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BEXAROTENE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bexarotene is a selective retinoid X receptor agonist involved in regulation of cell differentiation and proliferation. Tazarotene is a retinoid prodrug, which converts to its active form (tazarotenic acid) and binds to retinoic acid receptors (RAR) alpha, beta, and gamma.

Specific Substances

    A) BEXAROTENE
    1) 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethyenyl] benzoic acid
    2) LG-100069
    3) LGD-1069
    4) SR-11247
    5) Targretin(R)
    6) Molecular Formula: C24-H28-O2
    7) CAS 153559-49-0
    TAZAROTENE
    1) Ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate
    2) AGN-190168
    3) CAS 118292-40-3

    1.2.1) MOLECULAR FORMULA
    1) C24H28O2 (Prod Info TARGRETIN(R) oral capsules, 2015)

Available Forms Sources

    A) FORMS
    1) Bexarotene is available as 75 mg capsules and as a 1% gel for topical application (Prod Info Targretin(R) oral capsules, 2011; Prod Info Targretin(R) topical gel 1%, 2009) .
    2) Tazarotene is available topically as a 0.05% and 0.1% cream and gel, and as a 0.1% foam (Prod Info FABIOR(TM) topical foam, 2012; Prod Info TAZORAC(R) topical cream, 2011; Prod Info TAZORAC(R) topical gel, 2011).
    B) USES
    1) BEXAROTENE
    a) Bexarotene is indicated for the treatment of cutaneous T-cell lymphoma cutaneous manifestations in patients refractory to at least one prior systemic therapy (Prod Info Targretin(R) oral capsules, 2011; Prod Info Targretin(R) topical gel 1%, 2009).
    b) Bexarotene may also be effective for the treatment of AIDS-related Kaposi's sarcoma, as combination therapy with interferon alfa-2b for treatment of renal cell carcinoma, and as combination therapy with cisplatin and vinorelbine for treatment of patients with advanced non-small-cell lung cancer (Millikan et al, 2001; Khuri et al, 2001) Wilding et al, 2001).
    2) TAZAROTENE
    a) Tazarotene is used topically for the treatment acne vulgaris in patients 12 years of age and older (Prod Info FABIOR(TM) topical foam, 2012).
    b) Tazarotene is also indicated topically for the treatment of plaque psoriasis (Prod Info TAZORAC(R) topical cream, 2011; Prod Info TAZORAC(R) topical gel, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Bexarotene is indicated for the treatment of cutaneous T-cell lymphoma cutaneous manifestations in patients refractory to at least one prior systemic therapy. Tazarotene is indicated topically for the treatment of plaque psoriasis in adults, and for the topical treatment of acne vulgaris in patients 12 years of age and older.
    B) PHARMACOLOGY: Bexarotene is a selective retinoid X receptor agonist involved in regulation of cell differentiation and proliferation. Tazarotene is a retinoid prodrug, which converts to its active form (tazarotenic acid) and binds to retinoic acid receptors (RAR) alpha, beta, and gamma.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: BEXAROTENE: Commonly reported adverse effects, with an incidence of greater than 10% in patients receiving initial doses of 300 mg/m(2)/day, include hyperlipidemia, headache, hypothyroidism, neutropenia, asthenia, rash, nausea, peripheral edema, infection, abdominal pain, and dry skin. TAZAROTENE: Commonly reported adverse effects following topical administration, with an incidence up to 30%, include desquamation, dry skin, pruritus, erythema, and a burning sensation.
    2) INFREQUENT: Adverse effects that were reported less frequently during bexarotene clinical trials include alopecia, anemia, diarrhea, vomiting, anorexia, back pain, elevated liver enzymes, and insomnia. Photosensitivity has also been reported in patients exposed to direct sunlight.
    3) RARE: Liver failure and pancreatitis, with fatalities, were rarely reported following bexarotene therapy during clinical trials.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose data are limited. Oral doses up to 1000 mg/m(2)/day of bexarotene administered to patients with advanced cancer during short-term clinical trials have been well-tolerated, without acute toxic effects. It is anticipated that overdose effects may be an extension of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Bexarotene should not be administered during pregnancy. Tazarotene is classified as FDA pregnancy category X. Developmental abnormalities (ie, incomplete ossification, cleft palate, depressed eye bulge, microphthalmia, and small ears), and fetal developmental mortality have been reported with bexarotene in animal studies. Tazarotene exposure in rats and rabbits have resulted in a variety of retinoid malformations, including reduced skeletal ossification, spina bifida, hydrocephaly, and cardiac anomalies. Males and females must use effective contraception during treatment. Discontinue breastfeeding or discontinue bexarotene therapy. It is not known whether tazarotene is excreted into human breast milk.

