Bexarotene

What is bexarotene?

Bexarotene is a medicine mainly used to treat cutaneous T-cell lymphoma (CTCL). It is not available in New Zealand.

Indications for treatment with bexarotene

Bexarotene (Targretin®; Ligand Pharmaceuticals Inc., San Diego, CA, U.S.A) is a member of a subclass of retinoids called rexinoids that selectively activate retinoid X receptors (RXRs), which have a biological activity distinct from retinoic acid receptors (RARs). Bexarotene capsules and bexarotene gel are used for the treatment of:

• Early-stage cutaneous T-cell lymphoma (CTCL) in patients with refractory or persistent disease after other therapies or who have not tolerated other therapies (gel).
• Advanced-stage CTCL refractory to at least one oral therapy.
• Kaposi sarcoma

Mechanism of action of bexarotene

Bexarotene binds to and activates RXRs which function as ligand-activated transcription factors that control gene expression. This leads to the modulation of cell growth, apoptosis, and differentiation. Bexarotene inhibits the growth in vitro of some tumour cell lines of haematopoietic (blood) and squamous cell (skin) origin. It also induces tumour 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.

Pharmacology of bexarotene

• Half-life: 7 hr
• Peak plasma time: 2 hr
• Protein-bound: >99%
• Metabolism: by CYP3A4 enzymes
• Metabolites: 6- and 7- hydroxy- bexarotene, 6- and 7- oxo- bexarotene
• Excretion: bile

Dosage and administration of bexarotene

Bexarotene capsules

Each soft gelatin capsule for oral administration contains 75 mg of bexarotene. The recommended initial dose is 300 mg/m²/day.

• Bexarotene capsules should be taken as a single daily dose by mouth with a meal because safety and efficacy data are based on administration with food.
• Dose modification guidelines: The 300 mg/m²/day dose level of bexarotene capsules may be adjusted to 200 mg/m²/day then 100 mg/m²/day, or temporarily suspended, if necessitated by toxicity.
• If there is no tumour response after 8 weeks of treatment and if the initial dose of 300 mg/m²/day is well tolerated, the dose may be escalated to 400 mg/m²/day with careful monitoring.
• Duration of Therapy: in clinical trials in CTCL, bexarotene capsules have been administered for up to 97 weeks.
• Treatment should be continued as long as the patient is deriving benefit.

Bexarotene gel 1%

• Topical: Bexarotene gel is usually applied to affected areas once every other day for the first week, then increased at weekly intervals to once a day, then twice a day, then 3 times a day, and finally 4 times a day.
• Use on the skin only. Bexarotene gel must not be applied onto mucous membranes such as the eyes, nose, mouth, lips, vagina, the tip of the penis, rectum, or anus. Avoid applying to healthy areas of skin because irritation or redness can occur.
• Hands should be washed immediately with soap and water before and after using bexarotene gel. Cover the affected skin area with a generous layer of gel. Allow the gel to dry for 5 to 10 minutes before covering the area with clothing.
• The treated area should not be covered, bandaged, or wrapped. Wait at least 20 minutes after showering or bathing before applying topical bexarotene. Use a mild soap when washing the skin to reduce irritation. Avoid showering, bathing, or swimming for at least 3 hours after applying bexarotene gel.

Monitoring bexarotene

• Bexarotene capsules induce major lipid abnormalities in most patients (high blood fats). These must be monitored and treated during long-term therapy. Fasting blood lipid determinations should be performed before therapy is initiated and weekly until the lipid response to bexarotene 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 oral bexarotene therapy. Attempts should be made to maintain triglyceride levels below 400 mg/dL to reduce the risk of pancreatitis. Consideration should be considered in starting a lipid-lowering medication prior to bexarotene therapy in high-risk individuals.
• If fasting triglycerides become elevated during treatment with bexarotene, lipid-lowering medication should be started, and if necessary, the dose of bexarotene capsules reduced or suspended. Because of a potential drug-drug interaction, gemfibrozil is not recommended for use with bexarotene capsules. Instead, atorvastatin is recommended.
• Patients with CTCL who have risk factors for pancreatitis (prior pancreatitis, uncontrolled hyperlipidaemia, 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 bexarotene capsules.
• In patients with CTCL receiving an initial dose of 300 mg/m²/day of oral bexarotene, elevations in liver function tests (LFTs) have been observed. 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 treatment if test results reach greater than three times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin.
• Bexarotene capsules induce biochemical evidence of or clinical hypothyroidism (underactive thyroid) in about half of all patients treated. Baseline thyroid function tests should be obtained and patients monitored during treatment.
• Determination of white cell count (WBC) with differential should be obtained at baseline and periodically during treatment. leukopenia (lowered WBC) has been reported in about 43% of patients receiving an initial dose greater than 300 mg/m²/day of oral bexarotene.
• Patients treated with bexarotene capsules who experience visual difficulties should have an appropriate ophthalmologic evaluation.

