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ZENATANE ISOTRETINOIN ISOTRETINOIN ISOTRETINOIN BUTYLATED HYDROXYANISOLE EDETATE DISODIUM MEDIUM-CHAIN TRIGLYCERIDES SOYBEAN OIL WHITE WAX GELATIN GLYCERIN METHYLPARABEN PROPYLPARABEN D&C YELLOW NO. 10 FD&C BLUE NO. 1 Fd&C Blue No. 2 TITANIUM DIOXIDE FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL SHELLAC AMMONIA R135 ZENATANE ISOTRETINOIN ISOTRETINOIN ISOTRETINOIN BUTYLATED HYDROXYANISOLE EDETATE DISODIUM MEDIUM-CHAIN TRIGLYCERIDES SOYBEAN OIL WHITE WAX GELATIN GLYCERIN METHYLPARABEN PROPYLPARABEN D&C RED NO. 27 D&C RED NO. 30 FD&C BLUE NO. 2 TITANIUM DIOXIDE FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL SHELLAC AMMONIA R136 ZENATANE ISOTRETINOIN ISOTRETINOIN ISOTRETINOIN BUTYLATED HYDROXYANISOLE EDETATE DISODIUM MEDIUM-CHAIN TRIGLYCERIDES SOYBEAN OIL WHITE WAX GELATIN GLYCERIN METHYLPARABEN PROPYLPARABEN D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 TITANIUM DIOXIDE FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL SHELLAC AMMONIA R137 ZENATANE ISOTRETINOIN ISOTRETINOIN ISOTRETINOIN BUTYLATED HYDROXYANISOLE EDETATE DISODIUM MEDIUM-CHAIN TRIGLYCERIDES SOYBEAN OIL WHITE WAX GELATIN GLYCERIN METHYLPARABEN PROPYLPARABEN FERRIC OXIDE RED FERRIC OXIDE YELLOW FD&C BLUE NO. 2 TITANIUM DIOXIDE FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL SHELLAC AMMONIA reddish brown R1

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Zenatane 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 Zenatane 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 Zenatane 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, Zenatane is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS [see Warnings and Precautions ( 5.2 )]. WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY See full prescribing information for complete boxed warning. Zenatane 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 Zenatane 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) Zenatane is available only through a restricted program called the iPLEDGE REMS. (5.2)

Zenatane is indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, Zenatane is reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. Limitations of Use: If a second course of Zenatane treatment is needed, it is not recommended before a two-month waiting period because the patient's acne may continue to improve following a 15 to 20-week course of treatment [see Dosage and Administration (2.2)]. Zenatane is a retinoid indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, Zenatane is reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. (1) Limitations of Use:If a second course of Zenatane 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)

{template} Evaluations Prior to Prescribing and Use of Zenatane: In patients who can get pregnant, only prescribe Zenatane after verification and documentation that they are not pregnant. See the Full Prescribing Information for the detailed requirements prior to prescribing Zenatane (2.1, 8.3) Complete the following laboratory tests in all patients: fasting lipid profile and liver function tests. (2.1) Recommended dosage is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks (2.2) Adult patients with very severe disease (scarring, trunk involvement) may increase dosage to 2 mg/kg/day in two divided doses with food. (2.1) Once daily dosing is not recommended. (2.2) If a dose is missed, just skip that dose. Do not take two doses at the same time. (2.2) See the Full Prescribing Information for the recommended duration of use (2.3)

In patients who can get pregnant, only prescribe Zenatane 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 Zenatane, [see Use in Specific Populations (8.3)] Prior to Zenatane use in all patients, complete the following laboratory testing: A fasting lipid profile including triglycerides [see Warnings and Precautions (5.7, 5.14)]. Liver function tests [see Warnings and Precautions (5.9, 5.14)].