Laboratory Monitoring

    A) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    B) Monitor CBC with differential for several weeks after overdose. Leukopenia has been reported with oral bexarotene therapy, with time to onset 4 to 8 weeks after beginning therapy.
    C) Obtain liver enzymes in symptomatic patients or as indicated.
    D) Monitor serum lipid levels and thyroid function tests as indicated.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting and/or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor CBC with differential and vital signs for evidence of infection in a symptomatic patient. Severe neutropenia has developed in some cases; the effects were reversible upon discontinuation of bexarotene, with or without supportive care.
    C) DECONTAMINATION
    1) PREHOSPITAL: ORAL: Toxicity after an acute ingestion is not anticipated; activated charcoal is unlikely to be necessary following a minor ingestion. It is not known if gastric decontamination will be useful in treating acute bexarotene ingestions. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists.
    2) HOSPITAL: ORAL: Toxicity after an acute ingestion is unlikely, and is often only expected with chronic use. Consider activated charcoal only if coingestants with significant toxicity are involved. DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) NEUTROPENIA
    1) Administer colony stimulating factors in patients who develop severe neutropenia or neutropenic sepsis that does not improve with the discontinuation of bexarotene. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential daily for evidence of bone marrow suppression until recovery has occurred. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Due to the high degree (greater than 99%) of protein binding of bexarotene, it is unlikely that hemodialysis will be effective.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or have minimal gastrointestinal symptoms following exposure to bexarotene and are otherwise improving may be managed at home.
    2) OBSERVATION CRITERIA: Patients who develop significant symptoms or evidence of laboratory abnormalities (ie, increased liver enzymes, hematologic effects) need to have ongoing monitoring until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Only patients with systemic toxicity (ie, serious skin reactions, hepatotoxicity and hematologic effects) may require admission.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected bexarotene overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose may be similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, myelosuppression), so reliable follow-up is imperative.
    J) PHARMACOKINETICS
    1) BEXAROTENE: Greater than 99% protein-bound and appears to be primarily metabolized by the cytochrome P450 3A4 enzyme system. Elimination half-life ranges from approximately 2 to 7 hours. TAZAROTENE: Tazarotene is a prodrug. Esterase hydrolysis converts tazarotene to its active metabolite, tazarotenic acid. Tazarotenic acid is greater than 99% protein-bound. The mean half-life was 8.1 hours following topical administration of approximately 3.7 g of 0.1% tazarotene foam to approximately 15% of body surface area (ie, face, upper chest, upper back, and shoulders) once daily for 22 days to 13 patients 15 years of age or older with moderate to severe acne.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established. Bexarotene doses up to 1000 mg/m(2)/day have been tolerated without acute toxic effects following short-term administration to patients with advanced cancer.
    B) THERAPEUTIC DOSE: BEXAROTENE: ADULT: ORAL: 300 mg/m(2)/day as a single oral dose; after eight weeks, the total daily dosage may be escalated up to 400 mg/m(2). PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Heent

