Isotretinoin 35 mg Capsule, 30-count — NDC 59651-635-03 (Billing 59651-0635-03)
This is a package of 30 capsules of Isotretinoin 35 mg Capsule from Aurobindo Pharma Limited, marketed since Jan 2024 and currently FDA-listed. It is this product's only package size.
Other active recalls for Isotretinoin (different manufacturers) — 5 · tap to view
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 072731
- GCN: 37017
- HICL (First Databank): 002476
- AHFS class code: 84:28.00.00
- RxCUI (RxNorm): 197843
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Retinoid class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Isotretinoin is used to treat severe recalcitrant nodular acne (a certain type of severe acne) that has not been helped by other treatments, such as antibiotics. Isotretinoin is in a class of medications called retinoids. It works by slowing the production of certain natural substances that can cause acne.
Read the full MedlinePlus article ↗- Isotretinoin causes extremely serious birth defects — even one dose during pregnancy can cause devastating harm to a developing baby. Because of that risk, the FDA requires everyon...
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- For most brands — including Accutane, Amnesteem, Claravis, and generic isotretinoin — yes, taking it with food is essential. Studies show that a fatty meal more than doubles the am...
- Do I really need to take this with food every time?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Isotretinoin — tap one for details:
Isotretinoin may be associated with lower levels of 4 nutrients — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $17.38 | $521.33 / 30 capsules |
| Medicare drug plans payPart D · Q2 2026 | $22.02 | $660.64 / 30 capsules |
Where does this data come from?
- CMS NADAC weekly file
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 59651-0635-03 You're viewing this Main listing | 3 BLISTER PACK in 1 CARTON / 10 CAPSULE in 1 BLISTER PACK | 2024-01-29 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Isotretinoin 35 mg 00591-2501-15 | Actavis | 30 capsules | — | AB2 | FDA listed | — |
| Absorica 35 mg 10631-0134-31 | Sun | 30 capsules | — | AB2 | FDA listed | — |
| Isotretinoin 35 mg 57664-0024-97 | Sun | 30 capsules | — | AB2 | FDA listed | — |
| Isotretinoin 35 mgthis 59651-0635-03 | Aurobindo | 30 capsules | — | AB2 | FDA listed | — |
| Isotretinoin 35 mg 69238-1258-03 | Amneal | 30 capsules | — | — | FDA listed | — |
| Isotretinoin 35 mg 70710-1578-08 | Zydus | 30 capsules | — | AB2 | FDA listed | — |
| Isotretinoin 35 mg 70771-1666-08 | Zydus | 30 capsules | — | AB2 | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII H3R47K3TBD
FD&C Blue No. 1 is a synthetic blue dye approved for use in foods and medicines. It serves as a colorant to give the medication its distinctive appearance and help with product identification.
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A synthetic red dye approved by the FDA for use in foods, medicines, and cosmetics. It serves as a colorant to make tablets, capsules, and liquids visually distinctive for product identification.
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A synthetic yellow dye used to color medications. It helps identify the drug and make it visually distinctive, with no effect on how the medicine works.
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Gelatin is a protein derived from animal collagen, commonly used in medicines as a gelling agent and capsule material. It helps create soft or hard capsule shells that hold and release medication, and can also thicken liquid formulations.
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Potassium hydroxide is a strong alkaline chemical used in medicines to adjust and maintain the pH level of liquid formulations, helping keep the product stable and the active ingredients effective.
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Propyl gallate is a synthetic antioxidant derived from gallic acid. It prevents oils and fats in the medicine from oxidizing and spoiling, helping the product stay stable and effective during storage.
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UNII 6DC9Q167V3
Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
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UNII 46N107B71O
Shellac is a natural resin secreted by the lac beetle. It's used as a coating on tablets and capsules to control how quickly the medicine dissolves and to improve appearance and stability.
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Sorbitan oleate is an emulsifier derived from sorbitol and oleic acid. It helps mix oil and water-based ingredients together and keeps them from separating in the medicine.
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UNII 241ATL177A
Soybean oil is a natural plant oil derived from soybean seeds. It's used in medicines as a solvent and carrier to help dissolve or suspend active ingredients and improve how the body absorbs them.
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UNII G6EP177239
A waxy substance made from palm oil that has been chemically modified and combined with polyethylene glycol. It acts as an emulsifier and solubilizer to help mix oil and water-based ingredients and improve how the medicine dissolves and is absorbed.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
12 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: EMBRYO-FETAL TOXICITY - CONTRAINDICATED IN PREGNANCY Isotretinoin can cause life-threatening birth defects and is contraindicated in pregnancy . There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking any amount of isotretinoin even for short periods of time. Potentially any fetus exposed during pregnancy can be affected.
There are no accurate means of determining prenatally whether an exposed fetus has been affected . If pregnancy occurs, discontinue isotretinoin immediately and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling [see Contraindications (4) , Warnings and Precautions (5.1), and Use in Specific Populations (8.1) ] . Because of the risk of embryo-fetal toxicity, isotretinoin are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS [see Warnings and Precautions (5.2) ].
WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY See full prescribing information for complete boxed warning. I sotretinoin 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 isotretinoin 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 ) I sotretinoin are available only through a restricted program called the iPLEDGE ® REMS.
( 5.2 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Isotretinoin capsules are indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, isotretinoin capsules are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. Limitations of Use If a second course of isotretinoin capsules treatment is needed, it is not recommended before a 2-month waiting period because the patient’s acne may continue to improve following a 15 to 20-week course of treatment [see Dosage and Administration (2.2) ].
