DESCRIPTION

Isotretinoin, a retinoid, is available as Amnesteem in 10 mg, 20 mg and 40 mg soft gelatin capsules for oral administration. Each capsule contains yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin, with the following dye systems: 10 mg - red iron oxide paste and black ink; 20 mg - red iron oxide paste, yellow iron oxide paste, titanium dioxide and black ink; 40 mg - red iron oxide paste, yellow iron oxide paste, titanium dioxide, and black ink.

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

CLINICAL PHARMACOLOGY

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION ), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne

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

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 × 40 mg capsules) of isotretinoin under fasted and fed conditions. Both peak plasma concentration (C _max ) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with isotretinoin given under fasted conditions (see Table 2 below). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (T _max ) was also increased with food and may be related to a longer absorption phase. Therefore, isotretinoin capsules should always be taken with food (see DOSAGE AND ADMINISTRATION ). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4- oxo -isotretinoin, retinoic acid (tretinoin), and 4- oxo -retinoic acid (4- oxo -tretinoin). Retinoic acid and 13- cis -retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4- oxo -isotretinoin, which forms its geometric isomer 4- oxo -tretinoin.

After a single 80 mg oral dose of isotretinoin capsules to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (>/= 18 years), the exposure of patients to 4- oxo -isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of ¹⁴ C-isotretinoin as a liquid suspension, ¹⁴ C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t _1/2 ) of isotretinoin and 4- oxo -isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

Pediatric pharmacokinetic information related to the use of isotretinoin after single and multiple doses is approved for Hoffmann-La Roche's isotretinoin capsules. However, due to Hoffmann-La Roche's marketing exclusivity rights, this drug product is not labeled for pediatric use.

INDICATIONS AND USAGE

Severe Recalcitrant Nodular Acne

Amnesteem is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. "Severe," by definition, ² means "many" as opposed to "few or several" nodules. Because of significant adverse effects associated with its use, Amnesteem should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics . In addition, Amnesteem is indicated only for those females who are not pregnant, because isotretinoin can cause severe birth defects (see boxed CONTRAINDICATIONS AND WARNINGS ).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. ^{1 , 3 , 4} If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS : Skeletal : Bone Mineral Density , Hyperostosis and Premature Epiphyseal Closure ).

CONTRAINDICATIONS

Pregnancy:   Category X. See boxed CONTRAINDICATIONS AND WARNINGS .

Allergic Reactions

Amnesteem is contraindicated in patients who are hypersensitive to this medication or to any of its components.

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 ).
• Norethindrone/ethinyl estradiol:    In a study of 31 premenopausal women with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, isotretinoin 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).
• 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 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 1.0 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 Hoffmann-La Roche's isotretinoin capsules. However, due to Hoffmann-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 elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS ).

ADVERSE REACTIONS

Clinical Trials and Postmarketing Surveillance

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

Dose Relationship

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

Body as a Whole

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

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

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

Gastrointestinal

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

Hematologic

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

Musculoskeletal

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

Neurological

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

Psychiatric

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

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

Reproductive System

abnormal menses

Respiratory

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

Skin and Appendages

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

Special Senses :

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

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

Urinary System

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

Laboratory

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

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

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

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

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

OVERDOSAGE

The oral LD ₅₀ of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and >300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. All symptoms quickly resolved without apparent residual effects.

Isotretinoin causes serious birth defects at any dosage (see boxed CONTRAINDICATIONS AND WARNINGS ). Females of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS . Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in the boxed CONTRAINDICATIONS AND WARNINGS . Educational materials for such patients can be obtained by calling Bertek Pharmaceuticals Inc. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female who is or might become pregnant, for 30 days after the overdose. All patients with isotretinoin overdose should not donate blood for at least 30 days.

DOSAGE AND ADMINISTRATION

Amnesteem should be administered with a meal (see PRECAUTIONS : Information for Patients and Prescribers ).

