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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral tyrosine kinase inhibitor
    Used for renal cell carcinoma
    Most common ADRs include diarrhea, hypertension, fatigue, and decreased appetite

    COMMON BRAND NAMES

    INLYTA

    HOW SUPPLIED

    INLYTA Oral Tab: 1mg, 5mg

    DOSAGE & INDICATIONS

    For the treatment of renal cell cancer (RCC).
    For the first-line treatment of advanced or metastatic renal cell cancer (RCC)†.
    Oral dosage
    Adults

    Initially, give 5 mg PO twice daily (at approximately 12 hour intervals). Dose increase or reduction is based on individual safety and tolerability. The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily in normotensive patients (BP less than or equal to 150/90) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. In clinical trials, dose reductions to 3 mg twice were allowed, and then to 2 mg twice daily if necessary. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Axitinib significantly improved the objective response rate in patients with previously untreated, metastatic clear cell RCC compared with sorafenib (32% vs. 15%) in a multicenter, randomized, open-label phase 3 clinical trial. An improvement in median progression-free survival (PFS) was not statistically significant in the intent-to-treat population (10.1 months vs. 6.5 months); however, the improvement was significant in a subgroup analysis of patients with ECOG score of 0 (13.7 months vs. 6.6 months).

    For the treatment of advanced renal cell cancer after failure of 1 prior systemic therapy.
    Oral dosage
    Adults

    Initially, give 5 mg PO twice daily (at approximately 12 hour intervals). Dose increase or reduction is based on individual safety and tolerability. The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily in normotensive patients (not receiving antihypertensive medications) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. Reduce axitinib to 3 mg twice daily if a dose reduction is necessary; if further reduction is necessary, reduce axitinib to 2 mg twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Progression-free survival (primary endpoint) was significantly improved with axitinib 5 mg twice daily (increased up to 10 mg twice daily if no hypertension or greater than grade 2 adverse events) compared with sorafenib 400 mg twice daily (6.7 months vs. 4.7 months) in patients with progressive renal cell cancer in a multicenter, randomized, phase 3 study (n = 723).

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO.

    Geriatric

    20 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild impairment (Child-Pugh class A): No dose adjustment to the starting dose is required.
    Moderate impairment (Child-Pugh class B): Reduce the starting dose by approximately one-half, and then adjust the dose upwards or downwards based on safety and tolerability.
    Severe impairment (Child-Pugh class C): No studies have been performed; dosing recommendations are not available from the manufacturer.
    Treatment-Related Hepatotoxicity:
    If dose reduction from 5 mg twice daily is required due to adverse drug reactions, the recommended dose is 3 mg twice daily; reduce the dose to 2 mg twice daily if an additional dose reduction is necessary.

    Renal Impairment

    Baseline Renal Impairment:
    No dosage adjustment to the starting dose is necessary for patients with mild, moderate, or severe renal impairment. Data are not available for patients with end-stage renal disease (ESRD). A baseline urinalysis to monitor for proteinuria is recommended before axitinib administration and periodically during treatment.
    Treatment-Related Nephrotoxicity:
    If moderate to severe proteinuria develops, reduce the dose of axitinib or temporarily withhold treatment.
    If dose reduction from 5 mg twice daily is required due to adverse drug reactions, the recommended dose is 3 mg twice daily; reduce the dose to 2 mg twice daily if an additional dose reduction is necessary.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer axitinib orally with or without food.
    Swallow tablet whole with a glass of water.
    If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

    STORAGE

    INLYTA:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Thromboembolic disease

    Use axitinib with caution in patients who are risk for or have a history of thromboembolic disease because arterial thromboembolism (eg, cerebrovascular accident, transient ischemic attack, myocardial infarction, and retinal artery occlusion) and venous thromboembolism (e.g., pulmonary embolism, deep vein thrombosis, retinal vein occlusion, retinal vein thrombosis) have been reported in clinical trials, sometimes with fatal outcomes. Patients who had an arterial thromboembolic event within the previous 12 months or a venous thromboembolic event within the previous 6 months were excluded from clinical trials.

