Isotretinoin Capsule
FDA Label NDC 69238-1255

Isotretinoin 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 isotretinoin 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 isotretinoin 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, isotretinoin 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)].

Isotretinoin capsules 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, isotretinoin capsules 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 isotretinoin capsules 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)].

In patients who can get pregnant, only prescribe isotretinoin capsules 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 isotretinoin capsules, [see Use in Specific Populations (8.3)].

Prior to isotretinoin capsules 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)].

Isotretinoin capsules are not substitutable with ABSORICA LD [see Warnings and Precautions (5.3)]. The recommended dosage of:

• Isotretinoin capsules are 0.5 to 1 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 1).

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 primarily manifested on the trunk may require dosage adjustments up to 2 mg/kg/day for isotretinoin capsules in divided doses, as tolerated.

The safety and effectiveness of once daily dosing with isotretinoin capsules have not been established and is not recommended.

If a dose of isotretinoin capsules are missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time.

Table 1: Isotretinoin Capsules Daily Dosage by Body Weight1
Body Weight	Total Daily Dosage (mg)1
	0.5 mg/kg	1 mg/kg	2 mg/kg
40 kg	20	40	80
50 kg	25	50	100
60 kg	30	60	120
70 kg	35	70	140
80 kg	40	80	160
90 kg	45	90	180
100 kg	50	100	200
1 Administer in two divided doses with or without meals

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 isotretinoin capsules.

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

Isotretinoin capsules, USP are available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules.

• 10 mg: Hard gelatin capsule with gold opaque cap and gold opaque body printed “A1254” on cap and “10” on body with black ink.
• 20 mg: Hard gelatin capsule with Swedish orange opaque cap and Swedish orange opaque body printed “A1255” on cap and “20” on body with black ink.
• 25 mg: Hard gelatin capsule with green opaque cap and green opaque body printed “A1256” on cap and “25” on body with white ink.
• 30 mg: Hard gelatin capsule with brown opaque cap and brown opaque body printed “A1257” on cap and “30” on body with white ink.
• 35 mg: Hard gelatin capsule with dark blue opaque cap and dark blue opaque body printed “A1258” on cap and “35” on body with white ink.
• 40 mg: Hard gelatin capsule with brown opaque cap and red opaque body printed “A1259” on cap and “40” on body with white ink.

Isotretinoin 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)].

Isotretinoin is contraindicated in pregnancy [see Contraindications (4.1)]. Based on human data, isotretinoin 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 isotretinoin 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 isotretinoin treatment, immediately discontinue isotretinoin 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 isotretinoin 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 isotretinoin 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.

Isotretinoin is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].

Because of the risk of embryo-fetal toxicity, isotretinoin are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS [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 isotretinoin 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 isotretinoin.
  • 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.

Given that the bioavailability and the recommended dosage of isotretinoin and ABSORICA LD are different, isotretinoin and ABSORICA LD are not substitutable on a mg per mg basis. For example, isotretinoin and ABSORICA LD have a 20 mg strength; however, these strengths have different bioavailability and are not substitutable.

Isotretinoin 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 isotretinoin 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 isotretinoin and promptly contact their healthcare provider. Discontinuation of isotretinoin may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare 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 isotretinoin 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 isotretinoin 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 and discontinue isotretinoin 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 isotretinoin and instruct patients to seek medical attention.

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 subjects 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.

Perform fasting lipid tests before isotretinoin treatment and then at intervals until the lipid response to isotretinoin is known, which usually occurs within 4 weeks. Carefully consider the risk/benefit of isotretinoin 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 isotretinoin treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.15)]. Discontinue isotretinoin if hypertriglyceridemia cannot be controlled.

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. Discontinue isotretinoin treatment in patients who experience tinnitus or hearing impairment and refer them for specialized care for further evaluation.

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

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 isotretinoin capsules 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 isotretinoin 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 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 isotretinoin. Consider discontinuing isotretinoin 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 isotretinoin 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 isotretinoin capsules 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.

