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Amnesteem (Isotretinoin) - Warnings and Precautions

 
 



CONTRAINDICATLONS AND WARNINGS

Amnesteem capsules must not be used by females who are pregnant. Although not every fetus exposed to isotretinoin has resulted in a deformed child, there is an extremely high risk that a deformed infant can result if pregnancy occurs while taking isotretinoin capsules in any amount even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. Presently, there are no accurate means of determining, after isotretinoin exposure, which fetus has been affected and which fetus has not been affected.

Major human fetal abnormalities related to isotretinoin administration in females have been documented. There is an increased risk of spontaneous abortion. In addition, premature births have been reported.

Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted.

Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also been reported.

Amnesteem is contraindicated in females of childbearing potential unless the patient meets all of the following conditions:

  • Must NOT be pregnant or breast-feeding.
  • Must be capable of complying with the mandatory contraceptive measures required for Amnesteem therapy and understand behaviors associated with an increased risk of pregnancy.
  • Must be reliable in understanding and carrying out instructions.

Amnesteem must be prescribed under the System to Prevent Isotretinoin-Related Issues of Teratogenicity™ (S.P.I.R.I.T.™).

To prescribe Amnesteem, the prescriber must obtain a supply of yellow self-adhesive isotretinoin qualification stickers. To obtain these stickers:

  1. Read the booklet entitled System to Prevent Isotretinoin-Related Issues of Teratogenicity (S.P.I.R.I.T.) Guide to Best Practices.
  2. Sign and return the completed S.P.I.R.I.T. Letter of Understanding containing the following Prescriber Checklist:
    • I know the risk and severity of fetal injury/birth defects from isotretinoin
    • I know how to diagnose and treat the various presentations of acne
    • I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy
    • It is the informed patient's responsibility to avoid pregnancy during Amnesteem therapy and for 1 month after stopping Amnesteem. To help patients have the knowledge and tools to do so: Before beginning treatment of female patients with Amnesteem I will refer for expert, detailed pregnancy prevention counseling and prescribing, reimbursed by Bertek Pharmaceuticals Inc., OR I have the expertise to perform this function and elect to do so
    • I understand, and will properly use throughout the Amnesteem treatment course, the S.P.I.R.I.T. procedures for Amnesteem, including monthly pregnancy avoidance counseling, pregnancy testing and use of the yellow self-adhesive isotretinoin qualification stickers
  3. To use the yellow self-adhesive isotretinoin qualification stickers: Amnesteem should not be prescribed or dispensed to any patient (male or female) without a yellow self-adhesive isotretinoin qualification sticker.

For female patients, the yellow self-adhesive isotretinoin qualification sticker signifies that she:

  • Must have had 2 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) should be done during the first 5 days of the menstrual period immediately preceding the beginning of Amnesteem therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception). Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated every month prior to the female patient receiving each prescription.
  • Must have selected and have committed to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has undergone a hysterectomy. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of Amnesteem therapy, during Amnesteem therapy, and for 1 month after discontinuing Amnesteem therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.

Effective forms of contraception include both primary and secondary forms of contraception. Primary forms of contraception include: tubal ligation, partner's vasectomy, intrauterine devices, birth control pills, and topical/injectable/implantable/insertable hormonal birth control products. Secondary forms of contraception include diaphragms, latex condoms, and cervical caps; each must be used with a spermicide.

Any birth control method can fail. Therefore, it is critically important that women of childbearing potential use 2 effective forms of contraception simultaneously. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin. Although hormonal contraceptives are highly effective, there have been reports of pregnancy from women who have used oral contraceptives, as well as topical/injectable/implantable/insertable hormonal birth control products. These reports occurred while these patients were taking isotretinoin. These reports are more frequent for women who use only a single method of contraception. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

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 (see PRECAUTIONS).

  • Must have signed a Patient Information/Consent form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin.
  • Must have been informed of the purpose and importance of participating in the Isotretinoin Survey and have been given the opportunity to enroll (see PRECAUTIONS).

The yellow self-adhesive isotretinoin qualification sticker documents that the female patient is qualified, and includes the date of qualification, patient gender, cut-off date for filling the prescription, and up to a 30-day supply limit with no refills.

These yellow self-adhesive isotretinoin qualification stickers should also be used for male patients.

If a pregnancy does occur during treatment of a woman with Amnesteem, the prescriber and patient should discuss the desirability of continuing the pregnancy. Prescribers are strongly encouraged to report all cases of pregnancy to Bertek Medical Services @ 1-800-809-8237 where a Bertek Pregnancy Prevention Initiative Specialist will be available to discuss Bertek pregnancy information, or prescribers may contact the Food and Drug Administration MedWatch Program @ 1-800-FDA-1088.

Amnesteem should be prescribed only by prescribers who have demonstrated special competence in the diagnosis and treatment of severe recalcitrant nodular acne, are experienced in the use of systemic retinoids, have read the S.P.I.R.I.T. Guide to Best Practices, signed and returned the completed S.P.I.R.I.T. Letter of Understanding, and obtained yellow self-adhesive isotretinoin qualification stickers. Amnesteem should not be prescribed or dispensed without a yellow self-adhesive isotretinoin qualification sticker.

