Myorisan (isotretinoin 10 mg) Dailymed

Myorisan® must not be used by female patients who are or may become pregnant. There is an extremely high risk that life-threatening birth defects will result if pregnancy occurs while taking Myorisan® 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 Myorisan® 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 Myorisan®, Myorisan® 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 Myorisan’s ®teratogenicity and to minimize fetal exposure, Myorisan® is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This REMS is called iPLEDGE®. Myorisan® must only be prescribed by prscribers who are enrolled and activated with the iPLEDGE REMS. Myorisan® must only be dispensed by a pharmacy enrolled and activated with iPLEDGE, and must only be dispensed to patients who are enrolled and meet all the requirements of iPLEDGE. (see PRECAUTIONS).

Table 1 Monthly Required iPLEDGE Interactions Patients Who Can Become Pregnant Patients Who Cannot Become Pregnant PRESCRIBER Confirms patient counseling X X Enters the 2 contraception forms chosen by the patient X Enters pregnancy test results X PATIENT Answers educational questions before every prescription X Enters 2 forms of contraception X PHARMACIST Contacts system to get an authorization X X

Myorisan 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, means “many” as opposed to “few or several” nodules.   In addition, Myorisan is indicated only for those patients who are not pregnant, because Myorisan can cause life-threatening birth defects (see ).

Myorisan ® 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, Myorisan ®  should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Myorisan ® is indicated only for those patients who are not pregnant, because Myorisan ® can cause life-threatening 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 Myorisan ® . The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, Premature Epiphyseal Closure ).

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

To prescribe isotretinoin, the prescriber must be enrolled and activated with the pregnancy risk management program iPLEDGE. Prescribers can enroll by signing and returning the completed enrollment form. Prescribers can only activate their enrollment 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 REM requirements described in the booklet entitled iPLEDGE REMS Prescriber 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, not having any sexual contact with a partner that 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)  Enroll each patient in the iPLEDGE REMS. 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 enrolled and activated with the pregnancy risk management program iPLEDGE and only when the enrolled patient meets all the requirements of the iPLEDGE REMS. Meeting the requirements for a patient who can become pregnant signifies that the patient: • Has been counseled and has signed a Patient Enrollment Form for Patients who can get Pregnant 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 form 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 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 form, unless the patient commits to continuous abstinence not having any sexual contact with a partner that 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 Myorisan ® immediately, if on therapy 2. Have a pregnancy test at least 19 days after the last act of unprotected sexual contact with a partner that could result in pregnancy 3. Start using two forms of effective contraception simultaneously again for one month before resuming Myorisan ® 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 menuses or not. Effective forms of contraception include both primary and secondary forms of contraception: Primary methods •tubal sterilization •male vasectomy •intrauterine device •hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring) Secondary methods 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 Myorisan ® . 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 importance of choosing one primary form and a secondary form of contraception and that the patient must be compliant in use as outlined in the Guide for Patients who can get Pregnant. 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 Myorisan ® (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 Myorisan ® treatment, Myorisan ® 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 Myorisan ® 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).

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

Isotretinoin is contraindicated in patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions: • Must be enrolled with the iPLEDGE REMS by the prescriber • Must understand that life-threatening 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 Enrollment Form for Patients who cannot get Pregnant 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 not having any sexual contact with a partner that 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 responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy • Must have signed an additional Patient Enrollment Form for Patients who can get Pregnant, 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 REMS should the patient become pregnant while taking isotretinoin or within one month of the last dose

