Myorisan

Name: Myorisan

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to isotretinoin.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Pregnancy & Lactation

Pregnancy category: X (see Black Box Warnings)

Lactation: Unknown whether distributed into breast milk; because of potential for serious adverse reactions in nursing infants, do not administer to women who are breastfeeding

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Warnings

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 as ked 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 Adoles cents and Young Adults”), include s ad mood, hopelessness , feelings of guilt, worthlessness or helplessness, los s 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 us e 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 highdensity 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

Bone Mineral Density

Effects of multiple courses of Myorisan on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. 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 13-18 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 PRECAUTIONS: Pediatric Use).

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the Myorisan population. While causality to Myorisan has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Myorisan be given at the recommended doses for no longer than the recommended duration.

Hyperostosis

A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Myorisan treatment courses for acne are unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of Myorisan given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.

Premature Epiphyseal Closure

There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Myorisan. The effect of multiple courses of Myorisan on epiphyseal closure is unknown.

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).

Corneal Opacities

Corneal opacities have occurred in patients receiving Myorisan for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with Myorisan have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).

Decreased Night Vision

Decreased night vision has been reported during Myorisan therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.

What is the most important information I should know about Myorisan (isotretinoin)?

Isotretinoin in just a single dose can cause severe birth defects or death of a baby. Never use this medicine if you are pregnant or may become pregnant.

You must have a negative pregnancy test before taking isotretinoin. You will also be required to use two forms of birth control to prevent pregnancy while taking this medicine. Stop using isotretinoin and call your doctor at once if you think you might be pregnant.

Isotretinoin is available only under a special program called iPLEDGE. It is dangerous to try and purchase isotretinoin on the Internet or from vendors outside of the United States.

How should I take Myorisan (isotretinoin)?

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Each prescription of isotretinoin must be filled within 7 days of the date it was written by your doctor. You will receive no more than a 30-day supply of isotretinoin at one time.

Always take isotretinoin with a full glass of water. Do not chew or suck on the capsule. Swallow it whole.

Take isotretinoin with food.

Use this medicine for the full prescribed length of time. Your acne may seem to get worse at first, but should then begin to improve.

While using isotretinoin, you may need frequent blood tests.

Never share this medicine with another person, even if they have the same symptoms you have.

Store at room temperature away from moisture, heat, and light.

Commonly used brand name(s)

In the U.S.

  • Absorica
  • Accutane
  • Amnesteem
  • Claravis
  • Myorisan
  • Sotret
  • Zenatane

Available Dosage Forms:

  • Capsule
  • Capsule, Liquid Filled

Therapeutic Class: Antiacne

Chemical Class: Retinoid

Before Using Myorisan

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of isotretinoin in children younger than 12 years of age. Safety and efficacy have not been established.

This medicine should be used with caution in teenagers, especially those with bone problems or diseases.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of isotretinoin in the elderly. However, elderly patients may have a greater risk of problems and side effects when taking isotretinoin.

Pregnancy

Pregnancy Category Explanation
All Trimesters X Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Chlortetracycline
  • Demeclocycline
  • Desogestrel
  • Dienogest
  • Doxycycline
  • Drospirenone
  • Estradiol Cypionate
  • Estradiol Valerate
  • Ethinyl Estradiol
  • Ethynodiol Diacetate
  • Etonogestrel
  • Levonorgestrel
  • Lymecycline
  • Meclocycline
  • Medroxyprogesterone Acetate
  • Mestranol
  • Methacycline
  • Minocycline
  • Norelgestromin
  • Norethindrone
  • Norgestimate
  • Norgestrel
  • Oxytetracycline
  • Rolitetracycline
  • Tetracycline

