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  • CLASSES

    Protein Kinase Inhibitors

    BOXED WARNING

    Fistula, GI perforation

    Serious GI perforation and fistula have been reported with cabozantinib use; one patient death was attributed to a GI fistula. Fatal non-GI fistulas (i.e., tracheal/esophageal fistulas) have also occurred in cabozantinib-treated patients. Monitor patients for signs and symptoms of GI perforation and fistula. Permanently discontinue Cabometyx in patients who develop a fistula which cannot be appropriately managed or a GI perforation; Cometriq should be permanently discontinued in all patients with a perforation or fistula.

    Bleeding, GI bleeding

    Serious bleeding (e.g., GI bleeding, hemoptysis) has been reported with cabozantinib use; some cases were fatal. Cabozantinib capsules (Cometriq) carry a black box warning for hemorrhage. Monitor patients for signs and symptoms of bleeding. Do not use cabozantinib tablets (Cabometyx) in patients who have or are at risk for severe hemorrhage; Cometriq should not be given to patients with a recent history of bleeding or hemoptysis. Permanently discontinue therapy in patients who develop severe bleeding.

    DEA CLASS

    Rx

    DESCRIPTION

    Multi-tyrosine kinase inhibitor
    FDA approved for the treatment of progressive, metastatic medullary thyroid cancer (capsules, Cometriq) and advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy (tablets, Cabometyx)
    Gastrointestinal (GI) perforation, GI fistula, and severe hemorrhage have been reported

    COMMON BRAND NAMES

    Cabometyx, COMETRIQ

    HOW SUPPLIED

    Cabometyx Oral Tab: 20mg, 40mg, 60mg
    COMETRIQ Oral Cap: 20mg, 20-80mg

    DOSAGE & INDICATIONS

    For the treatment of progressive, metastatic medullary thyroid cancer.
    Oral dosage (capsules only; do not substitute with cabozantinib tablets)
    Adults

    140 mg orally once daily on an empty stomach until disease progression or unacceptable toxicity occurs. Avoid the concomitant use of strong CYP3A4 inhibitors or inducers if possible; a dosage adjustment may be necessary if coadministration is unavoidable. Treatment with cabozantinib led to a significantly improved median progression-free survival time (11.2 months vs. 4 months; hazard ratio = 0.28; 95% CI, 0.19 to 0.4; p < 0.0001) and objective response rate (27% vs. 0%) compared with placebo in 330 patients with progressive metastatic medullary thyroid cancer in a multinational, randomized, double-blind, phase III trial. All responses in the cabozantinib arm were partial responses and the median duration of response was 14.7 months. Overall survival was not significantly different between treatment arms at a planned interim analysis. In this study, 92% of patients had undergone a thyroidectomy, 48% of patients had the RET mutation, and 25% of patients had previously received 2 or more systemic therapies (including a tyrosine kinase inhibitor in 21% of patients).

    For the treatment of advanced or metastatic renal cell cancer (RCC).
    For the first-line treatment of metastatic renal cell cancer (RCC) in poor or intermediate risk patients†.
    Oral dosage (tablets only; do not substitute with cabozantinib capsules)
    Adults

    60 mg by mouth once daily until disease progression or unacceptable toxicity. First-line cabozantinib improved median progression free survival (PFS) over sunitinib in intermediate- or poor-risk patients with metastatic RCC in a multicenter, randomized, open-label, phase 2 clinical trial (8.2 months vs. 5.6 months (HR 0.66; p = 0.012). The secondary endpoint of ORR was also improved (46% vs. 18%); overall survival data were not mature (30.3 months vs. 21.8 months (HR 0.8; 95% CI, 0.5 to 1.26). Treatments were similarly tolerated.

    For the treatment of advanced renal cell cancer (RCC) in patients who have received prior anti-angiogenic therapy.
    Oral dosage (tablets only; do not substitute with cabozantinib capsules)
    Adults

    60 mg by mouth once daily on an empty stomach until disease progression or unacceptable toxicity. A dosage adjustment may be necessary if coadministration with strong CYP3A inhibitors or inducers is unavoidable. In a multicenter, randomized, open-label clinical trial of patients with advanced renal cell cancer (RCC) who had received at least 1 prior anti-angiogenic therapy, the primary outcome of median progression-free survival (PFS) by blinded independent radiology review in the first 375 patients randomized to the study was significantly improved in patients treated with cabozantinib (n = 187) compared with everolimus (n = 188) (7.4 months vs. 3.8 months; HR 0.58; p < 0.0001). In the total study population, median overall survival (21.4 months vs. 16.5 months; HR 0.66; p = 0.0003) and confirmed objective response rate (ORR) (17% vs. 3%; p < 0.0001) were also improved in cabozantinib-treated patients (n = 330) compared with those who received everolimus (n = 328).

    MAXIMUM DOSAGE

    Adults

    Cometriq: 140 mg/day PO; 180 mg/day PO if taking a strong CYP3A4 inducer and 100 mg/day PO if taking a strong CYP3A4 inhibitor.
    Cabometyx: 60 mg/day PO; 80 mg/day PO if taking a strong CYP3A4 inducer and 40 mg/day PO if taking a strong CYP3A4 inhibitor.

    Geriatric

    Cometriq: 140 mg/day PO; 180 mg/day PO if taking a strong CYP3A4 inducer and 100 mg/day PO if taking a strong CYP3A4 inhibitor.
    Cabometyx: 60 mg/day PO; 80 mg/day PO if taking a strong CYP3A4 inducer and 40 mg/day PO if taking a strong CYP3A4 inhibitor.

    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:
    Cometriq capsules:
    Mild or moderate hepatic impairment (Child-Pugh class A or B): Reduce the starting dose of cabozantinib to 80 mg once daily.
    Severe hepatic impairment (Child-Pugh class C): The use of cabozantinib in patients with mevere hepatic impairment is not recommended as the pharmacokinetics in this patient population have not been evaluated.
    Cabometyx tablets:
    Mild or moderate hepatic impairment (Child-Pugh class A or B): Reduce the starting dose of cabozantinib to 40 mg once daily.
    Severe hepatic impairment (Child-Pugh class C): Cabozantinib is not recommended for use in patients with severe hepatic impairment.