Carefully monitor for visual problems. If visual difficulties occur, discontinue isotretinoin 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 isotretinoin 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 (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. If a severe allergic reaction occurs, discontinue 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 isotretinoin treatment, and 1 month after the discontinuation of isotretinoin [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 isotretinoin 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 isotretinoin is known [see Warnings and Precautions (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.

The following adverse reactions with isotretinoin 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 pruritus, 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, photophobia, visual disturbances.

Renal and Urinary

Glomerulonephritis.

Avoid concomitant use of isotretinoin with supplements containing vitamin A.

Isotretinoin is closely related to vitamin A. Therefore, concomitant use of isotretinoin with vitamin A may lead to isotretinoin-associated adverse reactions.

Avoid concomitant use of isotretinoin 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)].

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 isotretinoin with other oral contraceptives.

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 isotretinoin 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

Isotretinoin 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 isotretinoin is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin, immediately discontinue isotretinoin 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.

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

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 isotretinoin treatment.

Pregnancy Testing Prior to Prescribing Isotretinoin: In patients who can get pregnant, only prescribe

isotretinoin 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 isotretinoin 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 isotretinoin 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 isotretinoin prescription within 7 days of the pregnancy test collection) and has not started isotretinoin 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 isotretinoin. The confirmatory pregnancy test must be repeated, as needed, until the patient receives isotretinoin.

Pregnancy Testing During Treatment with Isotretinoin: In patients who can get pregnant who are being treated with isotretinoin, 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 isotretinoin 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 isotretinoin treatment.

Pregnancy Testing in Patients Who Have Completed Isotretinoin Treatment: In patients who can get pregnant who have completed isotretinoin 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 isotretinoin treatment, AND
• 1 month after the discontinuation of isotretinoin.

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 isotretinoin treatment, during isotretinoin treatment, and for 1 month after discontinuing isotretinoin treatment. However, 2 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 post-menopausal. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate form of contraception during isotretinoin 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 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 1 month before, during, or 1 month after treatment, the patient must:

• Stop taking isotretinoin 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 isotretinoin 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.

The safety and effectiveness of isotretinoin 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 isotretinoin in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use of isotretinoin capsules 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 isotretinoin 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 isotretinoin. Consider discontinuing isotretinoin 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 isotretinoin capsules 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)].

Clinical studies of isotretinoin 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 isotretinoin treatment.

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 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 isotretinoin 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 isotretinoin 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.

Isotretinoin Capsules, USP

Isotretinoin capsules, USP contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin, USP (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin USP, 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 – D&C yellow #10, FD&C yellow #6, FD&C red #40, FD&C blue #1 and titanium dioxide
• 20 mg – iron oxide (red), FD&C red #40, FD&C blue #1 and titanium dioxide
• 25 mg – FD&C Yellow #6, FD&C blue #1 and titanium dioxide
• 30 mg – D&C yellow #10, FD&C red #40, FD&C blue #1 and titanium dioxide
• 35 mg – FD&C Yellow #6, FD&C red #40, FD&C Blue #1 and titanium dioxide
• 40 mg – iron oxide (black, red and yellow), FD&C red #40, FD&C Blue #1 and titanium dioxide

The black imprinting ink of 10 mg and 20 mg capsules contains the following ingredients: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonia solution (strong ammonia solution), iron oxide (black), potassium hydroxide and purified water.

The white imprinting ink of 25 mg, 30 mg, 35 mg and 40 mg capsules contains the following ingredients: shellac, titanium dioxide, isopropyl alcohol, ammonia solution (ammonium hydroxide), propylene glycol, butyl alcohol (n-Butyl alcohol) and simethicone.

Isotretinoin, USP

Chemically, isotretinoin, USP 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:



Structural Formula (Isotretinoin Capsules Usp Absorica 1)

FDA approved dissolution test specifications differ from USP.

The exact mechanism of action of isotretinoin in the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics is unknown.

Isotretinoin 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.

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

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 Isotretinoin Administration

The isotretinoin 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 isotretinoin 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 isotretinoin dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, isotretinoin 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 isotretinoin 40 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.

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 isotretinoin dosage of 1 mg/kg/day, respectively, 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 isotretinoin 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 isotretinoin 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 isotretinoin dosage of 1 mg/kg/day 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 isotretinoin dosage of 1 mg/kg/day after normalization for total body surface area).