The recommended dosage range for Amnesteem is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day ⁸ , it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects -- some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2.0 mg/kg/day, as tolerated. Failure to take Amnesteem with food will significantly decrease absorption. Before upward dose adjustments are made, the patient should be questioned about their compliance with food instructions.

The safety of once daily dosing with Amnesteem has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Amnesteem, even in low doses, has not been studied, and is not recommended. It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Amnesteem on bone loss is unknown (see WARNINGS : Skeletal : Bone Mineral Density , Hyperostosis , and Premature Epiphyseal Closure ).

Contraceptive measures must be followed for any subsequent course of therapy (see boxed CONTRAINDICATIONS AND WARNINGS ).

Information for Pharmacists

HOW SUPPLIED

Soft gelatin capsules, 10 mg (reddish brown), imprinted I10.

- Cartons of 30 containing 3 Prescription Paks of 10

capsules.........................NDC 62794-611-93

- Cartons of 100 containing 10 Prescription Paks of 10

capsules.........................NDC 62794-611-88

Soft gelatin capsules, 20 mg (reddish brown and cream), imprinted I20.

- Cartons of 30 containing 3 Prescription Paks of 10

capsules.........................NDC 62794-612-93

- Cartons of 100 containing 10 Prescription Paks of 10

capsules.........................NDC 62794-612-88

Soft gelatin capsules, 40 mg (orange-brown), imprinted I40.

- Cartons of 30 containing 3 Prescription Paks of 10

capsules........................NDC 62794-614-93

- Cartons of 100 containing 10 Prescription Paks of 10

capsules........................NDC 62794-614-88

Storage

Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.

PRODUCT PHOTO(S):

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13- cis -retinoic acid. N Engl J Med 300:329-333, 1979.
   
2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.
   
3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13- cis -retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980.
   
4. Jones H, Blanc D, Cunliffe WJ. 13- cis -retinoic acid and acne. Lancet 2:1048-1049, 1980.
   
5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980.
   
6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984.
   
7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13- cis -retinoic acid). Arch Dermatol 116:951-952, 1980.
   
8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 10:490-496, 1984.

OrthoNovum 7/7/7 is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.

PATIENT INFORMATION/CONSENT (FOR FEMALE PATIENTS CONCERNING BIRTH DEFECTS)

To be completed by the patient,
her parent/guardian * and signed by her prescriber.

Read each item below and initial in the space provided to show that you understand each item and agree to follow your prescriber's instructions. Do not sign this consent and do not take Amnesteem® (isotretinoin) if there is anything that you do not understand.

*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent.

______________________________________________________

(Patient's Name)

