PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Antineoplastic Retinoids
    Topical Antineoplastic Retinoids

    BOXED WARNING

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during treatment with bexarotene gel or capsules. Pregnancy testing should be performed in females of reproductive potential within 1 week prior to starting therapy. Start bexarotene on the second or third day of the patient’s normal menstrual period and only administer a 1-month supply of the medicine for each refill. Perform pregnancy testing once monthly and provide counseling regarding pregnancy avoidance and the risk of birth defects with bexarotene. Females of reproductive potential should avoid pregnancy and use effective contraception starting 1 month prior to and for at least 1 month after treatment with bexarotene. It is recommended that these women use 2 reliable forms of non-hormonal contraception or practice abstinence during therapy. Bexarotene may induce metabolic enzymes and cause a reduction in the plasma concentrations of oral or other systemic hormonal contraceptives. Patients who become pregnant while receiving bexarotene should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception (i.e., condoms) during therapy and for at least 1 month following the final dose of bexarotene.

    DEA CLASS

    Rx

    DESCRIPTION

    A synthetic retinoid that activates retinoid X receptors
    Used for the treatment of cutaneous manifestations (e.g., lesions) of refractory cutaneous T-cell lymphoma
    Do not use bexarotene during pregnancy; retinoid use is associated with birth defects

    COMMON BRAND NAMES

    Targretin

    HOW SUPPLIED

    Bexarotene/Targretin Oral Cap: 75mg
    Targretin Topical Gel: 1%

    DOSAGE & INDICATIONS

    For the treatment cutaneous T-cell lymphoma (CTCL), including mycosis fungoides.
    NOTE: Bexarotene has been designated an orphan drug by the FDA for this indication.
    For the treatment of cutaneous manifestations of CTCL in patients who are refractory to at least 1 prior systemic therapy.
    Oral dosage
    Adults

    300 mg/m2 orally once daily with food until disease progression; if there is no tumor response after 8 weeks of treatment and the initial dose is well tolerated, increase the dose to bexarotene 400 mg/m2 once daily and monitor patients carefully. The calculated dose should be rounded to the nearest dose using 75-mg capsules. Reduce the daily bexarotene dose in 100-mg increments (from 300 mg/m2 to 200 mg/m2 and from 200 mg/m2 to 100 mg/m2) if clinical toxicity occurs. Therapy may be resumed after the toxicity resolves and the bexarotene dose may be increased as tolerated. Bexarotene was evaluated in patients with cutaneous T-cell lymphoma (CTCL) in 2 multinational, open-label, controlled studies (n = 152); 102 patients had disease refractory to at least 1 prior systemic therapy (early stage, n = 12; advanced stage, n = 90). In 62 evaluable patients who received an initial bexarotene dose of 300 mg/m2 per day, the overall clinical tumor response rate was about 32% (complete response, 1.8%; partial response, 30%). Some responses were observed by week 4 of therapy. At a median follow-up time of 21 weeks, the median duration of response had not been reached in the 20 patients who had a tumor response; 6 of these patients had disease relapse defined as a 25% increase in target lesions (using a Composite Assessment of Index Lesion Disease Severity (CA)) or worsening of other aspects of disease. Bexarotene 300 mg/m2 per day resulted in a higher objective response rate (ORR) compared with bexarotene 150 mg/m2 per day in patients with CTCL in a phase IV clinical trial (n = 59). The ORRs were higher in the 300 mg/m2 per day arm when response was evaluated using a CA (34.5% vs. 23.3%), the Physicians Global Assessment (PGA; 37.9% vs. 20%), and percent body surface area involvement (%BSA; 34.5% vs. 23.3%). The median duration of response times were 86.5 days, 72 days, and 60 days and the median times to tumor progression were 77.5 days, 115.5 days, and 88 days using the CA, PGA, and %BSA assessment tools, respectively.

    For the treatment of cutaneous lesions of stage IA or IB CTCL in patients who have refractory or persistent disease after other therapies or who have not tolerated other therapies.
    Topical dosage
    Adults

    Apply to affected areas once every other day for the first week; increase the frequency of application in weekly intervals to once daily, twice daily, 3 times daily, and then 4 times daily as tolerated. Continue therapy as long as benefit is demonstrated; bexarotene gel was applied for up to 172 weeks in clinical trials. Most patients tolerate an application frequency of 2 to 4 times daily. Reduce the application frequency if application toxicity occurs. If severe irritation occurs, hold bexarotene for a few days; therapy may be resumed when the symptoms subside. The overall response rate (defined as the complete clinical response (CCR) plus partial response) on the basis of the primary end point classification (PEC) was 54% in patients with refractory or persistent stage IA, IB, or IIA CTCL after 2 or more prior therapies (median of 3 therapies; range, 2 to 7 therapies) who received topical bexarotene in a multinational, phase III trial (n = 50). The CCR rate was 10%. PEC response was determined using response criteria for either the Physicians Global Assessment (PGA) or Composite Assessment of Index Lesion Disease Severity (CA); the higher response was used from either the PGA or CA assessment. The projected median time to response (at least 50% improvement) was 142 days; the latest time to response was 504 days.

