Professional Drug Information > Targretin

Bexarotene (Systemic)

VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Targretin.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antineoplastic —

Indications

Accepted

Lymphoma, cutaneous T– cell (treatment)— Bexarotene is indicated in the treatment of cutaneous manifestations of cutaneous T– cell lymphoma in patients who are refractory to at least one prior systemic therapy.^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    348.48^{01}

Mechanism of action/Effect:

Bexarotene is a retinoid that selectively binds to and activates retinoid X receptor subtypes (RXR, RXRβ, RXRγ), which modulates transcription and expression of genes that control the process of cellular differentiation and proliferation in cells. Bexarotene inhibits the growth of some tumor cell lines of hematopoietic and squamous cell origin in vitro and induces tumor regression in vivoin some animal models. Its exact mechanism of action in the treatment of cutaneous T-cell lymphoma is unknown.^{01}

Absorption:

Maximal absorption of bexarotene occurs at approximately two hours after oral administration. Following a fat-containing meal, area under the plasma concentration-time curve (AUC) and peak plasma concentration (C_max) resulting from a 300 milligram (mg) dose were 35% and 48% higher, respectively, than after administration of a glucose solution.^{01}

Protein binding:

Very high (>99%)
^{01}
Biotransformation:

Four known metabolites: 6–hydroxybexarotene, 7–hydroxybexarotene, 6–oxo-bexarotene, and 7–oxo-bexarotene.

Oxidative metabolites formed via CYP 3A4 and then glucuronidated. In vitro studies have revealed retinoid receptor activation by the oxidative metabolites, however the relative contribution of the parent and any metabolites to the efficacy and safety of bexarotene is unknown.^{01}

Half-life:


Terminal half-life:

Seven hours.^{01}


Elimination:
    Primarily hepatobiliary.^{01}


Precautions to Consider

Cross-sensitivity and/or related problems

The manufacturer recommends caution when administering bexarotene to patients with a known hypersensitivity to retinoids. No clinical reports of cross-sensitivity have been noted at this time.^{01}

Carcinogenicity/Tumorigenicity

Long-term studies in animals have not been conducted.^{01}

Mutagenicity

Bexarotene was not mutagenic in the Ames assay or the mouse lymphoma assay, nor was it clastogenic in the mouse micronucleus test.^{01}

Pregnancy/Reproduction
Fertility—
Fertility studies have not been conducted. Oral bexarotene doses of 1.5 mg per kg of body weight (mg/kg) per day (resulting in an area under the plasma concentration-time curve (AUC) value that was approximately one-fifth the AUC value at the recommended human daily dose) for 91 days produced testicular degeneration in dogs. ^{01}

Pregnancy—
Bexarotene must not be given to a woman who is pregnant or who intends to become pregnant. It is recommended that women of childbearing potential be advised to avoid becoming pregnant during treatment because of the potential risks to the fetus. If a woman becomes pregnant during treatment, bexarotene must be discontinued immediately and the woman given appropriate counseling. ^{01}

Administration of bexarotene to a female patient requires that the following criteria be met:   • Two reliable forms of contraception (one non-hormonal form) should be used simultaneously for 1 month prior to the initiation, during, and for at least 1 month after discontinuation, of bexarotene therapy. ^{01}{04}
   • A negative pregnancy test with a sensitivity of at least 50 milli International Units per liter (mIU/L) should be obtained within 1 week before treatment is started. Bexarotene therapy should be initiated on the second or third day of a normal menstrual period.^{01}
   • Pregnancy testing and contraception counseling should be repeated on a monthly basis during treatment.^{01}


Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse during bexarotene therapy and for at least 1 month after the last dose of the drug.^{01}

Bexarotene caused malformations when given orally to pregnant rats on days 7 through 17 of gestation. Developmental abnormalities, including incomplete ossification at 4 mg/kg per day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg per day, occurred. The 4 mg/kg per day dose produces an AUC value in rats that is approximately one-third the AUC in humans at the recommended daily dose. Developmental mortality occurred at doses greater than 10 mg/kg per day. The no-effect dose for fetal effects in rats was 1 mg/kg per day, which produces an AUC value approximately one-sixth of the AUC in humans at the recommended daily dose.^{01}

FDA Pregnancy Category X.^{01}

Breast-feeding

It is not known whether bexarotene is distributed into human breast milk. However, breast-feeding is not recommended during treatment because of the potential risks to the infant.^{01}