    Bleeding

    Serious hemorrhagic events have been reported with axitinib use including cerebral hemorrhage, hematuria, and hemoptysis. Axitinib has not been studied in patients with untreated brain metastasis and should not be used in patients with this conditions due to the risk of bleeding. Temporarily discontinue therapy if a patient develops any bleeding that requires medical intervention.

    Fistula, GI bleeding, GI perforation

    Serious gastrointestinal toxicity has been reported with axitinib use including GI bleeding, GI perforation, and fistula. Axitinib has not been studied in patients with recent, active GI bleeding and should not be used in patients with this condition due to the risk of bleeding. Axitinib should be used with caution in patients at risk for GI perforation or fistula. Monitor patients for symptoms of GI perforation or fistula and temporarily discontinue therapy if a patient develops any bleeding that requires medical intervention.

    Surgery

    Discontinue axitinib at least 24 hours prior to scheduled surgery; no formal studies on the effect of axitinib on wound healing have been conducted. Therapy may be resumed based on clinical judgement of adequate wound healing.

    Hepatic disease

    The axitinib dosage should be reduced in patients with moderate (Child-Pugh Class B) hepatic disease; systemic exposure to axitinib is higher in subjects with moderate hepatic impairment compared to those with normal hepatic function. Axitinib has not been studied in patients with severe (Child-Pugh Class C) hepatic disease. Elevations in ALT have been reported during axitinib treatment; monitoring of liver function tests (ie, ALT, AST, bilirubin) is recommended prior to and periodically during therapy.

    Hypertension

    Blood pressure should be well controlled before starting axitinib. Monitor patients for hypertension and administer antihypertensive therapy as necessary prior to and during axitinib therapy. If a patient has persistent hypertension despite antihypertensive therapy, reduce the axitinib dosage; discontinue therapy if hypertension continues after a dosage reduction or if there is evidence of hypertensive crisis. After axitinib is discontinued, monitor blood pressure (for hypotension) in patients who were receiving antihypertensive medications.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Hyperthyroidism and hypothyroidism have been reported with axitinib use. Monitor thyroid function tests prior to and periodically during axitinib therapy; treat thyroid disease if necessary with standard thyroid medications.

    Proteinuria

    Proteinuria has been reported with axitinib use. Monitor for proteinuria prior to and periodically during axitinib therapy. Reduce the axitinib dosage or temporarily discontinue therapy if a patient develops moderate to severe proteinuria.

    Renal impairment

    Use axitinib with caution in patients with end-stage renal impairment (CrCL less than 15 mL/min). No significant change in axitinib clearance was demonstrated in healthy volunteers and patients with pre-existing mild to severe (CrCL 15 to 88 mL/min) renal impairment in a population pharmacokinetic study. However, only one patient with end-stage renal impairment was evaluated in this study.

    Encephalopathy

    Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been reported with axitinib use. Symptoms of RPLS include seizures, headache, visual disturbances, confusion, and altered mental status. Discontinue axitinib therapy if RPLS is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging. The safety of reinitiating axitinib therapy in patients previously experiencing RPLS is not known.

    Cardiac disease, heart failure

    Heart failure has been reported in 2% of patients treated with axitinib in a controlled, clinical study, including 2 fatalities (1%). Use caution in patients with cardiac disease or risk factors for heart failure. Monitor patients for signs or symptoms consistent with heart failure throughout treatment; evaluate and treat as necessary. If heart failure occurs, permanent discontinuation of axitinib may be required.