    For the treatment of advanced non-small cell lung cancer (NSCLC)†.
    As first-line treatment of NSCLC, in combination with other chemotherapy agents†.
    Oral dosage
    Adults

    400 mg/m2 orally once daily has been studied. First-line therapy with bexarotene plus cisplatin and vinorelbine did not improve the median overall survival (OS) time (8.7 months vs. 9.9 months), 2-year OS rate (13.2% vs. 15.7%), progression-free survival (PFS) time (4.3 months vs. 5 months), or overall response rate (ORR) (16.7% vs. 24.4%) compared with cisplatin and vinorelbine alone in a phase III trial in 623 NSCLC patients. Additionally, bexarotene plus carboplatin and paclitaxel did not improve the median OS time (8.5 months vs. 9.2 months), 2-year OS rate (12.4% vs. 16.3%), PFS time (4.1 months vs. 4.9 months), or ORR (19.3% vs. 23.5%) compared with carboplatin and paclitaxel alone as first-line therapy in 612 NSCLC patients in another phase III trial.

    As maintenance therapy in patients with stable or responsive NSCLC following platinum-containing chemotherapy†.
    Oral dosage
    Adults

    Dosage not established; 300 mg/m2 or 600 mg/m2 orally once daily has been studied. In 52 patients with advanced or recurrent NSCLC who had stable or responsive disease following platinum-containing chemotherapy, maintenance therapy with bexarotene 300 mg/m2/day PO, bexarotene 600 mg/m2/day PO, or placebo resulted in a median time to progression (TTP) of 82 days, 128 days, and 56 days, respectively, and median overall survival (OS) times of 382 days, 587 days, and 537 days, respectively. The TTP and OS times were not significantly different between the 3 study arms.

    For the treatment of AIDS-related Kaposi's sarcoma†.
    Oral dosage
    Adults

    650 mg/m2 orally once daily resulted in an overall response rate of 33% (complete response, n = 1) in a phase II study in 49 patients with AIDS-related Kaposi sarcoma. Response was defined as 50% or greater disease improvement using the AIDS Clinical Trials Group criteria.

    For the treatment of metastatic breast cancer†.
    Oral dosage
    Adults

    200 mg/m2 or 500 mg/m2 orally once daily demonstrated minimal benefit in 146 patients with progressive metastatic breast cancer refractory to chemotherapy and/or hormone therapy in a clinical study. Treatment with bexarotene resulted in a partial response in 5 patients and stable disease lasting at least 6 months in 26 patients; additionally, the median time to progression was 8.3 to 9.6 weeks. Patients with tamoxifen-resistant disease received tamoxifen in addition to bexarotene. No responses occurred in patients who received the higher dose of 500 mg/m2/day.

    For the treatment of severe plaque psoriasis†.
    Oral dosage
    Adults

    0.5 to 3 mg/kg orally once daily for 12 to 24 weeks resulted in a 50% or greater improvement in scores on a modified psoriasis area and severity index in 22% of patients with severe psoriasis in a phase II trial (n = 50). No dose-response effects were noted. Further studies are needed to determine the optimal dose.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    oral capsules, 400 mg/m2 per day; topical gel, 1 application 4 times daily.

    Geriatric

    oral capsules, 400 mg/m2 per day; topical gel, 1 application 4 times daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The clearance of bexarotene may be decreased in patients with hepatic impairment. Although specific guidelines for initial dosage adjustments in hepatic impairment are not available; interrupt or discontinue therapy in patients who develop elevated transaminase (e.g., AST or ALT) or bilirubin levels greater than 3-times the upper limit of normal during oral bexarotene therapy.

    Renal Impairment

    Bexarotene is extensively protein bound and its pharmacokinetics may be altered in patients with renal impairment. However, specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Oral Administration

    Take bexarotene as a single dose with food.

    Topical Administration

    For external application only.
    Use sufficient gel to cover the lesion with a generous coating; allow the gel to dry before covering with clothing.
    Do NOT use occlusive dressings with bexarotene gel.
    Avoid application of the gel to normal skin around the lesions to prevent irritation.
    Do NOT apply on or near mucosal areas of the body (e.g., eyes, nostrils, mouth, lips, vagina, tip of the penis, rectum, or anus).
    Wait 20 minutes after showering or bathing before applying the gel. Avoid bathing, showering, or swimming for at least 3 hours after any application, if possible.
    Do NOT use insect repellents containing N,N-diethyl-m-toluamide (DEET) or other products containing DEET during bexarotene therapy.