The recommended dosage range for Zenatane is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks (see Tables 1 and 2, respectively) [see Clinical Pharmacology (12.3)]. Table 1: Zenatane: Recommended Divided Doses (0.5 mg/kg/day dosage)

Body Weight	First Dose	Second Dose
40 kg	10 mg	10 mg
50 kg	12.5 mg	12.5 mg
60 kg	15 mg	15 mg
70 kg	17.5 mg	17.5 mg
80 kg	20 mg	20 mg
90 kg	22.5 mg	22.5 mg
100 kg	25 mg	25 mg

Table 2: Zenatane : Recommended Divided Doses (1 mg/kg/day dosage)

Body Weight	First Dose	Second Dose
40 kg	20 mg	20 mg
50 kg	25 mg	25 mg
60 kg	30 mg	30 mg
70 kg	35 mg	35 mg
80 kg	40 mg	40 mg
90 kg	45 mg	45 mg
100 kg	50 mg	50 mg

To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. Swallow capsules whole. Do not split, crush, chew, or suck on the capsules. During treatment, the dosage may be adjusted according to response of the disease and/or adverse reactions, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosage adjustments up to 2 mg/kg/day for Zenatane in divided doses with food, as tolerated (see Table 3). Table 3: Zenatane : Recommended Divided Doses (2 mg/kg/day dosage)

Body Weight	First Dose	Second Dose
40 kg	40 mg	40 mg
50 kg	50 mg	50 mg
60 kg	60 mg	60 mg
70 kg	70 mg	70 mg
80 kg	80 mg	80 mg
90 kg	90 mg	90 mg
100 kg	100 mg	100 mg

The safety and effectiveness of once daily dosing with Zenatane has not been established and is not recommended. If a dose of Zenatane is missed, just skip that dose. Do not take two doses of Zenatane at the same time.

A course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue Zenatane. 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 Zenatane in patients who have completed skeletal growth. The use of another course of Zenatane treatment is not recommended before a two-month waiting period because the patient's acne may continue to improve after a 15 to 20-week course of treatment. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Zenatane, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of Zenatane on bone loss is unknown [see Warnings and Precautions (5.11)].

Capsules: 10 mg: Zenatane (isotretinoin capsules USP) 10 mg are opaque blue elliptical soft gelatin capsules imprinted with black ink, “R135” on one side. 20 mg: Zenatane (isotretinoin capsules USP) 20 mg are opaque pink elliptical soft gelatin capsules imprinted with black ink, “R136” on one side. 30 mg: Zenatane (isotretinoin capsules USP) 30 mg are reddish brown colored opaque, elliptical shaped soft gelatin capsule imprinted with “RI” black colored ink along the length of body on one side. 40 mg: Zenatane (isotretinoin capsules USP) 40 mg are opaque green elliptical soft gelatin capsules imprinted with black ink, “R137” on one side. Capsules: 10 mg, 20 mg, 30 mg and 40 mg (3)

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

Psychiatric Disorders (depression, psychosis, suicidal thoughts and behavior, and aggressive and/or violent behaviors): Prior to and during treatment assess for these conditions; stop if these conditions occur on treatment (5.3) Intracranial Hypertension (Pseudotumor Cerebri): Avoid concomitant use with tetracyclines (5.4, 7.2) Serious Skin Reactions: Monitor for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions and discontinue treatment if they occur (5.5) Acute Pancreatitis: If pancreatitis symptoms occur, discontinue treatment (5.6) Lipid Abnormalities (hypertriglyceridemia, low HDL, and elevation of cholesterol): Monitor lipid levels at regular intervals; stop if hypertriglyceridemia cannot be controlled (5.7) Hearing Impairment: Discontinue and refer to specialized care (5.8) Hepatotoxicity: Monitor liver function tests prior to and during treatment (5.9, 5.14) Inflammatory Bowel Disease: Discontinue for abdominal pain, rectalbleeding, or severe diarrhea (5.10) Musculoskeletal Abnormalities: Arthralgias, back pain, decreases in bone mineral density and premature epiphyseal closure (5.11) Ocular Abnormalities e.g., corneal opacities, decreased night vision: If visual symptoms occur, discontinue, and refer for an ophthalmological exam (5.12)

Zenatane is contraindicated in pregnancy [see Contraindications (4)]. Based on human data, Zenatane 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 Zenatane 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 Zenatane treatment, immediately discontinue Zenatane 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 Zenatane treatment to the FDA via the MedWatch telephone number 1-800-FDA-1088, and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). Inform patients not to donate blood during Zenatane 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. Zenatane is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2)].