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

  • Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Alcoholism, severe or
  • Allergy to aspirin, history of or
  • Diabetes or
  • Metabolism disorder, family history of or
  • Severe weight problems—Use with caution. May increase risks for more serious problems.
  • Anorexia (eating disorder) or
  • Epiphyseal closure, premature or
  • Osteomalacia (softening of the bones) or
  • Osteoporosis (brittle bones), childhood or family history of or
  • Other bone disorders or diseases—Use with caution. It is not known whether this medicine affects bone loss.
  • Asthma or
  • Depression, history of or
  • Eye or vision problems or
  • Hearing problems or
  • Heart disease or
  • Hepatitis or
  • Hypertriglyceridemia (high triglycerides in the blood) or
  • Intestinal disorders, history of or
  • Pancreatitis (inflammation of the pancreas) or
  • Pseudotumor cerebri (swelling in the brain) or
  • Psychosis, history of or
  • Vitamin A overdose (too much vitamin A in the body)—Use with caution. May make these conditions worse.
  • Kidney disease or
  • Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of isotretinoin

This section provides information on the proper use of a number of products that contain isotretinoin. It may not be specific to Myorisan. Please read with care.

Isotretinoin comes with a patient information form and Medication Guide. It is very important that you read and understand this information. Be sure to carefully follow these instructions and ask your doctor if you have any questions.

Women of reproductive age must sign up for a pregnancy risk program called iPLEDGE™ in order to receive their isotretinoin prescription each month. You can sign up on the internet (www.ipledge.com) or by telephone (1-866-495-0654). Be sure to ask your doctor if you have any questions about this program. It is very important that you understand and follow all of the requirements. You will not get another prescription unless you follow the instructions for the program.

Swallow the capsule whole with a full glass (8 ounces) of water or other liquid. Accutane® and its generic products should be taken with food. Absorica® may be taken with or without food. Do not crush, break, chew, or suck the capsule.

It is very important that you take isotretinoin only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

It is very important that you not share this medicine with anyone else because of the risk of birth defects and other serious side effects.

Absorica® oral capsules should not be substituted with other forms of isotretinoin (eg, Accutane®). Different brands may not work the same way. If you refill your medicine and it looks different, check with your pharmacist.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (capsules):
    • For acne:
      • Adults and children 12 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 0.5 to 1 milligram (mg) per kilogram (kg) of body weight per day, divided and given in 2 doses. Your doctor may adjust your dose as needed.
      • Children younger than 12 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of low mood (depression), thoughts of killing yourself, nervousness, emotional ups and downs, thinking that is not normal, anxiety, or lack of interest in life.
  • Mean actions or thoughts of fighting.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Signs of esophagus problems like chest pain, trouble swallowing, or new or worse heartburn.
  • Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
  • Eye pain.
  • Muscle pain or weakness.
  • Bone or joint pain.
  • Any unexplained bruising or bleeding.
  • Feeling very tired or weak.
  • Not able to pass urine or change in how much urine is passed.
  • Back pain.
  • Hearing problems like change in hearing or ringing in the ears may happen. This may go away after stopping the drug but sometimes it may not.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
  • Very bad and sometimes deadly pancreas problems (pancreatitis) have happened with Myorisan. Call your doctor right away if you have very bad stomach pain, very bad back pain, or very upset stomach or throwing up.

Myorisan Description

Isotretinoin, a retinoid, is available as Myorisan in 10-mg, 20-mg, 30-mg and 40-mg soft gelatin capsules for oral administration. Each capsule contains 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.

USP Dissolution Test Pending.

Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:

Precautions

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

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

Wholesalers:

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

• Registering prior to distributing isotretinoin and re-registering annually thereafter

• Distributing only FDA approved isotretinoin product

• Only shipping isotretinoin to

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

- pharmacies licensed in the US and registered and activated in the iPLEDGE Program

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

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

• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not re-register annually

Prescribers:

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

• I know the risk and severity of fetal injury/birth defects from isotretinoin.

• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.

• I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer.

• I will comply with the iPLEDGE Program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide.

• Before beginning treatment of females of reproductive potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence.

• I will not prescribe isotretinoin to any females of reproductive potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test 1 month later.

