Bexarotene (Topical)
VA CLASSIFICATION
Primary: DE900
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 (topical) —
Indications
Accepted
Lymphoma, cutaneous T-cell (treatment)—Bexarotene administered topically is indicated for the treatment of cutaneous lesions in patients with cutaneous T-cell lymphoma, stage 1A and 1B, who have refractory or persistent disease after other therapies, or who have not tolerated other therapies.
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Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
348.48{01}
Solubility
Bexarotene is insoluble in water and slightly soluble in vegetable oils and ethanol, USP.{01}
Mechanism of action/Effect:
Bexarotene is a retinoid that selectively binds and activates retinoid X receptor subtypes (RXR
, RXRβ, RXRγ). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma is unknown, but it inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models.{01}Absorption:
The generally low plasma bexarotene concentrations (less than 5 ng/mL and not exceeding 55 ng/mL) indicate that, in patients receiving low to moderate doses, there is a low potential for significant systemic absorption. The quantifiable amount of absorption increased with an increase in percent body surface area treated and increasing quantity of bexarotene applied. The uptake of topical bexarotene by organs and tissues has not been evaluated.{01}
Protein binding:
Very highly (>99%){01}
Biotransformation:
Following oral administration of bexarotene four oxidative metabolites have been identified in the plasma: 6– and 7–hydroxy-bexarotene and 6– and 7–oxo-bexarotene, formed by the cytochrome P450 3A4 pathway. When bexarotene is applied topically, the contribution of the parent and any metabolite to the efficacy and safety is unknown.{01}
Onset of action:
After therapy is initiated a response may be seen as soon as four weeks, but most patients require longer application to achieve further benefit. In one study the longest time to onset of response was 392 days.{01}
Elimination:
Primarily hepatobiliary.{01}
Precautions to Consider
Cross-sensitivity and/or related problems
Bexarotene should be used with caution in patients with a known hypersensitivity to other retinoids. However, no clinical instances of cross-reactivity have been noted.{01}
Carcinogenicity
Long-term studies in animals have not been conducted{01}.
Mutagenicity
Bexarotene was not mutagenic to bacteria (Ames assay) or mammalian cell (mouse lymphoma assay). Bexarotene was not clastogenic in vivo (micronucleus test in mice).{01}
Pregnancy/Reproduction
Fertility—
Bexarotene caused testicular degeneration when oral doses of 1.5 milligrams per kilogram per day (mg/kg/day) were given to dogs for 91 days.{01}
Pregnancy—
Bexarotene is contraindicated during pregnancy. Studies in animals have shown that bexarotene causes serious adverse effects in the fetus. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while applying bexarotene and for at least one month after the last dose of drug.
Two reliable forms of contraception should be used, unless abstinence is followed, simultaneously for 1 month prior to the initiation, during, and for at least 1 month after discontinuation, of bexarotene therapy. {01}
A negative pregnancy test should be obtained within 1 week prior to initiation of topical bexarotene therapy. A pregnancy test should be repeated monthly while on topical bexarotene therapy.{01}
Animal studies with orally administered bexarotene in pregnant rats was shown to cause developmental abnormalities (incomplete ossification, cleft palate, depressed eye bulge/microphthalmia, and small ears) at dosages of 4 mg to 16 mg/kg/day. At dosages of greater than 10 mg/kg/day bexarotene caused developmental mortality. Plasma bexarotene concentrations after topical administration were generally less than one-hundredth the maximum plasma concentration (Cmax) associated with dysmorphogenesis in rats, although some patients had levels that were approximately one-eighth of the Cmax associated with dysmorphogenesis in rats{01}.
FDA Pregnancy Category X.{01}
Breast-feeding
It is not known whether bexarotene is distributed into breast milk; however 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 bexarotene to the mother{01}.