    STORAGE

    Targretin:
    - Avoid excessive humidity
    - Avoid extreme temperatures
    - Protect from light
    - Store between 36 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Retinoid hypersensitivity


    The use of bexarotene (both gel and capsules) is contraindicated in patients with a known hypersensitivity to bexarotene or other components of the product. Use bexarotene with caution in patients with retinoid hypersensitivity.

    Diabetes mellitus

    Use oral bexarotene with caution in patients with diabetes mellitus who are receiving insulin or medications that enhance insulin secretion (e.g., sulfonylureas) or that are insulin sensitizers (e.g., thiazolidinediones); bexarotene may increase the action of these agents and increase the risk of hypoglycemia.

    Alcoholism, biliary tract disease, pancreatitis

    Acute pancreatitis has been reported with oral bexarotene therapy, including 1 fatal case. Interrupt therapy and evaluate if pancreatitis is suspected. Patients with a history of pancreatitis; uncontrolled high cholesterol, triglyceride, or blood glucose levels; alcoholism; biliary tract disease; or patients who are on medications known to increase triglyceride levels or cause pancreatic toxicity may be at increased risk for pancreatitis.

    Cholestasis, hepatic disease, hepatotoxicity

    Hepatotoxicity (e.g., elevated hepatic enzymes, cholestasis) has been reported with oral bexarotene therapy; liver failure resulting in death occurred rarely. Use bexarotene with caution in patients with hepatic disease/impairment. Monitor liver function tests (LFTs) prior to starting bexarotene; at 1, 2, and 4 weeks after treatment initiation; and then at least every 8 weeks during treatment. Therapy interruption or discontinuation may be necessary in patients who develop elevated transaminase (e.g., AST or ALT) or bilirubin levels greater than 3-times the upper limit of normal. Bexarotene doses greater than 300 mg/m2 per day were associated with a higher incidence of elevated hepatic enzymes. In clinical trials, most elevated LFTs resolved within 30 days following a dose reduction or discontinuation of treatment.

    Hypothyroidism, thyroid disease

    Hypothyroidism has been reported with oral bexarotene therapy. Use bexarotene with caution in patients with thyroid disease. Monitor thyroid function tests prior to starting bexarotene and periodically during treatment. Treatment with thyroid hormone supplementation may be considered in patients who develop hypothyroidism.

    Leukopenia, neutropenia

    Leukopenia and neutropenia have been reported with oral bexarotene therapy. Monitor complete blood counts prior to starting bexarotene and periodically during treatment. The time to leukopenia onset is typically 4 to 8 weeks after the start of therapy; most cases resolve within 30 days following a dose reduction or discontinuation of treatment. Bexarotene doses greater than 300 mg/m2 per day were associated with a higher incidence of leukopenia.

    Cataracts

    New or worsening cataracts occurred in some patients who received oral bexarotene. Patients who develop vision problems during bexarotene therapy should have an ophthalmologic evaluation.

    Sunlight (UV) exposure

    Patients should minimize their sunlight (UV) exposure and exposure to artificial ultraviolet light during treatment with bexarotene gel or capsules. Sunburns and skin sensitivity to sunlight have been reported in patients who received oral bexarotene.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia have been reported commonly with oral bexarotene therapy. Prior to starting oral bexarotene, obtain a fasting lipid profile and ensure patients have normal fasting triglycerides; maintain triglyceride levels below 400 mg/dL during therapy. Monitor lipid panels weekly until the lipid response to bexarotene is determined (usually 2 to 4 weeks), then monitor lipid panels every 8 weeks during therapy. Start antilipemic therapy if fasting triglyceride levels are elevated or become elevated during treatment. Therapy interruption or discontinuation may be necessary if patients who develop elevated fasting triglyceride levels. Bexarotene doses greater than 300 mg/m2 per day were associated with a higher incidence of hyperlipidemia, hypertriglyceridemia, and decreased high density lipoprotein (HDL) cholesterol levels (i.e., < 25 mg/dL). Most cases of lipid abnormalities were reversible following a dose reduction and/or concomitant antilipemic therapy.

