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Bexarotene (Systemic)

Pronunciation

(beks AIR oh teen)

Index Terms

  • 3-methyl TTNEB

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Targretin: 75 mg

Generic: 75 mg

Brand Names: U.S.

  • Targretin

Pharmacologic Category

  • Antineoplastic Agent, Retinoic Acid Derivative

Pharmacology

Selectively binds to and activates retinoid X receptors (RXRs). Once activated, RXRs function as transcription factors to regulate the expression of genes which control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin and induces tumor regression in vivo in some animal models.

Absorption

Improved 48% by a fat-containing meal

Metabolism

Hepatic via CYP3A4 isoenzyme to four metabolites; further metabolized by glucuronidation

Excretion

Feces (primarily); urine (minimal, <1%)

Time to Peak

~2 hours

Half-Life Elimination

~7 hours

Protein Binding

>99% to plasma proteins

Use: Labeled Indications

Cutaneous T-cell lymphoma, refractory: Treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy

Contraindications

Known hypersensitivity to bexarotene or any component of the formulation; pregnancy

Documentation of allergenic cross-reactivity for retinoids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Cutaneous T-cell lymphoma, refractory: Oral: Initial: 300 mg/m2 once daily taken as a single daily dose; if well tolerated, but no tumor response after 8 weeks, may increase to 400 mg/m2 once daily; continue as long as clinical benefit is demonstrated (bexarotene was administered in studies for up to 97 weeks).

Mycosis fungoides/Sezary syndrome, refractory/resistant (off-label dose): Oral: 75 to 150 mg daily in combination with PUVA; maximum dose: 300 mg daily (Rupoli, 2010; Singh, 2004)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, although renal elimination is a minor excretion pathway, renal insufficiency may result in significant protein binding changes and alter pharmacokinetics of bexarotene.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, hepatic impairment would be expected to result in decreased clearance of bexarotene due to the extensive hepatic contribution to elimination.

Dosing: Adjustment for Toxicity

If necessitated by toxicity, may decrease dose from 300 mg/m2/day to 200 mg/m2/day, then to 100 mg/m2/day, or temporarily hold. Upon recovery, may titrate dose upward with careful monitoring.

Hepatotoxicity: If AST, ALT, or bilirubin >3 times ULN, consider withholding or discontinuing therapy.

Hypertriglyceridemia: Consider dose reduction, treatment interruption, and or antilipemic therapy.

Leukopenia and neutropenia: Leukopenia and neutropenia resolved after dose reduction or discontinuation.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH, 2014).

A 1 mg/mL oral suspension may be prepared with capsules. Cut one 75 mg capsule in half, rinse the interior contents of the capsule, and suspend with 75 mL sterile water. Administer immediately after preparation. To ensure administration of full dose, rinse empty glass with half a glass of water and administer residue.

Targretin data on file, Eisai Inc.

Administration

Administer with a meal. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Avoid contact with broken or leaking capsules; if contact occurs, wash immediately with soap and water. If it is necessary to manipulate the capsules (eg, to prepare an oral suspension), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH, 2014).

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 2°C to 25°C (36°F to 77°F). Protect from light. Avoid humidity and high temperatures after opening bottle.

Drug Interactions

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Bexarotene (Systemic) may decrease the serum concentration of AtorvaSTATin. Monitor therapy

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

CARBOplatin: May increase the serum concentration of Bexarotene (Systemic). Monitor therapy

Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Consider therapy modification

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Contraceptives (Estrogens): Bexarotene (Systemic) may decrease the serum concentration of Contraceptives (Estrogens). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Consider therapy modification

Contraceptives (Progestins): Bexarotene (Systemic) may decrease the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Gemfibrozil: May increase the serum concentration of Bexarotene (Systemic). Avoid combination

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning. Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

PACLitaxel (Conventional): May increase the serum concentration of Bexarotene (Systemic). Bexarotene (Systemic) may decrease the serum concentration of PACLitaxel (Conventional). Monitor therapy

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Management: Monitor for reduced rolapitant response. Recommended dexamethasone regimens should be used with rolapitant. Higher dexamethasone doses or more prolonged use may increase the potential for a significant interaction. Monitor therapy

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

Tamoxifen: Bexarotene (Systemic) may decrease the serum concentration of Tamoxifen. Monitor therapy

Tetracycline Derivatives: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Avoid combination

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Avoid combination

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Monitor therapy

Test Interactions

Treatment with bexarotene may interfere with CA125 assay values in patients with ovarian cancer (per manufacturer's labeling).

Adverse Reactions

Frequency not always defined.

