Targretin (Page 2 of 4)

Drug-Drug Interactions

No formal studies to evaluate drug interactions with bexarotene or Targretin® gel have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. Drugs that affect levels or activity of cytochrome P450 3A4 may potentially affect the disposition of bexarotene. Concomitant gemfibrozil was associated with increased bexarotene concentrations following oral administration of bexarotene.

Clinical Studies

Targretin® gel was evaluated for the treatment of patients with early stage (Stage IA-IIA) CTCL in one multicenter, open-label, clinical trial as well as in a Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial). These clinical studies enrolled a total of 117 patients.

In the multicenter, open-label clinical trial, Targretin® gel was evaluated for the treatment of patients with early stage CTCL who were refractory to, intolerant to, or reached a response plateau for at least six months on at least two prior therapies. The study was conducted in the U.S., Canada, Europe, and Australia and enrolled a total of 50 patients; 46% of these patients were male, 80% were Caucasian, and the median age was 64 years (range 13 to 85).

Targretin® gel was also evaluated for the treatment of patients with CTCL in a U.S. Phase I-II program involving patients with early stage CTCL. This program enrolled a total of 67 patients; 55% of these patients were male, 85% were Caucasian, and the median age was 61 years (range 30 to 87).

In the multicenter, open-label clinical trial, considering prior systemic, irradiation, and topical treatments, patients had been exposed to a median of 3 prior therapies (range 2-7). All patients failed at least two treatments; the majority (68%) of patients were either refractory to two or more therapies, or were refractory to one therapy and intolerant to at least one therapy.

Patients were treated with Targretin® gel 1% for a planned 16-week period with an option to continue provided that no unacceptable toxicity was occurring.

Tumor response was assessed in the multicenter study by observation of up to five baseline-defined index lesions using a Composite Assessment of Index Lesion Disease Severity (CA). This endpoint was based on a summation of the grades, for all index lesions, of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. New cutaneous lesions or tumors and extracutaneous disease manifestations were not considered in response or disease progression assessments.

All tumor responses required confirmation over at least two assessments separated by at least four weeks. A partial response was defined as an improvement of at least 50% in the index lesions. A complete clinical response required complete disappearance of the index lesions, but did not require confirmation by biopsy.

Targretin® gel produced an overall response rate of 26% (13/50) with a corresponding exact 95% confidence interval from 14.6% to 40.3% by the Composite Assessment of Index Lesion Severity. For the Stage IA and IB patients, the response rate was 28% (13/47) with a corresponding exact 95% confidence interval from 15.6% to 42.6%. For the Stage II patients the response rate was 0% (0/3). Two percent of patients (1/50) had a clinical complete response. The median time to best response on the Composite Assessment of Index Lesion Severity (n=13) was 85 days (range: 36-154).

The rate of relapse in responding patients by the Composite Assessment of Index Lesion Severity was 23% (3/13) over a median observation period of 149 days (range 56-342). Fourteen patients developed new lesions in untreated areas (14/50; 28%). Four patients developed clinically abnormal lymph nodes (≥ 1cm diam) (4/50; 8%). One patient developed a cutaneous tumor (1/50; 2%).

The Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial) was supportive of the multicenter study results.

INDICATIONS AND USAGE

Targretin® (bexarotene) gel 1% is indicated for the topical treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

CONTRAINDICATIONS

Targretin® gel 1% is contraindicated in patients with a known hypersensitivity to bexarotene or other components of the product.

Pregnancy: Category X

Targretin® gel 1% may cause fetal harm when administered to a pregnant woman.

Targretin® gel must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking Targretin® gel, Targretin® gel must be stopped immediately and the woman given appropriate counseling.

Bexarotene caused malformations when administered orally to pregnant rats during days 7-17 of gestation. Developmental abnormalities included incomplete ossification at 4 mg/kg/day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality. The no-effect oral dose in rats was 1 mg/kg/day. Plasma bexarotene concentrations in patients with CTCL applying Targretin® gel 1% were generally less than one hundredth the Cmax associated with dysmorphogenesis in rats, although some patients had Cmax levels that were approximately one eighth the concentration associated with dysmorphogenesis in rats.

Women of child-bearing potential should be advised to avoid becoming pregnant when Targretin® gel is used. The possibility that a woman of child-bearing potential is pregnant at the time therapy is instituted should be considered. A negative pregnancy test (e.g., serum beta-human chorionic gonadotropin, beta-HCG) with a sensitivity of at least 50 mIU/L should be obtained within one week prior to Targretin® gel therapy, and the pregnancy test must be repeated at monthly intervals while the patient remains on Targretin® gel. Effective contraception must be used for one month prior to the initiation of therapy, during therapy and for at least one month following discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while applying Targretin® gel and for at least one month after the last dose of drug. Targretin® gel therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of Targretin® gel should be given to the patient so that the results of pregnancy testing can be assessed and counseling regarding avoidance of pregnancy and birth defects can be reinforced.

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