    Renal Impairment

    Baseline Renal Impairment:
    Cometriq capsules and Cabometyx tablets: No cabozantinib dosage adjustment is recommended in patients with mild or moderate renal impairment. Cabozantinib clearance did not significantly change with creatinine clearance values 30 mL/min or higher in a population pharmacokinetic analysis. Specific guidelines for dosage adjustments in patients with severe renal impairment are not available.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Do not substitute cabozantinib tablets with cabozantinib capsules.
    Take cabozantinib on an empty stomach; do not eat for at least 2 hours before and at least 1 hour after taking cabozantinib.
    Swallow capsules and tablets whole; do not open or crush.
    Do not take cabozantinib with grapefruit juice or nutritional supplements that are known to inhibit CYP450.
    Do not take a missed dose within 12 hours of the next dose. If the next dose is in 12 hours or more, take the missed dose; if the next dose is in less than 12 hours, skip the missed dose and take the next dose at the scheduled time.

    STORAGE

    Cabometyx :
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    COMETRIQ:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Fistula, GI perforation

    Serious GI perforation and fistula have been reported with cabozantinib use; one patient death was attributed to a GI fistula. Fatal non-GI fistulas (i.e., tracheal/esophageal fistulas) have also occurred in cabozantinib-treated patients. Monitor patients for signs and symptoms of GI perforation and fistula. Permanently discontinue Cabometyx in patients who develop a fistula which cannot be appropriately managed or a GI perforation; Cometriq should be permanently discontinued in all patients with a perforation or fistula.

    Bleeding, GI bleeding

    Serious bleeding (e.g., GI bleeding, hemoptysis) has been reported with cabozantinib use; some cases were fatal. Cabozantinib capsules (Cometriq) carry a black box warning for hemorrhage. Monitor patients for signs and symptoms of bleeding. Do not use cabozantinib tablets (Cabometyx) in patients who have or are at risk for severe hemorrhage; Cometriq should not be given to patients with a recent history of bleeding or hemoptysis. Permanently discontinue therapy in patients who develop severe bleeding.

    Myocardial infarction, thromboembolic disease

    Serious arterial and venous thromboembolic disease has been reported with cabozantinib use, including fatalities. Permanently discontinue cabozantinib in patients who develop a serious arterial thromboembolic event such as myocardial infarction or any other arterial thromboembolic complication (e.g., cerebral infarction).

    Surgery, wound dehiscence

    Wound healing complications (e.g., wound dehiscence) have been reported with cabozantinib use. Therefore, temporary suspension of therapy is recommended at least 28 days before scheduled surgery, including dental surgery. Resume cabozantinib therapy based on clinical judgement of adequate wound healing. Hold therapy in patients who develop wound dehiscence or wound healing complications requiring medical intervention.

    Hypertension

    Hypertension has been reported with cabozantinib use. Monitor blood pressure prior to and regularly during cabozantinib treatment. Hold therapy in hypertensive patients not adequately controlled with medical management; resume therapy at a reduced cabozantinib dose. Permanently discontinue therapy if patients develop malignant hypertension, hypertensive crisis, or persistent uncontrolled hypertension despite optimal management.

    Dental disease, dental work

    An oral examination should be performed prior to starting cabozantinib therapy to evaluate patients for dental disease; good oral hygiene practices should be encouraged. Temporary suspension of therapy is recommended at least 28 days before invasive dental work or surgery. Resume cabozantinib therapy based on clinical judgement of adequate wound healing. Osteonecrosis of the jaw (ONJ) has been reported in cabozantinib-treated patients. Permanently discontinue cabozantinib capsules (Cometriq) in patients who develop ONJ.

    Skin disease

    Skin disease, specifically palmar-plantar erythrodysesthesia (hand and foot syndrome), has been reported with cabozantinib use. Hold therapy in patients who develop intolerable grade 2, or grade 3 or 4 hand and foot syndrome. Cabozantinib may be resumed at a reduced dose when toxicity has improved to grade 1.

    Proteinuria

    Proteinuria has been reported with cabozantinib use; one cabozantinib-treated patient developed nephrotic syndrome. Monitor urine protein regularly; permanently discontinue cabozantinib in patients who develop nephrotic syndrome.

    Diarrhea

    Severe diarrhea has also been reported with cabozantinib treatment. Patients with pre-existing diarrhea should be treated prior to receiving cabozantinib. Hold cabozantinib (Cabometyx) therapy for intolerable grade 2 diarrhea, or for grade 3 or higher diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to grade 1 or less; a dose reduction may be necessary. Patients with severe diarrhea should also be given fluid and electrolyte replacement if they become dehydrated.