    Children, infants, neonates

    The safety and efficacy of axitinib has not been established in adolescents, children, infants, or neonates. Thickening growth plates (in mice and dogs at doses of 15 mg/kg or more) and incisor teeth abnormalities (in mice at doses of 5 mg/kg or more) were observed in immature mice and dogs who received twice daily axitinib for 1 month or longer.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during axitinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant humans, axitinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving axitinib should be apprised of the potential hazard to the fetus. In developmental toxicity studies, axitinib was teratogenic, embryotoxic, and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. When administered to female mice prior to mating and through the first week of pregnancy at approximately 10 times the AUC in patients at the recommended starting dose, oral axitinib caused an increase in postimplantation loss. In another study, the following embryo-fetal toxicities were observed in the absence of maternal toxicity when axitinib was administered to pregnant mice during organogenesis: malformation (cleft palate) at approximately 0.5 times the AUC in patients at the recommended starting dose, and variation in skeletal ossification at approximately 0.15 times the AUC in patients at the recommended starting dose.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during axitinib treatment. Axitinib can be teratogenic if taken by the mother during pregnancy. Females and males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with axitinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of axitinib. Women who become pregnant while receiving axitinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of axitinib on human fertility, male and female infertility has been observed in animal studies including delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weighs and uterine atrophy in females, and decreased organ weight, atrophy or degeneration, decreased number of germinal cells, hypospermia or abnormal sperm forms, and reduced sperm density/count in males.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from axitinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether axitinib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    hypertension / Early / 16.0-16.0
    diarrhea / Early / 11.0-11.0
    fatigue / Early / 11.0-11.0
    anorexia / Delayed / 5.0-5.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 5.0-5.0
    asthenia / Delayed / 5.0-5.0
    hyponatremia / Delayed / 4.0-4.0
    vomiting / Early / 3.0-3.0
    nausea / Early / 3.0-3.0
    proteinuria / Delayed / 3.0-3.0
    lymphopenia / Delayed / 3.0-3.0
    dyspnea / Early / 3.0-3.0
    hyperkalemia / Delayed / 3.0-3.0
    pulmonary embolism / Delayed / 2.0-2.0
    heart failure / Delayed / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    weight loss / Delayed / 2.0-2.0
    arthralgia / Delayed / 2.0-2.0
    hyperglycemia / Delayed / 2.0-2.0
    hypophosphatemia / Delayed / 2.0-2.0
    hyperamylasemia / Delayed / 2.0-2.0
    hypertensive crisis / Early / 0-1.0
    thrombosis / Delayed / 1.0-1.0
    stroke / Early / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    retinal thrombosis / Delayed / 1.0-1.0
    hematuria / Delayed / 0-1.0
    GI bleeding / Delayed / 1.0-1.0
    hemoptysis / Delayed / 0-1.0
    intracranial bleeding / Delayed / 0-1.0
    bleeding / Early / 1.0-1.0
    stomatitis / Delayed / 1.0-1.0
    GI perforation / Delayed / 0-1.0
    constipation / Delayed / 1.0-1.0
    gastrointestinal fistula / Delayed / 1.0-1.0
    hypothyroidism / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    headache / Early / 1.0-1.0
    leukoencephalopathy / Delayed / 0-1.0
    rash / Early / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    cough / Delayed / 1.0-1.0
    hypocalcemia / Delayed / 1.0-1.0
    hypoglycemia / Early / 0-1.0
    hypernatremia / Delayed / 1.0-1.0

    Moderate

    dysphonia / Delayed / 31.0-31.0
    hypoalbuminemia / Delayed / 0-15.0
    leukopenia / Delayed / 11.0-11.0
    dehydration / Delayed / 6.0-6.0
    hypercalcemia / Delayed / 6.0-6.0
    hemorrhoids / Delayed / 4.0-4.0
    erythema / Early / 2.0-2.0
    melena / Delayed / 0-1.0
    hyperthyroidism / Delayed / 1.0-1.0
    polycythemia / Delayed / 1.0-1.0

