Amnesteem

• Isotretinoin is an oral drug used for the treatment and prevention of severe acne. Acne is caused by inflammation of the skin. It primarily affects teenagers, but it also affects adults. Severe acne causes permanent scarring of the skin. The inflammation is caused in part by an increased secretion of sebum (oily substance) from glands in the skin (sebaceous glands). The sebum provokes inflammation, and the inflammation resolves (heals) with the formation of a scar (keratinization). The exact mechanism of action of isotretinoin is not known; however, it may reduce acne by reducing the secretion of sebum. If less sebum is secreted it is likely that there will be less inflammation and keratinization.
• The Food and Drug Administration approved isotretinoin in May 1982.

• Isotretinoin is harmful to the fetus and therefore should not be used during pregnancy. Women of childbearing age must have two negative pregnancy test results before therapy is started, and a pregnancy test must be conducted during each month of therapy. Two effective forms of birth control must be used during therapy, and pregnancy should be avoided one month before, during, and at least one month after stopping isotretinoin.
• It is not known whether isotretinoin is secreted in breast milk, but because of its potentially serious side effects, it should not be used by nursing mothers.

Dosage Forms & Strengths

capsule

• 10mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
• 20mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
• 25mg (Absorica)
• 30mg (Absorica, Claravis)
• 35mg (Absorica)
• 40mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)

Severe, Recalcitrant Nodular Acne

Severe nodular acne unresponsive to conventional therapy, including systemic antibiotics

0.5-1 mg/kg/day PO divided BID for 15-20 weeks 

Dose up to 2 mg/kg/day (as tolerated) if disease is very severe with scarring or is primarily manifested on the trunk

Dosing considerations

• >2 months after discontinuation: If warranted by persistent or recurring, severe nodular acne, may initiate a 2nd course of therapy
• If total nodule count is reduced by >70% prior to completing 15-20 weeks, may discontinue drug

Administration

Swallow capsule whole with full glass of water to reduce esophageal irritation

Amnesteem, Claravis, Myorisan: Take with food (significantly improves absorption)

Absorica: May be taken with or without food

Dosage Forms & Strengths

capsule

• 10mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
• 20mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)
• 25mg (Absorica)
• 30mg (Absorica, Claravis)
• 35mg (Absorica)
• 40mg (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)

Severe, Recalcitrant Nodular Acne

Severe nodular acne unresponsive to conventional therapy, including systemic antibiotics

<12 years: Safety and efficacy not established

≥12 years: 0.5-1 mg/kg/day PO divided BID for 15-20 weeks 

Dose up to 2 mg/kg/day (as tolerated) if disease is very severe with scarring or is primarily manifested on the trunk

Dosing considerations

• >2 months after discontinuation: If warranted by persistent or recurring, severe nodular acne, may initiate a 2nd course of therapy
• If total nodule count is reduced by >70% prior to completing 15-20 weeks, may discontinue drug

Ichthyosis (Orphan)

Orphan designation for treatment of congenital ichthyosis

Orphan sponsor

• Patagonia Pharmaceuticals, LLC; 50 Tice Blvd, Suite A35; Woodcliff Lake, NJ 07677

Administration

Swallow capsule whole with full glass of water to reduce esophageal irritation

Amnesteem, Claravis, Myorisan: Take with food (significantly improves absorption)

Absorica: May be taken with or without food

Black Box Warnings

Embryofetal toxicity

• Do not use in female patients who are or may become pregnant, because therapy poses an extremely high risk for severe birth effects (with any dose or duration)
• Documented embryofetal effects include internal and external abnormalities, IQ scores of <85, spontaneous abortion, premature birth, and fetal death
• Documented external abnormalities include skull abnormality, ear abnormalities (including anotia, micropinna, small or absent external auditory canals), eye abnormalities (including microphthalmia), facial dysmorphia, and cleft palate
• Documented internal abnormalities include CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit), cardiovascular abnormalities, thymus gland abnormality, and parathyroid hormone deficiency
• Discontinue immediately if pregnancy occurs and refer patient to an obstetrician-gynecologist experienced in reproductive toxicity for evaluation
• Potentially any fetus exposed during pregnancy can be affected, but there are no accurate methods to determine whether an exposed fetus has been affected

Restricted distribution program

• Prescribers must register with iPLEDGE, an FDA-approved risk management program designed to minimize pregnancy exposures to isotretinoin (enhancement of earlier riskMAP [risk minimization action plan]); patients must be registered and meet all requirements of iPLEDGE
• Patients of childbearing potential must not be pregnant or breastfeeding, must be capable of complying with approved contraceptive methods, and must be reliable in following instructions