Pediatrics

The safety and efficacy of bexarotene in pediatric patients have not been established.^{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of bexarotene in the elderly. In clinical trials, 64% of the total patients with cutaneous T-cell lymphoma were 60 years or older, while 33% of patients were 70 years or older. No overall differences in safety were observed between patients 70 years or older and younger patients; however, greater sensitivity of some older patients to bexarotene cannot be ruled out.^{01}


Dental

The bone marrow depressant effects of bexarotene may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Blood dyscrasia–causing medications (see Appendix II)    (leukopenic and/or thrombocytopenic effects of bexarotene may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of the bone marrow depressant, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II) or
» Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Contraceptives, hormonal    (concomitant use may result in a increase of the rate of metabolism and a reduction in the plasma concentration of contraceptives; use of two forms of contraception (one non-hormonal) is strongly suggested.^{04})


» Cytochrome P450 3A4 enzyme inducers, such as:
Phenobarbital or
Phenytoin or
Rifampin    (may cause a reduction in plasma bexarotene concentrations^{01})


» Cytochrome P450 3A4 enzyme inhibitors, such as:
Erythromycin or
Grapefruit juice or
Itraconazole or
Ketoconazole    (may cause an increase in plasma bexarotene concentrations^{01})


» Gemfibrozil    (concomitant use with gemfibrozil is not recommended since it can substantially increase plasma bexarotene concentrations^{01}{02}{03})


» Insulin or
» Insulin secretion enhancers such as sulfonylureas or
» Insulin sensitizers     (bexarotene may enhance action of these agents, resulting in hypoglycemia; use caution with concomitant use^{01})


» Tamoxifen    (concomitant use with tamoxifen in women with breast cancer, progressing on tamoxifen therapy, resulted in a modest decrease in plasma concentrations of tamoxifen; occurred through possible cytochrome P450 induction^{04})


» Vitamin A    (use should be limited to £ 15,000 International Units daily; may cause additive toxic effects in higher doses^{01})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by bexarotene therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by bexarotene therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the bexarotene therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
CA125 assay values    (may be increased in patients with ovarian cancer^{01})

With physiology/laboratory test values
» Alanine aminotransferase (ALT [SGPT]) and
» Aspartate aminotransferase (AST [SGOT]) and
» Bilirubin and
Lactate dehydrogenase    ( elevations in liver function tests were observed in 5 to 7% (SGOT [AST]), 2 to 9% (SGPT [ALT]), and 0 to 6% (bilirubin) of patients; increases appear to be dose dependent; values returned to normal within 1 month in 80% of patients after a decrease in dose or discontinuation of therapy; bexarotene therapy should be suspended or discontinued if elevations beyond three times normal persist^{01})


Alkaline phosphatase    (values may be abnormal^{01})


Calcium, serum    (concentrations may be decreased^{01})


Glucose, blood    (concentrations may be increased^{01})


» Cholesterol, total, serum, and
» Triglycerides, fasting, serum     (may be significantly increased during bexarotene therapy; fasting triglyceride concentrations greater than 2.5 times the upper limit of normal were observed in 70% of patients and cholesterol increases greater than 300 mg per deciliter (mg/dL) were observed in 60 to 75% of patients; the effects on triglyceride and total cholesterol were reversible with discontinuation of therapy and were generally mitigated by dose reduction or concomitant antilipemic therapy ^{01})


Hemoglobin    (concentrations may be abnormal^{01})


High density lipoproteins (HDL)    (may be significantly decreased during bexarotene therapy; decreases to £ 25 mg/dL have been reported in 55 to 90% of patients; the effect on HDL cholesterol was reversible with discontinuation of therapy and was generally mitigated by dose reduction or concomitant antilipemic therapy^{01})


Potassium, serum    (concentrations may be increased^{01})


Sodium, blood    (concentrations may be increased or decreased^{01})


Thyroid-stimulating hormone (TSH) and
Thyroxine (T₄), total    (bexarotene therapy may induce biochemical evidence of or clinical hypothyroidism in half of all patients treated; TSH and total T₄ levels were decreased in about 60 and 45% of patients, respectively; thyroid hormone supplements should be considered in patients with laboratory evidence of hypothyroidism^{01})


White blood cell counts (WBC)    (bexarotene therapy may induce reversible leukopenia/neutropenia; leukopenia in the range of 1000 to < 3000 WBC per cubic millimeter (WBC/mm ³) occurred in 18 to 43% of patients; the time to onset of leukopenia was generally 4 to 8 weeks and in most patients was explained by neutropenia; the incidence of U.S. National Cancer Institute [NCI] grades 3 and 4 neutropenia was 12% and 4%, respectively; leukopenia/neutropenia resolved after dose reduction or discontinuation of therapy on average within 30 days in 93% of patients with cutaneous T-cell lymphoma and 82% of patients with non-cutaneous T-cell lymphoma; leukopenia/neutropenia were rarely associated with severe sequelae or serious adverse events^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to bexarotene or other retinoids^{01}
» Pregnancy^{01}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression, existing
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Cataracts    (bexarotene may cause new cataracts or worsening of previous cataracts^{01})


