CAUSES BIRTH DEFECTS

DO NOT GET PREGNANT

Table 1. Monthly Required iPLEDGE Interactions

Isotretinoin USP, a retinoid, is available in 10 mg, 20 mg, 30 mg and 40 mg soft gelatin capsules for oral administration. 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. The structural formula is:

C20H28O2  Molecular Weight: 300.44

Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium dihydrate, gelatin, glycerin, hydrogenated vegetable oil, purified water, soybean oil, titanium dioxide,  and white wax (beeswax).

In addition, the 10 mg capsule contains iron oxide black and iron oxide yellow. The 20 mg capsule contains iron oxide black, iron oxide red and iron oxide yellow. The 30 mg capsule contains FD&C yellow #6 aluminum lake. The 40 mg capsule contains FD&C yellow #6 aluminum lake.

Product meets USP Dissolution Test 4.

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Severe Recalcitrant Nodular Acne

Isotretinoin capsules are indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, isotretinoin capsules should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, isotretinoin capsules are indicated only for those  patients who are not pregnant, because isotretinoin capsules can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off isotretinoin capsules. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis and Premature Epiphyseal Closure).

Pregnancy

Teratogenic Effects

Category X

See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

Isotretinoin capsules are contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS, Hypersensitivity).

Psychiatric Disorders

Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS, Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of isotretinoin therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses and persistent physical symptoms unresponsive to treatment. Patients should stop isotretinoin and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of isotretinoin therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether isotretinoin therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin therapy.

Pseudotumor Cerebri

Isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue isotretinoin immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS, Neurological).

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 events may be serious and result in death, life-threatening events, hospitalization or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of isotretinoin should be considered if warranted.

Pancreatitis

Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Isotretinoin should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

Isotretinoin must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Isotretinoin must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive isotretinoin only from wholesalers registered with iPLEDGE.

iPLEDGE Program requirements for wholesalers, prescribers and pharmacists are described below:

Wholesalers

For the purpose of the iPLEDGE Program, the term wholesaler refers to wholesaler, distributor and/or chain pharmacy distributor. To distribute isotretinoin, wholesalers must be registered with iPLEDGE and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include:

• Registering prior to distributing isotretinoin and re-registering annually thereafter
• Distributing only FDA approved isotretinoin product
• Only shipping isotretinoin to

  -wholesalers registered in the iPLEDGE Program with prior written consent from the manufacturer

  or

  -pharmacies licensed in the U.S. and registered and activated in the iPLEDGE Program

• Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or non-activated pharmacy or unregistered wholesaler that attempts to order isotretinoin
• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE Program by the isotretinoin manufacturer (or delegate)
• Returning to the manufacturer (or delegate) any undistributed product if the wholesaler is deactivated by the iPLEDGE Program or if the wholesaler chooses to not re-register annually

Prescribers

To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.
• I have the expertise to provide the patient with detailed pregnancy prevention counseling, or I will refer the patient to an expert for such counseling, reimbursed by the manufacturer.
• I will comply with the iPLEDGE Program requirements described in the booklets entitled Guide To Best Practices for the iPLEDGE Program and Prescriber Contraception Counseling Guide.
• Before beginning treatment of patients who can become pregnant with isotretinoin, and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously for at least one month prior to initiation of isotretinoin treatment, during isotretinoin treatment and for one month after discontinuing isotretinoin treatment, unless the patient commits to continuous abstinence from any sexual contact with a partner which could result in pregnancy.
• I will not prescribe isotretinoin to any patient who can become pregnant until verifying the patient has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test one month later.
• I will report any pregnancy case that I become aware of while the patient who can become pregnant is on isotretinoin or one month after the last dose to the pregnancy registry.

To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

1. Register each patient in the iPLEDGE Program.

2. Confirm monthly that each patient has received counseling and education.

3. For  patients who can become pregnant:

• Enter patient’s two chosen forms of contraception each month.
• Enter monthly result from CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be prescribed to patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE Program. Meeting the requirements for a patient who can become pregnant signifies that the patient:

• Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for patients who can become pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.
• Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests should be at least 19 days.