Isotretinoin capsules are retinoids indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, isotretinoin capsules are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. ( 1 ) Limitations of Use : If a second course of isotretinoin capsules treatment is needed, it is not recommended before a 2-month waiting period because the patient’s acne may continue to improve following a 15 to 20-week course of treatment.
( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Evaluations Prior To Prescribing and Use of Isotretinoin Capsules: In patients who can get pregnant, only prescribe isotretinoin capsules after verification and documentation that they are not pregnant. See the Full Prescribing Information for the detailed requirements prior to prescribing isotretinoin capsules ( 2.1 , 8.3 ) Complete the following laboratory tests in all patients: fasting lipid profile and liver function tests. ( 2.1 ) Recommended dosage for ( 2.2 ): Isotretinoin capsules is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks Adult patients with very severe disease (scarring, trunk involvement) may increase dosage to 2 mg/kg/day of isotretinoin capsules in divided doses.
( 2.2 ) Once daily dosing is not recommended. ( 2.2 ) If a dose of isotretinoin capsules is missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time.
( 2.2 )
2.1Evaluations Prior To Prescribing and Use of Isotretinoin Capsules In patients who can get pregnant, only prescribe isotretinoin capsules after verification and documentation that they are not pregnant [see Contraindications (4) and Warnings and Precautions (5.1 , 5.2) ] . For the detailed requirements prior to prescribing isotretinoin capsules, see Use in Specific Populations (8.3) . Prior to isotretinoin capsules use in all patients, complete the following laboratory testing: A fasting lipid profile including triglycerides [see Warnings and Precautions (5.8 , 5.15) ] .
Liver function tests [see Warnings and Precautions (5.10 , 5.15) ] .
2.2Recommended Dosage The recommended dosage of: Isotretinoin capsules is 0.5 to 1 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. Swallow capsules whole.
Do not split, crush, chew, or suck on the capsules. During treatment, the dosage may be adjusted according to response of the disease and/or adverse reactions, some of which may be dose-related. Adult patients whose disease is very severe with scarring or primarily manifested on the trunk may require dosage adjustments up to 2 mg/kg/day for isotretinoin capsules in divided doses, as tolerated.
The safety and effectiveness of once daily dosing with isotretinoin capsules have not been established and is not recommended. If a dose of isotretinoin capsules is missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time.
Table 1: Isotretinoin Capsules Daily Dosage by Body Weight 1 Body Total Daily Dosage (mg) 1 Weight 0.5 mg/kg 1 mg/kg 2 mg/kg 40 kg 50 kg 60 kg 70 kg 80 kg 90 kg 100 kg 20 25 30 35 40 45 50 40 50 60 70 80 90 100 80 100 120 140 160 180 200 1 Administer in two divided doses with or without meals
2.3Recommended Duration of Use A normal course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue isotretinoin capsules. After a period of 2 months or more off treatment, and if warranted by persistent or recurring severe nodular acne, may initiate a second course of isotretinoin capsules in patients who have completed skeletal growth.
The use of another course of isotretinoin capsules treatment is not recommended before a 2-month waiting period because the patient’s acne may continue to improve after a 15 to 20-week course of treatment. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of isotretinoin capsules, even in low dosages, has not been studied, and is not recommended.
The effect of long-term use of isotretinoin capsules on bone loss is unknown [see Warnings and Precautions (5.12) ] .
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Isotretinoin capsules, USP are available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules. 10 mg: Dark yellow color cap/dark yellow color body, size ‘3’ hard gelatin band sealed capsule imprinted “ISO” on body and “10” on cap with BLACK TEK ink containing light orange or yellow color medicament. 20 mg: Red color cap/red color body, size ‘1’ hard gelatin band sealed capsule imprinted “ISO” on body and “20” on cap with BLACK TEK ink containing light orange or yellow color medicament.
25 mg: Green color cap/green color body, size ‘0’ hard gelatin capsule, imprinted “ISO” on body and “25” on cap with WHITE TEK ink containing light orange or yellow color medicament. 30 mg: Brown color cap/brown color body, size ‘0EL’ hard gelatin capsule imprinted “ISO” on body and “30” on cap with WHITE TEK ink containing light orange or yellow color medicament. 35 mg: Dark blue color cap/dark blue color body, size ‘00’ hard gelatin capsule, imprinted “ISO” on body and “35” on cap with WHITE TEK ink containing light orange or yellow color medicament.
40 mg: Brown color cap/red color body, size ‘00EL’ hard gelatin capsule imprinted “ISO” on body and “40” on cap with WHITE TEK ink containing light orange or yellow color medicament. Isotretinoin Capsules USP: 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Isotretinoin capsules are contraindicated in: Pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . Patients with hypersensitivity to isotretinoin (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred) [see Warnings and Precautions (5.14) ] . Isotretinoin capsules are contraindicated in: Pregnancy ( 4 , 8.1 ) Patients with hypersensitivity to isotretinoin (or Vitamin A) or any of its components ( 4 , 5.14 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Psychiatric Disorders (depression, psychosis, suicidal thoughts and behavior, and aggressive and/or violent behaviors): Prior to and during treatment assess for these conditions; stop if these conditions occur on treatment ( 5.4 ) Intracranial Hypertension (Pseudotumor Cerebri) : Avoid concomitant use with tetracyclines ( 5.5 ) Serious Skin Reactions : Monitor for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions and discontinue treatment if they occur ( 5.6 ) Acute Pancreatitis : If pancreatitis symptoms occur, discontinue treatment ( 5.7 ) Lipid Abnormalities (hypertriglyceridemia, low HDL, and elevation of cholesterol): Monitor lipid levels at regular intervals; stop if hypertriglyceridemia cannot be controlled ( 5.8 ) Hearing Impairment : Discontinue and refer to specialized care ( 5.9 ) Hepatotoxicity : Monitor liver function tests prior to and during treatment ( 5.10 , 5.15 ) Inflammatory Bowel Disease : Discontinue for abdominal pain, rectal bleeding, or severe diarrhea ( 5.11 ) Musculoskeletal Abnormalities : Arthralgias, back pain, decreases in bone mineral density and premature epiphyseal closure ( 5.12 ) Ocular Abnormalities e.g., corneal opacities, decreased night vision: If visual symptoms occur, discontinue and refer for an ophthalmological exam ( 5.13 )
5.1Embryo-Fetal Toxicity Isotretinoin is contraindicated in pregnancy [see Contraindications (4.1) ] . Based on human data, isotretinoin can cause fetal harm when administered to a pregnant patient. There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking any amount of isotretinoin even for short periods of time.
Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected. Major congenital malformations, spontaneous abortions, and premature births have been documented following exposure to isotretinoin during pregnancy [see Use in Specific Populations (8.1 )].
If a pregnancy occurs during isotretinoin treatment, immediately discontinue isotretinoin and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Immediately report any suspected fetal exposure during or 1 month after isotretinoin treatment to the FDA via the MedWatch telephone number 1-800-FDA-1088, and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). Inform patients not to donate blood during isotretinoin treatment and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin.
Isotretinoin is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ]. 5.2 iPLEDGE REMS Because of the risk of embryo-fetal toxicity, isotretinoin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS [see Warnings and Precautions (5.1) ] . Notable requirements of the iPLEDGE REMS include the following: Prescribers must be certified in the REMS and comply with the REMS requirements, including the following: Assess the reproductive status of all patients prior to initiating treatment and during treatment.
Counsel patients who cannot get pregnant on the risk and REMS requirements prior to initiating treatment. Counsel patients who can get pregnant on the risk and REMS requirements prior to and during treatment. Counsel patients who can get pregnant on pregnancy prevention requirements prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling.
Comply with the pregnancy testing requirements. Assess the pregnancy status for patients who can get pregnant by reviewing pregnancy tests and documenting a negative result prior to each prescription. Rep… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following adverse reactions with isotretinoin or other isotretinoin capsule products are described in more detail in other sections of the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] Psychiatric Disorders [see Warnings and Precautions (5.4) ] Intracranial Hypertension (Pseudotumor Cerebri) [see Warnings and Precautions (5.5) ] Serious Skin Reactions [see Warnings and Precautions (5.6) ] Pancreatitis [see Warnings and Precautions (5.7) ] Lipid Abnormalities [see Warnings and Precautions (5.8) ] Hearing Impairment [see Warnings and Precautions (5.9) ] Hepatotoxicity [see Warnings and Precautions (5.10) ] Inflammatory Bowel Disease [see Warnings and Precautions (5.11) ] Musculoskeletal Abnormalities [see Warnings and Precautions (5.12) ] Ocular Abnormalities [see Warnings and Precautions (5.13) ] Hypersensitivity Reactions [see Warnings and Precautions (5.14) ] The following adverse reactions associated with the use of isotretinoin capsules were identified in clinical trials or postmarketing reports.
Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dose Relationship Cheilitis and hypertriglyceridemia were dose related. Body as a Whole Fatigue, irritability, pain, allergic reactions, systemic hypersensitivity, edema, lymphadenopathy, weight loss.
Cardiovascular Vascular thrombotic disease, stroke, palpitation, tachycardia. Endocrine/Metabolism and Nutritional Decreased appetite, weight fluctuation, alterations in blood sugar. Gastrointestinal Dry lips, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting, inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis, esophageal ulceration, ileitis.
Hematologic Anemia and decreased RBC parameters, thrombocytopenia, increased platelet counts, decreased WBC counts, severe neutropenia, rare reports of agranulocytosis. Infections and Infestations Nasopharyngitis, hordeolum, infections (including disseminated herpes simplex and upper respiratory tract infection). Laboratory Abnormalities The following lab tests were increased: creatine phosphokinase (CPK), triglycerides, alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT), gamma-glutamyltransferase (GGTP), cholesterol, low density lipoprotein (LDL), alkaline phosphatase, bilirubin, LDH, fasting blood glucose, uric acid, and sedimentation rate.
However, high density lipoprotein (HDL) was decreased. Urine findings included increased white cells, proteinuria, microscopic or gross hematuria. Musculoskeletal and Connective Tissue Decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, arthralgia, musculoskeletal pain, neck pain, extremity pain, myalgia, musculoskeletal stiffness [see Warnings and Precautions (5.12) ] , skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient chest pain, and rare reports of rhabdomyolysis.
Neurological Headache, syncope, intracranial hypertension (pseudotumor cerebri), dizziness, drowsiness, lethargy, malaise, nervousness, paresthesia, seizures, stroke, weakness. Psychiatric Suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, violent behaviors, emotional instability, suicide attempts, suicide, aggression, psychosis and auditory hallucinations. Of the patients reporting depression, some reported that the depression subsided with discontinuation of treatment and recurred with reinstitution of treatment.
Reproductive System Abnormal menses and sexual dysfunction that may continue after discontinuation of treatment (including erectile dysfunction, decreased libido, decreased vaginal lubrication, and vaginal dryness). Respiratory Epistaxis, nasal dryness, bronchospasm (… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Vitamin A : avoid concomitant use ( 7.1 ) Tetracyclines : avoid concomitant use ( 7.2 )
7.1Vitamin A Avoid concomitant use of isotretinoin with supplements containing vitamin A. Isotretinoin is closely related to vitamin A. Therefore, concomitant use of isotretinoin with vitamin A may lead to isotretinoin-associated adverse reactions.
