Label: MYORISAN- isotretinoin capsule, liquid filled

Nodular Acne

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

Pharmacokinetics

Special Patient Populations

Severe Recalcitrant Nodular Acne

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).

Allergic Reactions

Myorisan® is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS: Hypersensitivity).

Psychiatric Disorders

Myorisan® may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Myorisan® therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop 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® therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether Myorisan® therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Myorisan® therapy.

Pseudotumor Cerebri

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

Serious Skin Reactions

There have been post-marketing reports of erythema multiforme and severe skin reactions [eg, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of Myorisan® should be considered if warranted.

Pancreatitis

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

Lipids

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Myorisan®. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Myorisan® in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Myorisan® therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Myorisan®.5

Blood lipid determinations should be performed before Myorisan® is given and then at intervals until the lipid response to Myorisan® is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Myorisan® therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Myorisan® therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).

The cardiovascular consequences of hypertriglyceridemia associated with Myorisan® are unknown.

Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

Hearing Impairment

Impaired hearing has been reported in patients taking Myorisan®; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Myorisan® treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to Myorisan® therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Myorisan®, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

Myorisan® has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after Myorisan® treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Myorisan® immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Vision Impairment

Visual problems should be carefully monitored. All Myorisan® patients experiencing visual difficulties should discontinue Myorisan® treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).

Wholesalers:

For the purpose of the iPLEDGE REMS, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Myorisan®, wholesalers must be enrolled with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must enroll 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:

• Enrolling prior to distributing isotretinoin and re-enrolling annually thereafter

• Distributing only FDA approved isotretinoin product

• Only shipping isotretinoin to

-  wholesalers enrolled in the iPLEDGE REMS with prior written consent from the manufacturer or

- pharmacies licensed in the US and enrolled and activated in the iPLEDGE REMS

• Notifying the isotretinoin manufacturer (or delegate) of any non-enrolled and/or non-activated pharmacy or unenrolled wholesaler that attempts to order isotretinoin

• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE REMS by the isotretinoin manufacturer (or delegate)

• Returning to the manufacturer (or delegate) any undistributed product if the wholesaler is deactivated by the iPLEDGE REMS or if the wholesaler chooses to not re-enroll annually

Prescribers:

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:

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).

Pharmacists:

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 specialist 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).

General

Although an effect of Myorisan® on bone loss is not established, physicians should use caution when prescribing Myorisan® 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 Myorisan® or following cessation of therapy with Myorisan® while involved in these activities. While causality to Myorisan® 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 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.

Laboratory Tests

• 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.

Carcinogenesis, Mutagenesis and Impairment of Fertility

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.

The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6x background) was noted in S.typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving Myorisan therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

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 Myorisan®.

Pediatric Use

The use of Myorisan® in pediatric patients less than 12 years of age has not been studied. The use of Myorisan® for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General). Use of Myorisan® in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (≥18 years). Results from this study demonstrated that Myorisan®, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients.

In studies with Myorisan®, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).

In an open-label clinical trial (N=217) of a single course of therapy with Myorisan for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in five of eight patients (62.5%).

In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of Myorisan® 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).

Geriatric Use

Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS).

Clinical Trials and Postmarketing Surveillance

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

Storage

Store at 20°-25°C (68° to 77°F). [See USP controlled room temperature]. Protect from light.

What is the most important information I should know about 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.

What is Myorisan®?

Myorisan® is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Myorisan can cause serious side effects (see “What is the most important information I should know about Myorisan®?”). Myorisan® can only be:

- prescribed by doctors that are enrolled in the iPLEDGE REMS

- dispensed by a pharmacy that is enrolled with the iPLEDGE REMS

- given to patients who are enrolled in the iPLEDGE REMS and agree to do everything required in the program.

What is severe nodular acne?

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

Who should not take 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 list of ingredients in Myorisan®.

What should I tell my doctor before taking 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 list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.

How should I take Myorisan®?

- 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.

What should I avoid while taking Myorisan®?

- 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.

What are the possible side effects of Myorisan®?

- Myorisan® can cause birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. See “What is the most important information I should know about Myorisan®?”

- Myorisan® may cause serious mental health problems. See “What is the most important information I should know about Myorisan®?”

- serious brain problems. Myorisan® can increase the pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking Myorisan® and call your doctor right away if you get any of these signs of increased brain pressure:

- bad headache

- blurred vision

- dizziness

- nausea or vomiting

- seizures (convulsions)

- stroke

- skin problems. Skin rash can occur in patients taking Myorisan. In some patients a rash can be serious. Stop using Myorisan and call your doctor right away if you develop conjunctivitis (red or inflamed eyes, like "pink eye"), a rash with a fever, blisters on legs, arms or face and/or sores in your mouth, throat, nose, eyes, or if your skin begins to peel.

- stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking Myorisan®. Stop taking Myorisan® and call your doctor if you get:

- severe stomach, chest or bowel pain

- trouble swallowing or painful swallowing

- new or worsening heartburn

- diarrhea

- rectal bleeding

- yellowing of your skin or eyes

- dark urine

- bone and muscle problems. Myorisan® may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with Myorisan®. Tell your doctor if you get:

- back pain

- joint pain

- broken bone. Tell all healthcare providers that you take Myorisan® if you break a bone.

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

Myorisan® may stop long bone growth in teenagers who are still growing.

- hearing problems. Stop using Myorisan® and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent.

- vision problems. Myorisan® may affect your ability to see in the dark. This condition usually clears up after you stop taking Myorisan®, but it may be permanent. Other serious eye effects can occur. Stop taking Myorisan® and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking Myorisan® and after treatment.

- lipid (fats and cholesterol in blood) problems. Myorisan® can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when Myorisan® treatment is finished.

- serious allergic reactions. Stop taking Myorisan® and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking Myorisan® and call your doctor if you get a fever, rash, or red patches or bruises on your legs.

- blood sugar problems. Myorisan® may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot.

- decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel weak.

- The common, less serious side effects of Myorisan®are dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does not go away.

These are not all of the possible side effects with Myorisan®. Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Akorn at 1-800-932-5676.

How should I store Myorisan®?

- Store Myorisan® at 68°-77°F (20° to 25°C). Protect from light.

- Keep Myorisan® and all medicines out of the reach of children.

General Information about Myorisan® 

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

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

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

What are the ingredients in Myorisan®?

Active Ingredient: Isotretinoin

Inactive Ingredients: yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, tocopherol, and soybean oil. Gelatin capsules contain gelatin, glycerin, and non-crystallizing sorbitol solution, with the following dye systems: 10 mg – ferric oxide (yellow) and titanium dioxide; 20 mg - titanium dioxide; 30 mg - titanium dioxide and ferric oxide (red); 40 mg - FD&C Yellow No. 6 and titanium dioxide.

The edible imprinting ink for all the capsules contains: shellac glaze, dehydrated alcohol, isopropyl alcohol, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

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

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