  - For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two methods of contraception for one month.

  - For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two methods of contraception for one month.

• Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the patient who can become pregnant receiving each prescription.
• Has selected and has committed to use two forms of effective contraception simultaneously, at least one of which must be a primary method, unless the patient commits to continuous abstinence from any sexual contact with a partner which could result in pregnancy, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use two forms of effective contraception for at least one month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for one month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.

If the patient has unprotected sexual contact with a partner that could result in pregnancy at any time one month before, during, or one month after therapy, the patient must:

1. Stop taking isotretinoin immediately, if on therapy
2. Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner which could result in pregnancy
3. Start using two forms of effective contraception simultaneously again for one month before resuming isotretinoin therapy
4. Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether the patient has regular menses or not.

Effective forms of contraception include both primary and secondary forms of contraception:

Primary forms 

• tubal sterilization
• male vasectomy
• intrauterine device
• hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring)

Secondary forms 

Barrier:

• male latex condom with or without spermicide
• diaphragm with spermicide
• cervical cap with spermicide

Other:

• vaginal sponge (contains spermicide)

Any birth control method can fail. There have been reports of pregnancy from patients who can become pregnant who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking isotretinoin. These reports are more frequent for patients who use only a single form of contraception. Therefore, it is critically important that patients who can become pregnant use two effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two forms of contraception simultaneously substantially reduces the chances that a patient will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin (see PRECAUTIONS, Drug Interactions). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.

If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE Pregnancy Registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

Isotretinoin is contraindicated in patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:

• Must be registered with the iPLEDGE Program by the prescriber
• Must understand that severe birth defects can occur with the use of isotretinoin by patients who can become pregnant
• Must be reliable in understanding and carrying out instructions
• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin
• Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for patients who can become pregnant
• Must obtain the prescription within 30 days of the office visit for patients who cannot become pregnant
• Must not donate blood while on isotretinoin and for one month after treatment has ended
• Must not share isotretinoin with anyone, even someone who has similar symptoms

Patients Who Can Become Pregnant

Isotretinoin is contraindicated in patients who are pregnant. In addition to the requirements for all patients described above, patients who can become pregnant must meet the following conditions:

• Must NOT be pregnant or breast-feeding
• Must comply with the required pregnancy testing at a CLIA-certified laboratory
• Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test
• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from any sexual contact with a partner which could result in pregnancy, and understand behaviors associated with an increased risk of pregnancy
• Must understand that it is the patient who can become pregnant’s responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for patients who can become pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin
• Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy and one month after the last dose to answer questions on the program requirements and to enter the patient’s two chosen forms of contraception
• Must have been informed of the purpose and importance of providing information to the iPLEDGE Program should the patient become pregnant while taking isotretinoin or within one month of the last dose

Pharmacists

To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I will train all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions on the iPLEDGE Program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE Program requirements described in the booklet entitled Pharmacist Guide, specifically the “Key Information for Pharmacists” section including the following dispensing information:
• Prescriptions must be obtained no later than the “Do Not Dispense To After” date, and if not obtained, then the RMA must be reversed in the iPLEDGE Program system and the product returned to inventory.
• I will only obtain isotretinoin capsules product from only iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.
• I will return to the manufacturer (or delegate) any unused product if the pharmacy is deactivated by the iPLEDGE Program or if the pharmacy chooses to not reactivate annually.
• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1. be trained by the Responsible Site Pharmacist concerning the iPLEDGE Program requirements.
2. obtain authorization from the iPLEDGE Program via the internet (www.ipledgeprogram.com), telephone (1-866-495-0654) or through electronic telecommunication verification (via submission of an isotretinoin prescription claim) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin.
3. write the Risk Management Authorization (RMA) number on the prescription.

Isotretinoin capsules must only be dispensed:

• in no more than a 30 day supply
• with an Isotretinoin Capsules Medication Guide
• after authorization from the iPLEDGE Program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for patients who cannot become pregnant and within 7 days of the date of specimen collection for patients who can become pregnant)
• with a new prescription for refills and another authorization from the iPLEDGE Program (No automatic refills are allowed)

An isotretinoin capsules Medication Guide must be given to the patient each time isotretinoin capsules is dispensed, as required by law. This isotretinoin capsules Medication Guide is an important part of the risk management program for the patients.

