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  • CLASSES

    Small Molecule Antineoplastic Vascular Endothelial Growth Factor Receptor (VEGFR) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral tyrosine kinase inhibitor
    Used for renal cell cancer, as monotherapy or in combination with avelumab or pembrolizumab
    Do not give axitinib for at least 2 days before elective surgery, and for at least 2 weeks after major surgery and until adequate wound healing

    COMMON BRAND NAMES

    INLYTA

    HOW SUPPLIED

    INLYTA Oral Tab: 1mg, 5mg

    DOSAGE & INDICATIONS

    For the treatment of renal cell cancer.
    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).

    For the first-line treatment of advanced renal cell cancer, in combination with pembrolizumab.
    Oral dosage
    Adults

    Initially, give axitinib 5 mg PO twice daily in combination with pembrolizumab (200 mg IV on day 1 every 3 weeks OR 400 mg IV on day 1 every 6 weeks). The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily at intervals of 6 weeks or longer 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. Continue treatment until disease progression or unacceptable toxicity, or for pembrolizumab, up to 24 months in patients without progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[48494] Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions; permanently discontinue therapy for severe or life-threatening infusion-related reactions.[57889] In the first interim analysis of an open-label phase 3 clinical trial (KEYNOTE-426), combination therapy with pembrolizumab and axitinib significantly improved overall survival and progression-free survival in patients with advanced renal cell cancer compared with sunitinib; the benefit may be greatest in poor or intermediate IMDC risk group patients with PD-L1 expression of 1% or more.[63966] In an exploratory analysis with extended follow-up (median, 30.6 months), patients treated with pembrolizumab and axitinib continued to have significantly improved overall survival compared with sunitinib (not reached vs. 35.7 months).

    For the first-line treatment of advanced renal cell cancer, in combination with avelumab.
    Oral dosage
    Adults

    5 mg PO twice daily initially, in combination with avelumab (800 mg IV over 1 hour every 2 weeks), until disease progression or unacceptable toxicity. 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. All patients should receive premedication with an antihistamine and acetaminophen 30 to 60 minutes prior to the first 4 avelumab infusions; premedication may be administered prior to subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Avelumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In the first interim analysis of an open-label phase 3 clinical trial (JAVELIN Renal 101), first-line combination therapy with avelumab and axitinib significantly improved PFS in patients with advanced renal cell carcinoma and PD-L1 expression of 1% or more compared with sunitinib monotherapy; the confirmed objective response rate almost doubled with combination therapy. Overall survival was not reached in either group and continues to be monitored.

    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.[48494]
     
    Treatment-Related Hepatotoxicity:
    Monotherapy
    If a dose reduction from 5 mg twice daily is required due to adverse reactions, the recommended dose is 3 mg twice daily; reduce the dose to 2 mg twice daily if an additional dose reduction is necessary.[48494]
    In combination with avelumab for renal cell carcinoma
    AST/ALT 3 to 4.9 times ULN: Hold both avelumab and axitinib therapy until AST/ALT recover to grade 1 or less. If transaminitis is persistent (greater than 5 days), consider corticosteroid therapy at an initial dose of prednisone 0.5 to 1 mg/kg/day or equivalent, followed by a taper. Consider rechallenge with a single drug or sequential challenge with both drugs after recovery. If an axitinib dose reduction from 5 mg twice daily is required due to adverse reactions, the recommended dose is 3 mg twice daily; reduce the axitinib dose to 2 mg twice daily if an additional dose reduction is necessary.
    AST/ALT 5 times ULN or more: Permanently discontinue both avelumab and axitinib therapy. Consider corticosteroid therapy at an initial dose of prednisone 1 to 2 mg/kg per day or equivalent, followed by a taper.
    Total bilirubin 1.5 to 2.9 times ULN: Hold both avelumab and axitinib therapy until total bilirubin recovers to grade 1 or less. If hyperbilirubinemia is persistent (greater than 5 days), consider corticosteroid therapy at an initial dose of prednisone 0.5 to 1 mg/kg/day or equivalent, followed by a taper. Consider rechallenge with a single drug or sequential challenge with both drugs after recovery. If an axitinib dose reduction from 5 mg twice daily is required due to adverse reactions, the recommended dose is 3 mg twice daily; reduce the axitinib dose to 2 mg twice daily if an additional dose reduction is necessary.
    Total bilirubin 3 times ULN or more: Permanently discontinue both avelumab and axitinib therapy. Consider corticosteroid therapy at an initial dose of prednisone 1 to 2 mg/kg per day or equivalent, followed by a taper.
    Concurrent AST/ALT greater than 3 times ULN with total bilirubin 2 times ULN or more: Permanently discontinue both avelumab and axitinib therapy. Consider corticosteroid therapy at an initial dose of prednisone 1 to 2 mg/kg per day or equivalent, followed by a taper.
    In combination with pembrolizumab for renal cell carcinoma
    ALT/AST 3 to less than 10 times ULN WITHOUT concurrent total bilirubin 2 times ULN or more: Hold both pembrolizumab and axitinib therapy and consider treatment with corticosteroids. When liver function tests recover to grade 1 or less, consider rechallenge with a single drug (i.e., pembrolizumab or axitinib), or a sequential rechallenge with both drugs. If an axitinib dose reduction from 5 mg twice daily is required due to adverse reactions, the recommended dose is 3 mg twice daily; reduce the axitinib dose to 2 mg twice daily if an additional dose reduction is necessary.
    ALT/AST 10 times ULN or more, or greater than 3 times ULN with concurrent total bilirubin 2 times ULN or more: Permanently discontinue both pembrolizumab and axitinib and consider corticosteroid therapy.[57889]

