Targretin bexarotene 75 mg Capsule, Liquid Filled, 100-count — NDC 0187-5526-75 (Billing 00187-5526-75)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRß, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation.

Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown.

12.3Pharmacokinetics Terminal half-life of bexarotene is approximately 7 hours. Studies in patients with advanced malignancies show approximate single dose linearity within the therapeutic range. Absorption After oral administration of TARGRETIN, bexarotene is absorbed with a T max of about 2 hours.

Plasma bexarotene AUC and C max values resulting from a 75 to 300 mg dose were 35% and 48% higher, respectively, after a fat-containing meal than after a glucose solution. Distribution 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.

Elimination Metabolism Four bexarotene metabolites have been identified in plasma: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest that cytochrome P450 3A4 is the major cytochrome P450 responsible for formation of the oxidative metabolites and that the oxidative metabolites may be glucuronidated. The oxidative metabolites are active in in vitro assays of retinoid receptor activation, but the relative contribution of the parent and any metabolites to the efficacy and safety of TARGRETIN is unknown.

Excretion The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose). Pharmacokinetics in Specific Populations Age: Based on the population pharmacokinetic analysis of data for 232 patients aged ≥65 years and 343 patients aged <65 years, age has no statistically significant effect on bexarotene pharmacokinetics.

Body Weight and Gender: Based on the population pharmacokinetics analysis of data for 614 patients with a weight range of 26 to 145 kg, the bexarotene apparent clearance increases with increasing body weight. Gender has no statistically significant effect on bexarotene pharmacokinetics. Race: Based on the population pharmacokinetic analysis of data for 540 Caucasian and 44 Black patients, bexarotene pharmacokinetics are similar in Blacks and Caucasians.

There are insufficient data to evaluate potential differences in the pharmacokinetics of bexarotene for other races. Renal Impairment: No formal studies have been conducted with TARGRETIN in patients with renal impairment. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose), but because renal impairment can result in significant protein binding changes, pharmacokinetics may be altered in patients with renal impairment.

Hepatic Impairment: No specific studies have been conducted with TARGRETIN in patients with hepatic impairment. Because less than 1% of the dose 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. Drug Interactions Effect of Other Drugs on TARGRETIN CYP3A4 Inhibitors/Inducers: In a clinical study, concomitant administration of multiple dos… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRß, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation.

Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown.

12.3Pharmacokinetics Terminal half-life of bexarotene is approximately 7 hours. Studies in patients with advanced malignancies show approximate single dose linearity within the therapeutic range. Absorption After oral administration of TARGRETIN, bexarotene is absorbed with a T max of about 2 hours.

Plasma bexarotene AUC and C max values resulting from a 75 to 300 mg dose were 35% and 48% higher, respectively, after a fat-containing meal than after a glucose solution. Distribution 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.

Elimination Metabolism Four bexarotene metabolites have been identified in plasma: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest that cytochrome P450 3A4 is the major cytochrome P450 responsible for formation of the oxidative metabolites and that the oxidative metabolites may be glucuronidated. The oxidative metabolites are active in in vitro assays of retinoid receptor activation, but the relative contribution of the parent and any metabolites to the efficacy and safety of TARGRETIN is unknown.

Excretion The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose). Pharmacokinetics in Specific Populations Age: Based on the population pharmacokinetic analysis of data for 232 patients aged ≥65 years and 343 patients aged <65 years, age has no statistically significant effect on bexarotene pharmacokinetics.

Body Weight and Gender: Based on the population pharmacokinetics analysis of data for 614 patients with a weight range of 26 to 145 kg, the bexarotene apparent clearance increases with increasing body weight. Gender has no statistically significant effect on bexarotene pharmacokinetics. Race: Based on the population pharmacokinetic analysis of data for 540 Caucasian and 44 Black patients, bexarotene pharmacokinetics are similar in Blacks and Caucasians.

There are insufficient data to evaluate potential differences in the pharmacokinetics of bexarotene for other races. Renal Impairment: No formal studies have been conducted with TARGRETIN in patients with renal impairment. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose), but because renal impairment can result in significant protein binding changes, pharmacokinetics may be altered in patients with renal impairment.

Hepatic Impairment: No specific studies have been conducted with TARGRETIN in patients with hepatic impairment. Because less than 1% of the dose 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. Drug Interactions Effect of Other Drugs on TARGRETIN CYP3A4 Inhibitors/Inducers: In a clinical study, concomitant administration of multiple doses of ketoconazole with TARGRETIN did not alter bexarotene plasma concentrations.

