TARGRETIN

Targretin ® (bexarotene) gel 1% contains bexarotene and is intended for topical application only. Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). The chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl] benzoic acid, and the structural formula is as follows: Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C 24 H 28 O 2 . It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP. Targretin gel is a clear gelled solution containing 1.0% (w/w) bexarotene in a base of dehydrated alcohol, USP, polyethylene glycol 400, NF, hydroxypropyl cellulose, NF, and butylated hydroxytoluene, NF. targretin-gel-01

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.

Targretin gel should be initially applied once every other day for the first week. The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily according to individual lesion tolerance. Generally, patients were able to maintain a dosing frequency of two to four times per day. Most responses were seen at dosing frequencies of two times per day and higher. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside. See CONTRAINDICATIONS, Pregnancy. Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel near mucosal surfaces of the body. A response may be seen as soon as four weeks after initiation of therapy but most patients require longer application. With continued application, further benefit may be attained. The longest onset time for the first response among the responders was 392 days based on the Composite Assessment of Index Lesion Severity in the multicenter study. In clinical trials, Targretin gel was applied for up to 172 weeks. Targretin gel should be continued as long as the patient is deriving benefit. Occlusive dressings should not be used with Targretin gel. Targretin gel is a topical therapy and is not intended for systemic use. Targretin gel has not been studied in combination with other CTCL therapies.

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

The safety of Targretin gel has been assessed in clinical studies of 117 patients with CTCL who received Targretin gel for up to 172 weeks. In the multicenter open-label study, 50 patients with CTCL received Targretin 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 Targretin 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 Targretin 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 Targretin Gel in the Multicenter CTCL Study * 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 Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. All Adverse Events Application Site Adverse Events COSTART 5 Body System/Preferred Term N = 50 n (%) N = 50 n (%) Skin and Appendages Contact Dermatitis 1 7 (14) 4 (8) Exfoliative Dermatitis 3 (6) 0 Pruritus 2 18 (36) 9 (18) Rash 3 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

Drug-Drug Interactions Patients who are applying Targretin 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 Targretin gel and other CTCL therapies.