Because of the risk of embryo-fetal toxicity, Zenatane is available only through a restricted program under a REMS called the iPLEDGE REMS [see Warnings and Precautions (5.1)]. Notable requirements of the iPLEDGE REMS include the following: Prescribers must be certified with the REMS and comply with the REMS requirements, including the following: Assess the reproductive status of all patients prior to initiating and during treatment Counsel patients who cannot get pregnant on the risk and REMS requirements prior to initiating treatment. Counsel patients who can get pregnant on:  The risk and REMS requirements prior to and during treatment. Pregnancy prevention requirements prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling Comply with the pregnancy testing requirements. Assess the pregnancy status for patients who can get pregnant by reviewing pregnancy tests and documenting a negative result prior to each prescription. Report all pregnancies to the REMS.   Patients who can become pregnant must be enrolled in the REMS and must comply with REMS requirements, including the following: Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3)] Demonstrate comprehension of the risk and REMS requirements before each prescription is dispensed Obtain the prescription within the 7-day prescription window (i.e., within 7 days of the pregnancy test collection) Patients who cannot become pregnant must be enrolled in the REMS and must comply with the REMS requirements, including to not share Zenatane and not donate blood Pharmacies that dispense Zenatane 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 Zenatane 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.

Zenatane 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 Zenatane 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 Zenatane and promptly contact their health care provider. Discontinuation of Zenatane may be insufficient; further evaluation may be necessary such as a referral to a mental health care professional.

Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Avoid concomitant use of Zenatane with tetracyclines [see Drug Interactions (7.2)]. Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Screen patients with these symptoms and, if present, immediately discontinue Zenatane and refer the patient to a neurologist for further diagnosis and care [see Adverse Reactions (6)].

There have been postmarketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Monitor patients closely for severe skin reactions, discontinue Zenatane if they occur.

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 Zenatane and instruct patients to seek medical attention.

Elevations of serum triglycerides above 800 mg/dL have been reported in patients treated with Zenatane. 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 Zenatane, respectively. These lipid changes were reversible upon Zenatane cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing Zenatane or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Perform fasting lipid tests before Zenatane treatment and then at intervals until the lipid response to Zenatane is known, which usually occurs within 4 weeks. Carefully consider the risk/benefit of Zenatane 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 Zenatane treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.14)]. Discontinue Zenatane if hypertriglyceridemia cannot be controlled.

Impaired hearing has been reported in patients taking Zenatane; in some cases, the hearing impairment has been reported to persist after treatment has been discontinued. Mechanism(s) and causality for this reaction have not been established. Discontinue Zenatane treatment in patients who experience tinnitus or hearing impairment and refer them for specialized care for further evaluation.

Clinical hepatitis has been reported with Zenatane treatment. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with Zenatane, some of which normalized with dosage reduction or continued administration of the drug. Discontinue Zenatane if normalization does not readily occur or if hepatitis is suspected during treatment.

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 Zenatane treatment has been stopped. Discontinue Zenatane immediately if patients experience abdominal pain, rectal bleeding or severe diarrhea [see Adverse Reactions (6)].

Osteoporosis and Fractures There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients treated with Zenatane or following cessation. Therefore, healthcare providers should use caution when prescribing Zenatane to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism or patients diagnosed with anorexia nervosa [see Use in Specific Populations (8.4)]. There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients while on treatment with isotretinoin or following cessation of treatment with isotretinoin. Patients in early and late adolescence who participate in sports with repetitive impact may be at an increased risk of spondylolisthesis with and without pars fractures, and hip growth plate injuries have been reported. Musculoskeletal Symptoms Approximately 16% of patients treated with Zenatane in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of isotretinoin. Evaluate the musculoskeletal system in patients who present with these symptoms during or after a course of Zenatane. Consider discontinuing Zenatane if any significant abnormality is found. Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of treatment with isotretinoin have more of an effect than a single course of treatment on the musculoskeletal system. It is important that Zenatane be given at the recommended dosage for no longer than the recommended duration. Hyperostosis A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day of Zenatane (approximately 1.1 times the maximum recommended daily dosage). Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Zenatane given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials of nodular acne patients treated with a single course of treatment at recommended doses. The skeletal effects of multiple Zenatane treatment courses for acne are unknown. Premature Epiphyseal Closure There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of Zenatane. The effect of multiple courses of Zenatane on epiphyseal closure is unknown.

