 5 of 8 subjects (63%). In a separate open-label extension trial of 10 pediatric subjects including those 13 years of age and older, who started a second course of isotretinoin capsules 4 months after the first course, two subjects showed a decrease in mean lumbar spine BMD up to 3.3%. Epiphyseal Closure There are reports of premature epiphyseal closure in acne patients who used isotretinoin at recommended doses. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 pediatric subjects 12 years of age and older who had hand radiographs taken to assess bone age, a total of 9 subjects had bone age changes that were clinically significant and for which an isotretinoin-related effect cannot be excluded [see Warnings and Precautions (5.12) ] . 8.5 Geriatric Use Clinical studies of ABSORICA/ABSORICA LD did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adult subjects. The effects of aging may increase some risks associated with ABSORICA/ABSORICA LD treatment.

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.

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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Decreased sebum secretion is related to the dose and duration of treatment with ABSORICA/ABSORICA LD. 12.3 Pharmacokinetics No clinically significant differences in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects without acne were reported in published literature. Absorption Following ABSORICA Administration The ABSORICA mean T max was 6.4 hours under fed conditions and 2.9 hours under fasting conditions following administration of a single 40 mg dose. Effect on Food No clinically significant differences in ABSORICA pharmacokinetics were observed following administration with a modified high-fat, high-calorie meal (123.2 calories from protein, 265.6 calories from carbohydrates, and 468 calories from fat; total calories 857 calories) with reduced vitamin A content. The mean AUC 0-t and C max of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg ABSORICA dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, ABSORICA may be given with or without meals [see Dosage and Administration (2.1) ]. Absorption Following ABSORICA LD Administration The ABSORICA LD median T max was 5 hours under fed conditions and 3.5 hours under fasting conditions following administration of a single 32 mg dose. Effect on Food No clinically significant differences in ABSORICA LD pharmacokinetics were observed following administration with a high-fat, high-calorie meal (150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat; total calories 900 calories). The mean AUC 0-t and C max of isotretinoin were 10209 ng*hr/mL and 646 ng/mL, respectively, following administration of a single 32 mg ABSORICA LD dose under fed conditions; which were approximately 20% and 6% higher, respectively, compared to fasting conditions. However, ABSORICA LD may be given with or without meals [see Dosage and Administration (2.1) ] . Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. Elimination The mean elimination half-lives of isotretinoin and its 4-oxo-isotretinoin metabolite were: •18 hours and 38 hours, respectively, after a single oral ABSORICA 40 mg dose. •Approximately 24 hours and 38 hours, respectively, after a single oral ABSORICA LD 32 mg dose. Metabolism : Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro. Isotretinoin and its metabolites are further metabolized into conjugates. Following oral administration of isotretinoin capsules, at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) have been identified in human plasma. The extent of formation of all metabolites was higher under fed conditions. All of these metabolites possess retinoid activity in vitro. The clinical significance is unknown. Excretion : Following oral administration of an 80 mg dose of radiolabeled-isotretinoin as a liquid suspension, the metabolites of isotretinoin were excreted in feces and urine in relatively equal amounts (total of 65% to 83%). Specific Populations Pediatric Patients: No clinically significant differences in the pharmacokinetics of isotretinoin were observed based on age (12 to 15 years (n=38), and ≥18 years (n=19)). In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed [see Use in Specific Populations (8.4) ] . Drug Interaction Studies Phenytoin: No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when used concomitantly with isotretinoin. Norethindrone and Ethinyl Estradiol: There were no clinically significant differences in the pharmacokinetics of norethindrone and ethinyl estradiol after the concomitant use of Isotretinoin Capsules 1 mg/kg/day with an oral contraceptive in premenopausal female patients with severe recalcitrant nodular acne. Additionally, there were no clinically significant differences in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in these patients.

12.2 Pharmacodynamics Decreased sebum secretion is related to the dose and duration of treatment with ABSORICA/ABSORICA LD.

