Label: AMNESTEEM- isotretinoin capsule

  • NDC Code(s): 0378-6611-85, 0378-6611-93, 0378-6612-85, 0378-6612-93, view more
    0378-6613-85, 0378-6613-93, 0378-6614-85, 0378-6614-93
  • Packager: Mylan Pharmaceuticals Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated July 15, 2026

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use AMNESTEEM® safely and effectively. See full prescribing information for AMNESTEEM®.
     
    AMNESTEEM® (Isotretinoin Capsules), for oral use
    Initial U.S. Approval: 1982

    WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY

    See full prescribing information for complete boxed warning.

    •
    Amnesteem 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 Amnesteem 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)
    •
    Amnesteem is available only through a restricted program called the iPLEDGE REMS. (5.2)

    INDICATIONS AND USAGE

    Amnesteem 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, Amnesteem 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 Amnesteem 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)

    DOSAGE AND ADMINISTRATION

    •
    Evaluations Prior to Prescribing and Use of Amnesteem:
    o
    In patients who can get pregnant, only prescribe Amnesteem after verification and documentation that they are not pregnant. See the Full Prescribing Information for the detailed requirements prior to prescribing Amnesteem (2.1, 8.3)
    o
    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)

    DOSAGE FORMS AND STRENGTHS

    Capsules: 10 mg, 20 mg, 30 mg and 40 mg (3)

    CONTRAINDICATIONS

    Amnesteem is contraindicated in:

    •
    Pregnancy (4, 8.1)
    •
    Patients with hypersensitivity to isotretinoin (or Vitamin A) or any of its components (4.2, 5.13)

    WARNINGS AND PRECAUTIONS

    •
    Psychiatric Disorders (depression, psychosis, suicidal thoughts and behavior, and aggressive and/or violent behaviors): Prior to and during treatment assess for these conditions; stop if these conditions occur on treatment (5.3)
    •
    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, rectal bleeding, 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)

    ADVERSE REACTIONS

    Most common adverse reactions are (incidence ≥ 5%): dry lips, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, increased creatine kinase, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, reduced visual acuity. (6)
     

    To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    Vitamin A: Avoid concomitant use (7.1)

    Tetracyclines: Avoid concomitant use (7.2)

    USE IN SPECIFIC POPULATIONS

    Lactation: Breastfeeding not recommended (8.2).

    In Patients Who Can Get Pregnant: Pregnancy testing is required prior to, during, and after Amnesteem treatment. See the Full Prescribing Information for the detailed pregnancy test and contraception requirements. (8.3).
     

    See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

    Revised: 7/2026

  • Table of Contents

    FULL PRESCRIBING INFORMATION: CONTENTS*

    WARNING: EMBRYO-FETAL TOXICITY - CONTRAINDICATED IN PREGNANCY

    1 INDICATIONS AND USAGE

    2 DOSAGE AND ADMINISTRATION

    2.1 Evaluations Prior to Prescribing and Use of Amnesteem

    2.2 Recommended Dosage

    2.3 Recommended Duration of Use

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Embryo-Fetal Toxicity

    5.2 iPLEDGE REMS

    5.3 Psychiatric Disorders

    5.4 Intracranial Hypertension (Pseudotumor Cerebri)

    5.5 Serious Skin Reactions

    5.6 Pancreatitis

    5.7 Lipid Abnormalities

    5.8 Hearing Impairment

    5.9 Hepatotoxicity

    5.10 Inflammatory Bowel Disease

    5.11 Musculoskeletal Abnormalities

    5.12 Ocular Abnormalities

    5.13 Hypersensitivity Reactions

    5.14 Laboratory Abnormalities and Laboratory Monitoring for Adverse Reactions

    6 ADVERSE REACTIONS

    7 DRUG INTERACTIONS

    7.1 Vitamin A

    7.2 Tetracyclines

    7.3 Oral Contraceptives

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.3 Females and Males of Reproductive Potential

    8.4 Pediatric Use

    8.5 Geriatric Use

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.2 Pharmacodynamics

    12.3 Pharmacokinetics

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    13.2 Animal Toxicology and/or Pharmacology

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
  • BOXED WARNING (What is this?)

    WARNING: EMBRYO-FETAL TOXICITY - CONTRAINDICATED IN PREGNANCY

    Amnesteem 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 Amnesteem 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 Amnesteem 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, Amnesteem 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)].

  • 1 INDICATIONS AND USAGE

    Amnesteem 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, Amnesteem 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 Amnesteem 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)].

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Evaluations Prior to Prescribing and Use of Amnesteem

    In patients who can get pregnant, only prescribe Amnesteem 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 Amnesteem, see Use in Specific Populations (8.3).

    Prior to Amnesteem use in all patients, complete the following laboratory testing:

    •
    A fasting lipid profile including triglycerides [see Warnings and Precautions (5.7, 5.14)].
    •
    Liver function tests [see Warnings and Precautions (5.9, 5.14)].

    2.2 Recommended Dosage

    The recommended dosage range for Amnesteem 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: Amnesteem: 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: Amnesteem: 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 Amnesteem in divided doses with food, as tolerated (see Table 3).

    Table 3: Amnesteem: 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 Amnesteem has not been established and is not recommended.

    If a dose of Amnesteem is missed, just skip that dose. Do not take two doses of Amnesteem at the same time.

    2.3 Recommended Duration of Use

    A course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue Amnesteem.

    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 Amnesteem in patients who have completed skeletal growth. The use of another course of Amnesteem 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 Amnesteem, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of Amnesteem on bone loss is unknown [see Warnings and Precautions (5.11)].

  • 3 DOSAGE FORMS AND STRENGTHS

    Amnesteem (Isotretinoin Capsules, USP) contains 10 mg, 20 mg, 30 mg or 40 mg of isotretinoin, USP.