    3.4.3) EYES
    A) CATARACTS
    1) WITH THERAPEUTIC USE
    a) HUMAN: During a phase II/III clinical trial of bexarotene, slitlamp eye examinations were performed on 31 of 58 patients (53%) at baseline, and in 54 (93%) of the patients at least once during the study. Although the baseline incidence of lens opacity, in at least one eye, was 65% (20 of 31 patients), a new lens opacity or possible worsening of bilateral cataracts were noted in only 2 of 18 patients approximately day 94 of the study (Duvic et al, 2001a). There was no reported loss of visual acuity.
    2) ANIMAL DATA: Rats and dogs, involved in preclinical toxicity studies of bexarotene, developed new posterior subcapsular cataracts or worsening of previous cataract formation following daily oral administration of bexarotene for 6 months (Prod Info TARGRETIN(R) oral capsules, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) During clinical trials, peripheral edema was reported in 13% and 11% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches, mild to moderate in severity, are frequent occurrences following therapeutic administration of bexarotene, at doses of 300 mg/m(2)/day or greater (Duvic et al, 2001; Duvic et al, 2001a; Millikan et al, 2001; Rizvi et al, 2001).
    b) INCIDENCE: During clinical trials, headaches were reported in 30% and 42% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia has been frequently reported with bexarotene therapy (Rizvi et al, 2001; Duvic et al, 2001) and may be associated with the development of bexarotene-induced hypothyroidism (Duvic et al, 2001a).
    b) INCIDENCE: During clinical trials, asthenia was reported in 20% and 45% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials, insomnia was reported in 5% and 11% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported following bexarotene administration as a sole therapy (Prod Info TARGRETIN(R) oral capsules, 2015) or as a combination therapy with other chemotherapeutic agents (Khuri et al, 2001).
    b) INCIDENCE: Nausea and vomiting were reported in 16% and 4% of patients (n=84), respectively, who were taking bexarotene at an initial dose of 300 mg/m(2)/day, and in 8% and 13% of patients (n=53), respectively, who were taking bexarotene at an initial dose greater than 300 mg/m(2)/day (Prod Info TARGRETIN(R) oral capsules, 2015).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is an infrequent dose-related occurrence with oral bexarotene therapy (Prod Info TARGRETIN(R) oral capsules, 2015; Duvic et al, 2001; Millikan et al, 2001) .
    C) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has been reported in several patients following administration of bexarotene at doses of greater than 300 mg/m(2)/day. The occurrence of pancreatitis appears to be associated with the development of hypertriglyceridemia (Duvic et al, 2001; Duvic et al, 2001a; Khuri et al, 2001). One fatality, due to pancreatitis, was reported in a patient with advanced noncutaneous T-cell lymphoma following bexarotene therapy (Prod Info TARGRETIN(R) oral capsules, 2015). The dose of bexarotene was not reported.
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) During clinical trials, abdominal pain was reported in 11% and 4% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) During clinical trials, anorexia was reported in 2% and 23% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzyme levels may occur as a dose-related adverse effect following therapeutic administration of bexarotene and usually resolves after a decrease in the bexarotene dose or discontinuation of therapy (Prod Info TARGRETIN(R) oral capsules, 2015; Duvic et al, 2001; Duvic et al, 2001a; Anon, 1998; Miller et al, 1997).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Liver failure has been rarely reported following bexarotene therapy during clinical trials (Prod Info TARGRETIN(R) oral capsules, 2015; Duvic et al, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia, primarily due to a decrease in neutrophils, is frequently reported, following therapeutic administration of bexarotene, as a dose-limiting toxicity (Millikan et al, 2001; Khuri et al, 2001; Duvic et al, 2001; Duvic et al, 2001a).
    b) INCIDENCE: Leukopenia was reported in 28% of the patients (n=58) who received oral bexarotene therapy during a phase II/III clinical trial (Duvic et al, 2001a).
    c) INCIDENCE: During clinical trials, leukopenia was reported in 17% and 47% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).
    d) In the majority of cases, neutropenia occurred as the predominant subtype of leukopenia. The time to onset of leukopenia was generally 4 to 8 weeks after initiating therapy, and generally appeared to resolve within an average of 30 days following either dose reduction or discontinuation of therapy (Prod Info TARGRETIN(R) oral capsules, 2015).
    B) BLOOD COAGULATION PATHWAY FINDING
    1) WITH THERAPEUTIC USE
    a) Coagulopathy and hemorrhage are uncommon adverse effects associated with therapeutic administration of bexarotene (Duvic et al, 2001).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials, anemia was reported in 6% and 25% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).
    b) Hypochromic anemia was reported, during clinical trials, in 4% and 13% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015)

