Lipid abnormalities: Targretin® capsules induce major lipid abnormalities in most patients. These must be monitored and treated during long-term therapy. About 70% of patients with CTCL who received an initial dose of≥300 mg/m2/day of Targretin® capsules had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% had values over 800 mg/dL with a median of about 1200 mg/dL in those patients. Cholesterol elevations above 300 mg/dL occurred in approximately 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m2/day or greater than 300 mg/m2/day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to less than 25 mg/dL were seen in about 55% and 90% of patients receiving an initial dose of 300 mg/m2/day or greater than 300 mg/m2/day, respectively, of Targretin® capsules. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction or concomitant antilipemic therapy.
Fasting blood lipid determinations should be performed before Targretin® capsules therapy is initiated and weekly until the lipid response to Targretin® capsules is established, which usually occurs within two to four weeks, and at eight week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating Targretin® capsules therapy. Attempts should be made to maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae (see WARNINGS: Pancreatitis). If fasting triglycerides are elevated or become elevated during treatment, antilipemic therapy should be instituted, and if necessary, the dose of Targretin® capsules reduced or suspended. In the 300 mg/m2/day initial dose group, 60% of patients were given lipid lowering drugs. Atorvastatin was used in 48% (73/152) of patients with CTCL. Because of a potential drug-drug interaction (see PRECAUTIONS: Drug-Drug Interactions), gemfibrozil is not recommended for use with Targretin® capsules.
Pancreatitis: Acute pancreatitis has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with Targretin® capsules; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in one patient. One patient with advanced non-CTCL cancer died of pancreatitis. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) should generally not be treated with Targretin® capsules (see WARNINGS: Lipids abnormalities and PRECAUTIONS: Laboratory Tests).
Liver function test abnormalities: For patients with CTCL receiving an initial dose of 300 mg/m2/day of Targretin® capsules, elevations in liver function tests (LFTs) have been observed in 5% (SGOT/AST), 2% (SGPT/ALT), and 0% (bilirubin). In contrast, with an initial dose greater than 300 mg/m2/day of Targretin® capsules, the incidence of LFT elevations was higher at 7% (SGOT/AST), 9% (SGPT/ALT), and 6% (bilirubin). Two patients developed cholestasis, including one patient who died of liver failure. In clinical trials, elevation of LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Baseline LFTs should be obtained, and LFTs should be carefully monitored after one, two and four weeks of treatment initiation, and if stable, at least every eight weeks thereafter during treatment. Consideration should be given to a suspension or discontinuation of Targretin® capsules if test results reach greater than three times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin.
Hepatic insufficiency: No specific studies have been conducted with Targretin® capsules in patients with hepatic insufficiency. 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. Targretin® capsules should be used only with great caution in this population.
Thyroid axis alterations: Targretin® capsules induce biochemical evidence of or clinical hypothyroidism in about half of all patients treated, causing a reversible reduction in thyroid hormone (total thyroxine [total T4]) and thyroid-stimulating hormone (TSH) levels. The incidence of decreases in TSH and total T4 were about 60% and 45%, respectively, in patients with CTCL receiving an initial dose of 300 mg/m2/day. Hypothyroidism was reported as an adverse event in 29% of patients. Treatment with thyroid hormone supplements should be considered in patients with laboratory evidence of hypothyroidism. In the 300 mg/m2/day initial dose group, 37% of patients were treated with thyroid hormone replacement. Baseline thyroid function tests should be obtained and patients monitored during treatment.
Leukopenia: A total of 18% of patients with CTCL receiving an initial dose of 300 mg/m2/day of Targretin® capsules had reversible leukopenia in the range of 1000 to<3000 WBC/mm3. Patients receiving an initial dose greater than 300 mg/m2/day of Targretin® capsules had an incidence of leukopenia of 43%. No patient with CTCL treated with Targretin® capsules developed leukopenia of less than 1000 WBC/mm3. The time to onset of leukopenia was generally four to eight weeks. The leukopenia observed in most patients was explained by neutropenia. In the 300 mg/m2/day initial dose group, the incidence of NCI Grade 3 and Grade 4 neutropenia, respectively, was 12% and 4%. The leukopenia and neutropenia experienced during Targretin® capsules therapy resolved after dose reduction or discontinuation of treatment, on average within 30 days in 93% of the patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Determination of WBC with differential should be obtained at baseline and periodically during treatment.