    Pregnancy


    The use of bexarotene (both gel and capsules) is contraindicated during pregnancy. Retinoid agents are associated with birth defects in humans; therefore, bexarotene may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy while taking bexarotene. Immediately discontinue bexarotene if a patient becomes pregnant during therapy and discuss the potential hazard to the fetus. Fetal abnormalities including incomplete ossification, cleft palate, depressed eye bulge/microphthalmia, and small ears were observed following oral bexarotene administration in pregnant rats during organogenesis (days 7 to 17 of gestation); fetal death occurred at doses greater than 10 mg/kg per day.

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during treatment with bexarotene gel or capsules. Pregnancy testing should be performed in females of reproductive potential within 1 week prior to starting therapy. Start bexarotene on the second or third day of the patient’s normal menstrual period and only administer a 1-month supply of the medicine for each refill. Perform pregnancy testing once monthly and provide counseling regarding pregnancy avoidance and the risk of birth defects with bexarotene. Females of reproductive potential should avoid pregnancy and use effective contraception starting 1 month prior to and for at least 1 month after treatment with bexarotene. It is recommended that these women use 2 reliable forms of non-hormonal contraception or practice abstinence during therapy. Bexarotene may induce metabolic enzymes and cause a reduction in the plasma concentrations of oral or other systemic hormonal contraceptives. Patients who become pregnant while receiving bexarotene should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception (i.e., condoms) during therapy and for at least 1 month following the final dose of bexarotene.

    Breast-feeding

    It is not known if bexarotene is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during bexarotene therapy.

    Vaccination

    Vaccination with live vaccines should be avoided due to increased risk of leukopenia/neutropenia and infection during systemic bexarotene treatment.[28068]

    ADVERSE REACTIONS

    Severe

    hypertriglyceridemia / Delayed / 6.7-46.0
    hyperlipidemia / Delayed / 26.0-41.0
    exfoliative dermatitis / Delayed / 6.0-28.0
    asthenia / Delayed / 1.0-21.0
    neutropenia / Delayed / 10.3-16.0
    leukopenia / Delayed / 4.0-13.0
    headache / Early / 4.0-11.0
    coagulopathy / Delayed / 0-10.0
    heart failure / Delayed / 0-10.0
    stroke / Early / 0-10.0
    pleural effusion / Delayed / 0-10.0
    pulmonary edema / Early / 0-10.0
    keratitis / Delayed / 0-10.0
    visual impairment / Early / 0-10.0
    hypercholesterolemia / Delayed / 2.0-9.0
    hyponatremia / Delayed / 1.0-9.0
    infection / Delayed / 0-8.0
    pancreatitis / Delayed / 0-6.0
    anorexia / Delayed / 0-6.0
    diarrhea / Early / 2.0-6.0
    hyperglycemia / Delayed / 1.0-6.0
    hyperbilirubinemia / Delayed / 0-4.0
    elevated hepatic enzymes / Delayed / 0-4.0
    hypothyroidism / Delayed / 0-4.0
    vomiting / Early / 0-4.0
    rash / Early / 0-3.0
    peripheral edema / Delayed / 0-3.0
    hyperkalemia / Delayed / 0-2.0
    hypernatremia / Delayed / 0-1.0
    hypocalcemia / Delayed / 0-1.0
    hepatic failure / Delayed / 0.2-0.2

    Moderate

    erythema / Early / 0-72.0
    cataracts / Delayed / 0-19.0
    contact dermatitis / Delayed / 0-14.0
    hyperamylasemia / Delayed / 0-10.0
    thrombocytopenia / Delayed / 0-10.0
    lymphocytosis / Delayed / 0-10.0
    eosinophilia / Delayed / 0-10.0
    skin ulcer / Delayed / 0-10.0
    bullous rash / Early / 0-10.0
    constipation / Delayed / 0-10.0
    colitis / Delayed / 0-10.0
    melena / Delayed / 0-10.0
    hypertension / Early / 0-10.0
    sinus tachycardia / Rapid / 0-10.0
    chest pain (unspecified) / Early / 0-10.0
    edema / Delayed / 10.0-10.0
    angina / Early / 0-10.0
    myasthenia / Delayed / 0-10.0
    bone pain / Delayed / 0-10.0
    confusion / Early / 0-10.0
    ataxia / Delayed / 0-10.0
    peripheral neuropathy / Delayed / 0-10.0
    hyperesthesia / Delayed / 0-10.0
    depression / Delayed / 0-10.0
    dyspnea / Early / 0-10.0
    hypoxia / Early / 0-10.0
    hemoptysis / Delayed / 0-10.0
    candidiasis / Delayed / 0-10.0
    blepharitis / Early / 0-10.0
    conjunctivitis / Delayed / 0-10.0
    bleeding / Early / 0-10.0
    dysuria / Early / 0-10.0
    hematuria / Delayed / 0-10.0
    urinary incontinence / Early / 0-10.0
    hypoalbuminemia / Delayed / 0-10.0
    lymphadenopathy / Delayed / 6.0-6.0
    subdural hematoma / Early / 0-1.0
    cholestasis / Delayed / 0.4-0.4