    Encephalopathy

    Reversible Posterior Leukoencephalopathy Syndrome (RPLS), which is a syndrome of subcortical vasogenic edema also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been reported with cabozantinib use. Symptoms of RPSL include seizures, headache, visual disturbances, confusion, and altered mental status. Discontinue cabozantinib therapy if RPLS is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, fetal harm may occur if cabozantinib is administered during pregnancy based on animal studies. Females of reproductive potential should avoid becoming pregnant during cabozantinib therapy. Women who become pregnant while receiving cabozantinib should be apprised of the potential hazard to the fetus. Toxicities reported in pregnant rats included loss of pregnancy (at Cometriq exposures less than 1% and Cabometyx less than 0.12-fold those achieved with recommended dosing), delayed fetal ossifications, and skeletal variations (at Cometriq exposures less than 0.03% and Cabometyx less than 0.04-fold those achieved with recommended dosing). Visceral malformations, reduced spleen size, and missing lung lobe were reported in pregnant rabbits who received cabozantinib doses (3 mg/kg) that achieved about 11% Cometriq exposure and 1.1-fold Cabometyx exposure at the recommended human doses.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during cabozantinib treatment. Cabozantinib can be teratogenic if taken by the mother during pregnancy. Females and men with a female partner who is able to become pregnant should avoid pregnancy and use effective contraception during and for at least 4 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of cabozantinib. Women who become pregnant while receiving cabozantinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, cabozantinib may cause impaired fertility or infertility in both males and females. Decreased sperm count and reduced reproductive organ weight were reported in male rats at cabozantinib doses (2.5 mg/kg or higher) about equal to the Cometriq exposure and 13-fold greater than Cabometyx exposures observed with recommended human doses. A decrease in live embryos and significant pre- and post-implantation losses occurred in female rats at cabozantinib doses (1 mg/kg or higher) that achieved about 50% of the Cometriq exposure and 5-fold greater Cabometyx exposure than is observed with recommended human doses. In a 6-month repeat dose study, hypospermia and absence of corpus lutea were reported in male and female dogs at cabozantinib doses that resulted in AUC values equal to 6% and 3% of recommended human doses of Cometriq, respectively, and 0.5-fold (males) and < 0.1-fold (females) of the expected Cabometyx exposures in humans based on the recommended dose. Ovarian necrosis occurred in female rats who received cabozantinib at doses (5 mg/kg/day X 14 days) that achieved exposure about equal to that observed with recommended human doses.

    Breast-feeding

    It is not known if cabozantinib or cabozantinib metabolites are excreted into human milk. Due to the potential for serious adverse reactions in the nursing infant, women should avoid breast-feeding during treatment and for 4 months after the last dose.

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 11.0-16.0
    lymphopenia / Delayed / 0-16.0
    hypertension / Early / 8.0-15.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 8.0-13.0
    hypocalcemia / Delayed / 0-12.0
    fatigue / Early / 9.0-9.0
    hypophosphatemia / Delayed / 3.0-8.0
    hyponatremia / Delayed / 2.0-8.0
    thromboembolism / Delayed / 0.9-7.3
    hypomagnesemia / Delayed / 1.0-7.0
    elevated hepatic enzymes / Delayed / 2.0-6.0
    asthenia / Delayed / 4.0-6.0
    stomatitis / Delayed / 2.0-5.0
    anorexia / Delayed / 3.0-5.0
    oral ulceration / Delayed / 2.0-5.0
    weight loss / Delayed / 2.0-5.0
    anemia / Delayed / 0-5.0
    dysphagia / Delayed / 4.0-4.0
    tracheoesophageal fistula / Delayed / 4.0-4.0
    abdominal pain / Early / 3.0-4.0
    nausea / Early / 1.0-4.0
    hypertriglyceridemia / Delayed / 0-4.0
    GI perforation / Delayed / 0.9-3.0
    GI bleeding / Delayed / 0-3.0
    bleeding / Early / 2.1-3.0
    dyspnea / Early / 0-3.0
    neutropenia / Delayed / 2.0-3.0
    vomiting / Early / 2.0-2.0
    proteinuria / Delayed / 0-2.0
    hypoalbuminemia / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    dehydration / Delayed / 0-2.0
    gastrointestinal fistula / Delayed / 1.0-1.2
    constipation / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    rash (unspecified) / Early / 1.0-1.0
    erythema / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    osteonecrosis / Delayed / 0-1.0
    nephrotic syndrome / Delayed / 0-1.0
    headache / Early / 0-1.0
    arthralgia / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    dysphonia / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    leukoencephalopathy / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    hypokalemia / Delayed / 4.0
    wound dehiscence / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    visual impairment / Early / Incidence not known
    infection / Delayed / Incidence not known

    Moderate

    hypothyroidism / Delayed / 21.0-57.0
    hemorrhoids / Delayed / 9.0-9.0
    peripheral neuropathy / Delayed / 0-7.0
    hemoptysis / Delayed / 0-3.0
    impaired wound healing / Delayed / 0-2.0
    hepatitis / Delayed / 0-1.0
    osteomyelitis / Delayed / Incidence not known
    confusion / Early / Incidence not known