12.3 Pharmacokinetics No clinically significant differences in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects without acne were reported in published literature. Absorption Following ABSORICA Administration The ABSORICA mean T max was 6.4 hours under fed conditions and 2.9 hours under fasting conditions following administration of a single 40 mg dose. Effect on Food No clinically significant differences in ABSORICA pharmacokinetics were observed following administration with a modified high-fat, high-calorie meal (123.2 calories from protein, 265.6 calories from carbohydrates, and 468 calories from fat; total calories 857 calories) with reduced vitamin A content. The mean AUC 0-t and C max of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg ABSORICA dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, ABSORICA may be given with or without meals [see Dosage and Administration (2.1) ]. Absorption Following ABSORICA LD Administration The ABSORICA LD median T max was 5 hours under fed conditions and 3.5 hours under fasting conditions following administration of a single 32 mg dose. Effect on Food No clinically significant differences in ABSORICA LD pharmacokinetics were observed following administration with a high-fat, high-calorie meal (150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat; total calories 900 calories). The mean AUC 0-t and C max of isotretinoin were 10209 ng*hr/mL and 646 ng/mL, respectively, following administration of a single 32 mg ABSORICA LD dose under fed conditions; which were approximately 20% and 6% higher, respectively, compared to fasting conditions. However, ABSORICA LD may be given with or without meals [see Dosage and Administration (2.1) ] . Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. Elimination The mean elimination half-lives of isotretinoin and its 4-oxo-isotretinoin metabolite were: •18 hours and 38 hours, respectively, after a single oral ABSORICA 40 mg dose. •Approximately 24 hours and 38 hours, respectively, after a single oral ABSORICA LD 32 mg dose. Metabolism : Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro. Isotretinoin and its metabolites are further metabolized into conjugates. Following oral administration of isotretinoin capsules, at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) have been identified in human plasma. The extent of formation of all metabolites was higher under fed conditions. All of these metabolites possess retinoid activity in vitro. The clinical significance is unknown. Excretion : Following oral administration of an 80 mg dose of radiolabeled-isotretinoin as a liquid suspension, the metabolites of isotretinoin were excreted in feces and urine in relatively equal amounts (total of 65% to 83%). Specific Populations Pediatric Patients: No clinically significant differences in the pharmacokinetics of isotretinoin were observed based on age (12 to 15 years (n=38), and ≥18 years (n=19)). In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed [see Use in Specific Populations (8.4) ] . Drug Interaction Studies Phenytoin: No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when used concomitantly with isotretinoin. Norethindrone and Ethinyl Estradiol: There were no clinically significant differences in the pharmacokinetics of norethindrone and ethinyl estradiol after the concomitant use of Isotretinoin Capsules 1 mg/kg/day with an oral contraceptive in premenopausal female patients with severe recalcitrant nodular acne. Additionally, there were no clinically significant differences in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in these patients.

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.

