Bexarotene - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Bexarotene, a synthetic vitamin A or retinoid, is beneficial in treating Cutaneous T-cell Lymphoma (CTCL) when delivered systemically through capsules. This drug relieves the cutaneous symptoms of CTCL, which include a rash and itchy skin. It inhibits the proliferation of cancer cells; however, the precise action method is uncertain. Bexarotene is approved for all stages of CTCL and can be administered alone or in combination with other medications. Bexarotene was approved by the Food and Drug Administration (FDA) on December 29, 1999, to treat skin symptoms of Cutaneous T-cell Lymphoma (CTCL) in patients who have attempted at least one systemic treatment. The approval was based on a trial using retinoids in CTCL and other cancer treatments, which showed a 40 percent response.

Drug Group

Bexarotene capsules belong to the retinoids class, which includes synthetic and naturally occurring vitamin A compounds used to treat skin problems and certain types of cancer, such as Cutaneous T-cell Lymphoma. Bexarotene is also classified as a miscellaneous antineoplastic drug class, which prevents and treats the growth of neoplasms, abnormal tissue growths, and tumors.

Indications

Bexarotene, a retinoid, treats cutaneous symptoms of cutaneous T-cell lymphoma in individuals who have not responded to at least previous systemic therapy.

Contraindications

• Pregnancy: When given to a pregnant woman, Bexarotene can harm the developing baby. Bexarotene, a retinoid medication, has been linked to birth abnormalities in humans and should not be used by pregnant women. Oral administration of Bexarotene to pregnant rats resulted in teratogenic effects and developmental death. Using Bexarotene during pregnancy or getting pregnant while using it, the patient should be warned of the potential risk to the fetus.

• Hypersensitivity: Patients with serious allergies to Bexarotene or other product components should avoid taking Bexarotene capsules.

Dosage Forms and Available Strengths

Bexarotene capsules are 75 milligrams (mg) of off-white, oblong, soft gelatin capsules.

Warnings and Precautions

• Hyperlipidemia: Bexarotene raises blood lipid levels. Assess baseline results and manage any rises during therapy with dose reduction, interruption, termination, or lipid-lowering therapy.

• Pancreatitis: If pancreatitis (pancreas inflammation) is suspected, stop taking Bexarotene and evaluate.

• Hepatotoxicity, Cholestasis, and Hepatic Failure: If the liver chemistry tests surpass three times the recommended limit of normal, discontinue Bexarotene to prevent hepatotoxicity (drug-induced liver damage), cholestasis (a condition in which the bile flow stops), or hepatic failure (liver failure).

• Hypothyroidism: Bexarotene therapy can lead to hypothyroidism (a condition when the thyroid gland produces not enough thyroid hormone). Monitor and restore thyroid hormones as needed.

• Neutropenia: Monitor for neutropenia (low neutrophil levels). Reduce the Bexarotene dose or discontinue as needed.

• Photosensitivity: To reduce photosensitivity, limit exposure to sunlight and artificial ultraviolet light throughout treatment.

For Patients

What Is Cutaneous T-Cell Lymphoma?

Cutaneous T-cell lymphoma (CTCL) is a rare cancer that develops from white blood cells known as T cells, which normally aid the immune system. CTCL generates aberrant T cells, resulting in cutaneous redness, elevated areas, and tumors. There are various forms, the most prevalent being mycosis fungoides. Sezary syndrome is less common and results in skin redness all over the body. CTCL is a type of non-Hodgkin lymphoma whose specific cause is uncertain. DNA (deoxyribonucleic acid) abnormalities in cells promote rapid cell growth and proliferation, resulting in aberrant T lymphocytes attacking the skin.

How Does Bexarotene Work?

Bexarotene, a retinoid, inhibits or prevents cell proliferation by binding to "retinoid X-receptors" (RXRs) found within cancer cells. This method is useful in treating disorders such as Cutaneous T-cell Lymphoma (CTCL), in which T cells attack the skin. However, the precise mechanism of action in CTCL treatment has yet to be understood.

What Are the Clinical Uses of Bexarotene?

Bexarotene is used to treat cutaneous symptoms of Cutaneous T-cell Lymphoma (CTCL) in people unresponsive to at least one previous systemic therapy. It is also used to treat cutaneous lesions in CTCL patients who have refractory or chronic disease after previous therapies or who have not tolerated alternative therapies. In addition to CTCL, Bexarotene has been given illegally for non-small cell lung cancer and breast cancer. It is also used to treat Kaposi's sarcoma (a malignant disorder in which cancer cells arise in the skin or mucous membranes of the digestive tract, including the stomach and intestines).

How Is Bexarotene Administered?

• Bexarotene is available in capsule form for oral use. It is typically taken once per day with food. Take Bexarotene at approximately the same time every day. Follow the directions on the prescription's packaging carefully, and request the pharmacist or doctor to explain anything unsure. Take Bexarotene precisely as prescribed. Do not take more or less of Bexarotene or more frequently than the physician recommends.

• Swallow the capsules entirely; do not chew or dissolve the capsules in water or the mouth. If people cannot swallow the capsules, consult the doctor.