    •
    The 10 mg capsules are reddish brown and imprinted with I10.
    •
    The 20 mg capsules are reddish brown and cream and imprinted with I20.
    •
    The 30 mg capsules are cream opaque and imprinted with I30.
    •
    The 40 mg capsules are orange-brown and imprinted with I40.
  • 4 CONTRAINDICATIONS

    Amnesteem 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)].
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Embryo-Fetal Toxicity

    Amnesteem is contraindicated in pregnancy [see Contraindications (4)]. Based on human data, Amnesteem 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 Amnesteem 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 Amnesteem treatment, immediately discontinue Amnesteem 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 Amnesteem 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 Amnesteem 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.

    Amnesteem is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2)].

    5.2 iPLEDGE REMS

    Because of the risk of embryo-fetal toxicity, Amnesteem 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:
    o
    Assess the reproductive status of all patients prior to initiating and during treatment.
    o
    Counsel patients who cannot get pregnant on the risk and REMS requirements prior to initiating treatment.
    o
    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.
    o
    Comply with the pregnancy testing requirements.
    o
    Assess the pregnancy status for patients who can get pregnant by reviewing pregnancy tests and documenting a negative result prior to each prescription.
    o
    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:
    o
    Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3)].
    o
    Demonstrate comprehension of the risk and REMS requirements before each prescription is dispensed.
    o
    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 Amnesteem and not donate blood.
    •
    Pharmacies that dispense Amnesteem must be certified in the REMS and must comply with the REMS requirements, including the following:
    o
    Obtain authorization to dispense and only dispense to patients who are authorized to receive Amnesteem.
    o
    Dispense a maximum of a 30-day supply with a Medication Guide.
    o
    Do not dispense refills.
    •
    Wholesalers and distributors must be registered in the REMS and must only distribute to certified pharmacies.

    Further information, including a list of qualified pharmacies and distributors, is available at www.ipledgeprogram.com or 1-866-495-0654.

    5.3 Psychiatric Disorders

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

    5.4 Intracranial Hypertension (Pseudotumor Cerebri)

    Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Avoid concomitant use of Amnesteem 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 Amnesteem and refer the patient to a neurologist for further diagnosis and care [see Adverse Reactions (6)].

    5.5 Serious Skin Reactions

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

    Monitor patients closely for severe skin reactions, discontinue Amnesteem if they occur.

    5.6 Pancreatitis

    Acute pancreatitis has been reported with isotretinoin use in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported.

    If symptoms of pancreatitis occur, discontinue Amnesteem and instruct patients to seek medical attention.

    5.7 Lipid Abnormalities

    Elevations of serum triglycerides above 800 mg/dL have been reported in patients treated with Amnesteem. 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 Amnesteem, respectively. These lipid changes were reversible upon Amnesteem cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing Amnesteem or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

    Perform fasting lipid tests before Amnesteem treatment and then at intervals until the lipid response to Amnesteem is known, which usually occurs within 4 weeks. Carefully consider the risk/benefit of Amnesteem 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 Amnesteem treatment is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.14)]. Discontinue Amnesteem if hypertriglyceridemia cannot be controlled.

    5.8 Hearing Impairment

    Impaired hearing has been reported in patients taking Amnesteem; 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 Amnesteem treatment in patients who experience tinnitus or hearing impairment and refer them for specialized care for further evaluation.

    5.9 Hepatotoxicity

    Clinical hepatitis has been reported with Amnesteem treatment. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with Amnesteem, some of which normalized with dosage reduction or continued administration of the drug.

    Discontinue Amnesteem if normalization does not readily occur or if hepatitis is suspected during treatment.

    5.10 Inflammatory Bowel Disease

    Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Amnesteem treatment has been stopped.

    Discontinue Amnesteem immediately if patients experience abdominal pain, rectal bleeding or severe diarrhea [see Adverse Reactions (6)].

    5.11 Musculoskeletal Abnormalities

    Osteoporosis and Fractures

    There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients treated with Amnesteem or following cessation. Therefore, healthcare providers should use caution when prescribing Amnesteem 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 Amnesteem 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 Amnesteem. Consider discontinuing Amnesteem 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 Amnesteem 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 Amnesteem (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 Amnesteem 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 Amnesteem 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 Amnesteem. The effect of multiple courses of Amnesteem on epiphyseal closure is unknown.

    5.12 Ocular Abnormalities

    Carefully monitor for visual problems. If visual difficulties occur, discontinue Amnesteem treatment and obtain an ophthalmological examination [see Adverse Reactions (6)].

    Corneal Opacities

    Corneal opacities have occurred in patients receiving Amnesteem 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 Amnesteem 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 Amnesteem 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 have been reported in patients during isotretinoin use. Patients who wear contact lenses may have trouble wearing them while on Amnesteem treatment and afterwards.

    5.13 Hypersensitivity Reactions

    Anaphylactic reactions and other allergic reactions have been reported with isotretinoin use. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura of the extremities and extracutaneous involvement (including renal) have been reported.

    If a severe allergic reaction occurs, discontinue Amnesteem treatment and initiate appropriate medical management.

    5.14 Laboratory Abnormalities and Laboratory Monitoring for Adverse Reactions

    Laboratory Monitoring

    Pregnancy Testing

    Obtain a screening and confirmatory pregnancy test prior to treatment initiation. Repeat a pregnancy test prior to each prescription, at the end of the entire course of Amnesteem treatment and 1 month after the discontinuation of Amnesteem [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 Amnesteem is known. The incidence of hypertriglyceridemia is 25% in patients treated with Amnesteem [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 Amnesteem, perform pretreatment and follow-up liver function tests periodically until the response to Amnesteem is known [see Warnings and Precautions (5.9)].