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

To dispense isotretinoin, pharmacies must be enrolled and activated with the pregnancy risk management program iPLEDGE. The Responsible Site Pharmacist must enroll the pharmacy by signing and returning the completed Pharmacy Enrollment Form. After enrolling, the Responsible Site Pharmacist can only activate the pharmacy enrollment 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 REM requirements. • I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE REMS 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 REMS system and the product returned to inventory. • I understand and will comply with Non-Compliance Action Policy. • I will only obtain Myorisan ® product from only iPLEDGE enrolled 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 REMS or if the pharmacy chooses to not reactivate annually. • I will not fill isotretinoin for any party other than a qualified patient. • I will comply with the audits by the iPLEDGE Sponsors or third party acting on behalf of the iPLEDGE Sponsors to ensure that all processes and procedures are in place and being followed for the iPLEDGE REMS To dispense isotretinoin, the pharmacist must: 1) be trained by the Responsible Site Pharmacist concerning the iPLEDGE REMS requirements. 2) obtain authorization from the iPLEDGE REMS 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 Myorisan ® . 3) write the Risk Management Authorization (RMA) number on the prescription. Myorisan ® must only be dispensed: • in no more than a 30-day supply • with a Myorisan ® Medication Guide • after authorization from the iPLEDGE REMS • 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 REMS (No automatic refills are allowed) A Myorisan ® Medication Guide must be given to the patient each time Myorisan ® is dispensed, as required by law. This Myorisan ®  Medication Guide is an important part of the risk management program for the patients. Myorisan ® must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE REMS. Only FDA-approved Myorisan ® products must be distributed, prescribed, dispensed, and used. Patients must obtain Myorisan ® prescriptions only at US licensed pharmacies. A description of the iPLEDGE REMS educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE REMS requirements and to reinforce the educational messages. 1) Prescriber Guide includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Myorisan ® prescription. 2) Pharmacist Guide includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription. 3) The iPLEDGE REMS is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE REMS includes information on the risks and benefits of Myorisan ® which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription. 4) The Fact Sheet for the iPLEDGE REMS includes information on the iPLEDGE REMS, the product indications and safety information. This handout is provided to both the patient who can become pregnant and the patient who cannot become pregnant. The Patient Enrollment Form for Patients who cannot get Pregnant is also provided to all patients. 5) Patients who can become pregnant are provided with a Guide for Patients who Can Get Pregnant, which contains information on isotretinoin therapy including precautions and warnings, and a second Patient Enrollment Form for Patients who can get Pregnant concerning birth defects, and a toll-free line which provides Myorisan® information in two languages. 6) The booklet for patients who can become pregnant, Contraception Counseling Guide, includes a referral program that offers patients free contraception counseling, reimbursed by the manufacturer, by a reproductive speciaul and a second Patient Enrollment Form for Patients who can get Pregnant concerning birth defects. 7) The Guide for Patients Who Can Get Pregnant outlines the effectiveness of the approved contraception options. (see 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 Myorisan® 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 REMS patient educational materials. All patients must sign the Patient Enrollment Form for Patients who cannot get Pregnant. • Patients who can become pregnant must be instructed that they must not be pregnant when Myorisan® therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Myorisan®, while taking Myorisan®, and for one month after Myorisan® has been stopped, unless they commit to continuous abstinence from not having any sexual contact with a partner that could result in pregnancy. They should also sign a second Patient Enrollment Form for Patients who can get Pregnant prior to beginning Myorisan® therapy. Patients who can become pregnant 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 Myorisan® prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS ). • Myorisan® is found in the semen of male patients taking Myorisan®, but the amount delivered to a patient who can become pregnant 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 Myorisan® 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 Myorisan® 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 Myorisan® 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 Myorisan® therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Myorisan® therapy. • Patients must be informed that some patients, while taking Myorisan® or soon after stopping Myorisan®, 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 Myorisan® 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 Myorisan® 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 Myorisan®. Some people have had other signs of depression while taking Myorisan®. • Patients must be informed that they must not share Myorisan® 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 patient whose fetus must not be exposed to Myorisan®. • Patients should be reminded to take Myorisan® 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 Myorisan® 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 Myorisan® 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 Myorisan®, 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 Myorisan® 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 Myorisan®. Consideration should be given to discontinuation of Myorisan® if any significant abnormality is found. • Neutropenia and rare cases of agranulocytosis have been reported. Myorisan® 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 post-marketing data. Myorisan® should be discontinued if clinically significant skin reactions occur.

• Vitamin A: Because of the relationship of Myorisan® to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. • Tetracyclines: Concomitant treatment with Myorisan® and tetracyclines should be avoided because Myorisan® 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 Myorisan® therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant 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 patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Myorisan®. Therefore, it is critically important for patients who can become pregnant 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, Myorisan® 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:   Myorisan ® 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: Myorisan® 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 Myorisan®. 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 Myorisan®. Therefore, caution should be exercised when using these drugs together.