    Mild

    skin irritation / Early / 0-72.0
    pruritus / Rapid / 0-40.0
    xerosis / Delayed / 9.0-17.0
    fever / Early / 5.0-17.0
    nausea / Early / 8.0-16.0
    chills / Rapid / 10.0-13.0
    alopecia / Delayed / 4.0-11.0
    abdominal pain / Early / 4.0-11.0
    back pain / Delayed / 2.0-11.0
    insomnia / Early / 5.0-11.0
    acne vulgaris / Delayed / 0-10.0
    maculopapular rash / Early / 0-10.0
    vesicular rash / Delayed / 0-10.0
    xerostomia / Early / 0-10.0
    cheilitis / Delayed / 0-10.0
    dyspepsia / Early / 0-10.0
    gingivitis / Delayed / 0-10.0
    flatulence / Early / 0-10.0
    syncope / Early / 0-10.0
    arthralgia / Delayed / 0-10.0
    myalgia / Early / 0-10.0
    hypoesthesia / Delayed / 0-10.0
    dizziness / Early / 0-10.0
    agitation / Early / 0-10.0
    pharyngitis / Delayed / 6.0-10.0
    cough / Delayed / 6.0-10.0
    rhinitis / Early / 0-10.0
    influenza / Delayed / 0-10.0
    xerophthalmia / Early / 0-10.0
    urinary urgency / Early / 0-10.0
    otalgia / Early / 0-10.0
    weight gain / Delayed / 0-10.0
    weight loss / Delayed / 0-10.0
    hyperhidrosis / Delayed / 0-6.0
    paresthesias / Delayed / 6.0-6.0
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with bexarotene, as coadministration may result in decreased dolutegravir plasma concentrations. Bexarotene is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Abemaciclib: (Major) Avoid coadministration of bexarotene with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29% respectively.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with bexarotene can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bexarotene is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bexarotene is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Acetohexamide: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Alteplase, tPA: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Telmisartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Coadministration of bexarotene and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of bexarotene and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Aprepitant, Fosaprepitant: (Major) Use caution if bexarotene and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant. Bexarotene is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for low-to-moderate inducers.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as bexarotene may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.
    Artemether; Lumefantrine: (Major) Bexarotene is a moderate CYP3A4 inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with bexarotene can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bexarotene is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bexarotene is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Atazanavir; Cobicistat: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Axitinib: (Major) Avoid coadministration of axitinib with bexarotene if possible, due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Bedaquiline: (Major) Avoid concurrent use of bexarotene with bedaquiline. Bexarotene is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Brexpiprazole: (Moderate) Because brexpiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as bexarotene may result in decreased plasma concentrations of brexpiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. An increase in brexpiprazole dosage may be clinically warranted in some patients.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and bexarotene are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; bexarotene is a moderate inducer of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and bexarotene may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; bexarotene induces CYP3A4.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as bexarotene, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with bexarotene can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bexarotene is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bexarotene is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with bexarotene can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bexarotene is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bexarotene is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Chlorpropamide: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Cholestyramine: (Moderate) Cholestyramine can bind with and possibly decrease the oral absorption of bexarotene. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.
    Clarithromycin: (Major) Coadministration of bexarotene and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
    Clindamycin: (Moderate) Concomitant use of clindamycin and bexarotene may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; bexarotene is a moderate inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of elvitegravir with bexarotene is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of elvitegravir with bexarotene is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with bexarotene due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and bexarotene is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Cod Liver Oil: (Severe) Patients should avoid or limit supplementation with vitamin A during treatment with retinoids to avoid potential additive toxic effects.
    Codeine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with bexarotene can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bexarotene is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bexarotene is a moderate CYP3A4 inducer.
    Colestipol: (Moderate) Colestipol can bind with and possibly decrease the oral absorption of orally administered vitamin A, such as bexarotene. Administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of colestipol.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as bexarotene. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dapsone: (Moderate) The metabolism of dapsone may be accelerated when administered concurrently with bexarotene, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of bexarotene with paritaprevir is contraindicated. Taking these drugs together may result in decreased concentrations of paritaprevir which may affect antiviral efficacy. Bexarotene is a moderate CYP3A4 inducer; paritaprevir is a CYP3A4 substrate.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and bexarotene. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; bexarotene is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Dienogest; Estradiol valerate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with bexarotene can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bexarotene is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bexarotene is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Dolutegravir: (Major) Avoid concurrent use of dolutegravir with bexarotene, as coadministration may result in decreased dolutegravir plasma concentrations. Bexarotene is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Major) Avoid concurrent use of dolutegravir with bexarotene, as coadministration may result in decreased dolutegravir plasma concentrations. Bexarotene is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Doravirine: (Moderate) Concurrent administration of doravirine and bexarotene may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and bexarotene may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer.
    Doxorubicin: (Major) Bexarotene is a CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of bexarotene and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with bexarotene is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; bexarotene is a moderate inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dronedarone and bexarotene should be avoided. Coadministration of CYP3A4 inducers, such as bexarotene, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy. Dronedarone is metabolized by CYP3A. Bexarotene induces CYP3A4.