The effectiveness of isotretinoin for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older has been established and is based on a double-blind, randomized, parallel group trial (Study 1) in subjects with severe recalcitrant nodular acne who received isotretinoin capsules or another isotretinoin capsule product under fed conditions. A total of 925 subjects were randomized 1:1 to receive isotretinoin capsules or another isotretinoin capsule product. Study subjects ranged from 12 to 54 years of age (including 397 pediatric subjects 12 years of age and older); 60% were male, 40% were female; and the racial groups included 87% White, 4% Black, 6% Asian, and 3% Other. Enrolled subjects had a weight of 40 to 110 kg and had at least 10 nodular lesions on the face and/or trunk. Subjects were treated with an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks, followed by 1 mg/kg/day in two divided doses for the following 16 weeks.

Change from baseline to Week 20 in total nodular lesion count and proportion of subjects with at least a 90% reduction in total nodular lesion count from baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1. A single course of isotretinoin capsules and another isotretinoin capsule product treatment for 15 to 20 weeks has been shown to result in complete and prolonged remission of acne in many patients.

Figure 1: Total Nodular (Facial and Truncal) Lesion Count in Subjects with Severe Recalcitrant Nodular Acne by Visit in Study 1

Figure 1 (Isotretinoin Capsules Usp Absorica 2)

* Another isotretinoin capsule product.

Isotretinoin Capsules, USP

Isotretinoin capsules, USP (opaque) are supplied as follows:

• 10 mg: Hard gelatin capsule with gold opaque cap and gold opaque body printed “A1254” on cap and “10” on body with black ink. Box of 30 capsules (3 x 10 Prescription Packs): NDC 69238-1254-3
• 20 mg: Hard gelatin capsule with Swedish orange opaque cap and Swedish orange opaque body printed “A1255” on cap and “20” on body with black ink. Box of 30 capsules (3 x 10 Prescription Packs): NDC 69238-1255-3
• 25 mg: Hard gelatin capsule with green opaque cap and green opaque body printed “A1256” on cap and “25” on body with white ink. Box of 30 capsules (3 x 10 Prescription Packs): NDC 69238-1256-3
• 30 mg: Hard gelatin capsule with brown opaque cap and brown opaque body printed “A1257” on cap and “30” on body with white ink. Box of 30 capsules (3 x 10 Prescription Packs): NDC 69238-1257-3
• 35 mg: Hard gelatin capsule with dark blue opaque cap and dark blue opaque body printed “A1258” on cap and “35” on body with white ink. Box of 30 capsules (3 x 10 Prescription Packs): NDC 69238-1258-3
• 40 mg: Hard gelatin capsule with brown opaque cap and red opaque body printed “A1259” on cap and “40” on body with white ink. Box of 30 capsules (3 x 10 Prescription Packs): NDC 69238-1259-3

Storage and Handling of Isotretinoin Capsules, USP

Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°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 isotretinoin 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 isotretinoin treatment. Instruct patients to not donate blood during isotretinoin treatment and for 1 month following discontinuation to avoid blood donation to a pregnant patient.

iPLEDGE REMS

Isotretinoin 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 7-day prescription window (i.e., within the 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.

Isotretinoin 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 isotretinoin [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 isotretinoin, and for at least 8 days after the last dose of isotretinoin [see Use in Specific Populations (8.2)].

Psychiatric Disorders

Instruct patients and/or their caregivers/families that isotretinoin may cause depression, psychosis, suicidal ideation, suicide attempts, and aggressive or violent behavior. Instruct patients to stop isotretinoin and to contact a healthcare provider if they develop any of these signs or symptoms [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 isotretinoin use including concomitant use with tetracyclines. Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue isotretinoin immediately if they have symptoms of intracranial hypertension [see Warnings and 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 isotretinoin 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 isotretinoin 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 isotretinoin 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 isotretinoin 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 isotretinoin treatment and for at least 6 months thereafter due to the possibility of scarring.
• To avoid prolonged exposure to UV rays or sunlight.

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 11-2026-03

All other trademarks are property of their respective owners.