    Additional Laboratory Abnormalities

    Glucose

    With Amnesteem use, some patients have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Amnesteem treatment.

    CPK

    Some patients undergoing vigorous physical activity while taking Amnesteem 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.

  • 6 ADVERSE REACTIONS

    The following adverse reactions with Amnesteem 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 Amnesteem 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 Amnesteem treatment but recurred with reinstitution of Amnesteem 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.

  • 7 DRUG INTERACTIONS

    7.1 Vitamin A

    Avoid concomitant use of Amnesteem with supplements containing vitamin A.

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

    7.2 Tetracyclines

    Avoid concomitant use of Amnesteem with tetracyclines.

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

    7.3 Oral Contraceptives

    It is not known if there is an interaction between Amnesteem with oral contraceptives that do not contain norethindrone and ethinyl estradiol.

    Amnesteem did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology (12.3)].

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Exposure Registry

    There is a pregnancy exposure registry that documents pregnancies in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after Amnesteem 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

    Amnesteem 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 Amnesteem is used during pregnancy, or if the patient becomes pregnant while taking Amnesteem, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking Amnesteem, immediately discontinue Amnesteem 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 Amnesteem exposure include malformations of the face, eyes, ears, skull, central nervous system (CNS), cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases, death has occurred as a result of the malformations.

    Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.

    8.2 Lactation

    Risk Summary

    There are no data on the presence of isotretinoin in either animal or human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with Amnesteem, and for at least 8 days after the last dose of Amnesteem.

    8.3 Females and Males of Reproductive Potential

    All patients who can become pregnant must comply with the iPLEDGE REMS requirements [see Warnings and Precautions (5.2)].

    Pregnancy Testing

    In patients who can get pregnant, pregnancy testing is required prior to, during, and after Amnesteem treatment.

    Pregnancy Testing Prior to Prescribing Amnesteem

    In patients who can get pregnant, only prescribe Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem prescription starting from the day of the pregnancy test through six days after the day of the pregnancy test) and have not started Amnesteem 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 Amnesteem. The confirmatory pregnancy test must be repeated, as needed, until the patient receives Amnesteem.

    Pregnancy Testing During Treatment with Amnesteem

    In patients who can get pregnant who are being treated with Amnesteem, 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 Amnesteem 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 prescribing additional Amnesteem treatment.

    Pregnancy Testing in Patients Who Have Completed Amnesteem Treatment

    In patients who can get pregnant who have completed Amnesteem 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 Amnesteem treatment, AND
    •
    One month after the discontinuation of Amnesteem.

    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 Amnesteem treatment, during Amnesteem treatment, and for one month after discontinuing Amnesteem 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 post-menopausal. Micro-dosed progesterone preparations ("minipills" that do not contain an estrogen) are an inadequate form of contraception during Amnesteem 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 Amnesteem. 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 Amnesteem 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 Amnesteem 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 Amnesteem treatment for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

    8.4 Pediatric Use

    The safety and effectiveness of Amnesteem 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 Amnesteem 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 Amnesteem, 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 Amnesteem in pediatric patients less than 12 years of age have not been established.

    Adverse Reactions in Pediatric Patients

    In trials with Amnesteem, 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 Amnesteem, 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 Amnesteem. Consider discontinuing Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem. The effect of multiple courses of Amnesteem on epiphyseal closure is unknown [see Warnings and Precautions (5.11)].

    8.5 Geriatric Use

    Clinical studies of Amnesteem 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 Amnesteem treatment.

  • 10 OVERDOSAGE

    Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia.

    Evaluate patients who can become pregnant who present with an isotretinoin overdosage for pregnancy. Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, instruct male patients treated with Amnesteem 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 Amnesteem 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.

  • 11 DESCRIPTION

    Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. Isotretinoin has high lipophilicity. The structural formula is:

    Isotretinoin Structural Formula

    Amnesteem 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 10 mg, 20 mg, 30 mg and 40 mg soft gelatin capsule contains the following inactive ingredients: butylhydroxyanisole, gelatin, glycerol, hydrogenated partially vegetable oil, medium chain triglycerides, sodium edetate, soy lecithin, soybean oil and yellow beeswax. The 10 mg, 20 mg, and 40 mg capsules also contain red iron oxide in glycerin, and the 20 mg, 30 mg and 40 mg capsules also contain titanium dioxide in glycerin and yellow iron oxide in glycerin.

    The black imprinting ink contains ammonium hydroxide, black iron oxide, polyethylene glycol, propylene glycol and polyvinyl acetate phthalate.

    Meets USP Dissolution Test 4.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

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

    12.2 Pharmacodynamics

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

    12.3 Pharmacokinetics

    The following parameters are presented as mean [coefficient of variation (CV%)] following a single oral dose of 80 mg of Amnesteem 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 Amnesteem 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-oxo-retinoic 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 Amnesteem. 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 Amnesteem (dosage of 1 mg/kg/day) with an oral contraceptive agent 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 in these patients.
    •
    Phenytoin: There were no clinically significant differences in the pharmacokinetics of phenytoin when used concomitantly with isotretinoin.
  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    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 Amnesteem 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 Amnesteem 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 Amnesteem 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.

    13.2 Animal Toxicology and/or Pharmacology

    In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 or 5.3 times the recommended clinical Amnesteem 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 Amnesteem dosage of 1 mg/kg/day, after normalization for total body surface area).

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Amnesteem (Isotretinoin Capsules, USP) contains 10 mg, 20 mg, 30 mg or 40 mg of isotretinoin, USP.