• I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or one month after the last dose to the pregnancy registry.

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

1)  Register each patient in the iPLEDGE Program.

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

3) For females of reproductive potential:

• Enter patient’s two chosen forms of contraception each month.

• Enter monthly result from CLIA-certified laboratory conducted pregnancy test.

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

Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE Program. Meeting the requirements for a female of reproductive potential signifies that she:

• Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.

• Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests should be at least 19 days.

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

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

• Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.

• Has selected and has committed to use two forms of effective contraception simultaneously, at least one of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be 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 heterosexual intercourse at any time one month before, during, or one month after therapy, she must:

1. Stop taking Myorisan immediately, if on therapy

2. Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse

3. Start using two forms of effective contraception simultaneously again for one month before resuming Myorisan therapy

4. Have a second pregnancy test after using two forms of effective contraception for one month as described above depending on whether she has regular menses or not.

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

Primary forms

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

Secondary forms

Barrier:

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

Other:

• vaginal sponge (contains spermicide)

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

Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for 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).

All Patients

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

• Must be registered with the iPLEDGE Program by the prescriber

• Must understand that severe birth defects can occur with the use of isotretinoin by female patients

• Must be reliable in understanding and carrying out instructions

• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin

• Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for females of reproductive potential

• Must obtain the prescription within 30 days of the office visit for male patients and females of non-reproductive potential

• Must not donate blood while on isotretinoin and for one month after treatment has ended

• Must not share isotretinoin with anyone, even someone who has similar symptoms

Females of Reproductive Potential

Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential must meet the following conditions:

• Must NOT be pregnant or breast-feeding

• Must comply with the required pregnancy testing at a CLIA-certified laboratory

• Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test

• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy

• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy

• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin

• Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and one month after the last dose to answer questions on the program requirements and to enter the patient’s two chosen forms of contraception

• Must have been informed of the purpose and importance of providing information to the iPLEDGE Program should she become pregnant while taking isotretinoin or within one month of the last dose

Pharmacists:

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

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

• I know the risk and severity of fetal injury/birth defects from isotretinoin.

• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE Program requirements.

• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE Program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program.

• I will obtain Myorisan product only from iPLEDGE registered wholesalers.

• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.

• I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually.

• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1) be trained by the Responsible Site Pharmacist concerning the iPLEDGE Program requirements.

2) obtain authorization from the iPLEDGE Program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive 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 Program

• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and females of non-reproductive potential and within 7 days of the date of specimen collection for females of reproductive potential)

• with a new prescription for refills and another authorization from the iPLEDGE Program (No automatic refills are allowed)

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

1) The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Myorisan prescription.

2) The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.

3) The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.

4) The iPLEDGE Program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE Program includes information on the risks and benefits of isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each Myorisan prescription.

5) Females of non-reproductive potential and male patients, and females of reproductive potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides Myorisan information in two languages.

6) The booklet for females of non-reproductive potential and male patients, The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share isotretinoin with others or to donate blood during Myorisan therapy and for one month following discontinuation of isotretinoin.

7) The booklet for females of reproductive potential, The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects.

8) The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line.

9) In addition, there are patient educational materials with the following videos "Be Prepared, Be Protected" and "Be Aware: The Risk of Pregnancy While on Isotretinoin" (see Information for Patients).

General

Although an effect of 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 Program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form.

• Females of reproductive potential must be instructed that they must not be pregnant when 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 heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Myorisan therapy. They should be given an opportunity to view the patient video provided by the manufacturer to the prescriber. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using two forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Myorisan at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another 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 female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete, and two had other possible explanations for the defects observed.

• Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of 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 Myorisan 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 female 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.

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

Drug Interactions

• Vitamin A: Because of the relationship of 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 female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Myorisan. Therefore, it is critically important for females of reproductive potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS).

• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, 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.

Laboratory Tests

• Pregnancy Test:

-Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial 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 female patient 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).

(web3)