Limitations of Use

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. 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 with isotretinoin has shown that patients may continue to improve following treatment with isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth [see Warnings and Precautions (5.12)].

As a part of the iPLEDGE program, Absorica™ may only be administered to patients enrolled in the program [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

The recommended dosage range for Absorica™ is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid [see Patient Counseling Information (17.1)].

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

In trials comparing 0.1, 0.5, and 1 mg/kg/day, 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 mg/kg/day, as tolerated.

2.3 Duration of Use

A normal course of treatment is 15 – 20 weeks. 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 Absorica™, even in low doses, has not been studied, and is not recommended. It is important that Absorica™ be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Absorica™ on bone loss is unknown [see Warnings and Precautions (5.12)].

2.4 Laboratory Testing

Absorica™ can cause fetal harm when administered to a pregnant woman. Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin in any amount and even for short periods of time. Absorica™ is contraindicated in females who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

4.2 Hypersensitivity

Hypersensitivity to this product (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components [see Warnings and Precautions (5.14)].

5 WARNINGS AND PRECAUTIONS

Because of the risk of teratogenicity and to minimize fetal exposure, Absorica™ is available only through a restricted program under a REMS called iPLEDGE. Under the Absorica™ REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program. Absorica™ must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used.

Required components of the iPLEDGE Program are:

• Absorica™ must only be prescribed by prescribers who are registered and activated with the iPLEDGE program and agree to comply with the REMS requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program, The iPLEDGE Program Prescriber Contraception Counseling Guide, and Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.
• Male patients and Female patients not of childbearing potential: To obtain Absorica™, these patients must understand the risks and benefits of Absorica™, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
• Female patients of childbearing potential: Absorica™ is contraindicated in female patients who are or may become pregnant [see Contraindications (4.1)].
• Female patients of childbearing potential who are not pregnant must understand the risks and benefits, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant and The iPLEDGE Program Birth Control Workbook (including the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6) and Patient Counseling Information (17.1)]), and sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form. Additionally, the patient must answer questions about the iPLEDGE program and pregnancy prevention monthly.
• Pharmacies that dispense Absorica™ must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive Absorica™, and agree to comply with the REMS requirements described in the booklet entitled The Pharmacist Guide for the iPLEDGE Program.
• Female patients of childbearing potential must fill and pick up the prescription within 7 days of the specimen collection for the pregnancy test; male patients and female patients not of childbearing potential must fill and pick up the prescription within 30 days of the office visit.
• Absorica™ must only be dispensed in no more than a 30-day supply with a Medication Guide. Refills require a new prescription and a new authorization from the iPLEDGE system.
• Wholesalers and distributors that distribute Absorica™ must be registered with iPLEDGE and agree to comply with the REMS requirements.

If a pregnancy does occur during Absorica™ treatment, Absorica™ must be discontinued immediately. The patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after Absorica™ therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

Further information, including a list of qualified pharmacies, is available at www.ipledgeprogram.com or 1-866-495-0654.

5.3 Unacceptable Contraception

Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these reactions [see Adverse Reactions (6.1)]. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Absorica™ therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (Recognizing Psychiatric Disorders in Adolescents and Young Adults), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Absorica™ and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Absorica™ therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Absorica™ therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Absorica™ therapy.

5.5 Pseudotumor Cerebri

Isotretinoin use has been associated with 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 Absorica™ immediately and be referred to a neurologist for further diagnosis and care [see Adverse Reactions (6.1)].

5.6 Serious Skin Reactions

There have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of Absorica™ should be considered if warranted.

5.7 Pancreatitis

Acute pancreatitis has been reported in isotretinoin-treated patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Absorica™ should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.

5.8 Lipid Abnormalities

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 of 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 the dose while continuing isotretinoin.

Blood lipid determinations should be performed before Absorica™ is given and then at intervals until the lipid response to Absorica™ 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 of triglyceridemia during Absorica™ therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Absorica™ therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended [see Warnings and Precautions (5.15)].

The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

5.9 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 reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue Absorica™ treatment and be referred for specialized care for further evaluation. [see Adverse Reactions (6.1)].

5.10 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 with isotretinoin, 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 Absorica™, the drug should be discontinued and the etiology further investigated.

5.11 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 Absorica™ immediately [see Adverse Reactions (6.1)].

5.12 Skeletal Abnormalities

Visual problems should be carefully monitored. All Absorica™ patients experiencing visual difficulties should discontinue Absorica™ treatment and have an ophthalmological examination [see Adverse Reactions (6.1)].

Anaphylactic reactions and other allergic reactions have been reported in isotretinoin-treated patients. 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.

5.15 Laboratory Monitoring for Adverse Reactions

Dose Relationship

Cheilitis and hypertriglyceridemia are adverse reactions that are usually dose related. Most adverse reactions reported in clinical trials with isotretinoin were reversible when therapy was discontinued; however, some persisted after cessation of therapy.

Body as a Whole

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): fatigue, irritability, pain. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: allergic reactions, including vasculitis, systemic hypersensitivity, edema, lymphadenopathy, weight loss.

Cardiovascular

The following adverse reactions have been reported with isotretinoin: vascular thrombotic disease, stroke, palpitation, tachycardia.