1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin capsules in any amount even for short periods of time. This is why I must not be pregnant while taking Amnesteem.
   Initial: ______
2. I understand that I must not take Amnesteem® (isotretinoin) if I am pregnant.
   Initial: ______
3. I understand that I must not get pregnant during the entire time of my treatment and for 1 month after the end of my treatment with Amnesteem.
   Initial: ______
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective forms of birth control (contraception) at the same time. The only exception is if I have had surgery to remove the womb (a hysterectomy).
   Initial: ______
5. I understand that birth control pills and topical/injectable/implantable/insertable hormonal birth control products are among the most effective forms of birth control. However, any form of birth control can fail. Therefore, I must use 2 different methods at the same time, every time I have sexual intercourse, even if 1 of the methods I choose is birth control pills or topical/injectable/implantable/insertable hormonal birth control.
   Initial: ______
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my Amnesteem treatment because hormonal birth control methods (for example, birth control pills) may not work if I am taking certain drugs or herbal products (for example, St. John's Wort).
   Initial: ______
7. I understand that the following are considered effective forms of birth control:
   Primary:Tubal ligation (tying my tubes), partner's vasectomy, birth control pills, topical/injectable/ implantable/insertable hormonal birth control products, and an IUD (intrauterine device).
   Secondary:Diaphragms, latex condoms, and cervical caps. Each must be used with a spermicide, which is a special cream or jelly that kills sperm.
   I understand that at least 1 of my 2 methods of birth control must be a primary method.
   Initial: ______
8. I understand that I may receive a free contraceptive (birth control) counseling session from a doctor or other family planning expert. My Amnesteem prescriber can give me an Amnesteem Patient Referral Form for this free consultation.
   Initial: ______
9. I understand that I must begin using the birth control methods I have chosen as described above at least 1 month before I start taking Amnesteem.
   Initial: ______
10. I understand that I cannot get a prescription for Amnesteem unless I have 2 negative pregnancy test results. The first pregnancy test should be done when my prescriber decides to prescribe Amnesteem. The second pregnancy test should be done during the first 5 days of my menstrual period right before starting Amnesteem therapy, or as instructed by my prescriber. I will then have 1 pregnancy test every month during my Amnesteem therapy.
    Initial: ______
11. I understand that I should not start taking Amnesteem until I am sure that I am not pregnant and have negative results from 2 pregnancy tests.
    Initial: ______
12. I have read and understand the materials my prescriber has given to me, including the Patient Product Information, Important Information Concerning Your Treatment with Amnesteem . My prescriber gave me and asked me to watch the videos about contraception. I was told about a confidential counseling line that I may call for more information about birth control. I have received information on emergency contraception (birth control).
    Initial: ______
13. I understand that I must stop taking Amnesteem right away and inform my prescriber if I get pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without using my 2 birth control methods at any time.
    Initial: ______
14. My prescriber gave me information about the confidential Isotretinoin Survey and explained to me how important it is to take part in the Isotretinoin Survey .
    Initial: ______
15. I understand that the yellow self-adhesive isotretinoin qualification sticker on my prescription for isotretinoin capsules means that I am qualified to receive an Amnesteem prescription, because I:
    
    • have had 2 negative urine or serum pregnancy tests before receiving the initial Amnesteem prescription. I must have a negative result from a urine or serum pregnancy test repeated each month prior to my receiving each subsequent prescription.
    • have selected and 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 I have undergone a hysterectomy. I must use 2 forms of contraception for at least 1 month prior to initiation of isotretinoin capsules therapy, during therapy, and for 1 month after discontinuing therapy. I must receive counseling, repeated on a monthly basis, about contraception and behaviors associated with an increased risk of pregnancy.
    • have signed a Patient Information/Consent form that contains warnings about the risk of potential birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
    • have been informed of the purpose and importance of participating in the Isotretinoin Survey and given the opportunity to enroll.
      Initial: ______

My prescriber has answered all my questions about Amnesteem and I understand that it is my responsibility not to get pregnant during Amnesteem treatment or for 1 month after I stop taking Amnesteem .

Initial: ______

I now authorize my prescriber ______________ to begin my treatment with Amnesteem.

Patient Signature: _____________________________________

Date

Parent/Guardian Signature (if under age 18):
_______________________________________________________

Date

Please print: Patient Name and Address _________________

_____________________________________

Telephone _____________________________________________

I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to females of childbearing potential. I have asked the patient if she has any questions regarding her treatment with Amnesteem and have answered those questions to the best of my ability.

Prescriber Signature: ___________________________________

Date

INFORMED CONSENT/PATIENT AGREEMENT (FOR ALL PATIENTS):

To be completed by patient
(parent or guardian if patient is under 18)
and signed by the prescriber.

Read each item below and initial in the space provided if you understand each item and agree to follow your prescriber's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement.

Do not sign this agreement and do not take Amnesteem® (isotretinoin) if there is anything that you do not understand about all the information you have received about using Amnesteem.