    The 10 mg capsules are reddish brown and imprinted with I10. They are available as follows:

    NDC 0378-6611-93
    cartons of 30 containing 3 prescription packs of 10 capsules

    The 20 mg capsules are reddish brown and cream and imprinted with I20. They are available as follows:

    NDC 0378-6612-93
    cartons of 30 containing 3 prescription packs of 10 capsules

    The 30 mg capsules are cream opaque and imprinted with I30. They are available as follows:

    NDC 0378-6613-93
    cartons of 30 containing 3 prescription packs of 10 capsules

    The 40 mg capsules are orange-brown and imprinted with I40. They are available as follows:

    NDC 0378-6614-93
    cartons of 30 containing 3 prescription packs of 10 capsules

    Store at 68° to 77°F (20° to 25°C). [See USP Controlled Room Temperature.]
    Protect from light.

    PHARMACIST: Dispense a Medication Guide with each prescription.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Embryo-Fetal Toxicity
    There is an extremely high risk of life-threatening birth defects when Amnesteem 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 Amnesteem treatment. Instruct patients to not donate blood during Amnesteem treatment and for 1 month following discontinuation to avoid blood donation to a pregnant patient.

    iPLEDGE REMS
    Amnesteem 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:
    o
    Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3)]
    o
    Demonstrate comprehension of the risk and REMS requirements prior to each prescription
    o
    Obtain the prescription within the 7-day prescription window (i.e., within 7 days of the pregnancy test collection)
    o
    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.

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

    Psychiatric Disorders
    Instruct patients and/or their caregivers/families that Amnesteem may cause depression, psychosis, suicidal ideation, suicide attempts, and aggressive or violent behavior. Instruct patients to stop Amnesteem 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 Amnesteem product with food [see Dosage and Administration (2.1)].

    Intracranial Hypertension (Pseudotumor Cerebri)
    Advise patients that intracranial hypertension (pseudotumor cerebri) has occurred with Amnesteem use including concomitant use with tetracyclines. Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem, 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 Amnesteem, instruct the patient to discontinue Amnesteem 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 Amnesteem [see Warnings and Precautions (5.7)].

    Additional Instructions
    Inform patients:

    •
    To not share Amnesteem 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 Amnesteem treatment and for at least 6 months thereafter due to the possibility of scarring.
    •
    To avoid prolonged exposure to UV rays or sunlight.
  • Medication Guide

    Amnesteem® [am-nes-team]

    (Isotretinoin Capsules, USP)

    for oral use

    Read the Medication Guide that comes with Amnesteem before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your health care provider about your medical condition or your treatment.

    What is the most important information I should know about Amnesteem?

    •
    Amnesteem can harm your unborn baby, including birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. Patients who are pregnant or who plan to become pregnant must not take Amnesteem.
    o
    Because of the risk of birth defects, Amnesteem is only available through a special program called the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS).
    o
    Your healthcare provider must be enrolled in the iPLEDGE REMS for you to be prescribed Amnesteem.
    o
    Before you start treatment with Amnesteem, you must enroll in the iPLEDGE REMS.
    o
    You must understand and agree to do everything required in the iPLEDGE REMS.
     
    Patients must not get pregnant:
    o
    for 1 month before starting Amnesteem
    o
    during treatment with Amnesteem
    o
    for 1 month after stopping Amnesteem
     
    If you get pregnant during treatment with Amnesteem, stop taking it right away and tell your health care provider. Health care providers and patients should report all cases of pregnancy that happen during treatment or 1 month after stopping treatment to:
    o
    FDA MedWatch at 1-800-FDA-1088, and
    o
    the iPLEDGE Pregnancy Registry at 1-866-495-0654 or www.ipledgeprogram.com
     
    If you have any questions about the iPLEDGE REMS, ask your healthcare provider, or go to www.ipledgeprogram.com or call 1-866-495-0654.
    •
    Serious mental health problems, including:
    o
    depression
    o
    psychosis (seeing or hearing things that are not real)
    o
    suicide. Some patients taking Amnesteem have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. Some people have ended their own lives.
     
    Stop taking Amnesteem and tell your health care provider right away if you or a family member notices that you get any of the following signs and symptoms of depression or psychosis:
    o
    start to feel sad or have crying spells
    o
    lose interest in activities you once enjoyed
    o
    sleep too much or have trouble sleeping
    o
    become more irritable, angry, or aggressive
    than usual (for example, temper outbursts,
    thoughts of violence)
    o
    have a change in your appetite or body
    weight
    o
    suicide attempts
    o
    have trouble concentrating
    o
    withdraw from your friends or family
    o
    feel like you have no energy
    o
    have feelings of worthlessness or guilt
    o
    start having thoughts about hurting
    yourself or taking your own life
    (suicidal thoughts)
    o
    start acting on dangerous impulses
    o
    start seeing or hearing things that are not
    real
     
    Your health care provider may tell you to see a mental health care professional if you have any of these symptoms.

     

    See “What are the possible side effects of Amnesteem?” for more information about side effects.

    What is Amnesteem?

    Amnesteem is a prescription medicine used in patients 12 years of age and older, who are not pregnant, for the treatment of severe acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Amnesteem can cause serious side effects (see “What is the most important information I should know about Amnesteem?”).

     

    Amnesteem can only be:

    •
    prescribed by health care providers that are enrolled in the iPLEDGE REMS
    •
    dispensed by a pharmacy that is enrolled in the iPLEDGE REMS
    •
    given to patients who are enrolled in the iPLEDGE REMS and agree to do everything required in the program.

    It is not known if Amnesteem is safe and effective in children less than 12 years of age.