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) BEXAROTENE: Skin rashes, including exfoliative dermatitis, eczema, and maculopapular rash, and pruritus were reported following oral and topical bexarotene therapy (Prod Info TARGRETIN(R) oral capsules, 2015; Prod Info Targretin(R) topical gel, 2013; Millikan et al, 2001; Leoung et al, 1996).
    b) TAZAROTENE: Pruritus, desquamation, contact dermatitis, and eczema have occurred during clinical trials with topical tazarotene cream (Prod Info TAZORAC(R) topical cream, 2013).
    B) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) Dry and flaking skin may occur following oral bexarotene administration (Prod Info TARGRETIN(R) oral capsules, 2015; Millikan et al, 2001; Rizvi et al, 2001) and with topical tazarotene therapy (Prod Info TAZORAC(R) topical cream, 2013).
    C) PAIN
    1) WITH THERAPEUTIC USE
    a) Dermal pain at the site of application may commonly occur following topical administration of bexarotene gel (Prod Info Targretin(R) topical gel, 2013; Anon, 1998; Leoung et al, 1996; Breneman D, Duvic M & Kuzel T et al, 2001) and tazarotene cream (Prod Info TAZORAC(R) topical cream, 2013).
    D) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Mild photosensitivity has been reported in patients who were exposed to direct sunlight while on oral bexarotene therapy (Prod Info TARGRETIN(R) oral capsules, 2015).
    E) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Facial flushing was reported in 9 of 52 patients following ingestion of bexarotene capsules and occurred 1 to 2 hours postingestion. It did not appear to be dose-related and the flushing decreased over time (Miller et al, 1997).
    F) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials, alopecia was reported in 4% and 11% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) During clinical trials, back pain was reported in 2% and 11% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Reduction in thyroid hormone (T4) levels and thyroid-stimulating hormone (TSH) levels, with clinical hypothyroidism, is frequently reported in patients following ingestion of bexarotene capsules (Prod Info TARGRETIN(R) oral capsules, 2015; Rizvi et al, 2001; Duvic et al, 2001; Duvic et al, 2001a; Heald & Duvic, 1999) and appeared to be reversible within one week of cessation of bexarotene therapy.
    b) INCIDENCE: Hypothyroidism was reported in 29% and 53% of patients who were taking bexarotene at dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n-=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) During clinical trials, infection was reported in 13% and 23% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).
    b) Bacterial infection was reported, during clinical trials, in 1% and 13% of patients with cutaneous T-cell lymphoma who received oral bexarotene therapy at initial dosages of 300 mg/m(2)/day (n=84) and greater than 300 mg/m(2)/day (n=53), respectively (Prod Info TARGRETIN(R) oral capsules, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Bexarotene should not be administered during pregnancy. Tazarotene is classified as FDA pregnancy category X. Developmental abnormalities (ie, incomplete ossification, cleft palate, depressed eye bulge, microphthalmia, and small ears), and fetal developmental mortality have been reported with bexarotene in animal studies. Tazarotene exposure in rats and rabbits have resulted in a variety of retinoid malformations, including reduced skeletal ossification, spina bifida, hydrocephaly, and cardiac anomalies. Males and females must use effective contraception during treatment. Discontinue breastfeeding or discontinue bexarotene therapy. It is not known whether tazarotene is excreted into human breast milk.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Although it is not known whether bexarotene results in fetal abnormalities in humans, the retinoid class to which bexarotene belongs has been associated with human birth defects (Prod Info TARGRETIN(R) oral capsules, 2003).
    B) ANIMAL STUDIES
    1) BEXAROTENE
    a) When pregnant animals were administered bexarotene during days 7 through 17 of gestation, oral doses at least one-third the AUC at the human recommended daily dose resulted in incomplete ossification. Oral doses more than the human recommended daily dose resulted in cleft palate, depressed eye bulge, microphthalmia, small ears, and developmental mortality (Prod Info TARGRETIN(R) oral capsules, 2015).
    b) When pregnant animals were administered bexarotene, topical doses less than one-hundredth the Cmax resulted in dysmorphogenesis, and doses one-eighth the Cmax resulted in abnormalities (Prod Info TARGRETIN(R) gel, 2000).
    2) TAZAROTENE
    a) RATS: Reduced skeletal ossification was reported in rats following topical exposure to tazarotene 0.05% gel at doses of 0.25 mg/kg/day (15 times the systemic exposure in acne patients who were treated topically with 2 mg/cm(2) of tazarotene 0.1% foam over a 15% body surface area) during gestation days 6 through 17 (Prod Info FABIOR(TM) topical foam, 2012).
    b) RABBITS: Single incidences of retinoid malformations, including spina bifida, hydrocephaly, and cardiac anomalies, were reported in rabbits following exposure to tazarotene 0.05% gel at doses of 0.25 mg/kg/day (166 times the systemic exposure in acne patients who were treated topically with 2 mg/cm(2) of tazarotene 0.1% foam over a 15% body surface area) during gestation days 6 through 17 (Prod Info FABIOR(TM) topical foam, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) BEXAROTENE
    a) Do not administer bexarotene to a woman who is pregnant or who plans to become pregnant (Prod Info TARGRETIN(R) gel, 2000). If pregnancy is discovered, immediately discontinue therapy and discuss the fetal risks with the patient (Prod Info TARGRETIN(R) oral capsules, 2015).
    B) PREGNANCY CATEGORY
    1) Tazarotene is classified as FDA pregnancy category X (Prod Info TAZORAC(R) topical cream, 2013; Prod Info FABIOR(TM) topical foam, 2012).