» Diabetes mellitus    (bexarotene may contribute to hypoglycemia in patients being treated for diabetes with insulin, insulin secretion enhancers, or insulin sensitizers; caution should be used^{01})


» Hepatic dysfunction    (may cause significant decreases in bexarotene clearance; caution should be used^{01})


» Hyperlipidemia, uncontrolled    (bexarotene may cause significant increases in serum lipids^{01})


» Infection
» Pancreatitis, history of or
» Risk factors for pancreatitis, such as:
Alcohol consumption, excessive or
Biliary tract disease or
Diabetes mellitus, uncontrolled or
Hyperlipidemia, uncontrolled or
Hypertriglyceridemia causing medications or
Pancreas toxic medications or    (bexarotene therapy may precipitate pancreatitis by increasing triglyceride levels; acute pancreatitis has been reported in patients receiving bexarotene; use of bexarotene in patients with risk factors for pancreatitis is not generally recommended^{01})


Photosensitivity    (mild phototoxicity manifested as sunburn and skin sensitivity to sunlight was reported in patients receiving bexarotene who were exposed to direct sunlight^{01})


Renal dysfunction    (pharmacokinetics may be altered in patients with renal insufficiency^{01})


Note: Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]) and
» Aspartate aminotransferase (AST [SGOT]) and
» Bilirubin and
Lactate dehydrogenase    ( measurements should be taken at baseline and one, two, and four weeks after initiation of treatment, then every eight weeks for duration of treatment; bexarotene therapy should be suspended or discontinued if elevations beyond three times the upper limit of normal persist^{01})


» Lipid panel, fasting    (fasting blood lipid determinations should be performed at baseline and then weekly until the lipid response to bexarotene is established (usually within 2–4 weeks), with continued monitoring every eight weeks; fasting triglyceride levels should be normalized prior to initiating bexarotene therapy; triglyceride levels should be maintained below 400 mg/dL; if fasting triglyceride levels become elevated during treatment, antilipemic therapy should be instituted and the dose of bexarotene should be reduced or suspended, if necessary; in clinical trials, 60% of patients were given antilipemic drugs (48% of patients received atorvastatin); use of gemfibrozil is not recommended due to a potential drug interaction^{01})


Ophthalmologic exam^{01}    (recommended in patients who experience visual difficulties during therapy^{01})


Thyroid function tests    (baseline measurements with periodic monitoring during therapy^{01})


» White blood cell count with differential and
» Platelet count    (baseline measurements with periodic monitoring during therapy^{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (10% or higher)
    
Anemia, hypochromic (unusual tiredness or weakness)—more frequent at doses > 300 mg per square meter of body surface area daily
    
exfoliative dermatitis (skin rash or other skin and mucous membrane lesions)—more frequent at doses >300 mg per square meter of body surface area daily
    
fever — more frequent at doses >300 mg per square meter of body surface area daily
    
hyperlipemia or hypercholesterolemia (increase in lipid or cholesterol levels)
    
hypothyroidism ( coldness; dry, puffy skin; unusual tiredness ; weight gain)
    
increased lactic dehydrogenase
    
infection, bacterial (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
    
leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
    
peripheral edema (swelling of the arms, feet, hands, or legs)
^{01}
Incidence less frequent ( less than 10%)
    
Bilirubinemia (yellow eyes or skin)
    
elevated hepatic enzymes
    
pancreatitis ( severe stomach pain with nausea or vomiting)
    
pneumonia (fever or chills; cough; shortness of breath)
^{01}


Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (10% or higher)
    