Isotretinoin capsules must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed and used. Patients must obtain isotretinoin prescriptions only at US licensed pharmacies.

A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages.

1. Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing and the method to complete a qualified isotretinoin prescription.
2. Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive forms, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.
3. Pharmacist Guide includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.
4. The iPLEDGE Program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE Program includes information on the risks and benefits of isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.
5. Patients who cannot become pregnant, and patients who can become pregnant, are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides isotretinoin information in two languages.
6. The booklet for patients who cannot become pregnant, Guide to Isotretinoin for Patients Who Cannot Become Pregnant, also includes information about patient reproduction and a warning not to share isotretinoin with others or to donate blood during isotretinoin therapy and for one month following discontinuation of isotretinoin
7. The booklet for patients who can become pregnant, Guide to Isotretinoin for Patients Who Can Become Pregnant, includes a referral program that offers patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for patients who can become pregnant) form concerning birth defects
8. The booklet, Birth Control Workbook includes information on the types of contraceptive forms, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line.
9. In addition to the booklets, patient educational materials also include the iPLEDGE Program Birth Control Information Sheet and the following — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see Information for Patients).

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of isotretinoin, and the postmarketing experience. The relationship of some of these events to isotretinoin therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving isotretinoin are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).

Body as a Whole

Allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS, Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss.

Cardiovascular

Palpitation, tachycardia, vascular thrombotic disease, stroke.

Endocrine/Metabolic

Hypertriglyceridemia (see WARNINGS, Lipids), alterations in blood sugar levels (see PRECAUTIONS, Laboratory Tests).

Gastrointestinal

Inflammatory bowel disease (see WARNINGS, Inflammatory Bowel Disease), hepatitis (see WARNINGS, Hepatotoxicity), pancreatitis (see WARNINGS, Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

Hematologic

Allergic reactions (see PRECAUTIONS, Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS, Information for Patients). See PRECAUTIONS, Laboratory Tests for other hematological parameters.

Musculoskeletal

Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS, Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia and arthralgia (see PRECAUTIONS, Information for Patients), transient pain in the chest (see PRECAUTIONS, Information for Patients), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS, Laboratory Tests).

Neurological

Pseudotumor cerebri (see WARNINGS, Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

Psychiatric

Suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS, Psychiatric Disorders), emotional instability. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

Abnormal menses.

Respiratory

Bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.

Skin and Appendages

Acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS, Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS, Information for Patients).

Special Senses: Hearing: hearing impairment (see WARNINGS, Hearing Impairment), tinnitus.

Vision: corneal opacities (see WARNINGS, Corneal Opacities), decreased night vision which may persist (see WARNINGS, Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances.

Urinary System: glomerulonephritis (see PRECAUTIONS, Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS, Laboratory Tests for other urological parameters).

Laboratory

Elevation of plasma triglycerides (see WARNINGS, Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment.

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS, Hepatotoxicity).

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS, Laboratory Tests), hyperuricemia.

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; (see PRECAUTIONS, Information for Patients), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.

White cells in the urine, proteinuria, microscopic or gross hematuria.

The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and >300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness and ataxia. These symptoms quickly resolve without apparent residual effects.

Isotretinoin causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Patients who can become pregnant who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.

Isotretinoin capsules should be administered with a meal (see PRECAUTIONS, Information for Patients).

The recommended dosage range for isotretinoin capsules is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5 and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects – 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 dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take isotretinoin capsules with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with isotretinoin capsules has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. 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 doses, has not been studied, and is not recommended. It is important that isotretinoin capsules be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of isotretinoin capsules on bone loss is unknown (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis and Premature Epiphyseal Closure).

Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS).

Table 4. Isotretinoin Capsules Dosing by Body Weight (Based on Administration With Food)

* See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day.