    Do not take Amnesteem if you:

    •
    are pregnant, plan to become pregnant, or become pregnant during Amnesteem treatment. Amnesteem can cause life-threatening birth defects. See “What is the most important information I should know about Amnesteem?”
    •
    are allergic to isotretinoin, vitamin A, or any of the ingredients in Amnesteem. See the end of this Medication Guide for a complete list of ingredients in Amnesteem.

    Before taking Amnesteem, tell your health care provider if you or a family member has any of the following health conditions:

    •
    mental health problems
    •
    asthma
    •
    liver problems
    •
    diabetes
    •
    heart disease
    •
    increase blood fat levels (cholesterol and triglycerides)
    •
    bone loss (osteoporosis), weak bones or any other bone problems
    •
    an eating problem called anorexia nervosa (where people eat too little)
    •
    bowel or digestion problems

    Tell your health care provider if you are pregnant or breastfeeding. Do not breastfeed during treatment or for at least 8 days after the last dose of Amnesteem.

     

    Tell your health care provider about all of the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements. Amnesteem and certain other medicines can affect each other, sometimes causing serious side effects.

     

    Do not take the following medicines during treatment with Amnesteem:

    •
    vitamin A supplements
    •
    tetracycline antibiotics

    Know the medicines you take. Keep a list of them to show to your health care provider and pharmacist. Do not take any new medicine without talking with your healthcare provider.

    You will not be prescribed Amnesteem if you cannot agree to or follow all the instructions of the iPLEDGE REMS.

    •
    You will get no more than a 30-day supply of Amnesteem at a time. This is to make sure you are following the Amnesteem iPLEDGE REMS.

    How should I take Amnesteem?

    You must take Amnesteem exactly as prescribed. You must also follow all the instructions of the iPLEDGE REMS. Before prescribing Amnesteem, your health care provider will:

    o
    explain the iPLEDGE REMS to you
    o
    have you sign the Patient Informed Consent form (for all patients). Patients who can get pregnant must also sign another consent form.
    o
    get pregnancy tests to make sure you are not pregnant before you start Amnesteem. You will take 2 pregnancy tests at least 30 days apart before starting treatment.
    •
    The amount of Amnesteem you take has been specially chosen for you. It is based on your body weight and may change during treatment.
    •
    Take Amnesteem two times a day with food. Swallow Amnesteem whole with a full glass of liquid. Do not split, crush, chew, or suck on the capsules. Amnesteem can hurt the tube that connects your mouth to your stomach (esophagus) if not swallowed whole.
    •
    Your health care provider will tell you how long you will receive treatment with Amnesteem.
    •
    If you miss a dose, just skip that dose. Do not take two doses at the same time.
    •
    If you take too much Amnesteem, call your health care provider or Poison Help line at 1-800-222-1222 right away.
    •
    Your acne may get worse when you first start taking Amnesteem. This should last only a short while. Talk with your health care provider if this is a concern for you. Your acne may continue to improve after treatment.
    •
    You must return to your health care provider as directed to make sure you don’t have signs of serious side effects. Your health care provider may do blood tests to check for serious side effects from Amnesteem and may stop treatment if you get certain side effects.
    •
    Patients who can get pregnant will get a pregnancy test before each prescription is given during treatment with Amnesteem, when you stop treatment, and 1 month after you stop treatment.
    •
    You must get your prescription within seven days of receiving your pregnancy test.
    •
    Patients who can get pregnant must:
    o
    Talk about birth control options with your health care provider or go for a free visit to talk about birth control with another health care provider or family planning expert. Your health care provider can arrange this free visit, which will be paid for by the company that makes Amnesteem.
    o
    Use your chosen pregnancy prevention methods. You must choose two separate forms of birth control at the same time or commit to not having sexual contact with a partner that could result in pregnancy for at least 1 month before treatment, during treatment, and for 1 month after treatment with Amnesteem.
    o
    Access the iPLEDGE REMS system to answer questions about the REMS requirements and enter your two chosen pregnancy prevention methods (two separate forms of birth control or commitment to not having sexual contact with a partner that could result in pregnancy). To access the iPLEDGE REMS system, go to www.ipledgeprogram.com or call 1-866-495-0654.
     
    If you have sex at any time without using two forms of birth control 1 month before, during, or 1 month after treatment, get pregnant, or miss your expected period, stop taking Amnesteem and call your health care provider right away.

    What should I avoid while taking Amnesteem?

    •
    Do not give blood during treatment with Amnesteem and for 1 month after stopping Amnesteem. If someone who is pregnant gets your donated blood, Amnesteem may cause miscarriage, premature birth, birth defects, or death of the baby.
    •
    Do not take other medicines or herbal products during treatment with Amnesteem unless you talk to your health care provider. See “Before taking Amnesteem”.
    •
    Do not drive at night until you know if Amnesteem has affected your vision. Amnesteem may decrease your ability to see in the dark.
    •
    Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, during treatment with Amnesteem and for at least 6 months after you stop. Amnesteem can increase your chance of scarring from these procedures. Check with your health care provider for advice about when you can have cosmetic procedures.
    •
    Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Amnesteem may make your skin more sensitive to light.
    •
    Do not share Amnesteem with other people. Amnesteem can cause life-threatening birth defects and other serious health problems.

    What are the possible side effects of Amnesteem?