Photosensitivity

Retinoids as a class have been associated with photosensitivity. Mild phototoxicity manifested as sunburn and skin sensitivity to sunlight has been observed in patients who are exposed to direct sunlight while receiving oral bexarotene. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light (including phototherapy and solaria) while receiving treatment with bexarotene.

Adverse events due to bexarotene

The safety of bexarotene capsules has been evaluated in clinical studies. The most common adverse events reported with an incidence of at least 10% in patients with CTCL treated at an initial dose of 300 mg/m²/day are:

• lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol and decreased HDL cholesterol)
• hypothyroidism
• a headache
• weakness
• rash
• leukopenia, anaemia (low white cell count and haemoglobin)
• nausea
• infection
• peripheral oedema (ankle swelling), abdominal pain, and dry skin.

Adverse effects reported with topical bexarotene (incidence >10%) include:

• Rash (72%)
• Pruritus / itch (36%)
• Pain (30%)
• Infection (18%)
• Contact dermatitis (14%)
• Headache (14%) .

Adverse events with topical bexarotene at an incidence of 1-10% have included:

• Oedema / swelling (10%)
• Hyperlipaemia (10%)
• Weakness (6%)
• Exfoliative dermatitis (6%)
• Leukopenia (6%), lymphadenopathy (6%), white cell changes (6%)
• Cough (6%), pharyngitis (6%)
• Sweating (6%)

Contraindications to bexarotene

• Bexarotene capsules are contraindicated in patients with a known hypersensitivity (allergy) to bexarotene or other components of the product.
• Occlusive dressings should not be used with 1% bexarotene gel.

Drug interactions

• No formal studies to evaluate drug interactions with bexarotene have been conducted. On the basis of the metabolism of bexarotene by cytochrome P450 3A4 enzymes, 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, rifampicin, phenytoin, phenobarbital, and other inducers of cytochrome P450 3A4 may lower plasma bexarotene concentrations.
• Administration of bexarotene capsules and gemfibrozil at the same time results 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 are not affected by concomitant administration with atorvastatin.

Use of bexarotene in specific populations

Pregnancy: Category X

• Bexarotene capsules may cause fetal harm when administered to a pregnant woman and treatment should not be administered to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking oral bexarotene, treatment must be stopped immediately and the woman given appropriate counselling. Women of child-bearing potential should be advised to avoid becoming pregnant when bexarotene capsules are used. A negative pregnancy test (eg, serum beta-human chorionic gonadotropin, beta-HCG) with a sensitivity of at least 50 mlU/L should be obtained within one week prior to oral therapy, and the pregnancy test must be repeated at monthly intervals while the patient remains on treatment.
• Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while taking bexarotene capsules and for at least one month after the last dose of the drug. Therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of capsules should be given to the patient so that the results of pregnancy testing can be assessed and counselling regarding avoidance of pregnancy and birth defects can be reinforced.

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, a decision should be made whether to discontinue nursing or to discontinue oral bexarotene, taking into account the importance of the drug to the mother.

Paediatric use

Safety and effectiveness in children have not been established.

Vitamin A supplementation

Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to ≤15,000 IU/day to avoid potential additive toxic effects.

Patients with diabetes mellitus

Caution should be used when administering bexarotene capsules to patients using insulin, agents enhancing insulin secretion (eg, sulfonylureas), or insulin-sensitizers (eg, thiazolidinedione class). Based on its mechanism of action, bexarotene capsules could enhance the action of these agents, resulting in hypoglycaemia (low blood sugar).

Renal insufficiency

No formal studies have been conducted in patients with renal insufficiency (kidney disease). 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 (drug concentrations) may be altered in patients with renal insufficiency.

Overdosage of bexarotene

There are no reports of clinical experience with an overdose. Any overdose with bexarotene capsules should be treated with supportive care for the signs and symptoms exhibited by the patient.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).