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 Amnesteem, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Special Patient Populations

Severe Recalcitrant Nodular Acne

Amnesteem 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, Amnesteem should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Amnesteem is indicated only for those patients who are not pregnant, because Amnesteem 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 Amnesteem. 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

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

Psychiatric Disorders

Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Amnesteem therapy.

Pseudotumor Cerebri

Amnesteem 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 Amnesteem 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 [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These events may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of Amnesteem 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. Amnesteem 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 Amnesteem. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Amnesteem 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 Amnesteem 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 Amnesteem.5

Blood lipid determinations should be performed before Amnesteem is given and then at intervals until the lipid response to Amnesteem 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 Amnesteem therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Amnesteem 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 Amnesteem are unknown.

Hearing Impairment

Impaired hearing has been reported in patients taking Amnesteem; 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 Amnesteem 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 Amnesteem 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 Amnesteem, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

Amnesteem 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 Amnesteem treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Amnesteem immediately (see ADVERSE REACTIONS: Gastrointestinal).

Skeletal

Vision Impairment

Visual problems should be carefully monitored. All Amnesteem patients experiencing visual difficulties should discontinue Amnesteem 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 Amnesteem, 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

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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/audit 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:

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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 REMS 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)

Register 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.

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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.

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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 Amnesteem 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 Amnesteem therapy

4.

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

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

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 Amnesteem. 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 warnings about the importance of choosing one primary method and a secondary method 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 Amnesteem (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 Amnesteem treatment, Amnesteem 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 Amnesteem therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE Pregnancy Registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

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

•

Must be enrolled with the iPLEDGE REMS by the prescriber

•

Must understand that life threatening birth defects can occur with the use of isotretinoin by patients who can become pregnant

•

Must be reliable in understanding and carrying out instructions

•

Must sign a Patient Enrollment Form for Patients who cannot get Pregnant that contains warnings about the potential risks associated with isotretinoin

•

Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for patients who can become pregnant

•

Must obtain the prescription within 30 days of the office visit for patients who cannot become pregnant

•

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

•

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

Patients Who Become Pregnant

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

•

Must NOT be pregnant or breast-feeding

•

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

•

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

•

Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence not having any sexual contact with a partner that could result in pregnancy, and understand behaviors associated with an increased risk of pregnancy

•

Must understand that it is the patient who can become pregnant responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy

•

Must have signed an additional Patient Enrollment Form for Patients who can get Pregnant, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin

•

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

•

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

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 REMS 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:

o

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 the Non-Compliance Action Policy.

•

I will obtain Amnesteem product only from 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 Amnesteem.

3)

write the Risk Management Authorization (RMA) number on the prescription.

Amnesteem must only be dispensed:

•

in no more than a 30-day supply

•

with an Amnesteem 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)

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

Amnesteem must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE REMS. Only FDA-approved Amnesteem products must be distributed, prescribed, dispensed, and used. Patients must obtain Amnesteem prescriptions only at U.S. 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)

The Prescriber Guide includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Amnesteem 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 Amnesteem 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 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 Amnesteem 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 Amnesteem on bone loss is not established, physicians should use caution when prescribing Amnesteem 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 Amnesteem or following cessation of therapy with Amnesteem while involved in these activities. While causality to Amnesteem 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 Amnesteem 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 Amnesteem therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Amnesteem, while taking Amnesteem, and for one month after Amnesteem 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 Amnesteem 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 Amnesteem prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS).

•

Amnesteem is found in the semen of male patients taking Amnesteem, 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 post-marketing 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 Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Amnesteem therapy.

•

Patients must be informed that some patients, while taking Amnesteem or soon after stopping Amnesteem, 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 Amnesteem 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 Amnesteem 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 Amnesteem. Some people have had other signs of depression while taking Amnesteem.

•

Patients must be informed that they must not share Amnesteem 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 Amnesteem.

•

Patients should be reminded to take Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare post-marketing 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 Amnesteem 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 Amnesteem. Consideration should be given to discontinuation of Amnesteem if any significant abnormality is found.

•

Neutropenia and rare cases of agranulocytosis have been reported. Amnesteem 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. Amnesteem 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 Amnesteem to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.

•

Tetracyclines: Concomitant treatment with Amnesteem and tetracyclines should be avoided because Amnesteem 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 Amnesteem therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Amnesteem. Therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS).

•

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

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Phenytoin: Amnesteem 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 Amnesteem. Therefore, caution should be exercised when using these drugs together.

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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 Amnesteem. Therefore, caution should be exercised when using these drugs together.

Laboratory Tests

Carcinogenesis, Mutagenesis, 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 1.6 x 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 Amnesteem therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

Pregnancy

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 Amnesteem.

Pediatric Use

The use of Amnesteem in pediatric patients less than 12 years of age has not been studied. The use of Amnesteem 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 Amnesteem 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 Amnesteem, 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 Amnesteem, 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 Amnesteem 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 Amnesteem 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 Post-marketing Surveillance

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

Dose Relationship

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

Body as a Whole: allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

Cardiovascular: palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic: hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)

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

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

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

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

Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System: abnormal menses

Respiratory: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

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

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

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

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

Laboratory

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

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

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

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

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