Carefully monitor for visual problems. If visual difficulties occur, discontinue Zenatane treatment and obtain an ophthalmological examination [see Adverse Reactions (6)]. Corneal Opacities Corneal opacities have occurred in patients receiving Zenatane and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with Zenatane 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 Zenatane treatment and in some instances the event has persisted after treatment was discontinued. Because the onset in some patients was sudden, advise patients of this potential problem and warn patients to be cautious when driving or operating any vehicle at night. Dry Eyes Dry eyes has been reported in patients during isotretinoin use. Patients who wear contact lenses may have trouble wearing them while on Zenatane treatment and afterwards.

Anaphylactic reactions and other allergic reactions have been reported with isotretinoin use. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura of the extremities and extracutaneous involvement (including renal) have been reported. If a severe allergic reaction occurs, discontinue Zenatane treatment and initiate appropriate medical management.

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 Zenatane treatment and 1 month after the discontinuation of Zenatane [see Use in Specific Populations (8.3)]. Lipid Tests: Obtain pretreatment and follow-up fasting lipid tests under fasting conditions. Wait 36 hours after consumption of alcohol before testing is performed. It is recommended that these tests be performed periodically until the lipid response to Zenatane is known. The incidence of hypertriglyceridemia is 25% in patients treated with Zenatane [see Warnings and Precautions (5.7)]. Liver Function Tests: As elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on Zenatane, perform pretreatment and follow-up liver function tests periodically until the response to Zenatane is known [see Warnings and Precautions (5.9)]. Additional Laboratory Abnormalities Glucose: With Zenatane use, some patients have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Zenatane treatment. CPK: Some patients undergoing vigorous physical activity while taking Zenatane have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis with isotretinoin use, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years old) with severe recalcitrant nodular acne, elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this clinical trial.

The following adverse reactions with Zenatane are described in more detail in other sections of the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] Psychiatric Disorders [see Warnings and Precautions (5.3)] Intracranial Hypertension (Pseudotumor Cerebri) [see Warnings and Precautions (5.4)] Serious Skin Reactions [see Warnings and Precautions (5.5)] Pancreatitis [see Warnings and Precautions (5.6)] Lipid Abnormalities [see Warnings and Precautions (5.7)] Hearing Impairment [see Warnings and Precautions (5.8)] Hepatotoxicity [see Warnings and Precautions (5.9)] Inflammatory Bowel Disease [see Warnings and Precautions (5.10)] Musculoskeletal Abnormalities [see Warnings and Precautions (5.11)] Ocular Abnormalities [see Warnings and Precautions (5.12)] Hypersensitivity Reactions [see Warnings and Precautions (5.13)] The following adverse reactions, presented alphabetically by body system, associated with the use of Zenatane were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions with a Dose Relationship Cheilitis and hypertriglyceridemia were dose related. Body as a Whole Allergic reactions, dry mouth, edema, fatigue, irritability, lymphadenopathy, pain, systemic hypersensitivity, vasculitis, weight loss. Cardiovascular Palpitation, stroke, tachycardia, vascular thrombotic disease Endocrine/Metabolism and Nutritional Alterations in blood sugar levels, decreased appetite, hypertriglyceridemia, weight fluctuation. Gastrointestinal Abdominal pain, bleeding and inflammation of the gums, colitis, constipation, diarrhea, esophageal ulceration, esophagitis, ileitis, nausea, hepatitis, inflammatory bowel disease, other nonspecific gastrointestinal symptoms, pancreatitis, vomiting. Hematologic Anemia, neutropenia including severe neutropenia, rare reports of agranulocytosis, thrombocytopenia. Infections and Infestations Infections (including disseminated herpes simplex, hordeolum, nasopharyngitis, upper respiratory tract infections). Laboratory Abnormalities The following lab test values were increased: alkaline phosphatase, ALT, AST, bilirubin, cholesterol, CPK, fasting blood glucose, gamma-glutamyltransferase, LDH, LDL, platelet counts, sedimentation rate, triglycerides, and uric acid (hyperuricemia). The following lab test values were decreased: high density lipoprotein (HDL), RBC parameters, and WBC counts. Urine findings included increased microscopic or gross hematuria, proteinuria, white cells. Musculoskeletal and Connective Tissue Arthritis, calcification of tendons and ligaments; decreases in bone mineral density; elevations of CPK/rare reports of rhabdomyolysis musculoskeletal symptoms (sometimes severe) including arthralgia, back pain, extremity pain, musculoskeletal pain or stiffness, myalgia, neck pain [see Warnings and Precautions (5.11)]; other types of bone abnormalities; premature epiphyseal closure; skeletal hyperostosis; tendonitis; and transient chest pain. Neurological Dizziness, drowsiness, intracranial hypertension (pseudotumor cerebri), headache, insomnia, lethargy, malaise, nervousness, paresthesia, seizures, syncope, stroke, and weakness. Psychiatric Aggression, auditory hallucinations, anger, depression, emotional instability, insomnia, irritability, panic attack, psychosis, suicidal ideation, suicide, suicide attempts, violent behaviors. In some patients who reported depression, their depression subsided with discontinuation of Zenatane treatment but recurred with reinstitution of Zenatane treatment Reproductive System Abnormal menses, sexual dysfunction that may continue after discontinuation of treatment (including erectile dysfunction, decreased libido, decreased vaginal lubrication, and vaginal dryness). Respiratory Bronchospasm (with or without a history of asthma), epistaxis, nasal dryness, respiratory infection, voice alteration. Skin and Subcutaneous Tissue Abnormal wound healing (delayed healing or exuberant granulation tissue with crusting), acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), contact dermatitis, dermatitis, dry mouth, dry nose, dry skin, epistaxis, erythema, eruptive xanthomas, erythema multiforme, flushing, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), skin fragility, Stevens-Johnson syndrome, sunburn, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including granulomatosis with polyangiitis), wound healing abnormal (delayed healing or exuberant granulation tissue with crusting). Senses Hearing: hearing impairment, tinnitus. Ocular: asthenopia, blurred vision, cataracts, color vision disorder, conjunctivitis, corneal opacities, decreased night vision which may persist, dry eyes, eye irritation, eye pruritis, eyelid inflammation, increased lacrimation, keratitis, ocular hyperemia, optic neuritis, photophobia, reduced visual acuity, visual disturbances. Renal and Urinary  Glomerulonephritis, nonspecific urogenital findings. Most common adverse reactions are (incidence ≥ 5%): dry lips, dry skin, backpain, 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 Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or iPLEDGE at (1-866-495-0654).