>10%:

Cardiovascular: Peripheral edema (11% to 13%)

Central nervous system: Headache (30% to 42%), chills (10% to 13%), insomnia (5% to 11%)

Dermatologic: Exfoliative dermatitis (10% to 28%), skin rash (17% to 23%), xeroderma (9% to 11%), alopecia (4% to 11%)

Endocrine & metabolic: Hyperlipidemia (79%), hypercholesterolemia (32% to 62%), hypothyroidism (29% to 53%), increased lactate dehydrogenase (7% to 13%)

Gastrointestinal: Diarrhea (7% to 42%), anorexia (2% to 23%), nausea (8% to 16%), vomiting (4% to 13%), abdominal pain (4% to 11%)

Hematologic & oncologic: Leukopenia (17% to 47%), anemia (6% to 25%), hypochromic anemia (4% to 13%)

Infection: Infection (13% to 23%; bacterial infection: 1% to 13%)

Neuromuscular & skeletal: Weakness (20% to 45%), back pain (2% to 11%)

Respiratory: Flu-like symptoms (4% to 13%)

Miscellaneous: Fever (5% to 17%)

1% to 10%:

Cardiovascular: Angina pectoris, cardiac failure (right), cerebrovascular accident, chest pain, hypertension, subdural hematoma, syncope, tachycardia

Central nervous system: Agitation, ataxia, confusion, depression, dizziness, hyperesthesia, myasthenia, neuropathy

Dermatologic: Acne vulgaris, allergic skin reaction, cellulitis, cheilitis, cutaneous nodule, maculopapular rash, skin photosensitivity, pustular rash, skin rash, sunburn, vesiculobullous dermatitis

Endocrine & metabolic: Albuminuria, hyperglycemia, weight gain, weight loss

Gastrointestinal: Colitis, constipation, dyspepsia, flatulence, gastroenteritis, gingivitis, increased serum amylase, melena, pancreatitis, xerostomia

Genitourinary: Dysuria, hematuria, mastalgia, urinary incontinence, urinary tract infection, urinary urgency

Hematologic & oncologic: Acquired blood coagulation disorder, eosinophilia, hemorrhage, hypoproteinemia, lymphocytosis, thrombocythemia, thrombocytopenia

Hepatic: Hepatic failure, increased serum ALT, increased serum AST, increased serum bilirubin

Infection: Candidiasis, sepsis

Neuromuscular & skeletal: Arthralgia, arthrosis, myalgia, ostealgia

Ophthalmic: Blepharitis, cataract (new and worsening), conjunctivitis, corneal lesion, keratitis, visual field defect, xerophthalmia

Otic: Otalgia, otitis externa

Renal: Increased serum creatinine, renal function abnormality

Respiratory: Bronchitis, cough, dyspnea, hemoptysis, hypoxia, pharyngitis, pleural effusion, pneumonia, pulmonary edema, rhinitis

Miscellaneous: Serous drainage

ALERT: U.S. Boxed Warning

Pregnancy:

Bexarotene capsules are a member of the retinoid class of drugs that is associated with birth defects in humans. Bexarotene capsules also caused birth defects when administered orally to pregnant rats. Bexarotene capsules must not be administered to a pregnant woman.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Dose-related elevations in ALT, AST, and bilirubin have been reported; cases of cholestasis and liver failure (fatal) have occurred. Monitor for liver function test abnormalities and temporarily withhold or discontinue if ALT, AST, or bilirubin are >3 times the upper limit of normal (ULN). Liver function test elevations resolved within 1 month in most patients following dose reduction or discontinuation.

• Hypothyroidism: Bexarotene rapidly suppresses thyroid-stimulating hormone (TSH) levels by directly inhibiting TSH secretion, and also affects thyroid hormone metabolism (Hamnvik, 2011). Reductions in total thyroxine (T4) and thyroid-stimulating hormone (TSH) are reversible. Hypothyroidism commonly occurs. Monitor thyroid functions tests, including free T4 levels at baseline and during treatment. Thyroid supplementation is usually required; patients already receiving thyroid hormone therapy may require increased thyroid hormone doses to achieve therapeutic levels (Hamnvik, 2011).

• Leukopenia: Grade 1 to 3 leukopenia has occurred (predominantly as neutropenia); the incidence is higher with doses >300 mg/m2/day. The onset of leukopenia was generally 4 to 8 weeks. Grade 3 and 4 neutropenia have occurred. Leukopenia and neutropenia typically resolved within 30 days after discontinuation or dose reduction. Monitor complete blood cell count (CBC) with differential at baseline and periodically during treatment. Leukopenia and neutropenia were rarely associated with severe conditions or serious adverse events.