Isotretinoin capsules, USP are available as:

10 mg: Oval, gray, soft gelatin capsules, printed with “A66”.

Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3

20 mg: Oval, brown, soft gelatin capsules, printed with “A67”.

Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3

30 mg: Oval, dark orange, soft gelatin capsules, printed with “A01”.

Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3

40 mg: Oval, orange, soft gelatin capsules, printed with “A68”.

Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3

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

Protect from light.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.

3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980.

4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980.

5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980.

6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.

Ortho-Novum 7/7/7 is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 08-2018-02

---------------------------------------------------------------------------------------------------------------------

To be completed by the patient (and their parent or guardian* if patient is under age 18) and signed by their doctor.

Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor’s instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand.

*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent.

______________________________________________________________________________

(Patient’s Name)

1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin.

   Initial: __________

2. I understand that I must not become pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin.

   Initial: __________

3. I understand that I must avoid having any sexual contact with a partner that could result in pregnancy completely, or I must use two separate, effective forms of birth control (contraception) at the same time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am post-menopausal.

   Initial: __________

4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings and intrauterine devices (IUDs). Any method of birth control can fail. That is why I must use two different birth control forms at the same time, starting one month before, during, and for one month after stopping therapy every time I have any sexual contact with a partner that could result in pregnancy, even if one of the forms I choose is hormonal birth control.

   Initial: __________

5. I understand that the following are effective forms of birth control:

   Primary forms 
   
   

   • tubal sterilization (tying my tubes)
   • male vasectomy
   • intrauterine device
   • hormonal (combination birth control pills, skin patches, shots, under-the skin implants, or vaginal ring.

   
   Secondary forms 

   Barrier:

   • male latex condom with or without spermicide
   • diaphragm with spermicide
   • cervical cap with spermicide

   Other:

   • vaginal sponge (contains spermicide)

   A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm.

   I understand that at least one of my two forms of birth control must be a primary form.

   Initial: __________

6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control forms may not work if I am taking certain medicines or herbal products.

   Initial: __________

7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an Isotretinoin Conctraception Referral Form for this free consultation.

   Initial: __________

8. I must begin using the birth control forms I have chosen as described above at least one month before I start taking isotretinoin.

   Initial: __________

9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment or as instructed by my doctor. I will then have one pregnancy test; in a lab.
   
   • every month during treatment
   • at the end of treatment
   • and 1 month after stopping treatment

   
   I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab.
   

   Initial:__________

10. I have read and understand the materials my doctor has provided to me, including the Guide to Isotretinoin for Patients Who Can Become Pregnant, Birth Control Workbook and Patient Introductory Brochure.

    I have received information on emergency birth control.

    My doctor provided me and asked me to watch a video about birth control and a video about birth defects and isotretinoin.

    Initial: __________

11. I must stop taking isotretinoin right away and call my doctor if I become pregnant, miss my expected menstrual period, stop using birth control, or have any sexual contact with a partner that could result in pregnancy without using my two birth control forms at any time.

    Initial: __________

12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health and my baby’s health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin, and government health regulatory authorities.

    Initial: __________

13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I:

• have had two negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription.
• have chosen and agreed to use two forms of effective birth control at the same time. At least one form must be a primary method of birth control, unless I have chosen never to have any sexual contact with a partner that could result in pregnancy (abstinence), or I have undergone a hysterectomy or bilateral oophorectomy, or I have been medically confirmed to be post-menopausal. I must use two forms of birth control for at least one month before I start isotretinoin therapy, during therapy, and for one month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy.
• have signed a Patient Information/Informed Consent About Birth Defects (for patients who can become pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of and understand the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within 1 month of the last dose.
• have interacted with the iPLEDGE Program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control.

Initial: ______

My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to become pregnant one month before, during isotretinoin treatment, or for one month after I stop taking isotretinoin.

Initial: ______

I now authorize my doctor ________________ to begin my treatment with isotretinoin.

Patient Signature:_____________________________________ Date: ______

Parent/Guardian Signature (if under age 18):________________ Date:______

Please print: Patient Name and Address_______________________________

______________________________ Telephone _______________________

I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to patients who can become pregnant. I have asked the patient if there are any questions regarding treatment with isotretinoin and have answered those questions to the best of my ability.