7.2Tetracyclines Avoid concomitant use of isotretinoin with tetracyclines because isotretinoin use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines [see Warnings and Precautions (5.5) ].
7.3Oral Contraceptives Isotretinoin Capsules did not result in clinically significant changes in the pharmacokinetics of norethindrone and ethinyl estradiol when used concomitantly with a norethindrone and ethinyl estradiol oral contraceptive [see Clinical Pharmacology (12.3) ] . It is not known if there is an interaction with the concomitant use of isotretinoin with other oral contraceptives.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended ( 8.2 ). In Patients Who Can Get Pregnant: Pregnancy testing is required prior to, during, and after isotretinoin treatment. See the Full Prescribing Information for the detailed pregnancy test and contraception requirements. ( 8.3 ).
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that documents pregnancies in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after isotretinoin treatment immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet ( www.ipledgeprogram.com) . Risk Summary Isotretinoin 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. If isotretinoin is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin, immediately discontinue isotretinoin and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Data Human Data: Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: central nervous system (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency.
In some cases, death has occurred as a result of the malformations. Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.
8.2Lactation Risk Summary There are no data on the presence of isotretinoin in either animal or human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with isotretinoin, and for at least 8 days after the last dose of isotretinoin.
8.3Females and Males of Reproductive Potential All patients who can get pregnant must comply with the iPLEDGE REMS requirements [see Warnings and Precautions (5.2) ] . Pregnancy Testing In patients who can get pregnant, pregnancy testing is required prior to, during, and after isotretinoin treatment. Pregnancy Testing Prior to Prescribing Isotretinoin : In patients who can get pregnant, only prescribe isotretinoin after verification and documentation that they are not pregnant: (1) Complete the first urine or serum pregnancy test (screening test) in a medical setting (e.g., prescriber’s office, clinic, laboratory) and verify and document that the test is negative, AND (2) For patients with: Regular menstrual cycles , complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and during the first five days of their menstrual period immediately preceding the beginning of isotretinoin treatment, AND (2) after the patient has used their chosen pregnancy prevention methods (i.e., two forms of contraception or committed to abstinence) for at least 30 days.
Verif… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that documents pregnancies in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after isotretinoin treatment immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet ( www.ipledgeprogram.com) . Risk Summary Isotretinoin 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. If isotretinoin is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin, apprise the patient of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin, immediately discontinue isotretinoin and refer the patient to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Data Human Data: Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: central nervous system (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency.
In some cases, death has occurred as a result of the malformations. Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of isotretinoin for the treatment of severe recalcitrant nodular acne have been established in non-pregnant pediatric patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics. Use of isotretinoin in this age group for this indication is supported by evidence from a clinical trial (Study 1) that compared the use isotretinoin to another isotretinoin capsule product in 397 pediatric subjects 12 years of age and older [see Clinical Studies (14) ] and pharmacokinetic data in pediatric subjects [see Clinical Pharmacology (12.3) ].
The safety and effectiveness of isotretinoin in pediatric patients less than 12 years of age have not been established. Adverse Reactions in Pediatric Subjects In trials with isotretinoin capsules, adverse reactions reported in pediatric subjects 12 years of age and older were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric subjects. In a trial of pediatric subjects 12 years of age and older treated with isotretinoin capsules, approximately 29% (104/358) developed back pain.
Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female subjects than male subjects. Arthralgias were experienced in 22% (79/358) of pediatric subjects including severe arthralgias in 8% (6/79) of subjects. Evaluate the musculoskeletal system of pediatric patients who present with these symptoms during or after a course of isotretinoin.
Consider discontinuing isotretinoin if any significant abnormality is found. Effects on Bone Mineral Density in Pediatric Subjects The effect on bone mineral density (BMD) of a 20-week course of treatment with isotretinoin or another isotretinoin capsule product was evaluated in a double-blind, randomized clinical trial involving 396 pediatric subjects with severe recalcitrant nodular acne (mean age 15.4 years old, range 12 to 17 years old, 80% males). Given that there were no statistically significant differences between the two isotretinoin capsule groups following 20 weeks of treatment, the results are presented for the pooled treatment groups.
The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 pediatric subjects, 27 (9%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck.
Repeat DXA scans within 2 to 3 months after the post treatment scan showed no recovery of BMD. Long-term follow-up at 4 to 11 months showed that 3 out of 7 subjects had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see Warnings and Precautions (5.12) ] .
In an open-label clinical trial (N=217) of a single course of treatment with isotretinoin capsules for pediatric subjects 12 years of age and older with severe recalcitrant nodular acne, BMD at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of subjects. One subject had a decrease in lumbar spine BMD >4% based on unadjusted data. Sixteen (8%) subjects had decreases in lumbar spine BMD >4%, and all the other subjects (92%) did not have significant decreases or had increases (adjusted for body mass index).
Nine subjects (5%) had a decrease in total hip BMD >5% based on unadjusted data. Twenty-one (11%) subjects had… [Excerpted — this section continues on DailyMed.]
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of isotretinoin did not include sufficient numbers of geriatric subjects (subjects aged 65 years of age and older) to determine whether they respond differently from younger adult subjects. The effects of aging may increase some risks associated with isotretinoin treatment.
🆘 Overdosage ▾
10 OVERDOSAGE Isotretinoin overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolved without apparent residual effects. Evaluate patients who can become pregnant who present with an isotretinoin overdosage for pregnancy.
Because an overdosage would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, instruct male patients treated with isotretinoin to use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for 1 month after the overdose. Instruct all patients with isotretinoin overdose to not donate blood for at least 1 month. If an overdose occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action The exact mechanism of action of isotretinoin in the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics is unknown. Isotretinoin is a retinoid, which inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion.