    Mild

    dysgeusia / Early / 11.0-11.0
    dyspepsia / Early / 10.0-10.0
    xerosis / Delayed / 10.0-10.0
    dizziness / Early / 9.0-9.0
    pruritus / Rapid / 7.0-7.0
    myalgia / Early / 7.0-7.0
    epistaxis / Delayed / 6.0-6.0
    alopecia / Delayed / 4.0-4.0
    tinnitus / Delayed / 3.0-3.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Avoid coadministration of axitinib with butalbital 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 primarily metabolized by CYP3A4. Butalbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of axitinib with butalbital 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 primarily metabolized by CYP3A4. Butalbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of axitinib with butalbital 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 primarily metabolized by CYP3A4. Butalbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Aldesleukin, IL-2: (Moderate) Use caution if coadministration of axitinib with aldesleukin, IL-2 is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate. Aldesleukin increases IL-6 concentrations; IL-6 is a CYP3A4 inhibitor. Aldesleukin has also been shown to weakly inhibit CYP3A4 directly. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Amobarbital: (Major) Avoid coadministration of axitinib with amobarbital 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 primarily metabolized by CYP3A4. Amobarbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Apalutamide: (Major) Avoid coadministration of axitinib with apalutamide due to decreased plasma concentrations of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased axitinib exposure by 80%.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of axitinib with butalbital 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 primarily metabolized by CYP3A4. Butalbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of axitinib with butalbital 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 primarily metabolized by CYP3A4. Butalbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Atazanavir: (Major) Avoid coadministration of axitinib with atazanavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after atazanavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of axitinib with atazanavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after atazanavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is primarily metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor increased the plasma exposure of axitinib by 106%
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of axitinib with phenobarbital, 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 primarily metabolized by CYP3A4. Phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of axitinib with phenobarbital, 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 primarily metabolized by CYP3A4. Phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Bexarotene: (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.
    Bosentan: (Major) Avoid coadministration of axitinib with bosentan 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 bosentan is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Butabarbital: (Major) Avoid coadministration of axitinib with butabarbital 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 primarily metabolized by CYP3A4. Butabarbital is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Carbamazepine: (Major) Avoid coadministration of axitinib with carbamazepine, 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 primarily metabolized by CYP3A4. Carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Ceritinib: (Major) Avoid coadministration of ceritinib with axitinib due to increased axitinib exposure. If coadministration is unavoidable, monitor for axitinib-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and axitinib is primarily metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the AUC of axitinib by 106%. The strength of inhibition of CYP3A4 by ceritinib is unknown.
    Chloramphenicol: (Major) Avoid coadministration of axitinib with chloramphenicol due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after chloramphenicol is discontinued. Axitinib is primarily metabolized by CYP3A4. Chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Clarithromycin: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Cobicistat: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is primarily metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor increased the plasma exposure of axitinib by 106%
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is primarily metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor increased the plasma exposure of axitinib by 106%
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is primarily metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor increased the plasma exposure of axitinib by 106%
    Cocaine: (Moderate) Use caution if coadministration of axitinib with cocaine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and cocaine is a weak CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Conivaptan: (Major) Avoid coadministration of conivaptan with axitinib, due to the risk of increased axitinib-related adverse reactions. According to the manufacturer of conivaptan, subsequent treatment with axitinib may be initiated no sooner than 1 week after the infusion of conivaptan is completed, although the manufacturer of axitinib suggests that reducing the dose by 50% is acceptable if avoidance is not possible. Subsequent doses can be increased or decreased based on individual safety and tolerability, resuming the original dose of axitinib approximately 3 to 5 half-lives after conivaptan is discontinued. Axitinib is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Dabrafenib: (Major) Avoid coadministration of axitinib with dabrafenib 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 dabrafenib is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Darunavir: (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Darunavir; Cobicistat: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is primarily metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor increased the plasma exposure of axitinib by 106% (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is primarily metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor increased the plasma exposure of axitinib by 106% (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Delavirdine: (Major) Avoid coadministration of axitinib with delavirdine due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after delavirdine is discontinued; inhibition of hepatic CYP3A activity by delavirdine is reversible within 1 