• Bexarotene may be hazardous if it comes into contact with the skin. If any capsules are broken or leaking, do not handle them or the powder they contain. If powder from a broken capsule spills on the skin, thoroughly rinse it with soap and water and notify the doctor.

• The physician will start on a normal dose of Bexarotene and may reduce it if people have side effects or raise it if their condition fails to improve.

• It may take many months or more to experience the full benefits of Bexarotene. Do not discontinue taking Bexarotene without consulting the doctor.

• Ask the healthcare professionals for an exact copy of the Bexarotene manufacturer's details for the patient.

What Are the Side Effects of Bexarotene?

Bexarotene may produce adverse reactions. Inform the physician if any of the following symptoms are severe or do not resolve:

• Headache.

• Weakness.

• Fatigue.

• Sensitivity to cold.

• Weight gain.

• Depression.

• Joint or muscle pain.

• Thin, brittle hair or nails.

• Constipation.

• Redness.

• Dry skin.

• Skin redness, scaling, and itching.

• Hair loss.

• Swelling of the ankles, feet, and legs.

• Difficulties falling or staying asleep.

• Nausea.

• Vomiting.

• Diarrhea.

Certain adverse effects of Bexarotene can be severe. If people suffer from any of the following symptoms, call the doctor right away:

• Back or stomach discomfort.

• Intense nausea and vomiting persist.

• Fever, sore throat, chills, and other infection signs.

• Vision changes.

Bexarotene may raise cholesterol and other fat levels in the blood and inhibit thyroid gland function. The doctor will monitor people under Bexarotene to see whether the people are having any of these adverse effects. If people suffer any adverse effects while using Bexarotene, the doctor may prescribe another medicine to help them manage them.

What Are the Things to Inform the Doctor Before Taking Bexarotene?

• Before taking Bexarotene, inform the doctor and pharmacist if people are allergic to Bexarotene or any other retinoid, including Acitretin, Etretinate, Isotretinoin, or Tretinoin.

• Inform the pharmacist and physician about any other prescription or nonprescription drugs, vitamins, nutritional supplements, or herbal products that people planning to take Bexarotene are taking or intend to use. Be sure to inform about the usage of the following drugs: Amiodarone; certain antifungals such as Ketoconazole and Itraconazole; Cimetidine; Clarithromycin; Diltiazem; Erythromycin; Fluvoxamine; Gemfibrozil; HIV protease inhibitors such as Indinavir, Nelfinavir, and Ritonavir. The healthcare provider may need to adjust the dosages of the drugs or closely monitor people for negative effects. Many other drugs may interact with Bexarotene, so inform the healthcare professional about everything people are taking, even those not on this list.

• Inform the doctor if people drink or have previously consumed substantial amounts of alcohol. Tell the doctor if people have had pancreatitis, high blood cholesterol and other fatty substances, diabetes (high blood glucose), cataracts (clouding of the eye lens), or gallbladder, thyroid, kidney, or liver problems.

• Tell the doctor if the patient is breastfeeding.

• Ask the doctor about the safe consumption of alcoholic beverages while on Bexarotene. Alcohol can worsen the adverse effects of Bexarotene.

• Try to prevent excessive or prolonged sun exposure and wear protective clothing, sunglasses, and sunscreen. Bexarotene may make the skin more susceptible to sunlight.

Dietary Considerations

Consult the doctor before consuming grapefruit or drinking grapefruit juice while on Bexarotene.

Missed Dose

Take the Bexarotene missing dose with a meal as soon as the patient remembers it. If it is almost time for the next dose, skip the missing Bexarotene dose and follow the usual dosing regimen. Do not take two doses to compensate for a missed Bexarotene one.

Overdose

In the event of a Bexarotene overdose, contact the poison control helpline. If an individual taking Bexarotene collapses, experiences a seizure, encounters difficulty breathing, or cannot be woken, contact emergency services immediately.

Storage and Handling

Keep Bexarotene in the container it came in, well sealed, and out of the reach of children. Keep it at room temperature and away from direct heat, light, and moisture (not in the bathroom).

Disposal

Unneeded Bexarotene should be disposed of in certain ways to prevent pets, children, and others from consuming it. However, do not flush this drug down the toilet. Instead, using a medicine take-back program is the easiest approach to disposing of Bexarotene. To learn about community take-back initiatives, speak with a pharmacist or contact the town's garbage or recycling department.

For Doctors

Pharmacodynamics

Bexarotene is a retinoid that stimulates retinoid X receptors (RXRs), which have different biological functions than Retinoic Acid Receptors (RARs). It treats patients with cutaneous T-cell lymphoma who have not responded to earlier treatments. Bexarotene binds to and activates RXR subtypes, forming heterodimers with other receptors such as RARs, vitamin D, thyroid, and Peroxisome Proliferator Activator Receptors (PPAR). These receptors govern gene expression, cellular differentiation, and proliferation. Bexarotene suppresses tumor cell growth in vitro and causes tumor regression in various animal models.