Doctor Signature: __________________________________ Date: ______

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT’S MEDICAL RECORD.

PLEASE PROVIDE A COPY TO THE PATIENT.

-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.

Read each item below and initial in the space provided if you understand each item and agree to follow your doctor’s instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement.

Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin.

1. I,____________________________________________________________________________ (Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.

   Initials: __________

2. My doctor has told me about my choices for treating my acne.

   Initials: __________

3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for patients who can become pregnant)].

   Initials: __________

4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below).

   Initials: __________

5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there.

   Initials: __________

6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems.

   Initials: __________

7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I:
   
   
   • Start to feel sad or have crying spells
   • Lose interest in activities I once enjoyed
   • Sleep too much or have trouble sleeping
   • Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
   • Have a change in my appetite or body weight
   • Have trouble concentrating
   • Withdraw from my friends or family
   • Feel like I have no energy
   • Have feelings of worthlessness or guilt
   • Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
   • Start acting on dangerous impulses
   • Start seeing or hearing things that are not real
   
   

   Initials: __________

8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress and to check for signs of side effects.

   Initials: __________

9. Isotretinoin will be prescribed just for me – I will not share isotretinoin with other people because it may cause serious side effects, including birth defects.

   Initials: __________

10. I will not give blood while taking isotretinoin or for one month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, their baby may be exposed to isotretinoin and may be born with serious birth defects.

    Initials: __________

11. I have read the Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received.

    Initials: __________

12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin.
    
    Initials: __________

I now allow my doctor _______________________ to begin my treatment with isotretinoin.

Patient Signature:_________________________________Date:____________________

Parent/Guardian Signature (if under age 18):____________________Date: ___________

Patient Name (print)__________________________________

Patient Address___________________________________ Telephone (____-____-____)

I have:

• fully explained to the patient, ______________________________, the nature and purpose of isotretinoin treatment, including its benefits and risks.
• provided the patient the appropriate educational materials, such as the Patient Introductory Brochure and asked the patient if there are any questions regarding their treatment with isotretinoin.
• answered those questions to the best of my ability.

Doctor Signature:_______________________________________Date:___________

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD.

PLEASE PROVIDE A COPY TO THE PATIENT.

Isotretinoin (EYE so TRET i noyn) Capsules

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 doctor about your medical condition or your treatment.

What is the most important information I should know about isotretinoin capsules?

• Isotretinoin capsules are used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics.
• Because isotretinoin capsules can cause birth defects, isotretinoin capsules are only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE Program.
• Isotretinoin capsules may cause serious mental health problems.

1. 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. Patients must not become pregnant:
   
   • for one month before starting isotretinoin capsules
   • while taking isotretinoin capsules
   • for one month after stopping isotretinoin capsules.

   If you become pregnant while taking isotretinoin capsules, stop taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to:
   

   • FDA MedWatch at 1-800-FDA-1088, and
   • the iPLEDGE Pregnancy Registry at 1-866-495-0654
2. Serious mental health problems. Isotretinoin capsules may cause:

• 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. And some people have ended their own lives.

Stop isotretinoin capsules and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis:

• start to feel sad or have crying spells
• lose interest in activities you once enjoyed
• sleep too much or have trouble sleeping
• become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
• have a change in your appetite or body weight
• have trouble concentrating
• withdraw from your friends or family
• feel like you have no energy
• have feelings of worthlessness or guilt
• 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

After stopping isotretinoin capsules, you may also need follow-up mental health care if you had any of these symptoms.

What are isotretinoin capsules?

Isotretinoin capsules are a medicine taken by mouth to treat the most severe form of 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 doctors that are registered in the iPLEDGE Program
• dispensed by a pharmacy that is registered with the iPLEDGE Program
• given to patients who are registered in the iPLEDGE Program and agree to do everything required in the program

What is severe nodular acne?

Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars.

Who should not take isotretinoin capsules?