    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.

    Impaired wound healing, surgery

    Impaired wound healing can occur in patients treated with vascular endothelial growth factor (VEGF) inhibitors such as axitinib. Discontinue axitinib at least 2 days prior to elective surgery; do not administer axitinib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming axitinib after resolution of wound healing complications has not been established.

    Hepatic disease, hepatotoxicity

    Reduce the dose of axitinib in patients with moderate hepatic disease (Child-Pugh B) at baseline; axitinib has not been studied in patients with severe hepatic disease (Child-Pugh C). Increased ALT has been reported during axitinib treatment; monitor liver function tests prior to starting axitinib and periodically during therapy. Dose reductions of axitinib may be necessary for treatment-related adverse reactions including increased liver function tests. When administered in combination with either avelumab or pembrolizumab, hepatotoxicity can occur with higher than expected frequencies compared to monotherapy with these drugs; consider more frequent monitoring of liver function tests if combination therapy is necessary. Treatment may need to be temporarily withheld or permanently discontinued if signs of hepatotoxicity occur; treatment with corticosteroids may also be necessary.

    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, diabetes mellitus, heart failure, hyperlipidemia, myocardial infarction

    Use caution in patients with cardiac disease or risk factors for heart failure. Heart failure has been reported in 2% of patients treated with axitinib in a controlled, clinical study, including 2 fatalities (1%). 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. When administered in combination with avelumab, severe and fatal cardiovascular events have been reported including myocardial infarction and congestive heart failure. Optimize management of cardiovascular risk factors such as hypertension, diabetes mellitus, or hyperlipidemia when administering combination therapy; consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Discontinue both axitinib and avelumab for grade 3 or 4 cardiovascular events.