Vitamin A: Avoid concomitant use (7.1) Tetracyclines: Avoid concomitant use (7.2)

Avoid concomitant use of Zenatane with supplements containing vitamin A. Zenatane is closely related to vitamin A. Therefore, concomitant use of Zenatane with vitamin A may lead to Zenatane-related adverse reactions.

Avoid concomitant use of Zenatane with tetracyclines. Zenatane use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use with tetracyclines [see Warnings and Precautions (5.4)].

It is not known if there is an interaction between Zenatane with oral contraceptives that do not contain norethindrone and ethinyl estradiol. Zenatane did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology (12.3)]

Lactation: Breastfeeding not recommended (8.2). In Patients Who Can Get Pregnant: Pregnancy testing is required prior to, during, and after Zenatane treatment. See the Full Prescribing Information for the detailed pregnancy test and contraception requirements. (8.3).

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 Zenatane 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 Zenatane is contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans [see Warnings and Precautions (5.1)]. If Zenatane is used during pregnancy, or if the patient becomes pregnant while taking Zenatane, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking Zenatane, immediately discontinue Zenatane 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 Zenatane exposure include malformations of the face, eyes, ears, skull, central nervous system (CNS), cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases, death has occurred as a result of the malformations. Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.

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 Zenatane, and for at least 8 days after the last dose of Zenatane.