    Amnesteem can cause serious side effects, including:

    •
    See “What is the most important information I should know about Amnesteem?”
    •
    increased pressure in the brain (intracranial hypertension). Amnesteem can increase the pressure in your brain. This can lead to permanent loss of eyesight, and in rare cases, death. Stop taking Amnesteem and tell your health care provider right away if you get any of these signs of increased brain pressure:
    o
    bad headache
    o
    blurred vision or other visual problems
    o
    dizziness
    o
    nausea or vomiting
    o
    seizures (convulsions)
    o
    stroke
    •
    serious skin problems. Skin rash can happen in patients taking Amnesteem. Sometimes rash can be severe and may be life-threatening and lead to hospitalization or death. Stop taking Amnesteem and tell your health care provider right away if you get:
    o
    conjunctivitis (red or inflamed eyes, like “pink eye”)
    o
    rash with a fever
    o
    blisters on legs, arms or face
    o
    sores in your mouth, throat, nose or
    eyes
    o
    peeling of your skin
    •
    inflammation of your pancreas (pancreatitis) can happen in patients who take Amnesteem and can lead to death. Stop taking Amnesteem and tell your health care provider right away if you get any of the following symptoms of pancreatitis:
    o
    severe upper stomach (abdomen) pain
    o
    swelling of your stomach
    o
    nausea and vomiting
    o
    fever
    •
    increased blood fat (lipid) levels. Amnesteem can raise blood fat levels (cholesterol and triglycerides). Your health care provider will do blood tests to check your lipids before and during treatment. These problems usually go away when Amnesteem treatment is finished.
    •
    hearing problems. Stop taking Amnesteem and tell your health care provider if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent.
    •
    liver problems, including hepatitis. Your health care provider will do tests to check your liver before and during treatment with Amnesteem. Tell your health care provider right away if you get:
    o
    yellowing of your skin or the whites
    of your eyes
    o
    pain on the right side of your stomach
    area (abdomen)
    o
    dark urine
    o
    bleeding or bruising more easily
    than normal
    •
    inflammation of your digestive tract (inflammatory bowel disease). Stop taking Amnesteem right away and tell your health care provider right away if you get:
    o
    severe stomach, chest or bowel pain
    o
    nausea or vomiting
    o
    trouble swallowing or painful swallowing
    o
    new or worsening heartburn
    o
    diarrhea
    o
    rectal bleeding
    •
    bone and muscle problems including bone pain, softening or thinning of bones (which may lead to fractures). Amnesteem may stop long bone growth in teenagers who are still growing. Teenagers who participate in sports with hard physical activity and repeated actions during treatment with Amnesteem may have a higher risk of bone fractures or injuries.. Tell your health care provider if you get:
    o
    bone pain
    o
    back pain
    o
    broken bone (fracture).
    o
    muscle problems. Stop taking Amnesteem and tell your health care provider right away if you have muscle or joint pain or weakness. Muscle weakness with or without pain can be a sign of serious muscle damage.
    •
    vision problems. Stop taking Amnesteem and tell your health care provider right away if you have any vision changes. Amnesteem may affect your ability to see in the dark. This usually goes away after you stop taking Amnesteem, but it may be permanent. Some patients get dry eyes during treatment. If you wear contact lenses, you may have trouble wearing them during and after you stop treatment with Amnesteem.
    •
    serious allergic reactions. Stop taking Amnesteem and get emergency medical help right away if you get hives, a swollen face or mouth, or have trouble breathing. Stop taking Amnesteem and tell your health care provider if you get a fever, rash, or red patches or bruises on your legs.
    •
    blood sugar problems, including diabetes. Tell your health care provider if you are very thirsty or urinate more than usual.

    The most common side effects of Amnesteem include:

    •
    dry lips
    •
    dry skin
    •
    back pain
    •
    dry eyes
    •
    joint pain
    •
    nose bleeds
    •
    headache
    •
    upper respiratory tract infection (common cold)
    •
    chapped lips or swelling of the lips
    •
    skin reactions
    •
    muscle problems
    •
    eye problems, including decreased vision

    These are not all of the possible side effects of Amnesteem.

     

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

    How should I store Amnesteem?

    •
    Store Amnesteem at room temperature, 68° to 77°F (20° to 25°C). Protect from light.

    Keep Amnesteem and all medicines out of the reach of children.

    General information about the safe and effective use of Amnesteem

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Amnesteem for a condition for which it was not prescribed. Do not give Amnesteem to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or health care provider for information about Amnesteem that is written for health professionals.

     

    You can also call iPLEDGE REMS at 1-866-495-0654 or visit www.ipledgeprogram.com.

    What are the ingredients in Amnesteem?

    Active ingredient: isotretinoin

    Inactive ingredients: butylhydroxyanisole, gelatin, glycerol, hydrogenated partially vegetable oil, medium chain triglycerides, sodium edetate, soy lecithin, soybean oil and yellow beeswax. The 10 mg, 20 mg and 40 mg capsules also contain red iron oxide in glycerin, and the 20 mg, 30 mg and 40 mg capsules also contain titanium dioxide in glycerin and yellow iron oxide in glycerin. The black imprinting ink contains ammonium hydroxide, black iron oxide, polyethylene glycol, propylene glycol and polyvinyl acetate phthalate.

     

    Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

    Manufactured by: Catalent Pharma Solutions, 67930 Beinheim France

     

    AMNESTEEM is a registered trademark of Mylan Bertek Pharmaceuticals, Inc., a Viatris Company.

     

    © 2026 Viatris Inc.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Manufactured by:
    Catalent Pharma Solutions
    74 rue Principale
    67930 Beinheim
    France

    Revised: 7/2026
    CAT:ISOTFR:R10

  • PRINCIPAL DISPLAY PANEL – 10 mg

    NDC 0378-6611-93

    Amnesteem®
    (Isotretinoin
    Capsules, USP)

    10 mg

    Each capsule contains 10 mg isotretinoin

    WARNING TO
    PATIENTS:
    AVOID PREGNANCY

    Rx only

    3 x 10-Count Prescription Packs

    Special Instructions to Pharmacists:

    •
    Only fill Amnesteem after authorization from the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting www.ipledgeprogram.com.
    •
    Dispense no more than a 30-day supply.
    •
    An Amnesteem Medication Guide is included in each Prescription Pack.
    •
    Dispense Prescription Packs intact.
    •
    Do not remove Prescription Packs from carton until dispensed.