The decrease in sebum secretion is temporary and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.
12.2Pharmacodynamics Decreased sebum secretion is related to the dose and duration of treatment with isotretinoin.
12.3Pharmacokinetics No clinically significant differences in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects without acne were reported in published literature. Absorption Following Isotretinoin Administration The isotretinoin mean T max was 6.4 hours under fed conditions and 2.9 hours under fasting conditions following administration of a single 40 mg dose. Effect on Food No clinically significant differences in isotretinoin pharmacokinetics were observed following administration with a modified high-fat, high-calorie meal (123.2 calories from protein, 265.6 calories from carbohydrates, and 468 calories from fat; total calories 857 calories) with reduced vitamin A content.
The mean AUC 0-t and C max of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg isotretinoin dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, isotretinoin may be given with or without meals [see Dosage and Administration (2.1) ]. Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Elimination The mean elimination half-lives of isotretinoin and its 4-oxo-isotretinoin metabolite were: 18 hours and 38 hours, respectively, after a single oral isotretinoin 40 mg dose. Metabolism: Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro . Isotretinoin and its metabolites are further metabolized into conjugates.
Following oral administration of isotretinoin capsules, at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) have been identified in human plasma. The extent of formation of all metabolites was higher under fed conditions. All of these metabolites possess retinoid activity in vitro .
The clinical significance is unknown. Excretion: Following oral administration of an 80 mg dose of radiolabeled-isotretinoin as a liquid suspension, the metabolites of isotretinoin were excreted in feces and urine in relatively equal amounts (total of 65% to 83%). Specific Populations Pediatric Patients: No clinically significant differences in the pharmacokinetics of isotretinoin were observed based on age (12 to 15 years (n=38), and ≥18 years (n=19)).
In both age groups, 4- oxo -isotretinoin was the major metabolite; tretinoin and 4- oxo -tretinoin were also observed [see Use in Specific Populations (8.4) ]. Drug Interaction Studies Phenytoin: No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when used concomitantly with isotretinoin. Norethindrone and Ethinyl Estradiol: There were no clinically significant differences in the pharmacokinetics of norethindrone and ethinyl estradiol after the concomitant use of Isotretinoin Capsules 1 mg/kg/day with an oral contraceptive in premenopausal female patients with severe recalcitrant nodular acne.
Additionally, there were no clinically significant differences in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in the serum levels of progestero… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action The exact mechanism of action of isotretinoin in the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater who are unresponsive to conventional therapy, including systemic antibiotics is unknown. Isotretinoin is a retinoid, which inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion.
The decrease in sebum secretion is temporary and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Isotretinoin capsules, USP are supplied as follows: 10 mg: Dark yellow color cap/dark yellow color body, size ‘3’ hard gelatin band sealed capsule imprinted “ISO” on body and “10” on cap with BLACK TEK ink containing light orange or yellow color medicament. Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-631-03 20 mg: Red color cap/red color body, size ‘1’ hard gelatin band sealed capsule imprinted “ISO” on body and “20” on cap with BLACK TEK ink containing light orange or yellow color medicament.
Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-632-03 25 mg: Green color cap/green color body, size ‘0’ hard gelatin capsule imprinted “ISO” on body and “25” on cap with WHITE TEK ink containing light orange or yellow color medicament. Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-633-03 30 mg: Brown color cap/brown color body, size ‘0EL’ hard gelatin capsule imprinted “ISO” on body and “30” on cap with WHITE TEK ink containing light orange or yellow color medicament. Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-634-03 35 mg: Dark blue color cap/dark blue color body, size ‘00’ hard gelatin capsule, imprinted “ISO” on body and “35” on cap with WHITE TEK ink containing light orange or yellow color medicament.
Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-635-03 40 mg: Brown color cap/red color body, size ‘00EL’ hard gelatin capsule imprinted “ISO” on body and “40” on cap with WHITE TEK ink containing light orange or yellow color medicament. Carton of 30 capsules (3 x 10 Prescription Packs) NDC 59651-636-03 Storage and Handling of Isotretinoin Capsules, USP Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light.
📋 Description ▾
11 DESCRIPTION Isotretinoin capsules, USP contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin USP (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin USP, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems: 10 mg – gelatin, iron oxide yellow and titanium dioxide; 20 mg – gelatin, iron oxide red and titanium dioxide; 25 mg – D&C Yellow #10, FD&C Blue #1, FD&C Yellow #6, gelatin and titanium dioxide; 30 mg – gelatin, iron oxide (black, red and yellow) and titanium dioxide; 35 mg – FD&C Blue #1, FD&C Red #3, FD&C Yellow #6, gelatin and titanium dioxide; 40 mg – gelatin, iron oxide (black, red and yellow) and titanium dioxide.
The black imprinting ink of 10 mg and 20 mg capsules contain the following ingredients: black iron oxide, potassium hydroxide, propylene glycol and shellac. The white imprinting ink of 25 mg, 30 mg, 35 mg and 40 mg capsules contain the following ingredients: potassium hydroxide, propylene glycol, shellac and titanium dioxide. In addition 10 mg and 20 mg capsules contain band sealing composition: gelatin and polysorbate 80.
Isotretinoin Chemically, isotretinoin USP is 13- cis -retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow or light-orange, crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in methylene chloride, slightly soluble in alcohol.
The structural formula is: FDA approved dissolution test specifications differ from USP. Structure
💬 Information for Patients ▾
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 isotretinoin is used in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Instruct patients who can become pregnant that they must not be pregnant during or up to 1 month after isotretinoin treatment.