1. I,_________________________________________________,
   (Patient's Name)
   understand that Amnesteem is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
   Initials: ______
2. My prescriber has told me about my choices for treating my acne.
   Initials: ______
3. I understand that there are serious side effects that may happen while I am taking isotretinoin capsules. These have been explained to me. These side effects include serious birth defects in babies of pregnant females. (Note: There is a second Informed Consent form for female patients concerning birth defects.)
   Initials: ______
4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of these problems include sad, "anxious" or empty mood, irritability, 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 isotretinoin 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 isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below).
   Initials: ______
5. Before I start taking Amnesteem, I agree to tell my prescriber if, to the best of my knowledge, I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there.
   Initials: ______
6. Before I start taking Amnesteem, I agree to tell my prescriber if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems.
   Initials: ______
7. Once I start taking Amnesteem, I agree to stop using Amnesteem and tell my prescriber right away if any of the following happen. I:
   
   • Start to feel sad or have crying spells
   • Lose interest in activities I once enjoyed
   • Sleep too much or have trouble sleeping
   • Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
   • Have a change in my appetite or body weight
   • Have trouble concentrating
   • Withdraw from my friends or family
   • Feel like I have no energy
   • Have feelings of worthlessness or inappropriate guilt
   • Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
     Initials: ______
8. I agree to return to see my prescriber every month I take Amnesteem to get a new prescription for Amnesteem, to check my progress, and to check for signs of side effects.
   Initials: ______
9. Amnesteem will be prescribed just for me -- I will not share Amnesteem with other people because it may cause serious side effects, including birth defects.
   Initials: ______
10. I will not give blood while taking Amnesteem or for 1 month after I stop taking Amnesteem. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects.
    Initials: ______
11. I have read the Patient Product Information, Important Information Concerning Your Treatment with Amnesteem, and other materials my provider gave me containing important safety information about Amnesteem. I understand all the information I received.
    Initials: ______
12. My prescriber and I have decided I should take Amnesteem. I understand that each of my Amnesteem prescriptions must have a yellow self-adhesive isotretinoin qualification sticker on it. I understand that I can stop taking Amnesteem at any time. I agree to tell my prescriber if I stop taking Amnesteem.
    Initials: ______

I now authorize my prescriber ________________________ to begin my treatment with Amnesteem.

Patient Signature: _____________________________________

Date

Parent/Guardian Signature (if under age 18):
_______________________________________________________

Date

Patient Name (print) __________________________________

Patient Address _______________________________________

Telephone _____________________________________________

I have:

• fully explained to the patient, __________________, the nature and purpose of Amnesteem treatment, including its benefits and risks
• given the patient the appropriate educational materials, A Personal Guide to Your Prescription, for Amnesteem and asked the patient if he/she has any questions regarding his/her treatment with Amnesteem
• answered those questions to the best of my ability
• placed the yellow self-adhesive isotretinoin qualification sticker on the prescription.

Prescriber Signature: __________________________________

Date

MEDICATION GUIDE

Read this Medication Guide every time you get a prescription or a refill for Amnesteem (am nes team). There may be new information. This information does not take the place of talking with your prescriber (doctor or other health care provider).

What is the most important information I should know about Amnesteem?

Amnesteem® (isotretinoin) is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics. However, isotretinoin can cause serious side effects. Before starting Amnesteem, discuss with your prescriber how bad your acne is, the possible benefits of Amnesteem, and its possible side effects, to decide if Amnesteem is right for you. Your prescriber will ask you to read and sign a form or forms indicating you understand some of the serious risks of Amnesteem.

Possible serious side effects of taking isotretinoin
capsules include birth defects and mental disorders .