    Reminders for Pharmacists:

    •
    Dispense isotretinoin only for registered
    patients after obtaining authorization from
    the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting
    www.ipledgeprogram.com.
    •
    Document the Risk Management
    Authorization number.
    •
    Dispense no more than a 30-day supply.
    No refills.
    •
    Dispense Prescription Packs intact.
    •
    Do not dispense after the “Do not
    dispense to Patient After” date for
    patients who can become pregnant.
    •
    A Medication Guide is included in each
    Prescription Pack.

    Contraindicated in Pregnancy.

    Each capsule contains 10 mg
    isotretinoin.

    Usual Dosage: For dosage
    recommendations and other
    important prescribing information,
    read accompanying insert.

    Store at 68° to 77°F (20° to 25°C).
    [See USP Controlled Room
    Temperature.]

    Protect from light.

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in France

    AMNESTEEM is a registered trademark of Mylan Bertek
    Pharmaceuticals, Inc., a Viatris Company.

    © 2026 Viatris Inc.

    Mylan.com

    MCAT:6611:93:30C:R5

    Amnesteem® (Isotretinoin Capsules, USP) 10 mg Carton Label
  • PRINCIPAL DISPLAY PANEL – 20 mg

    NDC 0378-6612-93

    Amnesteem®
    (Isotretinoin
    Capsules, USP)

    20 mg

    Each capsule contains 20 mg isotretinoin

    WARNING TO
    PATIENTS:
    AVOID PREGNANCY

    Rx only

    3 x 10-Count Prescription Packs

    Special Instructions to Pharmacists:

    •
    Only fill Amnesteem after authorization from the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting www.ipledgeprogram.com.
    •
    Dispense no more than a 30-day supply.
    •
    An Amnesteem Medication Guide is included in each Prescription Pack.
    •
    Dispense Prescription Packs intact.
    •
    Do not remove Prescription Packs from carton until dispensed.

    Reminders for Pharmacists:

    •
    Dispense isotretinoin only for registered
    patients after obtaining authorization from
    the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting
    www.ipledgeprogram.com.
    •
    Document the Risk Management
    Authorization number.
    •
    Dispense no more than a 30-day supply.
    No refills.
    •
    Dispense Prescription Packs intact.
    •
    Do not dispense after the “Do not
    dispense to Patient After” date for
    patients who can become pregnant.
    •
    A Medication Guide is included in each
    Prescription Pack.

    Contraindicated in Pregnancy.

    Each capsule contains 20 mg
    isotretinoin.

    Usual Dosage: For dosage
    recommendations and other
    important prescribing information,
    read accompanying insert.

    Store at 68° to 77°F (20° to 25°C).
    [See USP Controlled Room
    Temperature.]

    Protect from light.

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in France

    AMNESTEEM is a registered trademark of Mylan Bertek
    Pharmaceuticals, Inc., a Viatris Company.

    © 2026 Viatris Inc.

    Mylan.com

    MCAT:6612:93:30C:R5

    Amnesteem® (Isotretinoin Capsules, USP) 20 mg Carton Label
  • PRINCIPAL DISPLAY PANEL – 30 mg

    NDC 0378-6613-93

    Amnesteem®
    (Isotretinoin
    Capsules, USP)

    30 mg

    Each capsule contains 30 mg isotretinoin

    WARNING TO
    PATIENTS:
    AVOID PREGNANCY

    Rx only

    3 x 10-Count Prescription Packs

    Special Instructions to Pharmacists:

    •
    Only fill Amnesteem after authorization from the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting www.ipledgeprogram.com.
    •
    Dispense no more than a 30-day supply.
    •
    An Amnesteem Medication Guide is included in each Prescription Pack.
    •
    Dispense Prescription Packs intact.
    •
    Do not remove Prescription Packs from carton until dispensed.

    Reminders for Pharmacists:

    •
    Dispense isotretinoin only for registered
    patients after obtaining authorization from
    the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting
    www.ipledgeprogram.com.
    •
    Document the Risk Management
    Authorization number.
    •
    Dispense no more than a 30-day supply.
    No refills.
    •
    Dispense Prescription Packs intact.
    •
    Do not dispense after the “Do not
    dispense to Patient After” date for
    patients who can become pregnant.
    •
    A Medication Guide is included in each
    Prescription Pack.

    Contraindicated in Pregnancy.

    Each capsule contains 30 mg
    isotretinoin.

    Usual Dosage: For dosage
    recommendations and other
    important prescribing information,
    read accompanying insert.

    Store at 68° to 77°F (20° to 25°C).
    [See USP Controlled Room
    Temperature.]

    Protect from light.

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in France

    AMNESTEEM is a registered trademark of Mylan Bertek
    Pharmaceuticals, Inc., a Viatris Company.

    © 2026 Viatris Inc.

    Mylan.com

    MCAT:6613:93:30C:R2

    Amnesteem® (Isotretinoin Capsules, USP) 30 mg Carton Label
  • PRINCIPAL DISPLAY PANEL – 40 mg

    NDC 0378-6614-93

    Amnesteem®
    (Isotretinoin
    Capsules, USP)

    40 mg

    Each capsule contains 40 mg isotretinoin

    WARNING TO
    PATIENTS:
    AVOID PREGNANCY

    Rx only

    3 x 10-Count Prescription Packs

    Special Instructions to Pharmacists:

    •
    Only fill Amnesteem after authorization from the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting www.ipledgeprogram.com.
    •
    Dispense no more than a 30-day supply.
    •
    An Amnesteem Medication Guide is included in each Prescription Pack.
    •
    Dispense Prescription Packs intact.
    •
    Do not remove Prescription Packs from carton until dispensed.