Chemical Taxonomy

Bexarotene is a third-generation retinoid with the molecular formula C24H28O2. It specifically binds and activates retinoid X receptor subtypes (RXR α, RXR β, and RXR γ), which have biological activity in contrast to retinoic acid receptors. Bexarotene's chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid.

Mechanism of Action

Bexarotene primarily binds to and activates the retinoid X receptor subtypes. There are three subtypes in total: RXRα, RXRβ, and RXRγ. Bexarotene's precise mechanism of action in managing CTCL is unknown, although Bexarotene is effective at all clinical phases of CTCL.

Pharmacokinetics

Bexarotene has the following pharmacokinetic properties:

• Absorption: Following oral administration of Bexarotene capsules, it is absorbed with a Tmax (time to reach maximum plasma concentration) of approximately two hours. The terminal half-life of Bexarotene is approximately seven hours. Studies in patients with advanced cancers demonstrate approximately single-dose linearity within the therapeutic range and low accumulation with subsequent doses.

• Metabolism: CYP3A4 enzymes convert Bexarotene into 6- and 7-hydroxy-bexarotene, and 6- and 7-oxo-bexarotene.

• Excretion: Bexarotene is eliminated by bile.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Bexarotene's carcinogenic potential has not been investigated in animals. It is neither mutagenic to bacteria nor mammalian cells and has not been shown to produce clastogenic in vivo. Furthermore, no reproductive trials have been undertaken using Bexarotene, which has been shown to cause testicular degeneration in dogs.

Drug Interactions

• Effects of Other Drugs on Bexarotene: Concurrent dosing of Bexarotene with Gemfibrozil led to higher plasma concentrations of Bexarotene. Combining Gemfibrozil and Bexarotene is not recommended.

• Effect of Bexarotene on Other Drugs: Bexarotene may activate CYP3A4 enzymes and lower plasma concentrations of other CYP3A4 substrates. Oral and systemic hormonal contraceptives are among the affected drugs. If Bexarotene is prescribed for a female with reproductive potential, it is strongly advised to use non-hormonal contraception.

Clinical Studies

Bexarotene capsules were evaluated in two multicenter, open-label, historically-controlled clinical trials in 152 patients with advanced and early-stage cutaneous T-cell lymphoma in the U.S., Canada, Europe, and Australia, assessing disease refractoryness to prior systemic therapies. Patients in advanced stages were unresponsive to at least one prior systemic therapy and had received a median of five previous treatments. Early disease patients were intolerant of, had disease refractory to, or had achieved a six-month response plateau with at least two prior therapies. The trial included 152 patients: 102 with disease that had not responded to at least one previous systemic therapy, 90 with advanced disease, and 12 with early-stage disease. At the initial dose of 300 mg/m2/day (milligram per square meter per day), only 1.6 percent of patients achieved a complete clinical tumor response, whereas 30 percent achieved a partial response. The rate of relapse in 20 patients with a tumor response was 6 (30 percent) during a median of 21 weeks. Responses were seen as early as four weeks, with new responses appearing at subsequent visits.

Specific Considerations

• Pregnancy: Bexarotene, a retinoid, can cause fetal damage when provided to a pregnant woman and is therefore contraindicated during pregnancy. Bexarotene, a teratogenic medication, led to developmental death in rats after oral dosing during organogenesis. The overall risk of major birth defects and miscarriage is unclear for the indicated populations. Still, in the general population of the United States, significant birth defects account for two to four percent, and miscarriage accounts for between 15 and 20 percent of clinically recognized pregnancies. Bexarotene induced abnormalities in rats between days 7 and 17 of gestation, including inadequate ossification, cleft palate, sunken eye bulge or microphthalmia, and undersized ears. The plasma area under the curve (AUC) of Bexarotene in rats is about one-third that of humans at the recommended daily dose.

• Breastfeeding: The presence of Bexarotene in human milk and its implications on breastfed infants and milk production remain unknown. Breastfeeding should be ceased due to Bexarotene excretion in human milk and the risk of severe effects.

• Males and Females of Reproductive Potential: To avoid pregnancy and birth defects when taking Bexarotene, acquire a negative serum pregnancy test with a level of sensitivity of at least 50 mlU/L one week before treatment. While the patient is on Bexarotene, another pregnancy test should be performed at least once a month. Bexarotene can cause fetal harm when provided to a pregnant woman; hence, effective contraception must be utilized for one month before, during, and after therapy. Unless abstinence is desired, two dependable methods of contraception should be used concurrently. Bexarotene therapy should begin on the second or third day of a regular menstrual cycle, and the patient should be given no more than one month's supply. Male patients on Bexarotene should use condoms during sexual intercourse if their sexual partners are pregnant or may become pregnant.

• Pediatric Use: The safety and efficacy of Bexarotene in pediatric patients has yet to be established.

• Geriatric Use: In the Bexarotene clinical trials, 64 percent of CTCL patients were 60 or older, with 33 percent being 70 or older. There was no substantial difference in safety between older and younger patients, but certain elderly persons may be more sensitive to Bexarotene.

• Hepatic Impairment: Bexarotene has not been investigated in patients with hepatic impairment, likely leading to reduced clearance. Watch for any Bexarotene's potential toxicity as the exposure increases.