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.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity There is an extremely high risk of life-threatening birth defects when ABSORICA/ABSORICA LD is used in pregnancy [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )]. Instruct patients who can become pregnant that they must not be pregnant during or up to 1 month after ABSORICA/ABSORICA LD treatment. Instruct patients to not donate blood during ABSORICA/ABSORICA LD treatment and for 1 month following discontinuation to avoid blood donation to a pregnant patient. iPLEDGE REMS ABSORICA and ABSORICA LD are available only through a restricted program called the iPLEDGE REMS [see Warnings and Precautions ( 5.2 )]. Inform patients who can get pregnant of the following notable requirements. These patients must: Enroll in the REMS Comply with REMS requirements including: Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations ( 8.3 )]. Demonstrate comprehension of the risk and REMS requirements prior to each prescription. Obtain the prescription within the 7-day prescription window (i.e., within 7 days of the pregnancy test collection). Inform their prescriber if they get pregnant and stop treatment. Inform patients who cannot get pregnant of the following notable requirements. These patients must enroll in the REMS and comply with the REMS requirements. ABSORICA/ABSORICA LD is available only from certified pharmacies participating in the REMS. Therefore, provide patients with the telephone number and website for information on how to obtain ABSORICA/ABSORICA LD [see Warnings and Precautions (5.2) ]. Lactation 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 [see Use in Specific Populations (8.2) ] . Psychiatric Disorders 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 [see Warnings and Precautions (5.4) ] . Important Administration Instructions To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid [see Dosage and Administration (2.1) ] . Intracranial Hypertension (Pseudotumor Cerebri) Advise patients that intracranial hypertension (pseudotumor cerebri) has occurred with ABSORICA/ABSORICA LD use including concomitant use with tetracyclines. Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue ABSORICA/ABSORICA LD immediately if they have symptoms of intracranial hypertension [see Warningsand Precautions (5.5) ] . Serious Skin Reactions Advise patients that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in patients treated with isotretinoin and to discontinue ABSORICA/ABSORICA LD if clinically significant skin reactions occur [see Warnings and Precautions (5.6) ] . Inflammatory Bowel Disease Advise patients that inflammatory bowel disease (including regional ileitis) have occurred with isotretinoin use including those without a prior history of IBD and if they experience IBD symptoms, to discontinue ABSORICA/ABSORICA LD immediately [see Warnings and Precautions (5.11) ] . Musculoskeletal Abnormalities Inform patients that: There have been reports of osteoporosis and fractures and that isotretinoin may have a negative effect on bone mineral density [see Warnings and Precautions (5.12) ] . Isotretinoin use has been associated with musculoskeletal abnormalities (e.g., arthralgia, back pain) [see Warnings and Precautions (5.12) ] . Inform pediatric patients and their families that isotretinoin use in pediatric patients who participated in sports with repetitive impact increased their risk of spondylolisthesis or hip growth plate injuries [see Warnings and Precautions (5.12) ] . Inform pediatric patients and their caregivers that pediatric patients treated with isotretinoin capsules developed back pain including severe back pain, and arthralgias including severe arthralgias [see Use in Specific Populations (8.4) ] . Ocular Abnormalities Inform patients that they may experience dry eyes, corneal opacities, and decreased night vision and contact lens wearers may experience decreased tolerance to contact lenses during and after treatment [see Warnings and Precautions (5.13) ] . Rhabdomyolysis Inform patients there have been rare postmarketing reports of rhabdomyolysis in patients treated with isotretinoin capsules, some associated with strenuous physical activity [see Warnings and Precautions (5.15) ] . Hypersensitivity Reactions Given that anaphylactic reactions and other allergic reactions have been reported in patients treated with isotretinoin capsules, instruct the patient to discontinue ABSORICA/ABSORICA LD and contact their healthcare provider if they have a severe allergic reaction [see Warnings and Precautions (5.14) ] . Lipid Abnormalities Instruct patients that hypertriglyceridemia, decreased HDL, and increased cholesterol levels were reported in patients treated with isotretinoin capsules [see Warnings and Precautions (5.8) ] . Additional Instructions Inform patients: To not share ABSORICA/ABSORICA LD with anyone else because of the risk of birth defects and other serious adverse reactions. That transient exacerbation (flare) of acne has been seen, generally during the initial period of treatment. To avoid wax epilation and skin resurfacing procedures (such as dermabrasion, laser) during ABSORICA/ABSORICA LD treatment and for at least 6 months thereafter due to the possibility of scarring. To avoid prolonged exposure to UV rays or sunlight. Manufactured by: ABSORICA Galephar Pharmaceutical Research, Inc. Humacao, PR 00792 ABSORICA LD Ohm Laboratories Inc. New Brunswick, NJ 08901 Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 ABSORICA and ABSORICA LD are registered trademarks of Sun Pharmaceutical Industries, Inc. All other trademarks are property of their respective owners. ABSORICA LD 8 mg, 16 mg, 20 mg, 24 mg, 28 mg and 32 mg are protected by US Patent No. US 9,700,535 and US 9,750,711.