1. Birth defects. Isotretinoin can cause birth defects (deformed babies) if taken by a pregnant woman. It can also cause miscarriage (losing the baby before birth), premature (early) birth, or death of the baby. Do not take Amnesteem if you are pregnant or plan to become pregnant while you are taking Amnesteem. Do not get pregnant for 1 month after you stop taking Amnesteem. Also, if you get pregnant while taking Amnesteem, stop taking it right away and call your prescriber.
   All females should read the section in this Medication Guide "What are the important warnings for females taking Amnesteem?"
2. Mental problems and suicide. Some patients, while taking isotretinoin capsules or soon after stopping isotretinoin capsules, have become depressed or developed other serious mental problems. Symptoms of these problems include sad, "anxious" or empty mood, irritability, 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 isotretinoin capsules 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 isotretinoin becoming aggressive or violent. No one knows if isotretinoin capsules caused these behaviors or if they would have happened even if the person did not take isotretinoin capsules.
   All patients should read the section in this Medication Guide "What are the signs of mental problems?"
   For other possible serious side effects of isotretinoin capsules, see "What are the possible side effects of Amnesteem?" in this Medication Guide.

What are the important warnings for females taking Amnesteem?

You must not become pregnant while taking Amnesteem, or for 1 month after you stop taking Amnesteem. Isotretinoin can cause severe birth defects in babies of women who take it while they are pregnant, even if they take isotretinoin capsules for only a short time. There is an extremely high risk that your baby will be deformed or will die if you are pregnant while taking isotretinoin capsules. Taking isotretinoin capsules also increases the chance of miscarriage and premature births.

Female patients will not get their first prescription for Amnesteem unless there is proof they have had 2 negative pregnancy tests. The first test must be done when your prescriber decides to prescribe Amnesteem. The second pregnancy test must be done during the first 5 days of the menstrual period right before starting Amnesteem therapy, or as instructed by your prescriber. Each month of treatment, you must have a negative result from a urine or serum pregnancy test. Female patients cannot get another prescription for Amnesteem unless there is proof that they have had a negative pregnancy test.

A yellow self-adhesive isotretinoin qualification sticker on your prescription indicates to the pharmacist that you are qualified by your prescriber to get Amnesteem.

While you are taking Amnesteem, you must use effective birth control. You must use 2 separate effective forms of birth control at the same time for at least 1 month before starting Amnesteem, while you take it, and for 1 month after you stop taking it. You can either discuss effective birth control methods with your prescriber or go for a free visit to discuss birth control with another physician or family planning expert. Your prescriber can arrange this free visit, which will be paid for by Bertek Pharmaceuticals Inc.

You must use 2 separate forms of effective birth control because any method, including birth control pills and sterilization, can fail. There are only 2 reasons you would not need to use 2 separate methods of effective birth control:

1. You have had your womb removed by surgery (a hysterectomy).
2. You are absolutely certain you will not have genital-to-genital sexual contact with a male before, during, and for 1 month after isotretinoin capsules treatment.

If you have sex at any time without using 2 forms of effective birth control, get pregnant, or miss your period, stop using Amnesteem and call your prescriber right away.

All patients should read the rest of this Medication Guide.

What are the signs of mental problems?

Tell your prescriber if, to the best of your knowledge, you or someone in your family has ever had any mental illness, including depression, suicidal behavior, or psychosis. Psychosis means a loss of contact with reality, such as hearing voices or seeing things that are not there. Also, tell your prescriber if you take medicines for any of these problems.

Stop using Amnesteem and tell your prescriber right away if you:

• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)

What is Amnesteem?

Amnesteem is used to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars. However, because isotretinoin can have serious side effects, you should talk with your prescriber about all of the possible treatments for your acne, and whether Amnesteem's possible benefits outweigh its possible risks.

Who should not take Amnesteem?

• Do not take Amnesteem if you are pregnant, plan to become pregnant, or become pregnant during Amnesteem treatment. Isotretinoin causes severe birth defects. All females should read the section "What are the important warnings for females taking Amnesteem?" for more information and warnings about Amnesteem and pregnancy.
• Do not take Amnesteem unless you completely understand its possible risks and are willing to follow all of the instructions in this Medication Guide.

Tell your prescriber if you or someone in your family has had any kind of mental problems, asthma, liver disease, diabetes, heart disease, osteoporosis (bone loss), weak bones, anorexia nervosa (an eating disorder where people eat too little), or any other important health problems. Tell your prescriber about any food or drug allergies you have had in the past. These problems do not necessarily mean you cannot take Amnesteem, but your prescriber needs this information to discuss if isotretinoin capsules are right for you.