    C) CONTRACEPTION
    1) Women of childbearing potential must either remain abstinent or use 2 reliable forms of birth control, one of which is nonhormonal, beginning 1 month before initiation and ending no sooner than 1 month after discontinuation. Male patients with sexual partners of childbearing potential must use condoms during intercourse during treatment and for at least 1 month after discontinuation (Prod Info TARGRETIN(R) oral capsules, 2015).
    D) TAZAROTENE
    1) During clinical trials of topical tazarotene, pregnancy was reported in 13 patients. Of these 13 pregnancies, 9 patients were administered topical tazarotene and 4 were administered the vehicle agent. One patient electively terminated their pregnancy for reasons unrelated to tazarotene therapy. Of the remaining pregnancies, all 8 women developed healthy babies. The exact timing and extent of tazarotene exposure in relation to gestation time is unknown (Prod Info TAZORAC(R) topical cream, 2013).
    2) Data from several psoriatic patients who became pregnant during tazarotene gel therapy in clinical trials suggest the safety of this topical agent during pregnancy; no adverse fetal effects were reported at birth (Hall, 1995a). This is in sharp contrast to the potent teratogenic effects of other retinoids administered systemically (eg, isotretinoin, etretinate). There is some evidence that the potential safety margin of tazarotene is not solely related to its poor cutaneous absorption, as limited manufacturer studies in animals indicate no adverse/teratogenic effects after either topical or oral administration. The short half-life of the drug is suggested as a contributing safety factor (Hall, 1994).
    3) Additional teratogenicity studies in animals, and human studies evaluating maternal/fetal plasma levels of tazarotenic acid, are needed before routine topical use during pregnancy can be recommended. However, many dermatologists do prescribe tazarotene for the topical treatment of psoriasis in female patients of childbearing age who are using reliable contraception and are fully informed of the potential risks. Also, due to its rapid elimination, a washout period after discontinuing tazarotene therapy and before becoming pregnant is not necessary. Tazarotene-related fetal abnormalities have not been documented in humans; clinical studies with tazarotene, which included pregnant women (n of 6) have resulted in healthy babies. The significance of these findings in uncertain since both the time and extent of exposure in relations to the gestation time were not known (Menter, 2000).
    4) Tazarotene is contraindicated during pregnancy due to risk of fetal harm. Although there may be less systemic exposure in treatment of facial acne due to less surface area for application, it is not know what level of exposure is required for teratogenicity in humans. Women of reproductive potential should obtain a negative pregnancy test within 2 weeks before therapy initiation and use effective contraception during therapy. Treatment with tazarotene should be initiated during a menstrual cycle. If pregnancy occurs, apprise the patient of the potential for fetal harm (Prod Info TAZORAC(R) topical cream, 2013).
    E) ANIMAL STUDIES
    1) TAZAROTENE
    a) RATS: Reduced fetal body weights were reported following topical administration of tazarotene 0.05% gel at doses of 0.25 mg/kg/day during gestation days 6 through 17. Oral administration of tazarotene, in female rats, at doses of 2 mg/kg/day from 15 days prior to mating through gestation day 7 resulted in decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights (Prod Info FABIOR(TM) topical foam, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) There are no human studies to assess the effects of bexarotene on breast milk, breast milk production, or the breastfed infant (Prod Info TARGRETIN(R) oral capsules, 2015).
    2) Discontinue breastfeeding during bexarotene therapy (Prod Info TARGRETIN(R) oral capsules, 2015) or discontinue bexarotene, taking into consideration the importance of the drug to the mother (Prod Info TARGRETIN(R) gel, 2000).
    B) TAZAROTENE
    1) It is not known whether tazarotene is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Animal studies in lactating rats suggest that drug-related materials can be transferred to offspring. Until more data is available, discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother and the importance of nursing to the infant (Prod Info TAZORAC(R) topical cream, 2013).
    C) ANIMAL STUDIES
    1) TAZAROTENE
    a) RATS: Following topical administration of C(14)-tazarotene to the skin of lactating rats, radioactivity was detected in milk, indicating possible transfer of the drug from the mother to the offspring (Prod Info TAZORAC(R) topical cream, 2013; Prod Info FABIOR(TM) topical foam, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) BEXAROTENE
    a) TESTICULAR DEGENERATION: Fertility studies have not been conducted. In animal studies, 91 days of bexarotene oral doses approximately one-fifth the AUC at the human recommended daily dose resulted in testicular degeneration (Prod Info TARGRETIN(R) oral capsules, 2015).
    2) TAZAROTENE
    a) LACK OF EFFECT/MALE RATS: There appeared to be no fertility impairment in male rats who were topically treated for 70 days prior to mating with tazarotene doses up to 1 mg/kg/day (Prod Info FABIOR(TM) topical foam, 2012).
    b) LACK OF EFFECT/FEMALE RATS: There appeared to be no fertility impairment in female rats who were topically treated for 14 days prior to mating and continuing through gestation and lactation with tazarotene gel at doses of 0.125 mg/kg/day. Similarly, fertility did not appear to be affected in female rats who received tazarotene orally at doses up to 2 mg/kg/day 15 days prior to mating and continuing through gestation day 7, although there was a decreased number of implantation sites observed (Prod Info FABIOR(TM) topical foam, 2012).