    Reminders for Pharmacists:

    •
    Dispense isotretinoin only for registered
    patients after obtaining authorization from
    the iPLEDGE REMS program by calling
    1-866-495-0654 or visiting
    www.ipledgeprogram.com.
    •
    Document the Risk Management
    Authorization number.
    •
    Dispense no more than a 30-day supply.
    No refills.
    •
    Dispense Prescription Packs intact.
    •
    Do not dispense after the “Do not
    dispense to Patient After” date for
    patients who can become pregnant.
    •
    A Medication Guide is included in each
    Prescription Pack.

    Contraindicated in Pregnancy.

    Each capsule contains 40 mg
    isotretinoin.

    Usual Dosage: For dosage
    recommendations and other
    important prescribing information,
    read accompanying insert.

    Store at 68° to 77°F (20° to 25°C).
    [See USP Controlled Room
    Temperature.]

    Protect from light.

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in France

    AMNESTEEM is a registered trademark of Mylan Bertek
    Pharmaceuticals, Inc., a Viatris Company.

    © 2026 Viatris Inc.

    Mylan.com

    MCAT:6614:93:30C:R5

    Amnesteem® (Isotretinoin Capsules, USP) 40 mg Carton Label
  • INGREDIENTS AND APPEARANCE
    AMNESTEEM 
    isotretinoin capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0378-6611
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ISOTRETINOIN (UNII: EH28UP18IF) (ISOTRETINOIN - UNII:EH28UP18IF) ISOTRETINOIN10 mg
    Inactive Ingredients
    Ingredient NameStrength
    AMMONIA (UNII: 5138Q19F1X)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    EDETATE SODIUM (UNII: MP1J8420LU)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    CORN OIL (UNII: 8470G57WFM)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    POLYVINYL ACETATE PHTHALATE (UNII: 58QVG85GW3)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    SOYBEAN OIL (UNII: 241ATL177A)  
    YELLOW WAX (UNII: 2ZA36H0S2V)  
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    LECITHIN, SOYBEAN (UNII: 1DI56QDM62)  
    Product Characteristics
    ColorRED (reddish brown) Scoreno score
    ShapeCAPSULESize9mm
    FlavorImprint Code I10
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0378-6611-933 in 1 CARTON11/11/2002
    1NDC:0378-6611-8510 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07594511/11/2002
    AMNESTEEM 
    isotretinoin capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0378-6612
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ISOTRETINOIN (UNII: EH28UP18IF) (ISOTRETINOIN - UNII:EH28UP18IF) ISOTRETINOIN20 mg
    Inactive Ingredients
    Ingredient NameStrength
    AMMONIA (UNII: 5138Q19F1X)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    EDETATE SODIUM (UNII: MP1J8420LU)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    CORN OIL (UNII: 8470G57WFM)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    POLYVINYL ACETATE PHTHALATE (UNII: 58QVG85GW3)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    SOYBEAN OIL (UNII: 241ATL177A)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    YELLOW WAX (UNII: 2ZA36H0S2V)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    LECITHIN, SOYBEAN (UNII: 1DI56QDM62)  
    Product Characteristics
    ColorRED (reddish brown) , WHITE (cream) Scoreno score
    ShapeCAPSULESize13mm
    FlavorImprint Code I20
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0378-6612-933 in 1 CARTON11/11/2002
    1NDC:0378-6612-8510 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07594511/11/2002
    AMNESTEEM 
    isotretinoin capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0378-6613
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ISOTRETINOIN (UNII: EH28UP18IF) (ISOTRETINOIN - UNII:EH28UP18IF) ISOTRETINOIN30 mg
    Inactive Ingredients
    Ingredient NameStrength
    AMMONIA (UNII: 5138Q19F1X)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    EDETATE SODIUM (UNII: MP1J8420LU)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    CORN OIL (UNII: 8470G57WFM)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    POLYVINYL ACETATE PHTHALATE (UNII: 58QVG85GW3)  
    SOYBEAN OIL (UNII: 241ATL177A)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    YELLOW WAX (UNII: 2ZA36H0S2V)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    LECITHIN, SOYBEAN (UNII: 1DI56QDM62)  
    Product Characteristics
    ColorWHITE (cream opaque) Scoreno score
    ShapeCAPSULESize13mm
    FlavorImprint Code I30
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0378-6613-933 in 1 CARTON04/10/2025
    1NDC:0378-6613-8510 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07594504/10/2025
    AMNESTEEM 
    isotretinoin capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0378-6614
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ISOTRETINOIN (UNII: EH28UP18IF) (ISOTRETINOIN - UNII:EH28UP18IF) ISOTRETINOIN40 mg
    Inactive Ingredients
    Ingredient NameStrength
    AMMONIA (UNII: 5138Q19F1X)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    EDETATE SODIUM (UNII: MP1J8420LU)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    CORN OIL (UNII: 8470G57WFM)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    POLYVINYL ACETATE PHTHALATE (UNII: 58QVG85GW3)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    SOYBEAN OIL (UNII: 241ATL177A)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    YELLOW WAX (UNII: 2ZA36H0S2V)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    LECITHIN, SOYBEAN (UNII: 1DI56QDM62)  
    Product Characteristics
    ColorORANGE (orange brown) Scoreno score
    ShapeCAPSULESize13mm
    FlavorImprint Code I40
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0378-6614-933 in 1 CARTON11/11/2002
    1NDC:0378-6614-8510 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07594511/11/2002
    Labeler - Mylan Pharmaceuticals Inc. (059295980)
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