    Drospirenone; Estradiol: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Drospirenone; Ethinyl Estradiol: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with bexarotene. Bexarotene is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir. (Major) If possible, avoid concurrent administration of grazoprevir with bexarotene. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Bexarotene is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A.
    Elvitegravir: (Major) Coadministration of elvitegravir with bexarotene is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Encorafenib: (Major) Avoid coadministration of encorafenib and bexarotene due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Eravacycline: (Major) Avoid the concomitant use of bexarotene and eravacycline due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with both systemic retinoid and tetracycline use alone. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.
    Erlotinib: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with bexarotene; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and bexarotene is a moderate CYP3A4 inducer.
    Esomeprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Estradiol; Levonorgestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Estradiol; Norethindrone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Estradiol; Norgestimate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Estrogens: (Moderate) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including estrogens. It is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method, during oral bexarotene therapy. Because of the potential interaction with hormonal contraceptives, it is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy. Patients receiving estrogens or progestins should report any breakthrough bleeding to their prescribers.
    Ethinyl Estradiol; Desogestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Etonogestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Levonorgestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norelgestromin: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norethindrone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norgestimate: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ethinyl Estradiol; Norgestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Etonogestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide if used concomitantly with bexarotene. Bexarotene is an inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp).
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as bexarotene, is not recommended.
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with bexarotene. Bexarotene is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with bexarotene, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be increased. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Gemfibrozil: (Major) Concomitant administration of bexarotene capsules and gemfibrozil is not recommended; concurrent administration results in increased bexarotene plasma concentrations. Due to low systemic exposure, clinically significant drug interactions are unlikely with bexarotene topical gel.
    Glimepiride: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Glimepiride; Pioglitazone: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Glimepiride; Rosiglitazone: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Glipizide: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Glipizide; Metformin: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Glyburide: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Glyburide; Metformin: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Grapefruit juice: (Moderate) Bexarotene is metabolized by cytochrome P450 3A4 and grapefruit juice may increase the serum concentrations of bexarotene by inhibiting the metabolism of bexarotene via CYP3A4.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Guanfacine: (Major) Bexarotene may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if bexarotene is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If bexarotene is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and bexarotene is a moderate CYP3A4 inducer in vitro.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Hydroxyprogesterone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Ibrutinib: (Moderate) Use ibrutinib and bexarotene together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; bexarotene is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with bexarotene is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; bexarotene is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Insulins: (Moderate) Systemic bexarotene may enhance the action of insulin, resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with insulin therapy; monitor for hypoglycemia and need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Isavuconazonium: (Major) Concomitant use of isavuconazonium with bexarotene may result in decreased concentrations of isavuconazonium. Caution and close monitoring are advised if these drugs are used together. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate.
    Ivabradine: (Major) Avoid coadministration of ivabradine and bexarotene. Ivabradine is primarily metabolized by CYP3A4; bexarotene induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and bexarotene concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Co-administration with a strong CYP3A inducer decreased the ivacaftor exposure by approximately 9-fold.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as bexarotene may lead to reduced and subtherapeutic concentrations of ixabepilone. Caution should be utilized when CYP3A4 inducers are coadministered with ixabepilone, and alternative therapies with low enzyme induction potential should be considered.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lapatinib: (Moderate) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as bexarotene, will decrease the plasma concentrations of lapatinib. If treatment with bexarotene is necessary, consider a lapatinib dose escalation. If bexarotene is discontinued, reduce the lapatinib dose to the indicated dose.
    Leuprolide; Norethindrone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Levonorgestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and bexarotene may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; bexarotene induces CYP3A4.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of bexarotene and lopinavir; ritonavir as decreased plasma concentrations of lopinavir may occur resulting in reduced therapeutic effect. Consider alternative therapy. Bexarotene is a moderate CYP3A4 inducer and lopinavir is a CYP3A4 substrate.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and bexarotene concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Co-administration with a strong CYP3A inducer decreased the ivacaftor exposure by approximately 9-fold.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4. Concurrent use of lurasidone and CYP3A4 inducers, such as bexarotene, may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more).
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with bexarotene is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and bexarotene is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Medroxyprogesterone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Megestrol: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Meglitinides: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., meglitinides or "glinides") resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as meloxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mestranol; Norethindrone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Methotrexate: (Major) Concomitant use of systemic retinoids, such as bexarotene, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems.