Instruct patients to not donate blood during isotretinoin treatment and for 1 month following discontinuation to avoid blood donation to a pregnant patient. iPLEDGE REMS Isotretinoin is available only through a restricted program called the iPLEDGE REMS [see Warnings and Precautions (5.2) ]. Inform patients who can get pregnant of the following notable requirements. These patients must: Enroll in the REMS Comply with REMS requirements including: Comply with the pregnancy testing and pregnancy prevention requirements [see Use in Specific Populations (8.3) ].
Demonstrate comprehension of the risk and REMS requirements prior to each prescription. Obtain the prescription within the 7-day prescription window (i.e., within 7 days of the pregnancy test collection). Inform their prescriber if they get pregnant and stop treatment.
Inform patients who cannot get pregnant of the following notable requirements. These patients must enroll in the REMS and comply with the REMS requirements. Isotretinoin is available only from certified pharmacies participating in the REMS.
Therefore, provide patients with the telephone number and website for information on how to obtain isotretinoin [see Warnings and Precautions (5.2) ] . Lactation Because of the potential for serious adverse reactions in nursing infants from isotretinoin, advise patients that breastfeeding is not recommended during treatment with isotretinoin, and for at least 8 days after the last dose of isotretinoin [see Use in Specific Populations (8.2) ]. Psychiatric Disorders Instruct patients and/or their caregivers/families that isotretinoin may cause depression, psychosis, suicidal ideation, suicide attempts, and aggressive or violent behavior.
Instruct patients to stop isotretinoin and to contact a healthcare provider if they develop any of these signs or symptoms [see Warnings and Precautions (5.4) ]. Important Administration Instructions To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid [see Dosage and Administration (2.1) ]. Intracranial Hypertension (Pseudotumor Cerebri) Advise patients that intracranial hypertension (pseudotumor cerebri) has occurred with isotretinoin use including concomitant use with tetracyclines.
Thus, advise patients to avoid concomitant use with tetracyclines and to discontinue isotretinoin immediately if they have symptoms of intracranial hypertension [see Warnings and Precautions (5.5) ]. Serious Skin Reactions Advise patients that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in patients treated with isotretinoin and to discontinue isotretinoin if clinically significant skin reactions occur [see Warnings and Precautions (5.6) ]. Inflammatory Bowel Disease Advise patients that inflammatory bowel disease (including regional ileitis) have occurred with isotretinoin use including those without a prior history of IBD and if they experience IBD symptoms, to discontinue isotretinoin immediately [see Warnings and Precautions (5.11) ].
Musculoskeletal Abnormalities Inform patients that : There have been reports of osteoporosis and fractures and that isotretinoin may have a negative effect on bone mineral density [see Warnings and Precautions (5.12) ]. Isotretinoin use has been associated with musculoskeletal abnormalities (e.g., arthralgia, back pain) [see Warnings and Precautions (5.12) ]. Inform pediatric patients and their families that isotretinoin use in pediatric patients who participated in spor… [Excerpted — this section continues on DailyMed.]
💬 Medication Guide ▾
MEDICATION GUIDE Isotretinoin (eye″ soe tret′ i noyn) Capsules, USP for oral use Read the Medication Guide that comes with isotretinoin capsules 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 healthcare provider about your medical condition or your treatment.
What is the most important information I should know about isotretinoin capsules? Isotretinoin capsules can cause serious side effects, including: Isotretinoin capsules 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 isotretinoin capsules.
Because of the risk of birth defects, isotretinoin capsules are only available through a special program called the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS). Your healthcare provider must be enrolled in the iPLEDGE REMS for you to be prescribed isotretinoin capsules. Before you start treatment with isotretinoin capsules, you must enroll in the iPLEDGE REMS.
You must understand and agree to do everything required in the iPLEDGE REMS. Patients must not get pregnant: for 1 month before starting isotretinoin capsules during treatment with isotretinoin capsules for 1 month after stopping isotretinoin capsules If you get pregnant during treatment with isotretinoin capsules, stop taking it right away and tell your healthcare provider. Healthcare providers and patients should report all cases of pregnancy that happen during treatment or 1 month after stopping treatment to: FDA MedWatch at 1-800-FDA-1088, and 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: depression psychosis (seeing or hearing things that are not real) suicide. Some patients taking isotretinoin capsules 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 isotretinoin capsules and tell your healthcare provider right away if you or a family member notices that you get any of the following signs and symptoms of depression or psychosis: start to feel sad or have crying spells have trouble concentrating lose interest in activities you once enjoyed withdraw from your friends or family sleep too much or have trouble sleeping feel like you have no energy become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence) have feelings of worthlessness or guilt have a change in your appetite or body weight suicide attempts start having thoughts about hurting yourself or taking your own life (suicidal thoughts) start acting on dangerous impulses start seeing or hearing things that are not real Your healthcare provider may tell you to see a mental healthcare professional if you get any of these symptoms.
See “What are the possible side effects of isotretinoin capsules ?” for more information about side effects. What are isotretinoin capsules? Isotretinoin capsules are prescription medicines 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.
Isotretinoin capsules can cause serious side effects (see “What is the most important information I should know about isotretinoin capsules?” ). Isotretinoin capsules can only be: prescribed by healthcare 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… [Excerpted — this section continues on DailyMed.]