week of discontinuation. Axitinib is primarily metabolized by CYP3A4. Delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Dexamethasone: (Major) Avoid coadministration of axitinib with dexamethasone, 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 dexamethasone is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Efavirenz: (Major) Avoid coadministration of axitinib with efavirenz 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 primarily metabolized by CYP3A4. Efavirenz is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of axitinib with efavirenz 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 primarily metabolized by CYP3A4. Efavirenz is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of axitinib with efavirenz 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 primarily metabolized by CYP3A4. Efavirenz is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Elagolix: (Major) Avoid coadministration of axitinib with elagolix 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 elagolix is a weak to moderate CYP3A4 inducer.
    Enzalutamide: (Major) Avoid coadministration of axitinib with enzalutamide due to decreased plasma concentrations of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased axitinib exposure by 80%.
    Eslicarbazepine: (Major) Avoid coadministration of axitinib with eslicarbazepine 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 primarily metabolized by CYP3A4. Eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Etravirine: (Major) Avoid coadministration of axitinib with etravirine 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 primarily metabolized by CYP3A4. Etravirine is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Fosamprenavir: (Major) Avoid coadministration of axitinib with fosamprenavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after fosamprenavir is discontinued. Axitinib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor with the potential to also induce CYP3A4. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Fosphenytoin: (Major) Avoid coadministration of axitinib with fosphenytoin, 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 primarily metabolized by CYP3A4. Fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Grapefruit juice: (Major) Avoid coadministration of axitinib with grapefruit or grapefruit juice due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Idelalisib: (Major) Avoid coadministration of axitinib with idelalisib, due to the risk of increased axitinib-related adverse reactions. The manufacturer of axitinib suggests that reducing the axitinib dose by 50% is acceptable if avoidance is not possible. Subsequent doses can be increased or decreased based on individual safety and tolerability, resuming the original dose of axitinib approximately 3 to 5 half-lives after idelalisib is discontinued. Axitinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Indinavir: (Major) Avoid coadministration of axitinib with indinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after indinavir is discontinued. Axitinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of axitinib with rifampin, 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 primarily metabolized by CYP3A4. Rifampin is a strong CYP3A4 inducer. In a drug interaction study, coadministration of rifampin significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of axitinib with rifampin, 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 primarily metabolized by CYP3A4. Rifampin is a strong CYP3A4 inducer. In a drug interaction study, coadministration of rifampin significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Itraconazole: (Major) Avoid axitinib during and for 2 weeks after discontinuation of itraconazole treatment. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after itraconazole is discontinued. Axitinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Ketoconazole: (Major) Avoid coadministration of axitinib with ketoconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ketoconazole is discontinued. Axitinib is primarily metabolized by CYP3A4. Ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased the plasma exposure of axitinib in healthy volunteers.
    Letermovir: (Moderate) Concurrent administration with letermovir may result in elevated axitinib plasma concentrations. Avoid this combination if the patient is also receiving cyclosporine. If concurrent use cannot be avoided, a dose decrease of axitinib by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If concurrent administration of letermovir or cyclosporine is discontinued, the axitinib dose should be returned (after 3 to 5 half-lives of the inhibitor) to that used prior to initiation of letermovir and cyclosporine.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of axitinib with lopinavir; ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after lopinavir; ritonavir is discontinued. Axitinib is a CYP3A4 substrate and lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Lorlatinib: (Major) Avoid coadministration of axitinib with lorlatinib 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 lorlatinib is a moderate CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of axitinib with lumacaftor; ivacaftor, 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 lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Mephobarbital: (Major) Avoid coadministration of axitinib with mephobarbital, 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 primarily metabolized by CYP3A4. Mephobarbital is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Methohexital: (Major) Avoid coadministration of axitinib with methohexital 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 primarily metabolized by CYP3A4. Methohexital is a moderate CYP3A4. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Mifepristone: (Major) Avoid coadministration of axitinib with chronic mifepristone therapy (e.g., for Cushing's disease) due to the risk of increased axitinib-related adverse reactions. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after chronic mifepristone is discontinued. Axitinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Mitotane: (Major) Avoid coadministration of axitinib with mitotane, 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 mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Modafinil: (Major) Avoid coadministration of axitinib with modafinil 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 primarily metabolized by CYP3A4. Modafinil is a moderate CYP3A4. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Nafcillin: (Major) Avoid coadministration of axitinib with nafcillin 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 nafcillin is a moderate CYP3A4 inducer in vitro. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Nefazodone: (Major) Avoid coadministration of axitinib with nefazodone due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after nefazodone is discontinued. Axitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Nelfinavir: (Major) Avoid coadministration of axitinib with nelfinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after nelfinavir is discontinued. Axitinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Nevirapine: (Major) Avoid coadministration of axitinib with nevirapine 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 nevirapine is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Octreotide: (Moderate) Use caution if coadministration of axitinib with octreotide is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate. Somatostatin analogs, such as octreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Major) Avoid coadministration of axitinib with pentobarbital 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 primarily metabolized by CYP3A4. Pentobarbital is a moderate CYP3A4. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Phenobarbital: (Major) Avoid coadministration of axitinib with phenobarbital, 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 primarily metabolized by CYP3A4. Phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Phenytoin: (Major) Avoid coadministration of axitinib with phenytoin, 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 primarily metabolized by CYP3A4. Phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Posaconazole: (Major) Avoid coadministration of axitinib with posaconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after posaconazole is discontinued. Axitinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Primidone: (Major) Avoid coadministration of axitinib with primidone, 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 primarily metabolized by CYP3A4. Primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Ribociclib: (Major) Avoid coadministration of axitinib with ribociclib due to the increased risk of axitinib-related adverse reactions. If coadministration is necessary, a dose reduction of axitinib by approximately 50% is recommended; subsequent doses may be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib 3 to 5 half-lives after ribociclib is discontinued. Axitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased axitinib exposure by 106%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of axitinib with ribociclib due to the increased risk of axitinib-related adverse reactions. If coadministration is necessary, a dose reduction of axitinib by approximately 50% is recommended; subsequent doses may be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib 3 to 5 half-lives after ribociclib is discontinued. Axitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased axitinib exposure by 106%.
    Rifabutin: (Major) Avoid coadministration of axitinib with rifabutin, 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 rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Rifampin: (Major) Avoid coadministration of axitinib with rifampin, 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 primarily metabolized by CYP3A4. Rifampin is a strong CYP3A4 inducer. In a drug interaction study, coadministration of rifampin significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Rifapentine: (Major) Avoid coadministration of axitinib with rifapentine, 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 rifapentine is a CYP3A4 inducer. Induction of enzyme activities by rifapentine occurs within 4 days of the first dose, and returns to baseline 14 days after discontinuation. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Ritonavir: (Major) Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Saquinavir: (Major) Avoid coadministration of axitinib with saquinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after saquinavir is discontinued. Axitinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Secobarbital: (Major) Avoid coadministration of axitinib with secobarbital 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 primarily metabolized by CYP3A4. Secobarbital is a moderate CYP3A4. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of axitinib with St. John's Wort, 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 primarily metabolized by CYP3A4. St. John's Wort is a strong CYP3A4 inducer. However, the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Telithromycin: (Major) Avoid coadministration of axitinib with telithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after telithromycin is discontinued. Axitinib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Thiopental: (Major) Avoid coadministration of axitinib with thiopental 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 primarily metabolized by CYP3A4. Thiopental is a moderate CYP3A4. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Tipranavir: (Major) Avoid coadministration of axitinib with tipranavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after tipranavir is discontinued. Axitinib is primarily metabolized by CYP3A4. Tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    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.
    Voriconazole: (Major) Avoid coadministration of axitinib with voriconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after voriconazole is discontinued. Axitinib is primarily metabolized by CYP3A4. Voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased axitinib exposure by 106%.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during axitinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant humans, axitinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving axitinib should be apprised of the potential hazard to the fetus. In developmental toxicity studies, axitinib was teratogenic, embryotoxic, and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. When administered to female mice prior to mating and through the first week of pregnancy at approximately 10 times the AUC in patients at the recommended starting dose, oral axitinib caused an increase in postimplantation loss. In another study, the following embryo-fetal toxicities were observed in the absence of maternal toxicity when axitinib was administered to pregnant mice during organogenesis: malformation (cleft palate) at approximately 0.5 times the AUC in patients at the recommended starting dose, and variation in skeletal ossification at approximately 0.15 times the AUC in patients at the recommended starting dose.