Summary Of Exposure

    A) USES: Bexarotene is indicated for the treatment of cutaneous T-cell lymphoma cutaneous manifestations in patients refractory to at least one prior systemic therapy. Tazarotene is indicated topically for the treatment of plaque psoriasis in adults, and for the topical treatment of acne vulgaris in patients 12 years of age and older.
    B) PHARMACOLOGY: Bexarotene is a selective retinoid X receptor agonist involved in regulation of cell differentiation and proliferation. Tazarotene is a retinoid prodrug, which converts to its active form (tazarotenic acid) and binds to retinoic acid receptors (RAR) alpha, beta, and gamma.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: BEXAROTENE: Commonly reported adverse effects, with an incidence of greater than 10% in patients receiving initial doses of 300 mg/m(2)/day, include hyperlipidemia, headache, hypothyroidism, neutropenia, asthenia, rash, nausea, peripheral edema, infection, abdominal pain, and dry skin. TAZAROTENE: Commonly reported adverse effects following topical administration, with an incidence up to 30%, include desquamation, dry skin, pruritus, erythema, and a burning sensation.
    2) INFREQUENT: Adverse effects that were reported less frequently during bexarotene clinical trials include alopecia, anemia, diarrhea, vomiting, anorexia, back pain, elevated liver enzymes, and insomnia. Photosensitivity has also been reported in patients exposed to direct sunlight.
    3) RARE: Liver failure and pancreatitis, with fatalities, were rarely reported following bexarotene therapy during clinical trials.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose data are limited. Oral doses up to 1000 mg/m(2)/day of bexarotene administered to patients with advanced cancer during short-term clinical trials have been well-tolerated, without acute toxic effects. It is anticipated that overdose effects may be an extension of adverse effects following therapeutic doses.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    B) Monitor CBC with differential for several weeks after overdose. Leukopenia has been reported with oral bexarotene therapy, with time to onset 4 to 8 weeks after beginning therapy.
    C) Obtain liver enzymes in symptomatic patients or as indicated.
    D) Monitor serum lipid levels and thyroid function tests as indicated.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    B) Monitor CBC with differential for several weeks after overdose. Leukopenia has been reported with oral bexarotene therapy, with time to onset 4 to 8 weeks after beginning therapy (Prod Info TARGRETIN(R) oral capsules, 2015).
    C) Obtain liver enzymes in symptomatic patients or as indicated.
    D) Monitor serum lipid levels and thyroid function tests as indicated.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Only patients with systemic toxicity (ie, serious skin reactions, hepatotoxicity and hematologic effects) may require admission.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or have minimal gastrointestinal symptoms following exposure to bexarotene and are otherwise improving may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients who develop significant symptoms or evidence of laboratory abnormalities (ie, increased liver enzymes, hematologic effects) need to have ongoing monitoring until they are clearly improving and clinically stable.