🍼 Nursing Mothers ▾
8.3Females and Males of Reproductive Potential All patients who can get pregnant must comply with the iPLEDGE REMS requirements [see Warnings and Precautions (5.2) ] . Pregnancy Testing In patients who can get pregnant, pregnancy testing is required prior to, during, and after isotretinoin treatment. Pregnancy Testing Prior to Prescribing Isotretinoin : In patients who can get pregnant, only prescribe isotretinoin after verification and documentation that they are not pregnant: (1) Complete the first urine or serum pregnancy test (screening test) in a medical setting (e.g., prescriber’s office, clinic, laboratory) and verify and document that the test is negative, AND (2) For patients with: Regular menstrual cycles , complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and during the first five days of their menstrual period immediately preceding the beginning of isotretinoin treatment, AND (2) after the patient has used their chosen pregnancy prevention methods (i.e., two forms of contraception or committed to abstinence) for at least 30 days.
Verify and document that the confirmatory test is negative, OR Amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding , complete the second urine or serum pregnancy test (confirmatory test) in a medical setting (1) at least 30 days after the screening test and immediately preceding the beginning of isotretinoin treatment, AND (2) after the patient has used their chosen pregnancy prevention methods (i.e., two forms of contraception or committed to abstinence) for at least 30 days.
Verify and document that the confirmatory test is negative. If a patient who can get pregnant has had negative screening and confirmatory pregnancy tests but they missed the 7-day prescription window (the patient has not obtained their isotretinoin prescription within 7 days of the pregnancy test collection) and has not started isotretinoin treatment, repeat the urine or serum pregnancy test in a medical setting and verify and document that this repeat test is negative prior to prescribing isotretinoin. The confirmatory pregnancy test must be repeated, as needed, until the patient receives isotretinoin.
Pregnancy Testing During Treatment with Isotretinoin : In patients who can get pregnant who are being treated with isotretinoin, within 7 days before each prescription, obtain a urine or serum pregnancy test in a medical setting (e.g., prescriber’s office, laboratory, clinic) or instruct patients to use a home pregnancy test. If the patient who can get pregnant missed the 7-day prescription window (the patient has not obtained their isotretinoin prescription within 7 days of the pregnancy test collection), repeat the urine or serum pregnancy test within 7 days before the next prescription in a medical setting or instruct patients to use a home pregnancy test.
Verify and document the negative pregnancy test result prior to prescribing additional isotretinoin treatment. Pregnancy Testing in Patients Who Have Completed Isotretinoin Treatment: In patients who can get pregnant who have completed isotretinoin treatment, complete a urine or serum pregnancy test in a medical setting (e.g., prescriber’s office, laboratory, clinic) or instruct patients to use a home pregnancy test: At the end of the entire course of isotretinoin treatment, AND 1 month after the discontinuation of isotretinoin.
Contraception Patients who can get pregnant must use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, for at least 1 month prior to initiation of isotretinoin treatment, during isotretinoin treatment, and for 1 month after discontinuing isotretinoin treatment. However, 2 forms of contraception are not required if the patient commits to continuous abstinence from not having any sexual contact with a partner which may result in pregnancy, has undergone a hysterectomy or bila… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics No clinically significant differences in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects without acne were reported in published literature. Absorption Following Isotretinoin Administration The isotretinoin mean T max was 6.4 hours under fed conditions and 2.9 hours under fasting conditions following administration of a single 40 mg dose. Effect on Food No clinically significant differences in isotretinoin pharmacokinetics were observed following administration with a modified high-fat, high-calorie meal (123.2 calories from protein, 265.6 calories from carbohydrates, and 468 calories from fat; total calories 857 calories) with reduced vitamin A content.
The mean AUC 0-t and C max of isotretinoin were 6095 ng*hr/mL and 369 ng/mL, respectively, following administration of a single 40 mg isotretinoin dose under fed conditions; which were approximately 50% and 26% higher, respectively, compared to fasting conditions. However, isotretinoin may be given with or without meals [see Dosage and Administration (2.1) ]. Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Elimination The mean elimination half-lives of isotretinoin and its 4-oxo-isotretinoin metabolite were: 18 hours and 38 hours, respectively, after a single oral isotretinoin 40 mg dose. Metabolism: Isotretinoin is primarily metabolized by CYP2C8, 2C9, 3A4, and 2B6 in vitro . Isotretinoin and its metabolites are further metabolized into conjugates.
Following oral administration of isotretinoin capsules, at least three metabolites (4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)) have been identified in human plasma. The extent of formation of all metabolites was higher under fed conditions. All of these metabolites possess retinoid activity in vitro .
The clinical significance is unknown. Excretion: Following oral administration of an 80 mg dose of radiolabeled-isotretinoin as a liquid suspension, the metabolites of isotretinoin were excreted in feces and urine in relatively equal amounts (total of 65% to 83%). Specific Populations Pediatric Patients: No clinically significant differences in the pharmacokinetics of isotretinoin were observed based on age (12 to 15 years (n=38), and ≥18 years (n=19)).
In both age groups, 4- oxo -isotretinoin was the major metabolite; tretinoin and 4- oxo -tretinoin were also observed [see Use in Specific Populations (8.4) ]. Drug Interaction Studies Phenytoin: No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when used concomitantly with isotretinoin. Norethindrone and Ethinyl Estradiol: There were no clinically significant differences in the pharmacokinetics of norethindrone and ethinyl estradiol after the concomitant use of Isotretinoin Capsules 1 mg/kg/day with an oral contraceptive in premenopausal female patients with severe recalcitrant nodular acne.
Additionally, there were no clinically significant differences in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in the serum levels of progesterone, follicle-stimulating hormone and luteinizing hormone in these patients.
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Decreased sebum secretion is related to the dose and duration of treatment with isotretinoin.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES The effectiveness of isotretinoin for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older has been established and is based on a double-blind, randomized, parallel group trial (Study 1) in subjects with severe recalcitrant nodular acne who received isotretinoin or another isotretinoin capsule product under fed conditions. A total of 925 subjects were randomized 1:1 to receive isotretinoin or another isotretinoin capsule product. Study subjects ranged from 12 to 54 years of age (including 397 pediatric subjects 12 years of age and older); 60% were male, 40% were female; and the racial groups included 87% White, 4% Black, 6% Asian, and 3% Other.