• Lipid abnormalities: Bexarotene induces significant lipid abnormalities in a majority of patients (increased triglycerides and total cholesterol, and decreased high-density lipoprotein [HDL]) and usually occur within 2 to 4 weeks; effects are reversible on discontinuation or generally mitigated by dose reduction and/or antilipemic therapy. Monitor fasting lipid panel; may require dose reduction, treatment interruption, and/or concomitant antilipemic therapy. Fasting triglycerides should be normal (or normalized with appropriate therapy) prior to initiation; triglycerides should be maintained <400 mg/dL. In studies, HMG-CoA reductase inhibitors were used to manage lipids; gemfibrozil is not recommended due to potential for drug interactions.

• Pancreatitis: Pancreatitis associated with hypertriglyceridemia has been reported. Interrupt treatment and evaluate if pancreatitis is suspected. Cutaneous T-cell lymphoma patients with risk factors for pancreatitis (eg, prior pancreatitis, uncontrolled hyperlipidemia, excessive ethanol consumption, uncontrolled diabetes, biliary tract disease, concomitant medications causing hyperlipidemia or concomitant medications associated with pancreatic toxicity) may be at increased risk for bexarotene-associated pancreatitis.

• Photosensitivity: Retinoids are associated with photosensitivity; phototoxicity (sunburn, sunlight sensitivity) has occurred with bexarotene when patients were exposed to direct sunlight. Advise patients to minimize exposure to sunlight and artificial ultraviolet light during treatment.

• Visual disturbances: Any new visual abnormalities experienced by the patient should be evaluated by an ophthalmologist (cataracts may develop or worsen, especially in the geriatric population).

Disease-related concerns:

• Diabetes: Use with caution in patients with diabetes mellitus; may enhance the actions of insulin, sulfonylureas, or thiazolidinediones, resulting in hypoglycemia in patients receiving these agents (hypoglycemia has not been observed with bexarotene monotherapy). Monitor blood glucose as necessary.

• Hepatic impairment: Use with extreme caution in patients with hepatic impairment; bexarotene undergoes extensive hepatic elimination.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Vitamin A: Due to the potential for additive toxicities, patients should be advised to limit additional vitamin A intake (in studies, additional vitamin A was limited to ≤15,000 units/day).

Special populations:

• Pregnancy: [U.S. Boxed Warning]: Bexarotene is a retinoid, a drug class associated with birth defects in humans; do not administer during pregnancy. Bexarotene caused birth defects when administered orally to pregnant rats. Pregnancy test needed within 1 week before initiation and every month thereafter. Effective contraception must be in place 1 month before initiation, during therapy, and for at least 1 month after discontinuation. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant, must use condoms during sexual intercourse during treatment and for at least 1 month after last dose.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

If female, pregnancy test within 1 week before initiation then monthly while on bexarotene; fasting lipid panel (before initiation, then weekly until lipid response established [usually 2 to 4 weeks] and then at 8-week intervals thereafter); liver function tests (baseline, then at 1, 2, and 4 weeks after initiation, then at 8-week intervals thereafter if stable); monitor thyroid function tests (including free T4) at baseline and weekly for the first 5 to 7 weeks, then every 1 to 2 months (Hamnvik, 2011); CBC with differential (baseline and periodic); blood glucose (in diabetic patients); ophthalmic exam (if visual abnormalities occur)

Pregnancy Considerations

[U.S. Boxed Warning]: Bexarotene is a retinoid, a drug class associated with birth defects in humans; do not administer during pregnancy. Bexarotene caused birth defects when administered orally to pregnant rats. It must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking the drug, it must be stopped immediately and appropriate counseling be given. In women of childbearing potential, therapy should be started on the second or third day of a normal menstrual period. Either abstinence or 2 forms of reliable contraception (one should be nonhormonal) must be used for at least 1 month before initiating therapy, during therapy, and for 1 month following discontinuation of bexarotene. A negative pregnancy test (sensitivity of at least 50 milliunits/mL) within 1 week prior to beginning therapy, and monthly thereafter is required for women of childbearing potential. A maximum 1 month supply is recommended so that pregnancy tests may be evaluated. Male patients must use a condom during any sexual contact with women of childbearing age during therapy, and for at least 1 month following discontinuation of bexarotene.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, insomnia, lack of appetite, abdominal pain, nausea, vomiting, diarrhea, hair loss, dry skin, or back pain. Have patient report immediately to prescriber signs of infection, signs of a low thyroid level (constipation; difficulty handling heat or cold; memory impairment; mood changes; or burning, numbness, or tingling feeling), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), vision changes, swelling of arm or leg, or loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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