• Pregnancy Test: -Patients who can become pregnant must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Myorisan® prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Myorisan®. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days. -For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Myorisan® therapy and after the patient has used 2 forms of contraception for 1 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 Myorisan® therapy and after the patient has used 2 forms of contraception for 1 month. -Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the patient who can become pregnant receiving each prescription. • Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Myorisan® is established. The incidence of hypertriglyceridemia is one patient in four on Myorisan® therapy (see WARNINGS: Lipids ). • Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Myorisan® has been established (see WARNINGS: Hepatotoxicity ). • Glucose: Some patients receiving Myorisan® have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Myorisan® therapy, although no causal relationship has been established. • CPK: Some patients undergoing vigorous physical activity while on Myorisan® therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.



It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Myorisan.

It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Myorisan®.

- Myorisan® is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics. - Because Myorisan® can cause birth defects, Myorisan® is only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE REMS. - Myorisan® 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 Myorisan®. Patients must not get pregnant: - for 1 month before starting Myorisan®  - while taking Myorisan®  - for 1 month after stopping Myorisan®. If you get pregnant while taking Myorisan ® , 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. Myorisan® may cause: - depression - psychosis (seeing or hearing things that are not real) - suicide. Some patients taking Myorisan® 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 Myorisan ® 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 Myorisan®, you may also need follow-up mental health care if you had any of these symptoms.

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 Myorisan ® ? - Do not take Myorisan ® if you are pregnant, plan to become pregnant, or become pregnant during Myorisan ® treatment. Myorisan® causes life-threatening birth defects. See “What is the most important information I should know about Myorisan ® ?” - Do not take Myorisan ® if you are allergic to anything in it. See the end of this Medication Guide for a complete ul of ingredients in Myorisan®.

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 breastfeeding. Myorisan ® must not be used by patients who are pregnant or breastfeeding. Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Myorisan® 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 Myorisan®. Taking both together may increase your chance of getting side effects. - Tetracycline antibiotics. Tetracycline antibiotics taken with Myorisan® 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 Myorisan®. Ask your doctor or pharmacist if you are not sure what type you are using. - Dilantin (phenytoin). This medicine taken with Myorisan® may weaken your bones. - Corticosteroid medicines. These medicines taken with Myorisan® 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 Myorisan ® unless your doctor tells you it is okay. Know the medicines you take. Keep a ul of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.

- You must take Myorisan® exactly as prescribed. You must also follow all the instructions of the iPLEDGE REMS. Before prescribing Myorisan®, your doctor will: - explain the iPLEDGE REMS to you - have you sign the Patient Enrollment Form for Patients who cannot get pregnant. Patients who can get pregnant must also sign another enrollment form. You will not be prescribed Myorisan ® if you cannot agree to or follow all the instructions of the iPLEDGE REMS. - You will get no more than a 30-day supply of Myorisan® at a time. This is to make sure you are following the Myorisan® iPLEDGE REMS. You should talk with your doctor each month about side effects. - The amount of Myorisan® you take has been specially chosen for you. It is based on your body weight, and may change during treatment. - Take Myorisan® 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your Myorisan ® capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Myorisan® 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 two doses at the same time. - If you take too much Myorisan® or overdose, call your doctor or poison control center right away. - Your acne may get worse when you first start taking Myorisan®. 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 Myorisan®. Patients who can get pregnant will get a pregnancy test each month. - Patients who can get 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 Myorisan®. You must access the iPLEDGE REMS system to answer questions about the program requirements and to enter your two chosen forms of birth control. To access the iPLEDGE REMS system, go to www.ipledgeprogram.com or call 1-866-495-0654. You must talk about effective birth control forms 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 Myorisan®. If you have sex at any time without using two forms of effective birth control, get pregnant, or miss your expected period, stop using Myorisan ® and call your doctor right away.

- Do not get pregnant while taking Myorisan® and for one month after stopping Myorisan®. See “What is the most important information I should know about Myorisan ® ?” - Do not breast feed while taking Myorisan® and for one month after stopping Myorisan®. We do not know if Myorisan® can pass through your milk and harm the baby. - Do not give blood while you take Myorisan® and for one month after stopping Myorisan®. If someone who is pregnant gets your donated blood, their baby may be exposed to Myorisan® and may be born with birth defects. - Do not take other medicines or herbal products with Myorisan® unless you talk to your doctor. See “What should I tell my doctor before taking Myorisan ® ?” - Do not drive at night until you know if Myorisan ® has affected your vision. Myorisan® 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 Myorisan ® and for at least 6 months after you stop. Myorisan® 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. Myorisan® may make your skin more sensitive to light. - Do not share Myorisan ® with other people. It can cause birth defects and other serious health problems.