Pediatrics
No information is available. Appropriate studies have not been performed on the relationship of age to the effects of bexarotene in the pediatric population. Safety and efficacy 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 studies, with 38% of the tested population over 65 years of age, there were no overall differences in response, but greater sensitivity of some older individuals to bexarotene cannot be ruled out.{01}
Pharmacogenetics
Pharmacokinetic differences as a result of gender or race could not be assessed in clinical trials due to immeasurable plasma concentrations (<1 ng/ml).{01}
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):
» DEET (N,N-diethyl-m-toluamide) (increased DEET toxicity in concurrent use{01})
» Vitamin A supplementation (Concomitant use of vitamin A supplements in amounts >15,000 IU/day should be avoided to decrease the potential for additive toxic effects)
Note: Systemic interactions with gemfibrozil and cytochrome P450 3A4 inhibitors, such as ketoconazole, itraconazole, erythromycin, and grapefruit juice are unlikely, due to the low systemic exposure with topical bexarotene. Any increases in plasma bexarotene that occur are unlikely to be of sufficient magnitude to result in adverse effects.{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 problem exists:
» Hypersensitivity to Bexarotene or other components of the product{01}
» Pregnancy{01}
Risk-benefit should be considered when the following medical problems exist
Hepatic dysfunction (may lead to significant decreases in bexarotene clearance; caution should be used{01})
» Photosensitivity (may have the potential for photosensitization; minimize exposure to sunlight and artificial ultraviolet light during the use of topical bexarotene{01} )
Renal dysfunction ( urinary elimination is a minor excretory pathway (< 1% of an orally administered dose), but because renal insufficiency can result in significant protein binding changes, the pharmacokinetics of bexarotene, which is highly protein bound, may be altered in patients with renal insufficiency, {01})
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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):
» Pregnancy Test (A negative pregnancy test [such as serum beta-human chorionic gonadotropin, beta-HCG] with a sensitivity of at least 50 mIU/L should be obtained within one week prior to bexarotene use. The pregnancy test must be repeated at monthly intervals while the patient remains on bexarotene{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
Asthenia (lack or loss of strength)
edema (decreased urination: rapid weight gain, bloating)
exfoliative dermatitis (blisters on skin; chills; fever; general feeling of discomfort or illness; red, thickened, or scaly skin; swollen and/or painful glands; unusual bruising)
hyperlipemia (increase in lipid levels)
leukopenia (sore throat; fever)
lymphadenopathy (swollen, painful, or tender lymph glands in neck, armpit, or groin)
maculopapular rash (skin rash with lesions)
paresthesia (burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings)
peripheral edema (bloating or swelling of face, hands, lower legs, and/or feet)
skin disorder (skin inflammations; scratch ; sticky or tacky sensation)
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Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Contact dermatitis (blistering, burning, crusting, dryness, flaking of skin, itching, scaling, severe redness, soreness, swelling of skin)
cough increased
headache
infection ( fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
pain
pharyngitis ( sore throat)
pruritus (itching skin; itching of lesion)
rash
sweating
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Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Bexarotene (Topical).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to bexarotene or other retinoids
Pregnancy—Avoiding pregnancy during treatment; need to use two forms of reliable contraception 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 medication, especially DEET (N,N-diethyl-m-toluamide) or vitamin A
Other medical problems, especially photosensitivity
Proper use of this medication
» Proper application technique
To use
Avoid normal skin and mucosal membranes
Wash hands immediately after applying or use applicator stick
Dry before covering with clothes; no occlusive dressing
» Proper dosing
Applying as soon as possible; not applying if almost time for next scheduled dose; not doubling doses
Proper storage
Precautions while using this medication
» Regular visits to physician to check progress
Possible photosensitivity reactions, minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment)
Not taking Vitamin A supplements exceeding 15 ,000 IU/day
Side/adverse effects
Signs of potential side effects, especially asthenia, edema, exfoliative dermatitis, hyperlipemia, leukopenia, lymphadenopathy, maculopapular rash, paresthesia, peripheral edema, or skin disorders
General Dosing Information
Topical application
Bexarotene for topical use, is not intended for systemic use. Therapy should be continued as long as the patient is deriving benefit.
A sufficient amount of bexarotene should be applied to cover the lesion with a generous coating. Occlusive dressings should not be used. Allow to dry before covering with clothing. Avoid application of bexarotene to normal, unaffected skin surrounding the lesions to avoid irritation. Do not apply near mucosal surfaces of the body. Avoid exposure to sunlight. If application site toxicity occurs, the frequency of application can be reduced or temporarily discontinued for a few days until the symptoms subside.{01}
Diet and Nutrition
Since bexarotene is metabolized by cytochrome P450 3A4, the consumption of grapefruit juice should be avoided to decrease the possibility of an increase in bexarotene plasma concentrations.
Patients should be advised to limit vitamin A intake to £15,000 IU/day.
{01}Avoid contact with normal skin to decrease irritation.{01}
Topical Dosage Forms
BEXAROTENE GEL
Usual Adult Dose
Cutaneous T-cell lymphoma (Stage 1A and 1B)
Topical, to the skin, applied to generously cover the lesion, once every other day for the first week. Increase the application frequency at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily, dependent upon individual lesion tolerance. Usually, a dosing frequency of two to four times per day is tolerated. If severe irritation occurs, reduce the frequency or temporarily discontinue for a few days until symptoms subside.{01}
Usual adult prescribing limits
Up to four times daily{01}.
Usual Pediatric Dose
Safety and effectiveness in pediatric patients have not been established{01}
Usual Geriatric Dose
See Usual adult dose.
Usual geriatric prescribing limits
See Usual adult prescribing limits”.
Strength(s) usually available
U.S.—
1% (Rx) [Targretin (dehydrated alcohol ) (polyethylene glycol 400) (hydroxypropyl cellulose) (butylated hydroxytoluene)]
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Canada—
Not commercially available.{01}
Packaging and storage:
Store at 25 °C (77 °F), with excursions permitted between 15 and 30 °C (59 and 86 °F). Protect from light. Avoid exposure to high temperatures and humidity after the tube is opened.{01}
Auxiliary labeling:
• Use protection against sun and avoid use of sunlamp or tanning booth.
• For topical use only.
• Keep from heat and light.
Developed: 09/07/2001
Revised: 10/15/2001
References
- Product Information: Targretin®, bexarotene. Ligand Pharmaceuticals Incorporated, San Diego, CA, (PI revised 7/2000) reviewed 9/2001.