Monitoring

    A) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    B) Monitor CBC with differential for several weeks after overdose. Leukopenia has been reported with oral bexarotene therapy, with time to onset 4 to 8 weeks after beginning therapy.
    C) Obtain liver enzymes in symptomatic patients or as indicated.
    D) Monitor serum lipid levels and thyroid function tests as indicated.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Toxicity after an acute ingestion is not anticipated; activated charcoal is unlikely to be necessary following a minor ingestion. It is not known if gastric decontamination will be useful in treating acute bexarotene ingestions. DERMAL EXPOSURE : Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity after an acute ingestion is unlikely, and is often only expected with chronic use. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting and/or diarrhea.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor CBC with differential and vital signs for evidence of infection in a symptomatic patient. Severe neutropenia has developed in some cases; the effects were reversible upon discontinuation of bexarotene, with or without supportive care.
    B) MONITORING OF PATIENT
    1) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    2) Monitor CBC with differential for several weeks after overdose. Leukopenia has been reported with oral bexarotene therapy, with time to onset 4 to 8 weeks after beginning therapy.
    3) Obtain liver enzymes in symptomatic patients or as indicated.
    4) Monitor serum lipid levels and thyroid function tests as indicated.
    5) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) NEUTROPENIA
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to the high degree (greater than 99%) of protein binding of bexarotene (Prod Info TARGRETIN(R) oral capsules, 2015), it is unlikely that hemodialysis will be effective.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established. Bexarotene doses up to 1000 mg/m(2)/day have been tolerated without acute toxic effects following short-term administration to patients with advanced cancer.
    B) THERAPEUTIC DOSE: BEXAROTENE: ADULT: ORAL: 300 mg/m(2)/day as a single oral dose; after eight weeks, the total daily dosage may be escalated up to 400 mg/m(2). PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) BEXAROTENE
    1) ORAL
    a) CUTANEOUS T-CELL LYMPHOMA: In the treatment of refractory cutaneous T-cell lymphoma (early or advanced disease), the recommended daily dose is 300 mg/m(2) as a single oral dose taken with a meal (Prod Info Targretin(R) oral capsules, 2011). After eight weeks of therapy, the total daily dosage may be escalated up to 400 mg/m(2) in the absence of tumor response.
    1) DURATION OF THERAPY: Therapy can be continued for as long as the patient benefits from treatment (Prod Info Targretin(R) oral capsules, 2011).
    2) TOPICAL
    a) CUTANEOUS T-CELL LYMPHOMA: Initially, the 1% gel should be applied once every other day for the first week; thereafter, at weekly intervals, the frequency of application may be increased to once daily, twice daily, 3 times daily, and finally 4 times daily as tolerated. The gel should be applied to cover the lesion with a generous coating and allowed to dry before covering with clothing (Prod Info Targretin(R) topical gel 1%, 2009).
    1) DURATION OF THERAPY: Bexarotene therapy can be continued for as long as the patient benefits from treatment (Prod Info Targretin(R) topical gel 1%, 2009).
    B) TAZAROTENE
    1) ACNE: For the treatment of acne vulgaris of the face and/or upper trunk in adult patients, apply a thin layer of tazarotene 0.1% foam, gel, or cream topically once daily in the evening after washing with a mild cleanser and fully drying the affected area (Prod Info FABIOR(TM) topical foam, 2012; Prod Info TAZORAC(R) topical gel, 2011; Prod Info TAZORAC(R) topical cream, 2011).
    2) PSORIASIS: A thin film of tazarotene 0.05% or 0.1% gel is applied once daily, in the evening, in patients with stable plaque psoriasis of up to 20% body surface area involvement (Prod Info TAZORAC(R) topical gel, 2011). Tazarotene 0.05% or 0.1% cream is applied as a thin film once daily (Prod Info TAZORAC(R) topical cream, 2011).
    7.2.2) PEDIATRIC
    A) BEXAROTENE
    1) Safety and efficacy of topical or oral bexarotene administration in the pediatric population has not been established (Prod Info Targretin(R) oral capsules, 2011; Prod Info Targretin(R) topical gel 1%, 2009).
    B) TAZAROTENE
    1) ACNE/12 YEARS AND OLDER: For the treatment of acne vulgaris of the face and/or upper trunk in pediatric patients 12 years and older, apply a thin layer of tazarotene 0.1% gel, cream, or foam topically once daily in the evening after washing with a mild cleanser and fully drying the affected area (Prod Info FABIOR(TM) topical foam, 2012; Prod Info TAZORAC(R) topical gel, 2011; Prod Info TAZORAC(R) topical cream, 2011).
    2) PSORIASIS/12 YEARS AND OLDER: A thin film of tazarotene 0.05% or 0.1% gel is applied once daily, in the evening, in patients with stable plaque psoriasis of up to 20% body surface area involvement (Prod Info TAZORAC(R) topical gel, 2011). Tazarotene 0.05% or 0.1% cream is applied as a thin film once daily (Prod Info TAZORAC(R) topical cream, 2011).
    3) LESS THAN 12 YEARS: Safety and efficacy in pediatric patients less than 12 years of age for the treatment of acne or psoriasis have not been established (Prod Info FABIOR(TM) topical foam, 2012; Prod Info TAZORAC(R) topical gel, 2011; Prod Info TAZORAC(R) topical cream, 2011).

Maximum Tolerated Exposure

    A) GENERAL
    1) Bexarotene doses up to 1000 mg/m(2)/day have been tolerated without acute toxic effects following short-term administration to patients with advanced cancer (Prod Info TARGRETIN(R) oral capsules, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) BEXAROTENE
    1) Bexarotene is a selective retinoid X receptor (RXR) ligand available for topical or oral use. Binding of the drug to retinoic acid receptors (RAR) is minimal, and it may be devoid of significant transactivation of RAR-responsive genes, except at possibly higher dose levels (Rizvi et al, 2001; Miller et al, 1997; Gottardis et al, 1996). Activation of the RXR pathway leads to the regulation of cellular growth and differentiation and the induction of programmed cell death (apoptosis) (Prod Info Targretin(R) oral capsules, 2011; Lowe & Plosker, 2000) as well as other cellular activities (e.g., enhanced insulin effects) (Anon, 1998).
    B) TAZAROTENE
    1) A prodrug (ethyl ester), tazarotene is rapidly converted to its active metabolite, tazarotenic acid, following topical application (Prod Info FABIOR(TM) topical foam, 2012; Hall, 1995).
    2) Tazarotene binds to all three members of the retinoic acid receptor (RAR) family (alpha, beta, and gamma receptors); however, it binds selectively to beta and gamma receptors and probably modifies gene expression (Prod Info FABIOR(TM) topical foam, 2012).