This suggests that bexarotene elimination is not dependent on CYP3A4 metabolism. Paclitaxel plus Carboplatin: The co-administration of paclitaxel (200 mg/m 2 IV dose over 3 hours) plus carboplatin (at a dose expected to achieve an AUC of 6 mg●min/mL) with TARGRETIN (400 mg/m 2 orally once daily) increased the exposure to bexarotene (AUC 0-24 and C max ) by 2-fold compared to TARGRETIN alone. Atorvastatin: Bexarotene concentrations were not affected by concomitant atorvastatin administration.

Effect of TARGRETIN on Other Drugs Bexarotene did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. In vitro data… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES TARGRETIN was evaluated in two clinical trials in 152 patients with advanced and early stage cutaneous T-cell lymphoma (CTCL) in two multicenter, open-label, historically controlled clinical trials conducted in the U.S., Canada, Europe, and Australia. The advanced disease patients had disease refractory to at least one prior systemic therapy (median of two, range 1 to 6 prior systemic therapies) and had been treated with a median of five (range 1 to 11) prior systemic, irradiation, and/or topical therapies.

Early disease patients were intolerant to, had disease that was refractory to, or had reached a response plateau of 6 months on, at least two prior therapies. The patients entered had been treated with a median of 3.5 (range 2 to 12) therapies (systemic, irradiation, and/or topical). The two clinical trials enrolled a total of 152 patients, 102 of whom had disease refractory to at least one prior systemic therapy, 90 with advanced disease and 12 with early disease.

This is the patient population for whom TARGRETIN is indicated. Patients were initially treated with a starting dose of 650 mg/m 2 /day with a subsequent reduction of starting dose to 500 mg/m 2 /day. Neither of these starting doses was tolerated, and the starting dose was then reduced to 300 mg/m 2 /day.

If, however, a patient on 300 mg/m 2 /day of TARGRETIN showed no response after 8 or more weeks of therapy, the dose could be increased to 400 mg/m 2 /day. Tumor response was assessed in both trials 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.

Also considered in response assessment was the presence or absence of cutaneous tumors and extracutaneous disease manifestations. All tumor responses required confirmation over at least two assessments separated by at least 4 weeks. A partial response was defined as an improvement of at least 50% in the index lesions without worsening, or development of new cutaneous tumors or non-cutaneous manifestations.

A complete clinical response required complete disappearance of all manifestations of disease, but did not require confirmation by biopsy. At the initial dose of 300 mg/m 2 /day, 1/62 (1.6%) of patients had a complete clinical tumor response and 19/62 (30%) of patients had a partial tumor response. The rate of relapse (25% increase in CA or worsening of other aspects of disease) in the 20 patients who had a tumor response was 6/20 (30%) over a median duration of observation of 21 weeks, and the median duration of tumor response had not been reached.

Responses were seen as early as 4 weeks and new responses continued to be seen at later visits. In one post-approval clinical trial with a total of 59 subjects (29 in 300 mg/m 2 /day dose group and 30 in the 150 mg/m 2 /day dose), the objective response rate was higher in the TARGRETIN 300 mg/m 2 /day group than in the TARGRETIN 150 mg/m 2 /day group with respect to the CA (34.5% vs 23.3%), Physicians Global Assessment (PGA) (37.9% vs 20.0%), and percent BSA involvement (34.5% vs 23.3%). The median duration of response in the TARGRETIN 300 mg/m 2 /day group based on the CA, PGA, and percent BSA involvement was 86.5 days, 72.0 days and 60.0 days, respectively.

While in the TARGRETIN 150 mg/m 2 /day group the median duration of response based on the CA, PGA, and percent BSA involvement was 55 days, 119.0 days and 118.0 days, respectively. The median time to cutaneous tumor response (the time to cutaneous tumor response for a given subject is defined as the time interval from the first day of TARGRETIN treatment to the time of the first observation when the subject with subsequent confirmation of response meets criteria for CR, CCR or PR) in the TARGRETIN 300 mg/m 2 /day group based on the CA, PGA, a… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to assess the carcinogenic potential of bexarotene have not been conducted. Bexarotene is 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 (producing an AUC of approximately one fifth the AUC at the recommended human daily dose).