INFORMATION FOR PHARMACISTS:

AMNESTEEM MUST ONLY BE DISPENSED:

  • IN NO MORE THAN A 30-DAY SUPPLY
  • ONLY ON PRESENTATION OF AN ISOTRETINOIN CAPSULES PRESCRIPTION WITH A YELLOW SELF-ADHESIVE ISOTRETINOIN QUALIFICATION STICKER
  • WITHIN 7 DAYS OF THE QUALIFICATION DATE
  • REFILLS REQUIRE A NEW PRESCRIPTION WITH A YELLOW SELF-ADHESIVE ISOTRETINOIN QUALIFICATION STICKER
  • NO TELEPHONE OR COMPUTERIZED PRESCRIPTIONS ARE PERMITTED.

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 PATIENT.

Table 1. Use of Pregnancy Tests and Isotretinoin Qualification Stickers for Patients
Patient Type Pregnancy
Test Required
Qualification Date Isotretinoin
Qualification
Sticker Necessary
Dispense
Within
7 Days
of Qualification Date
All Males No Date Prescription Written Yes Yes
Females of
Childbearing Potential
Yes Date Sample Taken for
Confirmatory
Negative Pregnancy Test
Yes Yes
Females *
Not of
Childbearing Potential
No Date Prescription Written Yes Yes
*Females who have had a hysterectomy or who are postmenopausal are not considered to be of childbearing potential.

WARNINGS

PSYCHIATRIC DISORDERS

Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. Discontinuation of isotretinoin capsules therapy may be insufficient; further evaluation may be necessary. 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: Guide for Prescribers of Amnesteem.

PSEUDOTUMOR CEREBRI

Isotretinoin 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).

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 isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin 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 isotretinoin 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 isotretinoin.5

Blood lipid determinations should be performed before Amnesteem is given and then at intervals until the lipid response to isotretinoin 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 isotretinoin capsules are unknown.

Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).

HEARING IMPAIRMENT

Impaired hearing has been reported in patients taking isotretinoin; 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 isotretinoin 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

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

SKELETAL

Bone Mineral Density

Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin 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 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 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 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).

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

Hyperostosis

A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin capsules treatment courses for acne are unknown.

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

Premature Epiphyseal Closure

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

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).

Corneal Opacities

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

Decreased Night Vision

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

PRECAUTIONS

The Amnesteem Pregnancy Prevention Risk Management Programs consist of the System to Prevent Isotretinoin-Related Issues of Teratogenicity (S.P.I.R.I.T.) and the Amnesteem Pregnancy Prevention Initiative. S.P.I.R.I.T. should be followed for prescribing Amnesteem with the goal of preventing fetal exposure to isotretinoin. It consists of: 1) reading the booklet entitled System to Prevent Isotretinoin-Related Issues of Teratogenicity (S.P.I.R.I.T.) Guide to Best Practices, 2) signing and returning the completed S.P.I.R.I.T. Letter of Understanding containing the Prescriber Checklist, 3) a yellow self-adhesive isotretinoin qualification sticker to be affixed to the prescription page. In addition, the patient education material, A Personal Guide to Your Prescription, should be used with each patient. The following further describes each component:

  1. The S.P.I.R.I.T. Guide to Best Practices includes: isotretinoin teratogenic potential, information on pregnancy testing, specific information about effective contraception, the limitations of contraceptive methods and behaviors associated with an increased risk of contraceptive failure and pregnancy, the methods to evaluate pregnancy risk, and the method to complete a qualified Amnesteem prescription.
  2. The S.P.I.R.I.T. Letter of Understanding attests that Amnesteem prescribers understand that isotretinoin is a teratogen, have read the S.P.I.R.I.T. Guide to Best Practices, understand their responsibilities in preventing exposure of pregnant females to isotretinoin and the procedures for qualifying female patients as defined in the boxed CONTRAINDICATIONS AND WARNINGS.
    The Prescriber Checklist attests that Amnesteem prescribers know the risk and severity of injury/birth defects from isotretinoin; know how to diagnose and treat the various presentations of acne; know the risk factors for unplanned pregnancy and the effective measures for avoidance; will refer the patient for, or provide, detailed pregnancy prevention counseling to help the patient have knowledge and tools needed to fulfill their ultimate responsibility to avoid becoming pregnant; understand and properly use throughout the isotretinoin capsules treatment course, the revised risk management procedures, including monthly pregnancy avoidance counseling, pregnancy testing, and use of qualified prescriptions with the yellow self-adhesive isotretinoin qualification sticker.
  3. The yellow self-adhesive isotretinoin qualification sticker is used as documentation that the prescriber has qualified the female patient according to the qualification criteria (see boxed CONTRAINDICATIONS AND WARNINGS).
  4. Amnesteem Pregnancy Prevention Initiative is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The Amnesteem Pregnancy Prevention Initiative includes information on the risks and benefits of isotretinoin which is linked to the Amnesteem Medication Guide dispensed by pharmacists with each prescription.
    Male and female patients are provided with separate booklets. Each booklet contains information on Amnesteem therapy, including precautions and warnings, an Informed Consent/Patient Agreement form, and a toll-free line which provides Amnesteem information in English and Spanish.
    The booklet for male patients, A Personal Guide to Your Prescription for Men, also includes information about male reproduction, a warning not to share Amnesteem with others or to donate blood during Amnesteem therapy and for 1 month following discontinuation of Amnesteem.
    The booklet for female patients, A Personal Guide to Your Prescription for Women, also includes a referral program that offers females free contraception counseling, reimbursed by Bertek Pharmaceuticals Inc., by a reproductive specialist; a second Patient Information/Consent form concerning birth defects, obtaining her consent to be treated within this agreement; an enrollment form for the Isotretinoin Survey; and a qualification checklist affirming the conditions under which female patients may receive Amnesteem. In addition, there is information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, and the rates of possible contraceptive failure; a toll-free contraception counseling line; and patient education videos -- the video Don't Risk It: The importance of preventing pregnancy while you're taking Amnesteem®, and the video Birth Defects and Amnesteem®: Things You Should Know.