    Children, infants, neonates

    The safety and efficacy of axitinib has not been studied 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
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 5.0-6.0
    asthenia / Delayed / 5.0-5.0
    anorexia / Delayed / 2.1-5.0
    hyponatremia / Delayed / 4.0-4.0
    proteinuria / Delayed / 3.0-3.0
    lymphopenia / Delayed / 3.0-3.0
    dyspnea / Early / 3.0-3.0
    hyperkalemia / Delayed / 3.0-3.0
    nausea / Early / 0.9-3.0
    vomiting / Early / 3.0-3.0
    renal failure (unspecified) / Delayed / 0-2.3
    pulmonary embolism / Delayed / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    arthralgia / Delayed / 2.0-2.0
    hypophosphatemia / Delayed / 2.0-2.0
    hyperamylasemia / Delayed / 2.0-2.0
    weight loss / Delayed / 2.0-2.0
    hyperglycemia / Delayed / 2.0-2.0
    hypertensive crisis / Early / 0-1.0
    heart failure / Delayed / 1.0-1.0
    thrombosis / Delayed / 1.0-1.0
    retinal thrombosis / Delayed / 1.0-1.0
    stroke / Early / 0-1.0
    hematuria / Delayed / 0-1.0
    intracranial bleeding / Delayed / 0-1.0
    bleeding / Early / 1.0-1.0
    GI bleeding / Delayed / 1.0-1.0
    hemoptysis / Delayed / 0-1.0
    constipation / Delayed / 1.0-1.0
    hypothyroidism / Delayed / 0.2-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    headache / Early / 0.2-1.0
    rash / Early / 0-1.0
    cough / Delayed / 0.2-1.0
    hypocalcemia / Delayed / 1.0-1.0
    hypernatremia / Delayed / 1.0-1.0
    hypoalbuminemia / Delayed / 0-1.0
    gastrointestinal fistula / Delayed / 1.0-1.0
    GI perforation / Delayed / 1.0-1.0
    stomatitis / Delayed / 1.0-1.0
    dehydration / Delayed / 0-1.0
    leukoencephalopathy / Delayed / 0-1.0
    hypoglycemia / Early / 1.0-1.0
    thrombocytopenia / Delayed / 0-1.0
    dysphonia / Delayed / 0-0.5
    myocardial infarction / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    aortic dissection / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / 11.0-11.0
    hypercalcemia / Delayed / 6.0-6.0
    hemorrhoids / Delayed / 4.0-4.0
    anemia / 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
    colitis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    bone pain / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 11.0-11.0
    xerosis / Delayed / 10.0-10.0
    dyspepsia / Early / 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
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    back pain / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    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 a CYP3A4/5 substrate and amobarbital is a moderate CYP3A4 inducer.
    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 CYP3A4/5 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 the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Artesunate: (Moderate) Monitor for an increase in artesunate-related side effects if coadministered with axitinib. Coadministration may increase the exposure of the active metabolite of artesunate, dihydroartemisinin (DHA). DHA is a UGT substrate, and axitinib is a strong UGT inhibitor.
    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 a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
    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 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 atazanavir is discontinued. Axitinib is a CYP3A4/5 substrate and 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 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 atazanavir is discontinued. Axitinib is a CYP3A4/5 substrate and 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 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased 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 a CYP3A4/5 substrate and 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 CYP3A4/5 substrate and bexarotene is a moderate CYP3A4 inducer.
    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 CYP3A4/5 substrate and bosentan is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and butabarbital is a moderate CYP3A4 inducer.
    Butalbital; Acetaminophen: (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 a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
    Butalbital; Acetaminophen; 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 a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
    Butalbital; Acetaminophen; 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 a CYP3A4/5 substrate and butalbital is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Cenobamate: (Major) Avoid coadministration of axitinib with cenobamate 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 CYP3A4/5 substrate and cenobamate is a moderate CYP3A4 inducer.
    Ceritinib: (Major) Avoid coadministration of axitinib with ceritinib 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 ceritinib is discontinued. Axitinib is a CYP3A4/5 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Chloramphenicol: (Major) Avoid coadministration of axitinib with chloramphenical 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 chloramphenical is discontinued. Axitinib is a CYP3A4/5 substrate and chloramphenical is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    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 CYP3A4/5 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 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    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.
    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 CYP3A4/5 substrate and dabrafenib is a moderate CYP3A4 inducer.
    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 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 darunavir is discontinued. Axitinib is a CYP3A4/5 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 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat 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 darunavir 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 darunavir is discontinued. Axitinib is a CYP3A4/5 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 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat 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 darunavir 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 darunavir is discontinued. Axitinib is a CYP3A4/5 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 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 ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and 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 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 delavirdine is discontinued. Axitinib is a CYP3A4/5 substrate and 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 CYP3A4/5 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 a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
    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 CYP3A4/5 substrate and elagolix is a weak to moderate CYP3A4 inducer.
    Elagolix; Estradiol; Norethindrone acetate: (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 CYP3A4/5 substrate and elagolix is a weak to moderate CYP3A4 inducer.
    Elvitegravir; 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 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Elvitegravir; Cobicistat; 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 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Enzalutamide: (Major) Avoid coadministration of axitinib with enzalutamide 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 CYP3A4/5 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    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 a CYP3A4/5 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and etravirine is a moderate CYP3A4 inducer.