Contraindications

Pregnancy (see Black Box Warnings)

Hypersensitivity to isotretinoin or vitamin A

Cautions

Significant adverse effects are associated with isotretinoin use

Embryofetal toxicity; major congenital malformations, spontaneous abortions, and premature births documented (see Black Box Warnings)

Do not donate blood during therapy and for 1 month after discontinuing treatment, because of embryofetal toxicity risk

Restricted distribution program (iPLEDGE), a risk management program to minimize pregnancy exposure, has been implemented (see Black Box Warnings)

Microdosed, progesterone-only preparations (‘minipills’) are an inadequate method of contraception during treatment

Depression and psychosis reported; rare reports of suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors

Pseudotumor cerebri reported; some reports involved concomitant tetracycline use

Serious skin reactions reported (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis)

Acute pancreatitis reported with either elevated or normal serum triglyceride levels, including rare instances of fatal hemorrhagic pancreatitis; discontinue if unable to control hypertriglyceridemia

Increased triglycerides and total cholesterol levels reported; whereas, decreased HDL-cholesterol reported

Hearing impairment reported and may persist after discontinuing therapy

Hepatitis may occur; mild to moderate liver enzymes elevations also reported

Associated with inflammatory bowel disease (including regional ileitis); discontinue immediately if abdominal pain, rectal bleeding, or severe diarrhea occurs

Negative effect on bone mineral density reported; caution with childhood osteoporosis, osteomalacia, chronic corticosteroid use, or anorexia nervosa

Musculoskeletal symptoms, including arthralgia, may occur

Skeletal hyperostosis observed in clinical trial for keratinization disorders

Premature epiphyseal closure reported spontaneously with normal doses

Ocular abnormalities observed, including corneal opacities, decreased night vision, and dry eye

Hypersensitivity reactions (eg, anaphylactic, cutaneous, allergic vasculitis) reported; severe allergic reaction requires discontinuation and medical management

Laboratory monitoring

• Pretreatment monitoring: LFTs (1 day before starting initiating therapy), 2 pregnancy tests (negative result 2 weeks before), and fasting lipid profile (including triglycerides)
• During treatment: Monitor LFTs and lipids at weekly or biweekly intervals until response to isotretinoin established
• Blood glucose, CPK (particularly in those undergoing vigorous physical activity)
• Ongoing negative pregnancy tests required according to iPLEDGE rules

Amnesteem is part of the drug class:

• Retinoids for topical use in acne

Skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include headache, dizziness, vomiting, stomach pain, warmth or tingling in your face, swollen or cracked lips, and loss of balance or coordination.

• If you have an allergy to this medicine or any part of Amnesteem.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are able to get pregnant and are not using 2 kinds of birth control.
• If you are planning to get pregnant within 1 month before care, during care, or within 1 month after care has ended.
• If you are breast-feeding. Do not breast-feed while you take this medicine or for 1 month after you stop Amnesteem.
• If you are taking any of these drugs: Demeclocycline, doxycycline, minocycline, tetracycline, a product that has vitamin A in it, a product that is like vitamin A, or St. John's wort.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Amnesteem with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Amnesteem must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Amnesteem 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 Amnesteem 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 Amnesteem, 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 reregister annually

Prescribers

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

• I know the risk and severity of fetal injury/birth defects from isotretinoin. • I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy. • I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer. • I will comply with the iPLEDGE Program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide. • Before beginning treatment of females of reproductive potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during and one month after isotretinoin therapy, unless the patient commits to continuous abstinence. • I will not prescribe isotretinoin to any females of reproductive potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin capsules and another pregnancy test one month later. • I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or one month after the last dose to the pregnancy registry.

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

• Register each patient in the iPLEDGE Program. • Confirm monthly that each patient has received counseling and education. • For females of reproductive potential: 1. Enter patient’s two chosen forms of contraception each month. 2. 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:

• Stop taking Amnesteem immediately, if on therapy • Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse • Start using two forms of effective contraception simultaneously again for one month before resuming Amnesteem therapy • 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 Amnesteem. 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 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 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 females 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 females 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 Amnesteem 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:

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

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 Program. 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 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.