    Mild

    hair discoloration / Delayed / 0-34.0
    dysgeusia / Early / 24.0-34.0
    xerosis / Delayed / 11.0-19.0
    dizziness / Early / 11.0-14.0
    anxiety / Delayed / 0-9.0
    hyperkeratosis / Delayed / 0-7.0
    paresthesias / Delayed / 0-7.0
    maculopapular rash / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with abacavir is necessary, as plasma concentrations of cabozantinib may be increased. Abacavir is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with abacavir is necessary, as plasma concentrations of cabozantinib may be increased. Abacavir is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown. (Moderate) Monitor for an increase in dolutegravir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of dolutegravir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Abacavir; Lamivudine, 3TC: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with abacavir is necessary, as plasma concentrations of cabozantinib may be increased. Abacavir is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with abacavir is necessary, as plasma concentrations of cabozantinib may be increased. Abacavir is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Adefovir: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with adefovir is necessary, as plasma concentrations of cabozantinib may be increased. Adefovir is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Afatinib: (Moderate) If the concomitant use of cabozantinib and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of cabozantinib. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. Cabozantinib is a P-gp inhibitor; however, the clinical relevance of this finding is unknown. Administration of another P-gp inhibitor (ritonavir 200 mg twice daily for 3 days) 1 hour before administration of afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Aliskiren: (Moderate) Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Aliskiren; Amlodipine: (Moderate) Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Aliskiren; Valsartan: (Moderate) Monitor for an increase in aliskiren-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of aliskiren may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and aliskiren is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Amiodarone: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with amiodarone is necessary. Cabozantinib is primarily metabolized by CYP3A4 and amiodarone is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of atorvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Amobarbital: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and amobarbital is necessary. Cabozantinib is primarily metabolized by CYP3A4 and amobarbital is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid concomitant use of cabozantinib with clarithromycin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if clarithromycin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. (Minor) Monitor for an increase in lansoprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of lansoprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and lansoprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of cabozantinib with clarithromycin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if clarithromycin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. (Moderate) Monitor for an increase in omeprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of omeprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and omeprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Apixaban: (Moderate) Monitor for an increase in apixaban-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of apixaban may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and apixaban is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if cabozantinib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in cabozantinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Cabozantinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of cabozantinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Coadministration of cabozantinib with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Armodafinil: (Moderate) Monitor for an increase in armodafinil-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of armodafinil may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and armodafinil is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while armodafinil is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Aspirin, ASA; Omeprazole: (Moderate) Monitor for an increase in omeprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of omeprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and omeprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Atazanavir: (Severe) Atazanavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use atazanavir concomitantly with cabozantinib. Atazanavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration of cabozantinib with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Atazanavir; Cobicistat: (Severe) Atazanavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use atazanavir concomitantly with cabozantinib. Atazanavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration of cabozantinib with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with cobicistat is necessary. Cabozantinib is primarily metabolized by CYP3A4 and cobicistat is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of atorvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of atorvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid concomitant use of cabozantinib with phenobarbital due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if phenobarbital is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Azithromycin: (Moderate) Monitor for an increase in azithromycin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of azithromycin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and azithromycin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concomitant use of cabozantinib with phenobarbital due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if phenobarbital is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving cabozantinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving cabozantinib. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; cabozantinib inhibits P-gp.
    Bexarotene: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and bexarotene is necessary. Cabozantinib is primarily metabolized by CYP3A4 and bexarotene is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Boceprevir: (Severe) Boceprevir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use boceprevir concomitantly with cabozantinib. Boceprevir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration of cabozantinib with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and boceprevir is a substrate of P-gp in vitro. The clinical relevance of this finding is unknown; however, plasma concentrations of boceprevir may be increased.
    Bosentan: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and bosentan is necessary. Cabozantinib is primarily metabolized by CYP3A4 and bosentan is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Brigatinib: (Moderate) Monitor for decreased efficacy of cabozantinib if coadministration with brigatinib is necessary. Cabozantinib is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of cabozantinib may decrease. Coadministration with a strong CYP3A4 inducer decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77% in healthy subjects.
    Bromocriptine: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with bromocriptine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and bromocriptine is a CYP3A4 inhibitor in vitro. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Budesonide: (Moderate) Monitor for an increase in budesonide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of budesonide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and budesonide is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Budesonide; Formoterol: (Moderate) Monitor for an increase in budesonide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of budesonide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and budesonide is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Butabarbital: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and butabarbital is necessary. Cabozantinib is primarily metabolized by CYP3A4 and butabarbital is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Canagliflozin: (Moderate) Monitor for an increase in canagliflozin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of canagliflozin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and canagliflozin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Canagliflozin; Metformin: (Moderate) Monitor for an increase in canagliflozin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of canagliflozin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and canagliflozin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Avoid concomitant use of cabozantinib with carbamazepine due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if carbamazepine is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Carvedilol: (Moderate) Monitor for an increase in carvedilol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of carvedilol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and carvedilol is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Ceritinib: (Major) Avoid coadministration of ceritinib with cabozantinib due to increased cabozantinib exposure. If coadministration is unavoidable, monitor for cabozantinib-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and cabozantinib is primarily metabolized by CYP3A4. Administration of a strong CYP3A4 inhibitor increased single-dose plasma cabozantinib exposure by 38%. The strength of inhibition of CYP3A4 by ceritinib is unknown.
