Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 03 February 2017

Indication(s)

INDICATIONS AND USAGE Severe Recalcitrant Nodular Acne Claravis (isotretinoin capsules USP) is 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, Claravis should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Claravis is indicated only for those female patients who are not pregnant, because Claravis 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 Claravis. 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).

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contraindications
CONTRAINDICATIONS Pregnancy Teratogenic Effects Category X See Boxed CONTRAINDICATIONS AND WARNINGS . Allergic Reactions Claravis is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS, Hypersensitivity).
Special warnings and precautions
PRECAUTIONS Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Claravis 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 Claravis, 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 reregistering 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 registration is revoked by the manufacturer or if the wholesaler chooses to not reregister 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 her to an expert for such counseling, reimbursed by the manufacturer. •I will comply with the iPLEDGE Program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide. •Before beginning treatment of females of reproductive potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence. •I will not prescribe isotretinoin to any females of reproductive potential until verifying she 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 female patient 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 females of reproductive potential: ∘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 female 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 female of reproductive potential signifies that she: • Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get 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 forms 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 forms 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 female patient 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 form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be postmenopausal. 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 heterosexual intercourse at any time one month before, during, or one month after therapy, she must: 1.Stop taking isotretinoin immediately, if on therapy 2.Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse 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 she has regular menses or not. Effective forms of contraception include both primary and secondary forms of contraception: Primary forms •tubal sterilization •partner's vasectomy •intrauterine device •hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring) Secondary forms Barrier forms: •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 female patients 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 Claravis. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive potential 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 female 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 Claravis (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 the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). All Patients Isotretinoin is contraindicated in female 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 female patients • 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 females of reproductive potential • Must obtain the prescription within 30 days of the office visit for male patients and females of non-reproductive potential • 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 Females of Reproductive Potential Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential 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 heterosexual intercourse and understand behaviors associated with an increased risk of pregnancy • Must understand that it is her 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 female patients who can get 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 she 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 for the iPLEDGE Program. •I will obtain Claravis product only from 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 registration is revoked by the manufacturer 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) or telephone (1-866-495-0654) 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. Claravis must only be dispensed: •in no more than a 30 day supply •with a Claravis 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 male patients and females of non-reproductive potential and within 7 days of the date of specimen collection for females of reproductive potential) •with a new prescription for refills and another authorization from the iPLEDGE Program (No automatic refills are allowed) A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patients. Claravis 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 fill 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. The 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. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk. 3. The Pharmacist Guide for the iPLEDGE Program 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.Females of non-reproductive potential and male patients, and females of reproductive potential 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 females of non-reproductive potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male 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 females of reproductive potential, The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects. 8.The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line. 9.In addition, there are patient educational materials with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see Information for Patients). General Although an effect of Claravis on bone loss is not established, physicians should use caution when prescribing Claravis to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Claravis or following cessation of therapy with Claravis while involved in these activities. While causality to Claravis has not been established, an effect must not be ruled out. Information for Patients See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS . •Patients must be instructed to read the Medication Guide supplied as required by law when Claravis is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE Program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form. •Females of reproductive potential must be instructed that they must not be pregnant when Claravis therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Claravis, while taking Claravis, and for one month after Claravis has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Claravis therapy. They should be given an opportunity to view the patient video provided by the manufacturer to the prescriber. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using two forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Claravis at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Claravis prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS). •Claravis is found in the semen of male patients taking Claravis, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed. •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 treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment 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 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 treatment 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. •Patients must be informed 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. •Patients must be informed that they must not share Claravis with anyone else because of the risk of birth defects and other serious adverse events. •Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Claravis. •Patients should be reminded to take Claravis with a meal (see DOSAGE AND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. •Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. •Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Claravis therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS, Skin and Appendages). •Patients should be advised to avoid prolonged exposure to UV rays or sunlight. •Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. •Patients should be informed that approximately 16% of patients treated with Claravis in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Claravis, but in some cases persisted (see ADVERSE REACTIONS, Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests, CPK). •Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Claravis developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Claravis. Consideration should be given to discontinuation of Claravis if any significant abnormality is found. •Neutropenia and rare cases of agranulocytosis have been reported. Claravis should be discontinued if clinically significant decreases in white cell counts occur. •Patients should be advised that severe skin reactions (Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported in postmarketing data. Claravis should be discontinued if clinically significant skin reactions occur. Hypersensitivity Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Drug Interactions •Vitamin A: Because of the relationship of Claravis to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. •Tetracyclines: Concomitant treatment with Claravis and tetracyclines should be avoided because Claravis use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. •Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Claravis therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Claravis. Therefore, it is critically important for females of reproductive potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS). •Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Claravis at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. •St. John’s Wort: Claravis use is associated with depression in some patients (see WARNINGS, Psychiatric Disorders and ADVERSE REACTIONS, Psychiatric). 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. •Phenytoin: Claravis has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Claravis. Therefore, caution should be exercised when using these drugs together. •Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Claravis. Therefore, caution should be exercised when using these drugs together. Laboratory Tests Pregnancy Test - Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Claravis prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Claravis. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must
Adverse reactions
ADVERSE REACTIONS Clinical Trials and Postmarketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of Claravis, and the postmarketing experience. The relationship of some of these events to Claravis therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Claravis 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.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Claravis should be administered with a meal (see PRECAUTIONS, Information for Patients). The recommended dosage range for Claravis 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 Claravis 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 Claravis 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 Claravis, even in low doses, has not been studied, and is not recommended. It is important that Claravis be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Claravis 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. Claravis Dosing by Body Weight (Based on Administration With Food) Body Weight Total mg/day kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day. 40 88 20 40 80 50 110 25 50 100 60 132 30 60 120 70 154 35 70 140 80 176 40 80 160 90 198 45 90 180 100 220 50 100 200 INFORMATION FOR PHARMACISTS Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to obtain an authorization and the “do not dispense to patient after” date. Claravis must only be dispensed in no more than a 30 day supply. REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM. A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patient.
Pregnancy and lactation
Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Claravis.

Interactions

Drug Interactions •Vitamin A: Because of the relationship of Claravis to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. •Tetracyclines: Concomitant treatment with Claravis and tetracyclines should be avoided because Claravis use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. •Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Claravis therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Claravis. Therefore, it is critically important for females of reproductive potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS). •Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Claravis at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. •St. John’s Wort: Claravis use is associated with depression in some patients (see WARNINGS, Psychiatric Disorders and ADVERSE REACTIONS, Psychiatric). 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. •Phenytoin: Claravis has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Claravis. Therefore, caution should be exercised when using these drugs together. •Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Claravis. Therefore, caution should be exercised when using these drugs together.

More information

Category Value
Authorisation number ANDA076356
Agency product number EH28UP18IF
Orphan designation No
Product NDC 0555-1055,0555-1054,0555-1057,0555-1056
Date Last Revised 05-08-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 404059
Marketing authorisation holder Teva Pharmaceuticals USA, Inc.
Warnings CONTRAINDICATIONS AND WARNINGS Claravis™ must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Claravis 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. Birth defects which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted. If pregnancy does occur during treatment of a female patient who is taking Claravis, Claravis must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Special Prescribing Requirements Because of isotretinoin's teratogenicity and to minimize fetal exposure, Claravis is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Claravis 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 (see PRECAUTIONS).