    Methoxsalen: (Moderate) Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs, such as nabumetone, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Neratinib: (Major) Avoid concomitant use of bexarotene with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with bexarotene due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and bexarotene is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Norgestrel: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Olaparib: (Major) Avoid the coadministration of olaparib with bexarotene due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of bexarotene with paritaprevir is contraindicated. Taking these drugs together may result in decreased concentrations of paritaprevir which may affect antiviral efficacy. Bexarotene is a moderate CYP3A4 inducer; paritaprevir is a CYP3A4 substrate.
    Orlistat: (Moderate) Due the effect of orlistat on fat absorption and the lower serum levels of fat-soluble vitamins noted during clinical trials, the bioavailability of orally administered retinoids, such as bexarotene may also be decreased.
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with bexarotene due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of bexarotene occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Bexarotene is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Photosensitizing agents: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
    Porfimer: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with bexarotene, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Progesterone: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Progestins: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Reteplase, r-PA: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Rofecoxib: (Minor) An increased risk of bleeding may occur when NSAIDs, such as rofecoxib, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Roflumilast: (Major) Coadminister bexarotene and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Betaxortene induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like bexarotene, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as bexarotene, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and bexarotene. Induction of CYP3A4 by bexarotene may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of systemic bexarotene, which is a CYP3A4 substrate. Monitor patients for adverse effects of bexarotene, such as photosensitivity and hyperlipidemia.
    Sodium Thiosulfate; Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with bexarotene. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a substrate of CYP3A4; bexarotene is a moderate inducer of CYP3A.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with bexarotene. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a substrate of CYP3A4; bexarotene is a moderate inducer of CYP3A. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as bexarotene. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and bexarotene; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and bexarotene is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
    Sorafenib: (Major) Sorafenib is a CYP3A4 substrate, and concomitant use with a strong CYP3A4 inducer such as bexarotene may lead to reduced sorafenib concentrations. For example, concurrent use of sorafenib and the CYP3A4 inducer rifampicin resulted in an average 37% reduction in the sorafenib AUC. Avoid the use of sorafenib with a strong CYP3A4 inducer. If a strong CYP3A4 inducer must be coadministered with sorafenib, consider a sorafenib dose increase.
    St. John's Wort, Hypericum perforatum: (Major) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs such as retinoids.
    Streptokinase: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Sulfonylureas: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Sunitinib: (Major) Avoid coadministration of bexarotene with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the dose of sunitinib in 12.5 mg increments based on individual safety and tolerability to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily; monitor carefully for toxicity. The maximum daily dose administered in the pNET study was 50 mg. Sunitinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Tamoxifen: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen. Concomitant administration of bexarotene capsules and tamoxifen has also resulted in a modest decrease in plasma concentrations of tamoxifen, possibly due to an induction of CYP3A4.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and bexarotene. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as bexarotene, may reduce the efficacy of tasimelteon.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Telithromycin: (Major) Concomitant administration of CYP3A4 inducers, such as bexarotene, are expected to cause subtherapeutic concentrations of telithromycin and loss of efficacy. In addition, telithromycin is a competitive substrate and inhibitor of CYP3A4; coadministration of telithromycin with other drugs metabolized by CYP3A4, such as bexarotene, may result in increased plasma concentrations and an increase of therapeutic or adverse effects.
    Tenecteplase, TNK-tPA: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Tetracyclines: (Major) The concomitant use of systemic retinoid therapy, such as bexarotene, and systemic tetracyclines should be avoided due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with systemic retionoid use alone and early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and bexarotene concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Co-administration with a strong CYP3A inducer decreased the ivacaftor exposure by approximately 9-fold.
    Thiazolidinediones: (Moderate) Systemic bexarotene may enhance the action of insulin sensitizers (e.g., thiazolidinediones) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Thrombolytic Agents: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Tofacitinib: (Major) Bexarotene is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Tolazamide: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Tolbutamide: (Moderate) Systemic bexarotene may enhance the action of agents that enhance insulin secretion (e.g., sulfonylureas) resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with any of these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments. Hypoglycemia has not been associated with bexarotene monotherapy.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Bexarotene is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and bexarotene is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as bexarotene.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and bexarotene is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Urokinase: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Valdecoxib: (Minor) An increased risk of bleeding may occur when NSAIDs, such as valdecoxib, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with bexarotene is necessary, due to a possibly unpredictable effect on vandetanib efficacy and toxicity. Bexarotene is a moderate inducer of CYP3A4. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and bexarotene; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Verteporfin: (Moderate) Use photosensitizing agents and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including bexarotene. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including bexarotene. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as bexarotene. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy


    The use of bexarotene (both gel and capsules) is contraindicated during pregnancy. Retinoid agents are associated with birth defects in humans; therefore, bexarotene may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy while taking bexarotene. Immediately discontinue bexarotene if a patient becomes pregnant during therapy and discuss the potential hazard to the fetus. Fetal abnormalities including incomplete ossification, cleft palate, depressed eye bulge/microphthalmia, and small ears were observed following oral bexarotene administration in pregnant rats during organogenesis (days 7 to 17 of gestation); fetal death occurred at doses greater than 10 mg/kg per day.

    Counsel patients about the reproductive risk and contraception requirements during treatment with bexarotene gel or capsules. Pregnancy testing should be performed in females of reproductive potential within 1 week prior to starting therapy. Start bexarotene on the second or third day of the patient’s normal menstrual period and only administer a 1-month supply of the medicine for each refill. Perform pregnancy testing once monthly and provide counseling regarding pregnancy avoidance and the risk of birth defects with bexarotene. Females of reproductive potential should avoid pregnancy and use effective contraception starting 1 month prior to and for at least 1 month after treatment with bexarotene. It is recommended that these women use 2 reliable forms of non-hormonal contraception or practice abstinence during therapy. Bexarotene may induce metabolic enzymes and cause a reduction in the plasma concentrations of oral or other systemic hormonal contraceptives. Patients who become pregnant while receiving bexarotene should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception (i.e., condoms) during therapy and for at least 1 month following the final dose of bexarotene.

    MECHANISM OF ACTION

    Bexarotene is a synthetic retinoid agent that activates retinoid X receptor (RXR) subtypes RXR-alpha, RXR-beta, and RXR-gamma. These retinoid receptors have biologic activity that is different from that of retinoic acid receptors (RARs). RXR binding forms heterodimers with other receptors such as RARs, vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). These receptors regulate the expression of genes that control cellular differentiation and proliferation. The exact mechanism of bexarotene in cutaneous T cell lymphoma is not known. In vitro, bexarotene inhibits the growth of some types of hematopoietic and squamous cell lines. Tumor regression has been observed in animal models.

    PHARMACOKINETICS

    Bexarotene is administered orally or topically. It is highly protein bound (> 99%). The terminal half-life is 7 hours. Bexarotene undergoes oxidative metabolism via CYP3A4; the oxidative metabolites are then glucuronidated. Four metabolites have been identified in plasma: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. The oxidative metabolites are active in vitro, but the relative contribution of the parent or bexarotene metabolites to the efficacy and safety of therapy is not known. Bexarotene and its metabolites are eliminated primarily through the hepatobiliary system. Less than 1% of the dose is excreted in the urine as bexarotene or its metabolites.
     
    Affected cytochrome P450 isoenzymes: CYP2C8, CYP3A4
    In vitro, bexarotene is a CYP3A4 substrate, a CYP3A4 inducer, and a CYP2C8 inhibitor. In a clinical study, the bexarotene plasma concentration was not altered following multiple doses of ketoconazole, a strong CYP3A4 inhibitor; therefore, bexarotene elimination may not be dependent on CYP3A4 metabolism. Bexarotene has been shown to decrease the plasma levels of some CYP3A4 substrates (e.g., atorvastatin, tamoxifen, paclitaxel). It does not significantly inhibit the following isoenzymes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. No formal studies to evaluate drug interactions with bexarotene gel have been conducted; concomitant use of other drugs that affect CYP3A4 levels or activity may affect bexarotene disposition.

    Oral Route

    Following oral administration, bexarotene reaches its Tmax in about 2 hours. In patients with advanced malignancy, bexarotene exhibited linearity within the therapeutic range following a single dose.
    Effects of Food: Following a single dose of bexarotene (75 mg to 300 mg), the plasma AUC and Cmax values were 35% and 48% higher, respectively, following a fat-containing meal compared to a glucose solution.

    Topical Route

    There is a low potential for significant systemic bexarotene plasma concentrations following repeated topical administration in patients applying low to moderate doses. In clinical trials, plasma concentrations were typically less than 5 nanograms (ng)/mL and did not exceed 55 mg/mL following single or multiple daily application of bexarotene 1% gel for up to 132 weeks in patients with cutaneous T-cell lymphoma. More frequent application (e.g., 4 times daily) and larger treated body surface area (e.g., > 40% BSA lesions) were associated with increased systemic levels.