• The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified Amnesteem prescription. • 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. • The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription. • 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 Amnesteem which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription. • Females of non-reproductive potential and male patients, and females of reproductive potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form and a toll-free line which provides isotretinoin information in two languages. • 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 Amnesteem with others or to donate blood during isotretinoin therapy and for one month following discontinuation of isotretinoin. • 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 females who can get pregnant) form concerning birth defects. • 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. • 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 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 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 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 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 Amnesteem 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 Amnesteem 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 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 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 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 Amnesteem 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 female 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 (Steven-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 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 Amnesteem. 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, 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. • 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. • 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

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 Amnesteem prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Amnesteem. 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 Amnesteem 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 Amnesteem 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 Amnesteem is established. The incidence of hypertriglyceridemia is one patient in four on Amnesteem 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 Amnesteem has been established (see WARNINGS: Hepatotoxicity).

Glucose

Some patients receiving Amnesteem have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Amnesteem therapy, although no causal relationship has been established.

CPK

Some patients undergoing vigorous physical activity while on Amnesteem therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare post-marketing 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, 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 (isotretinoin) 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 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).

Applies to isotretinoin: oral capsule, oral capsule liquid filled

Along with its needed effects, isotretinoin (the active ingredient contained in Amnesteem) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking isotretinoin:

More common

• Bone or joint pain
• burning, redness, itching, or other signs of eye inflammation
• difficulty with moving
• nosebleeds
• scaling, redness, burning, pain, or other signs of inflammation of the lips
• skin infection or rash

Rare

• Abdominal or stomach pain (severe)
• attempts at suicide or thoughts of suicide (usually stops after medicine is stopped)
• back pain
• bleeding or inflammation of the gums
• blurred vision or other changes in vision
• changes in behavior
• decreased vision after sunset or before sunrise (sudden or may continue after medicine is stopped)
• diarrhea (severe)
• headache (severe or continuing)
• mental depression
• nausea and vomiting
• pain or tenderness of the eyes
• pain, tenderness, or stiffness in the muscles (long-term treatment)
• rectal bleeding
• yellow eyes or skin

Incidence not known

• Black, tarry stools
• bloating
• bloody cough
• bloody or cloudy urine
• bone pain, tenderness, or aching
• burning or stinging of the skin
• chest pain
• confusion
• constipation
• convulsions
• cough or hoarseness
• dark-colored urine
• decrease in height
• difficulty breathing
• difficulty speaking
• difficulty swallowing
• discharge from the eyes
• dizziness
• double vision
• ear pain
• excessive tearing
• fainting
• fast, irregular, pounding, or racing heartbeat or pulse
• fever with or without chills
• fractures and/or delayed healing
• heartburn
• high blood pressure
• hives or skin rash
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• inflamed tissue from infection
• irregular yellow patch or lump on the skin
• irritation
• joint pain, redness, stiffness, or swelling
• lack or slowing of normal growth in children
• loosening of the fingernails
• loss of appetite
• loss of bladder control
• loss or change in hearing
• muscle cramps, spasms, or weakness
• pain in the ribs, arms, or legs
• pain or burning in the throat
• pain or tenderness around the eyes and cheekbones
• painful cold sores or blisters on the lips, nose, eyes, or genitals
• painful or difficult urination
• pains in the chest, groin, or legs, especially calves of the legs
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• pinpoint red spots on the skin
• redness or soreness around the fingernails
• redness, soreness, or itching skin
• sensitivity of the eyes to sunlight
• sneezing
• sores, ulcers, or white spots on the lips or tongue or inside the mouth
• stuffy or runny nose
• sudden loss of consciousness
• sudden loss of coordination
• sudden onset of severe acne on the chest and trunk
• sudden onset of slurred speech
• swelling of the eyelids, face, lips, hands, lower legs, or feet
• swollen, painful or tender lymph glands in the neck, armpit, or groin
• tightness in the chest
• unusual bleeding or bruising
• unusual weight gain or loss
• use of extreme physical or emotional force
• watery or bloody diarrhea

Some side effects of isotretinoin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Crusting of the skin
• difficulty in wearing contact lenses (may continue after medicine is stopped)
• dryness of the eyes (may continue after treatment is stopped)
• dryness of the mouth or nose
• dryness or itching of the skin
• headache (mild)
• increased sensitivity of the skin to sunlight
• peeling of the skin on palms of the hands or soles of the feet
• stomach upset
• thinning of the hair (may continue after treatment is stopped)

Incidence not known

• Abnormal menstruation
• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feeling
• changes in fingernails or toenails
• continuing ringing or buzzing, or other unexplained noise in the ears
• dandruff
• darkening of the skin
• flushing
• hair abnormalities
• hair loss
• increased hair growth, especially on the face
• lightening of normal skin color
• lightening of treated areas of dark skin
• nervousness
• oily skin
• redness of the face
• severe sunburn
• skin rash, encrusted, scaly and oozing
• stomach burning
• sweating
• trouble sleeping
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusually warm skin of the face
• voice changes