Enrolled subjects had a weight of 40 to 110 kg and had at least 10 nodular lesions on the face and/or trunk. Subjects were treated with an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks, followed by 1 mg/kg/day in two divided doses for the following 16 weeks. Change from baseline to Week 20 in total nodular lesion count and proportion of subjects with at least a 90% reduction in total nodular lesion count from baseline to Week 20 are presented in Table 3.
Total nodular lesion counts by visit are presented in Figure 1. A single course of isotretinoin and another isotretinoin capsule product treatment for 15 to 20 weeks has been shown to result in complete and prolonged remission of acne in many patients. Table 3: Efficacy Results in Subjects with Severe Recalcitrant Nodular Acne at Week 20 (Study 1) Isotretinoin N=464 Another Isotretinoin Capsule Product* N=461 Nodular Lesions Mean Baseline Count Mean Reduction 18.4 -15.68 17.7 -15.62 Subjects Achieving 90% Reduction, n (%) 324 (70%) 344 (75%) Figure 1: Total Nodular (Facial and Truncal) Lesion Count in Subjects with Severe Recalcitrant Nodular Acne by Visit in Study 1 * Another isotretinoin capsule product.
Figure1
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis and 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 isotretinoin 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 isotretinoin dosage of 1 mg/kg/day, after normalization for total body surface area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis, but some sperm were observed in all testes examined, and in no instance were completely atrophic tubules seen.
13.2Animal Toxicology and/or Pharmacology In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 or 5.3 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, after normalization for total body surface area).
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis and 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 isotretinoin 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 isotretinoin dosage of 1 mg/kg/day, after normalization for total body surface area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical isotretinoin dosage of 1 mg/kg/day, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis, but some sperm were observed in all testes examined, and in no instance were completely atrophic tubules seen.
📄 Package Label / Principal Display Panel ▾
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 10 mg (3 x 10 Prescription Packs) NDC 59651-631-03 Rx only Isotretinoin Capsules, USP 10 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 10 mg . CAUSES BIRTH DEFECTS DO NOT GET PREGNANT 30 Capsules (3x10 Prescription Packs) AUROBINDO figure2
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 10 mg (Wallet Card) NDC 59651-631-10 Rx only Isotretinoin Capsules, USP 10 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 10 mg. PATIENT: READ INFORMATION CAREFULLY PHARMACISTS: DISPENSE INTACT PLACE PRESCRIPTION LABEL HERE 10 Capsules Prescription Pack AUROBINDO figure3
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 20 mg (3 x 10 Prescription Packs) NDC 59651-632-03 Rx only Isotretinoin Capsules, USP 20 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 20 mg. CAUSES BIRTH DEFECTS DO NOT GET PREGNANT 30 Capsules (3x10 Prescription Packs) AUROBINDO figure4
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 20 mg (Wallet Card) NDC 59651-632-10 Rx only Isotretinoin Capsules, USP 20 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 20 mg. PATIENT: READ INFORMATION CAREFULLY PHARMACISTS: DISPENSE INTACT PLACE PRESCRIPTION LABEL HERE 10 Capsules Prescription Pack AUROBINDO figure5
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 25 mg (3 x 10 Prescription Packs) NDC 59651-633-03 Rx only Isotretinoin Capsules, USP 25 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 25 mg. CAUSES BIRTH DEFECTS DO NOT GET PREGNANT 30 Capsules (3x10 Prescription Packs) AUROBINDO figure6
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 25 mg (Wallet Card) NDC 59651-633-10 Rx only Isotretinoin Capsules, USP 25 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 25 mg. PATIENT: READ INFORMATION CAREFULLY PHARMACISTS: DISPENSE INTACT PLACE PRESCRIPTION LABEL HERE 10 Capsules Prescription Pack AUROBINDO figure7
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 30 mg (3 x 10 Prescription Packs) NDC 59651-634-03 Rx only Isotretinoin Capsules, USP 30 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 30 mg. CAUSES BIRTH DEFECTS DO NOT GET PREGNANT 30 Capsules (3x10 Prescription Packs) AUROBINDO figure9
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 30 mg (Wallet Card) NDC 59651-634-10 Rx only Isotretinoin Capsules, USP 30 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 30 mg. PATIENT: READ INFORMATION CAREFULLY PHARMACISTS: DISPENSE INTACT PLACE PRESCRIPTION LABEL HERE 10 Capsules Prescription Pack AUROBINDO figure9
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 35 mg (3 x 10 Prescription Packs) NDC 59651-635-03 Rx only Isotretinoin Capsules, USP 35 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 35 mg. CAUSES BIRTH DEFECTS DO NOT GET PREGNANT 30 Capsules (3x10 Prescription Packs) AUROBINDO figure10
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 35 mg (Wallet Card) NDC 59651-635-10 Rx only Isotretinoin Capsules, USP 35 mg Attention Pharmacist: Dispense the Medication Guide Provided separately to each patient. Each capsule contains: Isotretinoin USP 35 mg. PATIENT: READ INFORMATION CAREFULLY PHARMACISTS: DISPENSE INTACT PLACE PRESCRIPTION LABEL HERE 10 Capsules Prescription Pack AUROBINDO figure11
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 40 mg (3 x 10 Prescription Packs) NDC 59651-636-03 Rx only Isotretinoin Capsules, USP 40 mg Attention Pharmacist: Dispense the Medication… [Excerpted — this section continues on DailyMed.]
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