    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 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 fosamprenavir is discontinued. Axitinib is a CYP3A4/5 substrate and fosamprenavir is a strong CYP3A4 inhibitor. 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 a CYP3A4/5 substrate and 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 administration of axitinib with grapefruit or grapefruit juice due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4/5 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. 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 idelalisib is discontinued. Axitinib is a CYP3A4/5 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 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 indinavir is discontinued. Axitinib is a CYP3A4/5 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 a CYP3A4/5 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with 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 a CYP3A4/5 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with 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 CYP3A4/5 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 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 ketoconazole is discontinued. Axitinib is a CYP3A4/5 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased the plasma exposure of axitinib in healthy volunteers.
    Lansoprazole; Amoxicillin; 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 CYP3A4/5 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.
    Letermovir: (Moderate) Avoid coadministration of axitinib with letermovir if the patient is also taking cyclosporine 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 letermovir or cyclosporine is discontinued. Axitinib is a CYP3A4/5 substrate. Letermovir is a moderate CYP3A4 inhibitor which requires no dose adjustment with axitinib; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Lonafarnib: (Major) Avoid coadministration of axitinib with lonafarnib 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 lonafarnib is discontinued. Axitinib is a CYP3A4/5 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Lopinavir; 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 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 ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and 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 CYP3A4/5 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 CYP3A4/5 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 a CYP3A4/5 substrate and mephobarbital is 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 a CYP3A4/5 substrate and methohexital is a moderate CYP3A4 inducer.
    Mifepristone: (Major) Avoid coadministration of axitinib with mifepristone 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 mifepristone is discontinued. Axitinib is a CYP3A4/5 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. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    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 CYP3A4/5 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 a CYP3A4/5 substrate and modafinil is a moderate CYP3A4 inducer.
    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 CYP3A4/5 substrate and nafcillin is a moderate CYP3A4 inducer.
    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 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 nefazodone is discontinued. Axitinib is a CYP3A4/5 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 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 nelfinavir is discontinued. Axitinib is a CYP3A4/5 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 CYP3A4/5 substrate and nevirapine is a moderate CYP3A4 inducer.
    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 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 ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Omeprazole; Amoxicillin; 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 CYP3A4/5 substrate and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    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 a CYP3A4/5 substrate and pentobarbital is a moderate CYP3A4 inducer.
    Pexidartinib: (Major) Avoid coadministration of axitinib with pexidartinib 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 CYP3A4/5 substrate and pexidartinib is a moderate CYP3A4 inducer.
    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 a CYP3A4/5 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Phenobarbital; Hyoscyamine; Atropine; 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 a CYP3A4/5 substrate and 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 a CYP3A4/5 substrate and 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 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 posaconazole is discontinued. Axitinib is a CYP3A4/5 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 a CYP3A4/5 substrate and 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 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 ribociclib is discontinued. Axitinib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Ribociclib; Letrozole: (Major) Avoid coadministration of axitinib with ribociclib 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 ribociclib is discontinued. Axitinib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    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 CYP3A4/5 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 a CYP3A4/5 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with 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 CYP3A4/5 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Rifaximin: (Moderate) In patients with hepatic impairment, avoid coadministration of axitinib with rifaximin 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 CYP3A4/5 substrate. In patients with normal hepatic function, rifaximin is not expected to induce CYP3A4 at the recommended dosing regimen. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.
    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 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 ritonavir is discontinued. Axitinib is a CYP3A4/5 substrate and 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 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 saquinavir is discontinued. Axitinib is a CYP3A4/5 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.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    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 a CYP3A4/5 substrate and secobarbital is a moderate CYP3A4 inducer.
    Sotorasib: (Major) Avoid coadministration of axitinib with sotorasib 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 CYP3A4/5 substrate and sotorasib is a moderate CYP3A4 inducer.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of axitinib with St. Johns 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 a CYP3A4/5 substrate and St. Johns Wort is a strong CYP3A4 inducer. 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 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 telithromycin is discontinued. Axitinib is a CYP3A4/5 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 a CYP3A4/5 substrate and thiopental is a moderate CYP3A4 inducer.
    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 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 tipranavir is discontinued. Axitinib is a CYP3A4/5 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Tucatinib: (Major) Avoid coadministration of axitinib with tucatinib 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 tucatinib is discontinued. Axitinib is a CYP3A4/5 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    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 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 voriconazole is discontinued. Axitinib is a CYP3A4/5 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.

    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.