Bexarotene (Page 2 of 3)

INDICATIONS AND USAGE

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

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

Pregnancy

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

Bexarotene gel must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking Bexarotene gel, Bexarotene 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 Bexarotene 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 Bexarotene 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 Bexarotene gel therapy, and the pregnancy test must be repeated at monthly intervals while the patient remains on Bexarotene 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 Bexarotene gel and for at least one month after the last dose of drug. Bexarotene gel therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of Bexarotene 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.

PRECAUTIONS

Pregnancy : See CONTRAINDICATIONS.

General: Bexarotene gel should be used with caution in patients with a known hypersensitivity to other retinoids. No clinical instances of cross-reactivity have been noted.

Vitamin A Supplementation: In clinical studies, patients were advised to limit vitamin A intake to ≤15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

Photosensitivity: Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. There were no reports of photosensitivity in patients in the clinical studies. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light during the use of Bexarotene gel.

Information for Patients

Please see accompanying “Patient’s Instructions for Use”.

Drug-Drug Interactions

Patients who are applying Bexarotene gel should not concurrently use products that contain DEET (N,N -diethyl-m -toluamide), a common component of insect repellent products. An animal toxicology study showed increased DEET toxicity when DEET was included as part of the formulation.

No formal studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4.

On the basis of the metabolism of bexarotene by cytochrome P450 3A4, concomitant ketoconazole, itraconazole, erythromycin and grapefruit juice could increase bexarotene plasma concentrations. Similarly, based on data that gemfibrozil increases bexarotene concentrations following oral bexarotene administration, concomitant gemfibrozil could increase bexarotene plasma concentrations. However, due to the low systemic exposure to bexarotene after low to moderately intense gel regimens (see CLINICAL PHARMACOLOGY), increases that occur are unlikely to be of sufficient magnitude to result in adverse effects.

No drug interaction data are available on concomitant administration of Bexarotene gel and other CTCL therapies.

Renal Insufficiency

No formal studies have been conducted with Bexarotene gel in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (<1% of an orally administered dose), but because renal insufficiency can result in significant protein binding changes, and bexarotene is >99% protein bound, pharmacokinetics may be altered in patients with renal insufficiency.

Hepatic Insufficiency

No specific studies have been conducted with Bexarotene gel in patients with hepatic insufficiency. Because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance.

Protein Binding

Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to assess the carcinogenic potential of bexarotene have not been conducted. Bexarotene was not mutagenic to bacteria (Ames assay) or mammalian cells (mouse lymphoma assay). Bexarotene was not clastogenic in vivo (micronucleus test in mice). No formal fertility studies were conducted with bexarotene. Bexarotene caused testicular degeneration when oral doses of 1.5 mg/kg/day were given to dogs for 91 days.

Use in Nursing Mothers

It is not known whether bexarotene is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bexarotene, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total patients with CTCL in clinical studies of Bexarotene gel, 62% were under 65 years and 38% were 65 years or older. No overall differences in safety were observed between patients 65 years of age or older and younger patients, but greater sensitivity of some older individuals to Bexarotene gel cannot be ruled out. Responses to Bexarotene gel were observed across all age group decades, without preference for any individual age group decade.

ADVERSE REACTIONS

The safety of Bexarotene gel has been assessed in clinical studies of 117 patients with CTCL who received Bexarotene gel for up to 172 weeks. In the multicenter open-label study, 50 patients with CTCL received Bexarotene gel for up to 98 weeks. The mean duration of therapy for these 50 patients was 199 days. The most common adverse events reported with an incidence at the application site of at least 10% in patients with CTCL were rash, pruritus, skin disorder, and pain.

Adverse events leading to dose reduction or study drug discontinuation in at least two patients were rash, contact dermatitis, and pruritus.

Of the 49 patients (98%) who experienced any adverse event, most experienced events categorized as mild (9 patients, 18%) or moderate (27 patients, 54%). There were 12 patients (24%) who experienced at least one moderately severe adverse event. The most common moderately severe events were rash (7 patients, 14%) and pruritus (3 patients, 6%). Only one patient (2%) experienced a severe adverse event (rash).

In the patients with CTCL receiving Bexarotene gel, adverse events reported regardless of relationship to study drug at an incidence of ≥5% are presented in Table 1.

A similar safety profile for Bexarotene gel was demonstrated in the Phase I-II program. For the 67 patients enrolled in the Phase I-II program, the mean duration of treatment was 436 days (range 12-1203 days). As in the multicenter study, the most common adverse events regardless of relationship to study drug in the Phase I-II program were rash (78%), pain (40%), and pruritus (40%).

Table 1: Incidence of All Adverse Events* and Application Site Adverse Events with Incidence ≥5% for All Application Frequencies of Bexarotene Gel in the Multicenter CTCL Study

All Adverse
Events

Application Site Adverse Events

COSTART 5
Body System/Preferred Term

N = 50
n (%)

N = 50
n (%)

Skin and Appendages

Contact Dermatitis1

7 (14)

4 (8)

Exfoliative Dermatitis

3 (6)

0

Pruritus2

18 (36)

9 (18)

Rash3

36 (72)

28 (56)

Maculopapular Rash

3 (6)

0

Skin Disorder (NOS)4

13 (26)

9 (18)

Sweating

3 (6)

0

Body as a Whole

Asthenia

3 (6)

0

Headache

7 (14)

0

Infection

9 (18)

0

Pain

15 (30)

9 (18)

Cardiovascular

Edema

5 (10)

0

Peripheral Edema

3 (6)

0

Hemic and Lymphatic

Leukopenia

3 (6)

0

Lymphadenopathy

3 (6)

0

WBC Abnormal

3 (6)

0

Metabolic and Nutritional

Hyperlipemia

5 (10)

0

Nervous

Paresthesia

3 (6)

3 (6)

Respiratory

Cough Increased

3 (6)

0

Pharyngitis

3 (6)

0

*Regardless of association with treatment
Includes Investigator terms such as:

1 Contact dermatitis, irritant contact dermatitis, irritant dermatitis

2 Pruritus, itching, itching of lesion

3 Erythema, scaling, irritation, redness, rash, dermatitis

4 Skin inflammation, excoriation, sticky or tacky sensation of skin;
NOS = Not Otherwise Specified

To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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