    Chloramphenicol: (Major) Avoid concomitant use of cabozantinib with chloramphenicol due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if chloramphenicol is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Cidofovir: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with cidofovir is necessary, as plasma concentrations of cabozantinib may be increased. Cidofovir is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Ciprofloxacin: (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with ciprofloxacin is necessary. Cabozantinib is primarily metabolized by CYP3A4 and ciprofloxacin is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Clarithromycin: (Major) Avoid concomitant use of cabozantinib with clarithromycin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if clarithromycin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Clobazam: (Moderate) Monitor for an increase in clobazam-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of clobazam may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and clobazam is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Clopidogrel: (Major) Cabozantinib may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and cabozantinib together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Cabozantinib is an inhibitor of CYP2C19. In addition, because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other drugs that affect hemostasis. Clopidogrel should be used cautiously in patients with thrombocytopenia following the administration of myelosuppressive antineoplastic agents or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding. Monitor for reduced efficacy of clopidogrel and for increased bleeding.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with cobicistat is necessary. Cabozantinib is primarily metabolized by CYP3A4 and cobicistat is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with cobicistat is necessary. Cabozantinib is primarily metabolized by CYP3A4 and cobicistat is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with cobicistat is necessary. Cabozantinib is primarily metabolized by CYP3A4 and cobicistat is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. (Moderate) Monitor for an increase in tenofovir, PMPA-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of cobimetinib may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and cobimetinib is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Colchicine: (Major) Monitor for an increase in colchicine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of colchicine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and colchicine is a substrate of P-gp with a narrow therapeutic index (NTI); the clinical relevance of this finding is unknown.
    Conivaptan: (Major) According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates such as cabozantinib should be avoided due to the risk of increased cabozantinib-related toxicities. Subsequent treatment with CYP3A substrates should be initiated no sooner than 1 week after completion of conivaptan therapy. If coadministration is absolutely necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day. Cabozantinib is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%
    Cyclosporine: (Moderate) Monitor for an increase in cabozantinib- and cyclosporine-related adverse events if concomitant use of cabozantinib and cyclosporine is necessary; consider closer monitoring of cyclosporine serum concentrations. Cabozantinib is primarily metabolized by CYP3A4 and cyclosporine is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and cyclosporine is a substrate of P-gp; plasma concentrations of cyclosporine may be increased. However, the clinical relevance of this finding is unknown.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with cabozantinib, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like cabozantinib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with cabozantinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and dabrafenib is necessary. Cabozantinib is primarily metabolized by CYP3A4 and dabrafenib is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Dalfopristin; Quinupristin: (Major) Avoid concomitant use of cabozantinib with dalfopristin; quinupristin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if dalfopristin; quinupristin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Danazol: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with danazol is necessary. Cabozantinib is primarily metabolized by CYP3A4 and danazol is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Dapagliflozin; Saxagliptin: (Moderate) Monitor for an increase in saxagliptin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of saxagliptin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and saxagliptin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Darunavir: (Major) Avoid concomitant use of cabozantinib with darunavir due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day. Resume the prior cabozantinib dose after 2 to 3 days if darunavir is discontinued. Additionally, monitor for a possible increase in darunavir-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and darunavir is a substrate of P-gp in vitro. The clinical relevance of this finding is unknown; however, plasma concentrations of darunavir may be increased.
    Darunavir; Cobicistat: (Major) Avoid concomitant use of cabozantinib with darunavir due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day. Resume the prior cabozantinib dose after 2 to 3 days if darunavir is discontinued. Additionally, monitor for a possible increase in darunavir-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and darunavir is a substrate of P-gp in vitro. The clinical relevance of this finding is unknown; however, plasma concentrations of darunavir may be increased. (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with cobicistat is necessary. Cabozantinib is primarily metabolized by CYP3A4 and cobicistat is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ombitasvir is a P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ombitasvir may be increased. Because ombitasvir is only available in products containing ritonavir, coadministration with cabozantinib is contraindicated due to the potential for ritonavir to increase cabozantinib concentrations. (Severe) Cabozantinib is a P-glycoprotein (P-gp) inhibitor and paritaprevir is a P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of paritaprevir may be increased. Because paritaprevir is only available in products containing ritonavir, coadministration with cabozantinib is contraindicated due to the potential for ritonavir to increase cabozantinib concentrations. (Severe) Ritonavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with cabozantinib. Ritonavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; ritonavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ritonavir may be increased and concentrations of cabozantinib further increased.
    Daunorubicin: (Major) Monitor for an increase in daunorubicin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of daunorubicin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and daunorubicin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Deferasirox: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and deferasirox is necessary. Cabozantinib is primarily metabolized by CYP3A4 and deferasirox is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Delavirdine: (Severe) Delavirdine is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use delavirdine concomitantly with cabozantinib. Delavirdine is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration of cabozantinib with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Desloratadine: (Minor) Monitor for an increase in desloratadine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of desloratadine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and desloratadine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Desloratadine; Pseudoephedrine: (Minor) Monitor for an increase in desloratadine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of desloratadine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and desloratadine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Dexamethasone: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and dexamethasone is necessary. Cabozantinib is primarily metabolized by CYP3A4 and dexamethasone is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and dexamethasone is a substrate of P-gp; plasma concentrations of dexamethasone may be increased. However, the clinical relevance of this finding is unknown.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in quinidine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of quinidine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and quinidine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as cabozantinib; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as cabozantinib; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Digoxin: (Moderate) Monitor serum digoxin concentrations and watch for an increase in digoxin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of digoxin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and digoxin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Diltiazem: (Moderate) Monitor for an increase in cabozantinib- and diltiazem-related adverse events if concomitant use of cabozantinib and diltiazem is necessary. Cabozantinib is primarily metabolized by CYP3A4 and diltiazem is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and diltiazem is a substrate of P-gp; plasma concentrations of diltiazem may be increased. However, the clinical relevance of this finding is unknown.
    Docetaxel: (Major) Monitor for an increase in docetaxel-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of docetaxel may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and docetaxel is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of dolutegravir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for an increase in dolutegravir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of dolutegravir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Doxorubicin: (Major) Monitor for an increase in doxorubicin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of doxorubicin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with cabozantinib is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; cabozantinib is a weak inhibitor of CYP2C9 and 3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with dronedarone is necessary. Cabozantinib is primarily metabolized by CYP3A4 and dronedarone is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Edoxaban: (Moderate) Coadministration of edoxaban and cabozantinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cabozantinib is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cabozantinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and efavirenz is necessary. Cabozantinib is primarily metabolized by CYP3A4 and efavirenz is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for an increase in tenofovir, PMPA-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir is a substrate of P-gp; the clinical relevance of this finding is unknown. (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and efavirenz is necessary. Cabozantinib is primarily metabolized by CYP3A4 and efavirenz is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Eletriptan: (Moderate) Monitor for an increase in eletriptan-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of eletriptan may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and eletriptan is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir, PMPA-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir, PMPA-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Enzalutamide: (Major) Avoid concomitant use of cabozantinib with enzalutamide if possible due to decreased plasma concentrations of cabozantinib. If concomitant use is unavoidable, increase the cabozantinib capsule (Cometriq) dose by 40 mg per day as tolerated (maximum daily dose, 180 mg); increase the cabozantinib tablet (Cabometyx) dose by 20 mg per day as tolerated (maximum daily dose, 80 mg). Resume the prior cabozantinib dose after 2 to 3 days if enzalutamide is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased cabozantinib exposure by 77%.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with cabozantinib is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both cabozantinib and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Cabozantinib is a weak CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%. Coadministration with cabozantinib may also increase erlotinib exposure.