All patients who can become pregnant must comply with the iPLEDGE REMS requirements [see Warnings and Precautions (5.2)]. Pregnancy Testing In patients who can get pregnant, pregnancy testing is required prior to, during, and after Zenatane treatment. Pregnancy Testing Prior to Prescribing Zenatane: In patients who can get pregnant, only prescribe Zenatane after verification and documentation that they are not pregnant: (1) 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 (2) 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 Zenatane 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 Zenatane 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 Zenatane prescription starting from the day of the pregnancy test through six days after the day of the pregnancy test) and have not started Zenatane treatment, repeat a urine or serum pregnancy test in a medical setting and verify and document that this repeat test is negative prior to prescribing Zenatane. The confirmatory pregnancy test must be repeated, as needed, until the patient receives Zenatane. Pregnancy Testing During Treatment with Zenatane: In patients who can get pregnant who are being treated with Zenatane, 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 Zenatane prescription starting from the day of the pregnancy test through six days after the day of the pregnancy test), repeat the urine or serum pregnancy test within seven 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 the prescribing additional Zenatane treatment. Pregnancy Testing in Patients Who Have Completed Zenatane Treatment: In patients can get pregnant who have completed Zenatane 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 Zenatane treatment, ANDOne month after the discontinuation of Zenatane.  Contraception Patients who can get pregnant must use two forms of contraception simultaneously, at least one of which must be a primary form (see Table 4), for at least one month prior to initiation of Zenatane treatment, during Zenatane treatment, and for one month after discontinuing Zenatane treatment. However, two forms of contraception are 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 postmenopausal. Micro-dosed progesterone preparations ("minipills" that do not contain an estrogen) are an inadequate form of contraception during Zenatane 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 Zenatane. These reports are more frequent for patients who use only a single method of contraception. Therefore, it is critically important that patients who can become pregnant use two methods of contraception simultaneously. Table 4: Primary and Secondary Forms of Contraception

Primary forms	Secondary forms
Tubal sterilization Male partner vasectomy Intrauterine device Hormonal (combination oral contraceptives, vaginal systems, vaginal inserts, transdermal systems, injections, or implants)	Barrier: male latex condom with or without spermicide diaphragm with spermicide 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 one month before, during, or 1 month after treatment, the patient must: a. Stop taking Zenatane immediately, if on treatment b. Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy c. Start using two forms of contraception simultaneously again for one month before resuming Zenatane treatment d. Have a second pregnancy test after using two forms of contraception for one month. Infertility 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 Zenatane treatment for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

The safety and effectiveness of Zenatane 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 treatment, including systemic antibiotics. Use of Zenatane in this age group for this indication is supported by evidence from a clinical trial comparing 103 pediatric patients (13 to 17 years) to 197 adults (both with severe recalcitrant nodular acne). Results from this study demonstrated that Zenatane, at a dosage of 1 mg/kg/day given in two divided doses, was similarly effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. The safety and effectiveness of Zenatane in pediatric patients less than 12 years of age have not been established. Adverse Reactions in Pediatric Patients In trials with Zenatane, adverse reactions reported in pediatric patients aged 12 to 17 years old 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 patients. In a trial of pediatric patients aged 12 to 17 years old treated with Zenatane, 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 patients than male patients. Arthralgias occurred in 22% (79/358) of pediatric patients including severe arthralgias in 8% (6/79) of patients. Evaluate the musculoskeletal system in pediatric patients 12 years of age and older who present with these symptoms during or after a course of Zenatane. Consider discontinuing Zenatane if any significant abnormality is found. Effects on Bone Mineral Density in Pediatric Patients In an open-label clinical trial (N=217) of a single course of treatment with Zenatane for adolescents with severe recalcitrant nodular acne, BMD at several skeletal sites were assessed: One patient had a decrease in lumbar spine BMD >4% based on unadjusted data; 16 (8%) patients had decreases in lumbar spine BMD >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (5%) had a decrease in total hip BMD >5% based on unadjusted data. Twenty-one (11%) patients had decreases in total hip BMD >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the patients with decreased BMD for up to 11 months thereafter demonstrated increasing BMD in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine BMD measurements below baseline values. Total hip BMD remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (63%). In a separate open-label extension trial of 10 patients including those ages 13 to 17 years, who started a second course of Zenatane 4 months after the first course, two patients showed a decrease in mean lumbar spine BMD up to 3.3%. Epiphyseal Closure There have been spontaneous literature reports of premature epiphyseal closure in acne patients who received the recommended dosage of Zenatane. The effect of multiple courses of Zenatane on epiphyseal closure is unknown [see Warnings and Precautions (5.11)].

Clinical studies of Zenatane did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. The effects of aging may increase some risks associated with Zenatane treatment.

Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. Evaluate patients who can become pregnant who present with an isotretinoin overdosage for pregnancy. Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, instruct male patients treated with Zenatane 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 Zenatane overdose not donate blood for at least 1 month. If an overdose occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to slightly orange crystalline powder with a molecular weight of 300.44. Isotretinoin has high lipophilicity. The structural formula is: Zenatane (isotretinoin capsules, USP) contains 10 mg, 20 mg, 30 mg, or 40 mg of isotretinoin (a retinoid) for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil (Type-I and Type-II), medium chain triglyceride, refined soybean oil and white wax. Gelatin capsules contain ferric oxide red, ferric oxide yellow (for 30 mg), gelatin, glycerin, methyl paraben, propyl paraben, lake blend blue (LB-332) containing D&C Yellow No.10, FD&C Blue No.1 (for 10 mg), lake blend red (LB-1574) containing D&C Red No.27, D&C Red No.30 (for 20 mg), lake blend green (LB-333) containing D&C Yellow No.10, FD&C Blue No.1 (for 40 mg), lake blend white (TLB-1774) containing FD&C Blue No.2, titanium dioxide, and opacode black S-1-17823 containing iron oxide black, N-butyl alcohol, propylene glycol, ammonium hydroxide and shellac. Meets USP Dissolution Test 5.

The exact mechanism of action of Zenatane in the treatment of severe recalcitrant nodular acne in nonpregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics is unknown. Isotretinoin, a retinoid, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.

Decreased sebum secretion is related to the dose and duration of treatment with Zenatane.

The following parameters are presented as mean [coefficient of variation (CV%)] following a single oral dose of 80 mg of Zenatane in healthy adult subjects unless otherwise stated. Isotretinoin Cmax is 862 (22%) ng/mL and AUC0-inf is 10,004 (22%) ng*h/mL when Zenatane was administered with food in healthy adults. Isotretinoin accumulation ratio ranged from 0.90 to 5.43 in patients with cystic acne after multiple doses. No clinically significant differences in the pharmacokinetics of isotretinoin were observed between patients with nodular acne and healthy subjects without acne. Absorption Isotretinoin time to maximum concentration (Tmax) is 5.3 hours (77%) when administered with food. Effect on Food: Isotretinoin AUC0-inf increased 2.7-fold and Cmax increased 2.9-fold relative to the fasted state following a high-fat meal. In addition, the extent of formation of all metabolites was higher, Tmax increased to 5.3 hours (77%), and the elimination half-life was unchanged under fed conditions [see Dosage and Administration (2.1)]. Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily to albumin. Elimination The mean ± SD elimination half-life of isotretinoin is 21± 8.2 hours and 24 ± 5.3 hours for its 4-oxo-isotretinoin metabolite. Metabolism: Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro. Isotretinoin and its metabolites are further metabolized into conjugates. Isotretinoin is metabolized into at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxoretinoic acid (4-oxo-tretinoin)) which are detected in human plasma. Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. The exposure of adult cystic acne patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. All of these metabolites possess retinoid activity in vitro, however the clinical significance is unknown. Excretion: Following administration of 80 mg 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 statistically significant differences in isotretinoin pharmacokinetics were observed based on age (12 to 15 years, and ≥18 years) in patients who received single and multiple doses of Zenatane. In both age groups, 4-oxo-isotretinoin was the major metabolite compared to tretinoin and 4-oxo-tretinoin. Drug Interaction Studies Clinical Studies: Norethindrone and Ethinyl Estradiol: There were no clinically significant differences in the pharmacokinetics of norethindrone and ethinyl estradiol after the concomitant use of Zenatane (dosage of 1 mg/kg/day) with an oral contraceptive agent in premenopausal female patients with severe recalcitrant nodular acne. Additionally, there was no clinically significant differences in the serum levels of progesterone, folliclestimulating hormone, and luteinizing hormone in in these patients. Phenytoin: There was no clinically significant differences in the pharmacokinetics of phenytoin when used concomitantly with isotretinoin.

Carcinogenesis In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 or 5.3 times the recommended clinical Zenatane dosage of 1 mg/kg/day, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to humans is uncertain. Mutagenesis The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative, while in the second laboratory, a weakly positive response (less than 1.6 times background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen, and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative. Impairment of Fertility In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical Zenatane dosage of 1 mg/kg/day, after normalization for total body surface area). In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical Zenatane dosage of 1 mg/kg/day, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis, but some sperm were observed in all testes examined, and in no instance were completely atrophic tubules seen.

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 or 5.3 times the recommended clinical Zenatane dosage of 1 mg/kg/day, respectively, after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical Zenatane dosage of 1 mg/kg/day, after normalization for total body surface area).