Endocrine/Metabolism and Nutritional

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): decreased appetite, weight fluctuation, hyperlipidaemia. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: hypertriglyceridemia, alterations in blood sugar.

Gastrointestinal

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): lip dry, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, and other nonspecific gastrointestinal symptoms.

Hematologic

The following adverse reactions have been reported with isotretinoin: allergic reactions, anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis.

Infections and infestations

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): nasopharyngitis, hordeolum, upper respiratory tract infection. In addition to the above adverse reactions, the following adverse reaction has been reported with isotretinoin: infections (including disseminated herpes simplex).

Laboratory Abnormalities

The following changes in laboratory tests have been noted in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): blood creatine phosphokinase (CPK) increased, blood triglycerides increased, alanine aminotransferase (SGPT) increased, aspartate aminotransferase (SGOT) increased, gamma-glutamyltransferase (GGTP) increased, blood cholesterol increased, low density lipoprotein (LDL) increased, white blood cell count decreased, blood alkaline phosphatase increased, blood bilirubin increased, blood glucose increased, high density lipopoprotein (HDL) decreased, bone mineral density decreased. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: increased LDH, elevation of fasting blood sugar, hyperuricemia, decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis), elevated sedimentation rates, elevated platelet counts, thrombocytopenia, white cells in the urine, proteinuria, microscopic or gross hematuria.

Musculoskeletal and Connective Tissue

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, athralgia, musculoskeletal discomfort, musculoskeletal pain, neck pain, pain in extremity, myalgia, musculoskeletal stiffness [see Warnings and Precautions (5.12)]. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient pain in the chest, and rare reports of rhabdomyolysis.

Neurological

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): headache, syncope. In addition to the above adverse reactions, other adverse reactions reported with isotretinoin include: pseudotumor cerebri, dizziness, drowsiness, lethargy, malaise, nervousness, paresthesias, seizures, stroke, weakness.

Psychiatric

The following adverse reactions have been reported in clinical trials conducted with Absorica™ and a generic product of Accutane® (isotretinoin): suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: suicide attempts, suicide, aggression, psychosis and hallucination auditory. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

The following adverse reaction has been reported with isotretinoin: abnormal menses.

Respiratory

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): epistaxis, nasal dryness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.

Skin and Subcutaneous Tissue

The following adverse reactions have been reported in a clinical trial conducted with Absorica™ and a generic product of Accutane® (isotretinoin): dry skin, dermatitis, eczema, rash, dermatitis contact, alopecia, pruritus, sunburn, erythema. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: acne fulminans, alopecia (which in some cases persists), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting).

Special Senses

Absorica™ is closely related to vitamin A. Therefore, the use of both vitamin A and Absorica™ at the same time may lead to vitamin A side effects. Patients should be advised against taking vitamin supplements containing Vitamin A to avoid additive toxic effects.

7.2 Tetracyclines

Concomitant treatment with Absorica™ 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.

7.3 Phenytoin

Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a trial 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 CYP2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical trials 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.

7.4 St. John's Wort

Isotretinoin use is associated with depression in some patients. 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.

7.5 Systemic Corticosteroids

Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials 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.

7.6 Norethindrone/ethinyl estradiol

In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Norethindrone/ethinyl estradiol 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). 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X.

It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Absorica™, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The use of Absorica™ in pediatric patients less than 12 years of age has not been studied. The use of Absorica™ 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 Warnings and Precautions (5.12)]. Use of Absorica™ in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical trial of Absorica™ compared to a generic product of Accutane® (isotretinoin) in 397 pediatric patients (12 to 17 years). Results from this trial demonstrated that both Absorica™ and the other isotretinoin drug product, at a dose of 1 mg/kg/day given in two divided doses, was effective in treating severe recalcitrant nodular acne in pediatric patients.

In trials 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. In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Absorica™. Consideration should be given to discontinuation of Absorica™ if any significant abnormality is found.

The effect on bone mineral density (BMD) of a 20-week course of therapy with Absorica™ or a generic product of Accutane® (isotretinoin) was evaluated in a double-blind, randomized clinical trial involving 396 adolescents with severe recalcitrant nodular acne (mean age 15.4, range 12-17, 80% males). Following 20 weeks of treatment, there were no statistically significant differences between the treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 adolescents, 27 (8.8%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2-3 months after the post treatment scan showed no recovery of BMD. Longer-term follow up at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see Warnings and Precautions (5.12)].

In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for adolescents with 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 trials 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 trial of 10 patients, ages 13 to 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%.

There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 adolescents who had hand radiographs taken to assess bone age, a total of 9 patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded [see Warnings and Precautions (5.12)].

8.5 Geriatric Use

Clinical trials of Absorica™ did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with Absorica™ therapy.

8.6 Females of Childbearing Potential

All females of childbearing potential must comply with the iPLEDGE program requirements [see Warnings and Precautions (5.2)].

Absorica™ is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. 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 and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of Absorica™ is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of Absorica™ are unknown.

12.3 Pharmacokinetics

In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.

The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen.

In trials 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.

13.2 Animal Toxicology

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

14 CLINICAL STUDIES