    Erythromycin: (Moderate) Monitor for an increase in cabozantinib- and erythromycin-related adverse events if concomitant use of cabozantinib and erythromycin is necessary. Cabozantinib is primarily metabolized by CYP3A4 and erythromycin is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and erythromycin is a substrate of P-gp; plasma concentrations of erythromycin may be increased. However, the clinical relevance of this finding is unknown.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for an increase in cabozantinib- and erythromycin-related adverse events if concomitant use of cabozantinib and erythromycin is necessary. Cabozantinib is primarily metabolized by CYP3A4 and erythromycin is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and erythromycin is a substrate of P-gp; plasma concentrations of erythromycin may be increased. However, the clinical relevance of this finding is unknown.
    Eslicarbazepine: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and eslicarbazepine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and eslicarbazepine is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Desogestrel: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norethindrone: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norgestimate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ethinyl estradiol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ethinyl estradiol is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Etoposide, VP-16: (Moderate) Monitor for an increased incidence of etoposide-related adverse effects if concomitant use with cabozantinib is necessary, as plasma concentrations of etoposide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and etoposide, VP-16 is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Etravirine: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and etravirine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and etravirine is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Everolimus: (Moderate) Monitor for an increase in everolimus-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of everolimus may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and everolimus is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of simvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and simvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Fentanyl: (Moderate) Monitor for an increase in fentanyl-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of fentanyl may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and fentanyl is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Fexofenadine: (Minor) Monitor for an increase in fexofenadine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of fexofenadine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and fexofenadine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Fexofenadine; Pseudoephedrine: (Minor) Monitor for an increase in fexofenadine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of fexofenadine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and fexofenadine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Fluconazole: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with fluconazole is necessary. Cabozantinib is primarily metabolized by CYP3A4 and fluconazole is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Flutamide: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and flutamide is necessary. Cabozantinib is primarily metabolized by CYP3A4 and flutamide is a CYP3A4 inducer in vitro. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of umeclidinium may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and umeclidinium is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. (Moderate) Monitor for an increase in vilanterol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vilanterol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both umeclidinium and vilanterol are substrates of P-gp in vitro; the clinical relevance of this finding is unknown.
    Fluticasone; Vilanterol: (Moderate) Monitor for an increase in vilanterol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vilanterol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both umeclidinium and vilanterol are substrates of P-gp in vitro; the clinical relevance of this finding is unknown.
    Fosamprenavir: (Severe) Fosamprenavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use fosamprenavir concomitantly with cabozantinib. due to the risk of increased fosamprenavir exposure and either increased or decreased cabozantinib exposure. Cabozantinib is primarily metabolized by CYP3A4, and is also a P-glycoprotein (P-gp) inhibitor. Fosamprenavir is a strong CYP3A4 inhibitor, a moderate CYP3A inducer, and a P-gp substrate. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The clinical relevance of cabozantinib P-gp inhibition is unknown.
    Fosphenytoin: (Major) Avoid concomitant use of cabozantinib with fosphenytoin due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsules (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if fosphenytoin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Furosemide: (Major) Monitor for an increase in cabozantinib-related adverse events if concomitant use with furosemide is necessary, as plasma concentrations of cabozantinib may be increased. Furosemide is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and cabozantinib as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); cabozantinib is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and cabozantinib as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); cabozantinib is an inhibitor of P-gp.
    Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of glyburide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and glyburide is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of glyburide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and glyburide is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Grapefruit juice: (Major) Avoid concomitant use of cabozantinib with grapefruit juice due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if grapefruit juice is discontinued. Cabozantinib is primarily metabolized by CYP3A4. Grapefruit juice is a strong CYP3A4 inhibitor; however, the effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Griseofulvin: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and griseofulvin is necessary. Cabozantinib is primarily metabolized by CYP3A4 and griseofulvin is a CYP3A4 inducer in vitro. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Idelalisib: (Major) Avoid concomitant use of cabozantinib with idelalisib due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if idelalisib is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Imatinib: (Moderate) Monitor for an increase in cabozantinib- and imatinib, STI-571-related adverse events if concomitant use of cabozantinib and imatinib is necessary. Cabozantinib is primarily metabolized by CYP3A4 and imatinib is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and imatinib is a substrate of P-gp; plasma concentrations of imatinib may be increased. However, the clinical relevance of this finding is unknown.
    Indinavir: (Major) Avoid concomitant use of cabozantinib with indinavir due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if indinavir is discontinued. Additionally, monitor for a possible increase in indinavir-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and indinavir is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of indinavir may be increased.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with cabozantinib, a weak CYP3A4 inhibitor in vitro, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of irinotecan may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and irinotecan is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Isavuconazonium: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with isavuconazonium is necessary. Cabozantinib is primarily metabolized by CYP3A4 and isavuconazonium is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Isoniazid, INH: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with isoniazid, INH is necessary. Cabozantinib is primarily metabolized by CYP3A4 and isoniazid is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of cabozantinib with rifampin due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if rifampin is discontinued. Additionally, monitor for a possible increase in rifampin-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin (600 mg daily for 31 days) decreased cabozantinib (single dose) exposure by 77%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and rifampin is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of rifampin may be increased. (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with isoniazid, INH is necessary. Cabozantinib is primarily metabolized by CYP3A4 and isoniazid is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of cabozantinib with rifampin due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if rifampin is discontinued. Additionally, monitor for a possible increase in rifampin-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin (600 mg daily for 31 days) decreased cabozantinib (single dose) exposure by 77%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and rifampin is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of rifampin may be increased. (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with isoniazid, INH is necessary. Cabozantinib is primarily metabolized by CYP3A4 and isoniazid is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Itraconazole: (Major) Avoid concomitant use of cabozantinib during and for 2 weeks after itraconazole due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if itraconazole is discontinued. Additionally, monitor for a possible increase in itraconazole-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and itraconazole is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of itraconazole may be increased.
    Ketoconazole: (Major) Avoid concomitant use of cabozantinib with ketoconazole due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if ketoconazole is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor; coadministration of ketoconazole (400 mg daily for 27 days) increased cabozantinib (single dose) exposure by 38%.