Zenatane (isotretinoin capsules, USP) is supplied as follows: Zenatane (isotretinoin capsules USP) 10 mg are opaque blue elliptical soft gelatin capsules imprinted with black ink, “R135” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and in boxes of 100 containing 10 prescription packs of 10 capsules, as unit dose blisters. Boxes of 30 (3 Prescription Packs of 10 capsules) NDC 55111-135-81 Boxes of 100 (10 Prescription Packs of 10 capsules) NDC 55111-135-78 Zenatane (isotretinoin capsules USP) 20 mg are opaque pink elliptical soft gelatin capsules imprinted with black ink, “R136” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and in boxes of 100 containing 10 prescription packs of 10 capsules, as unit dose blisters. Boxes of 30 (3 Prescription Packs of 10 capsules) NDC 55111-136-81 Boxes of 100 (10 Prescription Packs of 10 capsules) NDC 55111-136-78 Zenatane (isotretinoin capsules USP) 30 mg are reddish brown colored opaque, elliptical shaped soft gelatin capsule imprinted with “RI” black colored ink along the length of body on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and in boxes of 100 containing 10 prescription packs of 10 capsules, as unit dose blisters. Boxes of 30 (3 Prescription Packs of 10 capsules) NDC 55111-113-81 Boxes of 100 (10 Prescription Packs of 10 capsules) NDC 55111-113-78 Zenatane (isotretinoin capsules USP) 40 mg are opaque green elliptical soft gelatin capsules imprinted with black ink, “R137” on one side and are supplied in boxes of 30 containing 3 prescription packs of 10 capsules and 100 containing 10 prescription packs of 10 capsules, as unit dose blisters. Boxes of 30 (3 prescription packs of 10 capsules) NDC 55111-137-81 Boxes of 100(10 prescription packs of 10 capsules) NDC 55111-137-78 Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature]. Protect from light.

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 Zenatane 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 one month after Zenatane treatment. Instruct patients to not donate blood during Zenatane treatment and for 1 month following discontinuation to avoid blood donation to a pregnant patient. iPLEDGE REMS Zenatane is 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 health care provider if they become 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. Zenatane 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 Zenatane [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 Zenatane, and for at least 8 days after the last dose of Zenatane [see Use in Specific Populations (8.2)]. Psychiatric Disorders Instruct patients and/or their caregivers/families that Zenatane may cause depression, psychosis, suicidal ideation, suicide attempts, and aggressive or violent behavior. Instruct patients to stop Zenatane and to contact a health care provider if they develop any of these signs or symptoms [see Warnings and Precautions (5.3)]. Important Administration Instructions To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. Instruct patients to administer this Zenatane product with food [see Dosage and Administration (2.1)]. Intracranial Hypertension (Pseudotumor Cerebri) Advise patients that intracranial hypertension (pseudotumor cerebri) has occurred with Zenatane use including concomitant use with tetracyclines. Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue Zenatane immediately if they have symptoms of intracranial hypertension [see Warnings and Precautions (5.4)]. 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 Zenatane if clinically significant skin reactions occur [see Warnings and Precautions (5.5)]. 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 Zenatane immediately [see Warnings and Precautions (5.10)]. 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 (5.11)]. Isotretinoin use has been associated with musculoskeletal abnormalities (e.g., arthralgia, back pain) [see Warnings and Precautions (5.11)]. 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 (5.11)]. Inform pediatric patients and their caregivers that pediatric patients treated with Zenatane 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 (5.12)]. Rhabdomyolysis Inform patients there have been rare postmarketing reports of rhabdomyolysis in patients treated with Zenatane, some associated with strenuous physical activity [see Warnings and Precautions (5.14)]. Hypersensitivity Reactions Given that anaphylactic reactions and other allergic reactions have been reported in patients treated with Zenatane, instruct the patient to discontinue Zenatane and contact their health care provider if they have a severe allergic reaction [see Warnings and Precautions (5.13)]. Lipid Abnormalities Instruct patients that hypertriglyceridemia, decreased HDL, and increased cholesterol levels were reported in patients treated with Zenatane [see Warnings and Precautions (5.7)]. Additional Instructions Inform patients:To not share Zenatane 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 Zenatane treatment and for at least 6 months thereafter due to the possibility of scarring.To avoid prolonged exposure to UV rays or sunlight. Rx Only Distributor: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 Revised: 09/2026