• Do not take isotretinoin capsules if you are pregnant, plan to become pregnant, or become pregnant during isotretinoin capsules treatment. Isotretinoin capsules cause severe birth defects. See “What is the most important information I should know about isotretinoin capsules?”
• Do not take isotretinoin capsules if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in isotretinoin capsules.

What should I tell my doctor before taking isotretinoin capsules?

Tell your doctor if you or a family member has any of the following health conditions:

• mental problems
• asthma
• liver disease
• diabetes
• heart disease
• bone loss (osteoporosis) or weak bones
• an eating problem called anorexia nervosa (where people eat too little)
• food or medicine allergies

Tell your doctor if you are pregnant or breast-feeding. Isotretinoin capsules must not be used by women who are pregnant or breast-feeding.

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Isotretinoin capsules and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take:

• Vitamin A supplements. Vitamin A in high doses has many of the same side effects as isotretinoin capsules. Taking both together may increase your chance of getting side effects.
• Tetracycline antibiotics. Tetracycline antibiotics taken with isotretinoin capsules can increase the chances of getting increased pressure in the brain.
• Progestin-only birth control pills (mini-pills). They may not work while you take isotretinoin capsules. Ask your doctor or pharmacist if you are not sure what type you are using.
• Dilantin (phenytoin). This medicine taken with isotretinoin capsules may weaken your bones.
• Corticosteroid medicines. These medicines taken with isotretinoin capsules may weaken your bones.
• St. John’s Wort. This herbal supplement may make birth control pills work less effectively.

These medicines should not be used with isotretinoin capsules unless your doctor tells you it is okay.

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

How should I take isotretinoin capsules?

• You must take isotretinoin capsules exactly as prescribed. You must also follow all the instructions of the iPLEDGE Program. Before prescribing isotretinoin capsules, your doctor will:
• explain the iPLEDGE Program to you
• have you sign the Patient Information/Informed Consent form (for all patients). Patients who can become pregnant must also sign another consent form.

You will not be prescribed isotretinoin capsules if you cannot agree to or follow all the instructions of the iPLEDGE Program.

• You will get no more than a 30 day supply of isotretinoin capsules at a time. This is to make sure you are following the isotretinoin capsules iPLEDGE Program. You should talk with your doctor each month about side effects.
• The amount of isotretinoin capsules you take has been specially chosen for you. It is based on your body weight, and may change during treatment.
• Take isotretinoin capsules 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your isotretinoin capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Isotretinoin capsules can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole.
• If you miss a dose, just skip that dose. Do not take 2 doses at the same time.
• If you take too much isotretinoin capsules or overdose, call your doctor or poison control center right away.
• Your acne may get worse when you first start taking isotretinoin capsules. This should last only a short while. Talk with your doctor if this is a problem for you.
• You must return to your doctor as directed to make sure you don’t have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from isotretinoin capsules. Patients who can become pregnant will get a pregnancy test each month.
• Patients who can become pregnant must agree to use two separate forms of effective birth control at the same time one month before, while taking, and for one month after taking isotretinoin capsules. You must access the iPLEDGE program system to answer questions about the program requirements and to enter your two chosen methods of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654.

You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes isotretinoin capsules.

If you have sex at any time without using two forms of effective birth control, become pregnant, or miss your expected period, stop using isotretinoin capsules and call your doctor right away.

What should I avoid while taking isotretinoin capsules?

• Do not become pregnant while taking isotretinoin capsules and for one month after stopping isotretinoin capsules. See "What is the most important information I should know about isotretinoin capsules?”
• Do not breast feed while taking isotretinoin capsules and for one month after stopping isotretinoin capsules. We do not know if isotretinoin can pass through your milk and harm the baby.
• Do not give blood while you take isotretinoin capsules and for one month after stopping isotretinoin capsules. If someone who is pregnant gets your donated blood, their baby may be exposed to isotretinoin capsules and may be born with birth defects.
• Do not take other medicines or herbal products with isotretinoin capsules unless you talk to your doctor. See “What should I tell my doctor before taking isotretinoin capsules?”
• Do not drive at night until you know if isotretinoin capsules have affected your vision. Isotretinoin capsules may decrease your ability to see in the dark.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, while you are using isotretinoin capsules and for at least 6 months after you stop. Isotretinoin capsules can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Isotretinoin capsules may make your skin more sensitive to light.
• Do not share isotretinoin capsules with other people. It can cause birth defects and other serious health problems.