How should I take Amnesteem?

• You will get no more than a 30-day supply of Amnesteem at a time, to be sure you check in with your prescriber each month to discuss side effects.
• Your prescription should have a special yellow self-adhesive sticker attached to it. The sticker is YELLOW. If your prescription does not have this yellow self-adhesive sticker, call your prescriber. The pharmacy should not fill your prescription unless it has the yellow self-adhesive sticker.
• The amount of Amnesteem you take has been specially chosen for you and may change during treatment.
• You will take Amnesteem 2 times a day with a meal, unless your prescriber tells you otherwise. Swallow your Amnesteem with a full glass of liquid. This will help prevent the medication inside the capsule from irritating the lining of your esophagus (connection between mouth and stomach). For the same reason, do not chew or suck on the capsule.
• If you miss a dose, just skip that dose. Do not take 2 doses the next time.
• You should return to your prescriber as directed to make sure you don't have signs of serious side effects. Because some of isotretinoin's serious side effects show up in blood tests, some of these visits may involve blood tests (monthly visits for female patients should always include a urine or serum pregnancy test).

What should I avoid while taking Amnesteem?

• Do not get pregnant while taking Amnesteem. See "What is the most important information I should know about Amnesteem?" and "What are the important warnings for females taking Amnesteem?"
• Do not breast feed while taking Amnesteem and for 1 month after stopping Amnesteem. We do not know if isotretinoin can pass through your milk and harm the baby.
• Do not give blood while you take Amnesteem and for 1 month after stopping Amnesteem. If someone who is pregnant gets your donated blood, her baby may be exposed to isotretinoin and may be born with birth defects.
• Do not take vitamin A supplements. Vitamin A in high doses has many of the same side effects as isotretinoin. Taking both together may increase your chance of getting side effects.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser procedures, while you are using Amnesteem and for at least 6 months after you stop. Isotretinoin can increase your chance of scarring from these procedures. Check with your prescriber for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Isotretinoin may make your skin more sensitive to light.
• Do not use birth control pills that do not contain estrogen ("minipills"). They may not work while you take Amnesteem. Ask your prescriber or pharmacist if you are not sure what type you are using.
• Talk with your doctor if you plan to take other drugs or herbal products. This is especially important for patients using birth control pills and other hormonal types of birth control because the birth control may not work as effectively if you are taking certain drugs or herbal products. You should not take the herbal supplement St. John's Wort because this herbal supplement may make birth control pills not work as effectively.
• Talk with your doctor if you are currently taking an oral or injected corticosteroid or anticonvulsant (seizure) medication prior to using Amnesteem. These drugs may weaken your bones.
• Do not share Amnesteem with other people. It can cause birth defects and other serious health problems.
• Do not take Amnesteem with antibiotics unless you talk to your prescriber. For some antibiotics, you may have to stop taking Amnesteem until the antibiotic treatment is finished. Use of both drugs together can increase the chances of getting increased pressure in the brain.

What are the possible side effects of Amnesteem?

