Zenatane Isotretinoin 20 mg Capsule, Gelatin Coated — NDC 55111-136-81 (Billing 55111-0136-81)

Special Patient Populations Pediatric Patients The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received Zenatane for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients.

There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean ( ± SD), N=38* Parameter Isotretinoin (Single Dose) Isotretinoin (Steady-State) C max (ng/mL) 573.25 (278.79) 731.98 (361.86) AUC (0-12) (ng⋅hr/mL) 3033.37 (1394.17) 5082 (2184.23) AUC (0-24) (ng⋅hr/mL) 6003.81 (2885.67) – T max (hr)† 6 (1 to 24.6) 4 (0 to12) C ss min (ng/mL) – 352.32 (184.44) T 1/2 (hr) – 15.69 (5.12) CL/F (L/hr) – 17.96 (6.27) *The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2 . † Median (range) In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t 1/2 ) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively.

The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

WARNINGS Psychiatric Disorders Zenatane may cause depression, psycho sis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults : A Guide for Prescribers of Isotretinoin .

Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Zenatane 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 Zenatane 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 Zenatane 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 Zenatane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Zenatane therapy. Pseudotumor Cerebri Zenatane use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concom… [Excerpted — this section continues on DailyMed.]

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

Dose Relationship Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS ). Body as a Whole allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS : Hypersensitivity ), edema, fatigue, lymphadenopathy, weight loss Cardiovascular palpitation, tachycardia, vascular thrombotic disease, stroke Endocrine/Metabolic hypertriglyceridemia (see WARNINGS : Lipids ), alterations in blood sugar levels (see PRECAUTIONS : Laboratory Tests ) Gastrointestinal inflammatory bowel disease (see WARNINGS : Inflammatory Bowel Disease ), hepatitis (see WARNINGS : Hepatotoxicity ), pancreatitis (see WARNINGS : Lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

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

Neurological pseudotumor cerebri (see WARNINGS : Pseudotumor Cerebri ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness Psychiatric suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS : Psychiatric Disorders ), emotional instability. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System abnormal menses. Respiratory bronchospasms (with or without a history of asthma), respiratory infection, voice alteration Skin and Appendages acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, 7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS : Hypersensitivity ), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS : Information for Patients ) Special Senses Hearing hearing impairment (see WARNINGS : Hearing Impairment ), tinnitus.

Vision corneal opacities (see WARNINGS : Corneal Opacities ), decreased night vision which may persist… [Excerpted — this section continues on DailyMed.]

Drug Interactions Drug Interactions Vitamin A: Because of the relationship of Zenatane to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. Tetracyclines: Concomitant treatment with Zenatane and tetracyclines should be avoided because Zenatane 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 Zenatane therapy.

Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Zenatane.

Therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS ). Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Ortho-Novum ® 7/7/7 Tablets as an oral contraceptive agent, Zenatane at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. St. John’s Wort: Zenatane use is associated with depression in some patients (see WARNINGS : Psychiatric Disorders and ADVERSE REACTIONS : Psychiatric).

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St.John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St.John's Wort.

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

PRECAUTIONS Zenatane must only be prescribed by prescribers who are enrolled and activated with the iPLEDGE REMS. Zenatane must only be dispensed by a pharmacy enrolled and activated with iPLEDGE, and must only be dispensed to patients who are enrolled and meet all the requirements of iPLEDGE. Enrolled and activated pharmacies must receive Zenatane only from wholesalers enrolled with iPLEDGE. iPLEDGE REMS requirements for wholesalers, prescribers, and pharmacists are described below: Wholesalers: For the purpose of the iPLEDGE REMS, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor.

To distribute Zenatane, wholesalers must be enrolled with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must enroll with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include: Enrolling prior to distributing isotretinoin and re-enrolling annually thereafter Distributing only FDA approved isotretinoin product Only shipping isotretinoin to - wholesalers enrolled in the iPLEDGE REMS with prior written consent from the manufacturer or - pharmacies licensed in the US and enrolled and activated in the iPLEDGE REMS Notifying the isotretinoin manufacturer (or delegate) of any non-enrolled and/or non-activated pharmacy or unenrolled wholesaler that attempts to order isotretinoin Complying with inspection/audit of wholesaler records for verification of compliance with the iPLEDGE REMS by the isotretinoin manufacturer (or delegate) Returning to the manufacturer (or delegate) any undistributed product if the wholesaler is deactivated by the iPLEDGE REMS or if the wholesaler chooses to not re-enroll annually Prescribers: To prescribe isotretinoin, the prescriber must be enrolled and activated with the pregnancy risk management program iPLEDGE.

Prescribers can enroll by signing and returning the completed enrollment form. Prescribers can only activate their enrollment by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.

I have the expertise to provide the patient with detailed pregnancy prevention counseling, or I will refer the patient to an expert for such counseling, reimbursed by the manufacturer. I will comply with the iPLEDGE REMS requirements described in the booklet entitled iPLEDGE REMSPrescriber Guide. Before beginning treatment of patients who can become pregnant with isotretinoin, and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously for at least one month prior to initiation of isotretinoin treatment, during isotretinoin treatment and for one month after discontinuing isotretinoin treatment, unless the patient commits to continuous abstinence, not having any sexual contact with a partner that could result in pregnancy.

I will not prescribe isotretinoin to any patient who can become pregnant until verifying the patient has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test one month later. I will report any pregnancy case that I become aware of while the patient who can become pregnant is on isotretinoin or one month after the last dose to the pregnancy registry.

To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to: 1) Enroll each patient in the iPLEDGE REMS. 2) Confirm monthly that each pa… [Excerpted — this section continues on DailyMed.]