What are the possible side effects of isotretinoin capsules?

• Isotretinoin capsules can cause birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby and early (premature) births. See “What is the most important information I should know about isotretinoin capsules?”
• Isotretinoin capsules may cause serious mental health problems. See “What is the most important information I should know about isotretinoin capsules?”
• serious brain problems. Isotretinoin capsules can increase the pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking isotretinoin capsules and call your doctor right away if you get any of these signs of increased brain pressure:
• bad headache
• blurred vision
• dizziness
• nausea or vomiting
• seizures (convulsions)
• stroke
• skin problems. Skin rash can occur in patients taking isotretinoin capsules. In some patients a rash can be serious. Stop using isotretinoin capsules and call your doctor right away if you develop conjunctivitis (red or inflamed eyes, like “pink eye”), a rash with a fever, blisters on legs, arms or face and/or sores in your mouth, throat, nose, eyes, or if your skin begins to peel.
• stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines) and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking isotretinoin capsules. Stop taking isotretinoin capsules and call your doctor if you get:
• severe stomach, chest or bowel pain
• trouble swallowing or painful swallowing
• new or worsening heartburn
• diarrhea
• rectal bleeding
• yellowing of your skin or eyes
• dark urine
• bone and muscle problems. Isotretinoin capsules may affect bones, muscles and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with isotretinoin capsules. Tell your doctor if you get:
• back pain
• joint pain
• broken bone. Tell all healthcare providers that you take isotretinoin capsules if you break a bone.

Stop isotretinoin capsules and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage.

Isotretinoin capsules may stop long bone growth in teenagers who are still growing.

• hearing problems. Stop using isotretinoin capsules and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent.
• vision problems. Isotretinoin capsules may affect your ability to see in the dark. This condition usually clears up after you stop taking isotretinoin capsules, but it may be permanent. Other serious eye effects can occur. Stop taking isotretinoin capsules and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking isotretinoin capsules and after treatment.
• lipid (fats and cholesterol in blood) problems. Isotretinoin capsules can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when isotretinoin capsules treatment is finished.
• serious allergic reactions. Stop taking isotretinoin capsules and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking isotretinoin capsules and call your doctor if you get a fever, rash, or red patches or bruises on your legs.
• blood sugar problems. Isotretinoin capsules may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot.
• decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel weak.
• The common, less serious side effects of isotretinoin capsules are dry skin, chapped lips, dry eyes and dry nose that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does not go away.

These are not all of the possible side effects with isotretinoin capsules. Your doctor or pharmacist can give you more detailed information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Amneal Pharmaceuticals at 1-877-835-5472.

How should I store isotretinoin capsules?

• Store isotretinoin capsules at 20° to 25°C (68° to 77°F). Protect from light.
• Keep isotretinoin capsules and all medicines out of the reach of children.

General Information about isotretinoin capsules.

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use isotretinoin capsules for a condition for which it was not prescribed. Do not give isotretinoin capsules to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about isotretinoin capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about isotretinoin capsules that is written for healthcare professionals.

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

What are the ingredients in isotretinoin capsules?

Active Ingredient: Isotretinoin

Inactive Ingredients: Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium dihydrate, gelatin, glycerin, hydrogenated vegetable oil, purified water, soybean oil, titanium dioxide and white wax (beeswax).

In addition, the 10 mg capsule contains iron oxide black and iron oxide yellow. The 20 mg capsule contains iron oxide black, iron oxide red and iron oxide yellow. The 30 mg capsule contains FD&C yellow #6 aluminum lake. The 40 mg capsule contains FD&C yellow #6 aluminum lake.

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

Dilantin is a registered trademark of Warner-Lambert Company LLC.

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ  08807

Rev. 08-2018-02