Amnesteem has possible serious side effects

• Isotretinoin capsules can cause birth defects, premature births, and death in babies whose mothers took isotretinoin capsules while they were pregnant. See "What is the most important information I should know about Amnesteem?" and "What are the important warnings for females taking Amnesteem?"
• Serious mental health problems. See "What is the most important information I should know about Amnesteem?"
• Serious brain problems. Isotretinoin capsules can increase the pressure in your brain. This can lead to permanent loss of sight, or in rare cases, death. Stop taking Amnesteem and call your prescriber right away if you get any of these signs of increased brain pressure: bad headache, blurred vision, dizziness, nausea, or vomiting. Also, some patients taking isotretinoin capsules have had seizures (convulsions) or stroke.
• Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking isotretinoin capsules. Stop taking Amnesteem and call your prescriber if you get severe stomach, chest or bowel pain, trouble swallowing or painful swallowing, new or worsening heartburn, diarrhea, rectal bleeding, yellowing of your skin or eyes, or dark urine.
• Bone and muscle problems. Isotretinoin may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your prescriber if you plan vigorous physical activity during treatment with isotretinoin. Tell your prescriber if you develop pain, particularly back pain or joint pain. There are reports that some patients have had stunted growth after taking isotretinoin for acne as directed. There are also some reports of broken bones or reduced healing of broken bones after taking isotretinoin for acne as directed. No one knows if taking isotretinoin for acne will affect your bones. If you have a broken bone, tell your provider that you are taking isotretinoin. Muscle weakness with or without pain can be a sign of serious muscle damage. If this happens, stop taking Amnesteem and call your prescriber right away.
• Hearing problems. Some people taking isotretinoin have developed hearing problems. It is possible that hearing loss can be permanent. Stop using Amnesteem and call your prescriber if your hearing gets worse or if you have ringing in your ears.
• Vision problems. While taking isotretinoin you may develop a sudden inability to see in the dark, so driving at night can be dangerous. This condition usually clears up after you stop taking isotretinoin, but it may be permanent. Other serious eye effects can occur. Stop taking Amnesteem and call your prescriber right away if you have any problems with your vision or dryness of the eyes that is painful or constant.
• Lipid (fats and cholesterol in blood) problems. Many people taking isotretinoin develop high levels of cholesterol and other fats in their blood. This can be a serious problem. Return to your prescriber for blood tests to check your lipids and to get any needed treatment. These problems generally go away when isotretinoin capsules treatment is finished.
• Allergic reactions. In some people, isotretinoin can cause serious allergic reactions. Stop taking Amnesteem and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking Amnesteem and call your prescriber if you develop a fever, rash, or red patches or bruises on your legs.
• Signs of other possibly serious problems. Isotretinoin may cause other problems. Tell your prescriber if you have trouble breathing (shortness of breath), are fainting, are very thirsty or urinate a lot, feel weak, have leg swelling, convulsions, slurred speech, problems moving, or any other serious or unusual problems. Frequent urination and thirst can be signs of blood sugar problems.

Serious permanent problems do not happen often. However, because the symptoms listed above may be signs of serious problems, if you get these symptoms, stop taking Amnesteem and call your prescriber. If not treated, they could lead to serious health problems. Even if these problems are treated, they may not clear up after you stop taking Amnesteem.

Amnesteem has less serious possible side effects

The common less serious side effects of Amnesteem are dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds. People who wear contact lenses may have trouble wearing them while taking Amnesteem and after therapy. Sometimes, people's acne may get worse for a while. They should continue taking Amnesteem unless told to stop by their prescriber.

These are not all of isotretinoin's possible side effects. Your prescriber or pharmacist can give you more detailed information that is written for health care professionals.

This Medication Guide is only a summary of some important information about Amnesteem. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any concerns or questions about Amnesteem, ask your prescriber. Do not use Amnesteem for a condition for which it was not prescribed.

Active Ingredient: Isotretinoin.

Inactive ingredients: yellow wax, butylated hydroxyanisole, edetate disodium, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin, with the following dye systems: 10 mg -- red iron oxide paste and black ink; 20 mg -- red iron oxide paste, yellow iron oxide paste, titanium dioxide, and black ink; 40 mg -- red iron oxide paste, yellow iron oxide paste, titanium dioxide, and black ink.

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

Rx only

Manufactured by:

Cardinal Health France 404

74 rue Principale

67930 Beinheim

France

Cardinal Health

Packaging Services

3001 Red Lion Road

Philadelphia, PA 19114

Distributed by:

Bertek Pharmaceuticals Inc.

Research Triangle Park, NC 27709

BKISO:R3                           October 2004

BERTEK

PHARMACEUTICALS INC.