GENERAL

Although an effect of isotretinoin 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 treatment with isotretinoin or following cessation of treatment with isotretinoin while involved in these activities. While causality to isotretinoin has not been established, an effect cannot be ruled out.

INFORMATION FOR PATIENTS AND PRESCRIBERS

  • Patients should be instructed to read the Medication Guide supplied as required by law when isotretinoin capsules are dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients should also read the Patient Product Information, Important Information Concerning Your Treatment with Amnesteem. All patients should sign the Informed Consent/Patient Agreement.
  • Females of childbearing potential should be instructed that they must not be pregnant when Amnesteem therapy is initiated, and that they should use 2 forms of effective contraception 1 month before starting Amnesteem, while taking Amnesteem, and for 1 month after Amnesteem has been stopped. They should also sign a consent form prior to beginning Amnesteem therapy. They should be given an opportunity to enroll in the Isotretinoin Survey and to review the patient videotapes provided by Bertek Pharmaceuticals Inc. to the prescriber. The videos include information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a woman who is pregnant takes isotretinoin at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test performed each month during treatment to confirm negative pregnancy status before another Amnesteem prescription is written (see boxed CONTRAINDICATIONS AND WARNINGS).
  • Isotretinoin is found in the semen of male patients taking isotretinoin capsules, but the amount delivered to a female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible with features of retinoid exposed fetuses. None of these cases had the combination of malformations characteristic of retinoid exposure, and all had other possible explanations for the defects observed.
  • 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 or not Amnesteem therapy is appropriate in this setting (see WARNINGS: Psychiatric Disorders).
  • Patients should be informed that they must not share Amnesteem with anyone else because of the risk of birth defects and other serious adverse events.
  • Patients should not donate blood during therapy and for 1 month following discontinuance of the drug because the blood might be given to a pregnant woman whose fetus must not be exposed to isotretinoin.
  • 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 isotretinoin 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 isotretinoin, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests: CPK)
  • Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with isotretinoin developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female 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 isotretinoin. Consideration should be given to discontinuation of isotretinoin if any significant abnormality is found.
  • Neutropenia and rare cases of agranulocystosis have been reported. Amnesteem should be discontinued if clinically significant decreases in white cell counts 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 isotretinoin to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
  • Tetracyclines: Concomitant treatment with isotretinoin and tetracyclines should be avoided because isotretinoin 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 isotretinoin capsules therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from women who have used combined oral contraceptives, as well as topical/injectable/implantable/insertable hormonal birth control products. These reports are more frequent for women who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with isotretinoin. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has undergone a hysterectomy (see boxed CONTRAINDICATIONS AND WARNINGS).
  • Phenytoin: Isotretinoin 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 isotretinoin. 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 isotretinoin. Therefore, caution should be exercised when using these drugs together.

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. Isotretinoin 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.

LABORATORY TESTS

Pregnancy Test

Female patients of childbearing potential must have negative results from 2 urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Amnesteem prescription. The first test is obtained by the prescriber when the decision is made to pursue qualification of the patient for Amnesteem (a screening test). The second pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual period immediately preceding the beginning of Amnesteem therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception).

Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month 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 isotretinoin is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin 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 isotretinoin has been established (see WARNINGS: Hepatotoxicity).
  • Glucose: Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established.
  • CPK: Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.

Carcinogenesis, Mutagenesis and Impairment of Fertility

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1.0 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 × 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 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 1.0 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 1.0 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 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 isotretinoin capsules.

PEDIATRIC USE

The use of isotretinoin in pediatric patients less than 12 years of age has not been studied. The use of isotretinoin 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).

Evidence supporting the use of isotretinoin in this age group for severe recalcitrant nodular acne is approved for Hoffman La-Roche's isotretinoin capsules. However, due to Hoffman La-Roche's marketing exclusivity rights, this drug is not labeled for pediatric use.

In studies with isotretinoin, 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 isotretinoin 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 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 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 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course of isotretinoin 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 number 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 the elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS).

Page last updated: 2006-05-05

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