    Counsel patients about the reproductive risk and contraception requirements during axitinib treatment. Axitinib can be teratogenic if taken by the mother during pregnancy. Females and males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with axitinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of axitinib. Women who become pregnant while receiving axitinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of axitinib on human fertility, male and female infertility has been observed in animal studies including delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weighs and uterine atrophy in females, and decreased organ weight, atrophy or degeneration, decreased number of germinal cells, hypospermia or abnormal sperm forms, and reduced sperm density/count in males.

    MECHANISM OF ACTION

    Axitinib is an oral kinase inhibitor. At therapeutic concentrations, axitinib inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. Axitinib inhibited tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models and VEGF-mediated endothelial cell proliferation and survival in vitro and in mouse models. Inactivation of the von-Hippel Lindau (VHL) gene, reported in up to 91% of patients with noninherited clear-cell renal cell cancer (RCC), results in hypoxia inducible factors (HIF) accumulation. Elevated HIF levels trigger increased gene transcription of VEGF and platelet-derived growth factor that control cell proliferation, glucose uptake, and angiogenesis.

    PHARMACOKINETICS

    Axitinib is administered orally. It is highly protein bound (> 99%), mostly to albumin with moderate binding to alpha-1 acid glycoprotein. Carboxylic acid, sulfoxide, and N-glucuronide metabolites have been identified. N-glucuronide and sulfoxide metabolites are >= 400 times less potent against VEGFR-2 in vitro compared with axitinib. Following a radioactive 5-mg oral dose, 41% and 23% of the radioactivity was recovered in the feces and urine, respectively. Unchanged axitinib accounted for 12% of dose recovered in the feces. Unchanged axitinib was not found in urine; however, carboxylic acid and sulfoxide metabolites were responsible for most of the radioactivity in urine. The N-glucuronide metabolite accounted for 50% of the radioactivity in plasma with unchanged axitinib and the sulfoxide metabolite each accounting for 20% of the radioactivity. The plasma half-life ranges from 2.5 to 6.1 hours and steady state is estimated to occur within 2 to 3 days.
     
    Affected cytochrome P450 isoenzymes and drug transporter: CYP3A4, CYP1A2, CYP2C19, UGT1A1
    Axitinib is metabolized in the liver primarily via CYP3A4/5 and to a lesser extent, by CYP1A2, CYP2C19, and UGT1A1. In vitro studies suggest that axitinib has the potential to inhibit CYP1A2 and CYP2C8, but in vivo studies did not demonstrate this for CYP2C8. It is also an inhibitor of P-glycoprotein (P-gp) in vitro; however, it is not expected to inhibit P-gp at therapeutic plasma concentrations. Axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 or UGT1A1 in vitro. It also does not induce CYP1A1, CYP1A2, or CYP3A4/5 in vitro.

    Oral Route

    A 2-compartment disposition model with first order absorption and lag time was determined from pooled data in a population pharmacokinetic analysis in patients and healthy subjects who received axitinib in 17 trials. Following a single oral 5-mg axitinib dose, the mean absolute bioavailability was 58% and the median Tmax ranged from 2.5 to 4.1 hours. Linear kinetics are exhibited over a dosage range of 1 mg to 20 mg at steady state. Axitinib 5 mg twice daily dosing led to about 1.4 times the accumulation compared with a single 5-mg dose.
    In 20 patients with advanced renal cell carcinoma who received axitinib 5 mg twice daily with food (fed state), the geometric mean Cmax was 27.8 ng/mL (coefficient of variation (CV%), 79%), AUC (0 to 24 hour) was 265 ng x hour/mL (CV%, 77%), total clearance was 38 L/hr (CV%, 80%), and apparent volume of distribution was 160 L (CV%, 105%). Compared with patients who received axitinib after fasting overnight, 10% lower AUC and 19% higher AUC values were observed following the administration of axitinib with a moderate fat meal and a high fat, high-calorie meal, respectively. Axitinib may be given with or without food. Although the solubility of axitinib is pH dependent, with higher pH resulting in lower solubility, coadministration with rabeprazole did not significantly alter the Cmax or AUC of axitinib; no dose adjustment is recommended for concomitant use with antacids, H2 antagonists, or proton pump inhibitors.