    Lansoprazole: (Minor) Monitor for an increase in lansoprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of lansoprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and lansoprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Lansoprazole; Naproxen: (Minor) Monitor for an increase in lansoprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of lansoprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and lansoprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Ledipasvir; Sofosbuvir: (Moderate) Monitor for an increase in ledipasvir; sofosbuvir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ledipasvir and sofosbuvir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both ledipasvir and sofosbuvir are substrates of P-gp; the clinical relevance of this finding is unknown.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4, CYP2C8, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with cabozantinib, an inhibitor of CYP3A4, CYP2C8, and P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4, CYP2C8, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with cabozantinib, an inhibitor of CYP3A4, CYP2C8, and P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Severe) Lopinavir; ritonavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use lopinavir; ritonavir concomitantly with cabozantinib. Both lopinavir and ritonavir are strong CYP3A4 inhibitors. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; ritonavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ritonavir may be increased and concentrations of cabozantinib further increased. (Severe) Ritonavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with cabozantinib. Ritonavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; ritonavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ritonavir may be increased and concentrations of cabozantinib further increased.
    Loratadine: (Minor) Monitor for an increase in loratadine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of loratadine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and loratadine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Loratadine; Pseudoephedrine: (Minor) Monitor for an increase in loratadine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of loratadine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and loratadine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of lovastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and lovastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of lovastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and lovastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of cabozantinib with lumacaftor; ivacaftor due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if lumacaftor; ivacaftor is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of cabozantinib with lumacaftor; ivacaftor due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if lumacaftor; ivacaftor is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of maraviroc may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and maraviroc is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of mefloquine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and mefloquine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Mephobarbital: (Major) Avoid concomitant use of cabozantinib with mephobarbital due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if mephobarbital is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and mephobarbital is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Metformin; Saxagliptin: (Moderate) Monitor for an increase in saxagliptin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of saxagliptin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and saxagliptin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Methadone: (Moderate) Monitor for an increase in methadone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of methadone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and methadone is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Methohexital: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and methohexital is necessary. Cabozantinib is primarily metabolized by CYP3A4 and methohexital is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Methylprednisolone: (Moderate) Monitor for an increase in methylprednisolone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of methylprednisolone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and methylprednisolone is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Metyrapone: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and metyrapone is necessary. Cabozantinib is primarily metabolized by CYP3A4 and metyrapone is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Mifepristone, RU-486: (Major) The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Monitor for an increase in cabozantinib-related adverse events if concomitant use with mifepristone is necessary. Cabozantinib is primarily metabolized by CYP3A4 and mifepristone is a strong CYP3A4 inhibitor. Coadministration of cabozantinib with another strong CYP3A4 inhibitor increased cabozantinib exposure by 38%. Increased cabozantinib exposure may increase the risk of exposure-related toxicity. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors. Reduce the daily dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.
    Mirabegron: (Moderate) Monitor for an increase in mirabegron-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of mirabegron may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and mirabegron is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Mitomycin: (Moderate) Monitor for an increase in mitomycin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of mitomycin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and mitomycin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Mitotane: (Major) Avoid the chronic concomitant use of mitotane with cabozantinib; if coadministration cannot be avoided, monitor for decreased efficacy of cabozantinib. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if rifampin is discontinued. Mitotane is a strong CYP3A4 inducer and cabozantinib is primarily metabolized by CYP3A4; coadministration may result in decreased plasma concentrations of cabozantinib. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Modafinil: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and modafinil is necessary. Cabozantinib is primarily metabolized by CYP3A4 and modafinil is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of morphine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and morphine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of morphine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and morphine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Nefazodone: (Major) Avoid concomitant use of cabozantinib with nefazodone due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if nefazodone is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Nelfinavir: (Severe) Nelfinavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use nelfinavir concomitantly with cabozantinib. Nelfinavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration of cabozantinib with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Cabozantinib is has been shown to be a primary 3A4 substrate in-vitro. The plasma concentrations of cabozantinib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Cabozantinib has been shown to be a mild CYP3A4 inhibitor in-vitro. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
    Nevirapine: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and nevirapine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and nevirapine is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4. Cabozantinib is also a Multidrug Resistance Protein 2 (MRP2) substrate and nevirapine is an MRP2 inhibitor; plasma concentrations of cabozantinib may be increased. However, the clinical relevance of this finding is unknown.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of simvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and simvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Nicardipine: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with nicardipine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and nicardipine is a CYP3A4 inhibitor in vitro. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Nilotinib: (Moderate) Monitor for an increase in cabozantinib- and nilotinib-related adverse events if concomitant use of cabozantinib and nilotinib is necessary. Cabozantinib is primarily metabolized by CYP3A4 and nilotinib is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and nilotinib is a substrate of P-gp; plasma concentrations of nilotinib may be increased. However, the clinical relevance of this finding is unknown.
    Nintedanib: (Moderate) Monitor for an increase in nintedanib-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of nintedanib may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and nintedanib is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Octreotide: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with octreotide is necessary. Cabozantinib is primarily metabolized by CYP3A4; somastatin analogs such as octreotide decrease growth hormone secretion, which in turn may inhibit CYP3A4 enzyme function. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ombitasvir is a P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ombitasvir may be increased. Because ombitasvir is only available in products containing ritonavir, coadministration with cabozantinib is contraindicated due to the potential for ritonavir to increase cabozantinib concentrations. (Severe) Cabozantinib is a P-glycoprotein (P-gp) inhibitor and paritaprevir is a P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of paritaprevir may be increased. Because paritaprevir is only available in products containing ritonavir, coadministration with cabozantinib is contraindicated due to the potential for ritonavir to increase cabozantinib concentrations. (Severe) Ritonavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with cabozantinib. Ritonavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; ritonavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ritonavir may be increased and concentrations of cabozantinib further increased.