Abdominal pain —more frequent at doses of 300 mg per square meter of body surface area daily
    
alopecia (hair loss)— more frequent at doses >300 mg per square meter of body surface area daily
    
anorexia ( loss of appetite)—more frequent at doses >300 mg per square meter of body surface area daily
    
asthenia (loss of strength or energy ; tiredness or weakness)
    
back pain —more frequent at doses >300 mg per square meter of body surface area daily
    
chills —more frequent at doses >300 mg per square meter of body surface area daily
    
diarrhea — more frequent at doses >300 mg per square meter of body surface area daily
    
dry skin —more frequent at doses of 300 mg per square meter of body surface area daily
    
flu-like syndrome (chills and fever ; diarrhea; cough; general feeling of discomfort or illness)— more frequent at doses >300 mg per square meter of body surface area daily
    
insomnia ( trouble in sleeping)— more frequent at doses >300 mg per square meter of body surface area daily
    
headache
    
nausea — more frequent at doses of 300 mg per square meter of body surface area daily
    
rash
    
vomiting — more frequent at doses >300 mg per square meter of body surface area daily
^{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Note: Bexarotene has been given to patients with advanced cancer in doses of up to 1000 mg per square meter of body surface area per day without acute toxic effects. No cases of overdose have been reported.^{01}


Treatment of overdose
Supportive care should be made available.^{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Bexarotene (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to bexarotene or other retinoids

Pregnancy—Avoiding pregnancy during treatment; need to use two forms of reliable contraception (one should be non-hormonal) simultaneously starting 1 month prior to initiation of therapy and continuing at least 1 month after discontinuation of treatment; use of condoms by male patients





Breast-feeding—Not recommended because of risk of serious side effects in nursing infants
Other medications, especially other blood dyscrasia-causing medications, other bone marrow depressants, previous cytotoxic drug or radiation therapy, medications that induce hepatic metabolism such as phenobarbital, phenytoin, and rifampin; medications or substances that inhibit hepatic metabolism such as erythromycin, grapefruit juice, itraconazole, and ketoconazole; gemfibrozil, insulin, insulin secretion enhancers such as sulfonylureas, insulin sensitizers, tamoxifen, or vitamin A
Other medical problems, especially chickenpox, existing bone marrow depression, herpes zoster, diabetes mellitus, hepatic dysfunction, uncontrolled hyperlipidemia, infection, history of pancreatitis or risk of developing pancreatitis

Proper use of this medication
» Taking with a meal

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to assess effectiveness

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine, or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
Possible photosensitivity reactions


Side/adverse effects
Signs of potential side effects including hypochromic anemia, exfoliative dermatitis, fever, hyperlipemia or hypercholesterolemia, hypothyroidism, increased lactic dehydrogenase, bacterial infection, leukopenia, peripheral edema, bilirubinemia, elevated hepatic enzymes, pancreatitis, or pneumonia


General Dosing Information
Patients receiving bexarotene should be under supervision of a physician experienced in cancer chemotherapy.

Treatment should continue for as long as the patient continues to receive benefit^{01}.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of bexarotene. These may include extra care in performing invasive procedures, regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusion may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Bexarotene should be taken with a meal.^{01}

Diet/Nutrition
Patients should avoid drinking grapefruit juice while receiving bexarotene treatment.^{01}


Oral Dosage Forms

BEXAROTENE CAPSULES

Usual adult dose
Lymphoma, cutaneous T– cell
Initial, oral, 300 mg per square meter of body surface area per day in a single dose with a meal. May be decreased to 200 mg per square meter of body surface area per day, then to 100 mg per square meter of body surface area per day, or temporarily suspended if patient exhibits signs of toxicity. Once toxicity is controlled, the dose may be retitrated upwards. If there is no tumor response after eight weeks of therapy and if the initial dose of 300 mg per square meter of body surface area per day is well-tolerated, the dose may be increased to 400 mg per square meter of body surface area per day with careful monitoring.^{01}


Usual adult prescribing limits
400 mg per square meter of body surface area per day.^{01}

Usual pediatric dose
Safety and efficacy have not been established.^{01}

Usual geriatric dose
See Usual adult dose^{01}

Strength(s) usually available
U.S.—


75 mg (Rx) [Targretin (polyethylene glycol 400 NF) (polysorbate 20 NF) (povidone USP) (butylated hydroxyanisole NF)]

Packaging and storage:
Store at 2–25 °C (36–77 °F). Avoid exposure to high temperatures and humidity once the bottle is opened. Protect from light.^{01}

Auxiliary labeling:
   • Take with food.
   • Keep out of reach of children.

Developed: 03/30/2000
Revised: 08/29/2001

References

1. Product Information: Targretin®, bexarotene. Ligand Pharmaceuticals, San Diego, CA, (PI revised 12/99) reviewed 2/2000.
   

2. Manufacturer comment, 4/28/00.
   

3. Reviewer comment, 5/9/00.
   

4. Product Information: Targretin®, bexarotene. Ligand Pharmaceuticals, San Diego, CA, (PI revised 01/2001) PI reviewed 8/2001.
   

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