Physicochemical

Physical Characteristics

    A) Bexarotene is an off-white to white powder that is insoluble in water and slightly soluble in vegetable oils and ethanol, USP (Prod Info TARGRETIN(R) oral capsules, 2015; Budavari, 2001).

Molecular Weight

    A) 348.48 (Prod Info TARGRETIN(R) oral capsules, 2015)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Anon: LGD 1069. Adis International, 1998.
    3) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    4) Breneman D, Duvic M & Kuzel T et al: Efficacy and safety of bexarotene gel in patients with previously untreated CTCL (poster). Presented at the Annual Meeting of the American Academy of Dermatology, Washington, D.C. (Mar), 2001.
    5) Budavari S: The Merck Index, 13th ed (CD-ROM version). Merck & Co, Inc. Whitehouse Station, NJ. 2001.
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    7) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    8) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    9) Duvic M, Hymes K, & Heald P: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 2001; 19:2456-2471.
    10) Duvic M, Martin AG, & Kim Y: Phase 2 and 3 clinical trial of oral bexarotene (targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 2001a; 137:581-593.
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    14) Gottardis MM, Bischoff ED, & Shirley MA: Chemoprevention of mammary carcinoma by LGD1069 (targretin): an RXR-selective ligand. Cancer Res 1996; 56:5566-5570.
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    21) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    22) Heald PW & Duvic M: Palliation and remission of erythrodermic cutaneous T-cell lymphoma with a novel oral RXR-selective retinoid (abstract 428), American Society of Hematology, New Orleans, LA, 1999.
    23) Khuri FR, Rigas JR, & Figlin RA: Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small- cell lung cancer. J Clin Oncol 2001; 19:2626-2637.
    24) Leoung GS, Aboulafia D, & Millikan L: Treatment of kaposi's sarcoma using targretin(Rm) (LGD1069), a topical retinoid gel (abstract). 11th Int Conf on AIDS 1996; 2:98.
    25) Lowe MN & Plosker GL: Bexarotene. Am J Clin Dermatol 2000; 1:245-250.
    26) Menter A: Pharmacokinetics and safety of tazarotene. J Am Acad Dermatol 2000; 43(2):S31-S35.
    27) Miller VA, Benedetti FM, & Rigas JR: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol 1997; 15:790-795.
    28) Millikan L, Mustafa M, & Yocum R: RXR-selective oral retinoid bexarotene (Targretin(R)) shows efficacy and safety in AIDS-related Kaposi's sarcoma (poster), Fifth Annual AIDS Malignancy Conference, Bethesda, MD, 2001.
    29) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    30) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    31) Product Information: FABIOR(TM) topical foam, tazarotene 0.1% topical foam. Stiefel Laboratories, Inc. (per Manufacturer), Research Triangle Park, NC, 2012.
    32) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    33) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    34) Product Information: TARGRETIN(R) gel, bexarotene gel. Ligand Pharmaceuticals Inc, San Diego, CA, 2000.
    35) Product Information: TARGRETIN(R) oral capsules, targretin oral capsules. Ligand Pharmaceuticals,Inc, St.Petersburg, FL, 2003.
    36) Product Information: TARGRETIN(R) oral capsules, bexarotene oral capsules. Valeant Pharmaceuticals North America LLC (per FDA), Bridgewater, NJ, 2015.
    37) Product Information: TAZORAC(R) topical cream, tazarotene 0.05% 0.1% topical cream. Allergan, Inc. (per FDA), Irvine, CA, 2013.
    38) Product Information: TAZORAC(R) topical cream, tazarotene 0.05%, 0.1% topical cream. Allergan, Inc, Irvine, CA, 2011.
    39) Product Information: TAZORAC(R) topical gel, tazarotene 0.05%, 0.1% topical gel. Allergan, Inc., Irvine, CA, 2011.
    40) Product Information: Targretin(R) oral capsules, bexarotene oral capsules. Eisai Inc. (per DailyMed), Woodcliff Lake, NJ, 2011.
    41) Product Information: Targretin(R) topical gel 1%, bexarotene topical gel 1%. Eisai Inc (per FDA), Woodcliff Lake, NJ, 2009.
    42) Product Information: Targretin(R) topical gel, bexarotene 1% topical gel. Valeant Pharmaceuticals North America LLC (per DailyMed) , Bridgewater, NJ, 2013.
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    45) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    46) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    47) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.