Cataracts: Posterior subcapsular cataracts were observed in preclinical toxicity studies in rats and dogs administered bexarotene daily for 6 months. In 15 of 79 patients who had serial slit lamp examinations, new cataracts or worsening of previous cataracts were found. Because of the high prevalence and rate of cataract formation in older patient populations, the relationship of Targretin® capsules and cataracts cannot be determined in the absence of an appropriate control group. Patients treated with Targretin® capsules who experience visual difficulties should have an appropriate ophthalmologic evaluation.
Pregnancy: Category X. See CONTRAINDICATIONS.
General: Targretin® capsules should be used with caution in patients with a known hypersensitivity to retinoids. Clinical instances of cross-reactivity have not 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.
Patients with Diabetes Mellitus: Caution should be used when administering Targretin® capsules in patients using insulin, agents enhancing insulin secretion (e.g., sulfonylureas), or insulin-sensitizers (e.g., thiazolidinedione class). Based on the mechanism of action, Targretin® capsules could enhance the action of these agents, resulting in hypoglycemia. Hypoglycemia has not been associated with the use of Targretin® capsules as monotherapy.
Photosensitivity: Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. Mild phototoxicity manifested as sunburn and skin sensitivity to sunlight was observed in patients who were exposed to direct sunlight while receiving Targretin® capsules. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light while receiving Targretin® capsules.
Blood lipid determinations should be performed before Targretin® capsules are given. Fasting triglycerides should be normal or normalized with appropriate intervention prior to therapy. Hyperlipidemia usually occurs within the initial two to four weeks. Therefore, weekly lipid determinations are recommended during this interval. Subsequently, in patients not hyperlipidemic, determinations can be performed less frequently (see WARNINGS: Lipid abnormalities).
A white blood cell count with differential should be obtained at baseline and periodically during treatment. Baseline liver function tests should be obtained and should be carefully monitored after one, two and four weeks of treatment initiation, and if stable, periodically thereafter during treatment. Baseline thyroid function tests should be obtained and then monitored during treatment as indicated (see WARNINGS: Leukopenia, Liver function test abnormalities, and Thyroid axis alterations).
In all clinical trials, patients were instructed to take Targretin® capsules with or immediately following a meal. In one clinical study, plasma bexarotene AUC and Cmax values were substantially higher following a fat-containing meal versus those following the administration of a glucose solution. Because safety and efficacy data are based upon administration with food, it is recommended that Targretin® capsules be administered with food (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).
No formal studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed by cytochrome P450 3A4.
On the basis of the metabolism of bexarotene by cytochrome P450 3A4, ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit juice, and other inhibitors of cytochrome P450 3A4 would be expected to lead to an increase in plasma bexarotene concentrations. Furthermore, rifampin, phenytoin, phenobarbital, and other inducers of cytochrome P450 3A4 may cause a reduction in plasma bexarotene concentrations.
Concomitant administration of Targretin® capsules and gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene, probably at least partially related to cytochrome P450 3A4 inhibition by gemfibrozil. Under similar conditions, bexarotene concentrations were not affected by concomitant atorvastatin administration. Concomitant administration of gemfibrozil with Targretin® capsules is not recommended.
Based on interim data, concomitant administration of Targretin® capsules and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen, possibly through an induction of cytochrome P450 3A4. Based on this known interaction, bexarotene may theoretically increase the rate of metabolism and reduce plasma concentrations of other substrates metabolized by cytochrome P450 3A4, including oral or other systemic hormonal contraceptives (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions and CONTRAINDICATIONS: Pregnancy: Category X). Thus, if treatment with Targretin® capsules is intended in a woman with child-bearing potential, it is strongly recommended that two reliable forms of contraception be used concurrently, one of which should be non-hormonal.
No formal studies have been conducted with Targretin® capsules in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (<1% of 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.
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.
Drug/Laboratory Test Interactions
CA125 assay values in patients with ovarian cancer may be increased by Targretin® capsule therapy.
Carcinogenesis, 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).
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.
Safety and effectiveness in pediatric patients have not been established.
Of the total patients with CTCL in clinical studies of Targretin® capsules, 64% were 60 years or older, while 33% were 70 years or older. No overall differences in safety were observed between patients 70 years or older and younger patients, but greater sensitivity of some older individuals to Targretin® capsules cannot be ruled out. Responses to Targretin® capsules were observed across all age group decades, without preference for any individual age group decade.