    Omeprazole: (Moderate) Monitor for an increase in omeprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of omeprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and omeprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for an increase in omeprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of omeprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and omeprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Ondansetron: (Moderate) Monitor for an increase in ondansetron-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ondansetron may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ondansetron is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Oxcarbazepine: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and oxcarbazepine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and oxcarbazepine is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of paclitaxel may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and paclitaxel is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Moderate) Monitor for an increase in paliperidone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of paliperidone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and paliperidone is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Panobinostat: (Moderate) Monitor for an increase in panobinostat-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of panobinostat may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and panobinostat is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Pantoprazole: (Moderate) Monitor for an increase in pantoprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of pantoprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and pantoprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Pazopanib: (Moderate) Monitor for an increase in pazopanib-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of pazopanib may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and pazopanib is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while pazopanib is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and pentobarbital is necessary. Cabozantinib is primarily metabolized by CYP3A4 and pentobarbital is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Phenobarbital: (Major) Avoid concomitant use of cabozantinib with phenobarbital due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if phenobarbital is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Phenytoin: (Major) Avoid concomitant use of cabozantinib with phenytoin due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsules (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if phenytoin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Posaconazole: (Major) Avoid concomitant use of cabozantinib with posaconazole due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if posaconazole is discontinued. Additionally, monitor for a possible increase in posaconazole-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and posaconazole is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of posaconazole may be increased.
    Prednisone: (Moderate) Monitor for an increase in prednisone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of prednisone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and prednisone is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Primidone: (Major) Avoid concomitant use of cabozantinib with primidone due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if primidone is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Probenecid: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with probenecid is necessary, as plasma concentrations of cabozantinib may be increased. Probenecid is a Multidrug Resistance Protein 2 (MRP2) inhibitor and cabozantinib is a substrate of MRP2; the clinical relevance of this finding is unknown.
    Quinidine: (Moderate) Monitor for an increase in quinidine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of quinidine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and quinidine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Quinine: (Major) Avoid the concomitant use of quinine with cabozantinib due to the risk of increased quinine exposure and either increased or decreased cabozantinib exposure. Cabozantinib is primarily metabolized by CYP3A4, and is also a P-glycoprotein (P-gp) inhibitor. Quinine is a CYP3A4 inducer and inhibitor, as well as a P-gp substrate. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The clinical relevance of cabozantinib P-gp inhibition is unknown.
    Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ranolazine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ranolazine is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ranolazine is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with cabozantinib is necessary, as the systemic exposure of cabozantinib may be increased resulting in an increase in cabozantinib-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and cabozantinib is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with cabozantinib is necessary, as the systemic exposure of cabozantinib may be increased resulting in an increase in cabozantinib-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and cabozantinib is a CYP3A4 substrate.
    Rifabutin: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and rifabutin is necessary. Cabozantinib is primarily metabolized by CYP3A4 and rifabutin is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Rifampin: (Major) Avoid concomitant use of cabozantinib with rifampin due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if rifampin is discontinued. Additionally, monitor for a possible increase in rifampin-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin (600 mg daily for 31 days) decreased cabozantinib (single dose) exposure by 77%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and rifampin is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of rifampin may be increased.
    Rifapentine: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and rifapentine is necessary. Cabozantinib is primarily metabolized by CYP3A4 and rifapentine is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Rifaximin: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and rifaximin is necessary. Cabozantinib is primarily metabolized by CYP3A4. Rifaximin is a CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and rifaximin is a substrate of P-gp in vitro; plasma concentrations of rifaximin may be increased. However, the clinical relevance of this finding is unknown.
    Riociguat: (Moderate) Monitor for an increase in riociguat-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of riociguat may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and riociguat is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Risperidone: (Moderate) Monitor for an increase in risperidone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of risperidone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and risperidone is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Ritonavir: (Severe) Ritonavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with cabozantinib. Ritonavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; ritonavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ritonavir may be increased and concentrations of cabozantinib further increased.
    Rivaroxaban: (Moderate) Monitor for an increase in rivaroxaban-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of rivaroxaban may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and rivaroxaban is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Romidepsin: (Moderate) Monitor for an increase in romidepsin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of romidepsin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and romidepsin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Saquinavir: (Major) Avoid concomitant use of cabozantinib with saquinavir due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if saquinavir is discontinued. Additionally, monitor for a possible increase in saquinavir-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; saquinavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of saquinavir may be increased and concentrations of cabozantinib further increased.
    Saxagliptin: (Moderate) Monitor for an increase in saxagliptin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of saxagliptin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and saxagliptin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Secobarbital: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and secobarbital is necessary. Cabozantinib is primarily metabolized by CYP3A4 and secobarbital is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Selexipag: (Moderate) Monitor for an increase in selexipag-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of selexipag may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and selexipag is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Silodosin: (Moderate) Monitor for an increase in silodosin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of silodosin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and silodosin is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Simeprevir: (Moderate) Monitor for an increase in simeprevir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of simeprevir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and simeprevir is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while simeprevir is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of simvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and simvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of simvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and simvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Moderate) Monitor for an increase in sirolimus-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of sirolimus may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and sirolimus is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Sofosbuvir: (Moderate) Monitor for an increase in ledipasvir; sofosbuvir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ledipasvir and sofosbuvir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both ledipasvir and sofosbuvir are substrates of P-gp; the clinical relevance of this finding is unknown.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in ledipasvir; sofosbuvir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ledipasvir and sofosbuvir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both ledipasvir and sofosbuvir are substrates of P-gp; the clinical relevance of this finding is unknown. (Moderate) Use caution when administering velpatasvir with cabozantinib. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); cabozantinib is an inhibitor of P-gp.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in ledipasvir; sofosbuvir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ledipasvir and sofosbuvir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both ledipasvir and sofosbuvir are substrates of P-gp; the clinical relevance of this finding is unknown. (Moderate) Use caution when administering velpatasvir with cabozantinib. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); cabozantinib is an inhibitor of P-gp.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of cabozantinib with St. John's Wort, Hypericum perforatum due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsule (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if St. John's Wort is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and St. John's Wort is a strong CYP3A4 inducer, although the effect varies widely and is preparation-dependent. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Streptogramins: (Major) Avoid concomitant use of cabozantinib with dalfopristin; quinupristin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if dalfopristin; quinupristin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Telithromycin: (Major) Avoid concomitant use of cabozantinib with telithromycin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if telithromycin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and cabozantinib is necessary, as the systemic exposure of cabozantinib may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of cabozantinib as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of cabozantinib if necessary. Cabozantinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and cabozantinib is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with cabozantinib is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate in vitro and cabozantinib is a P-gp inhibitor. The clinical relevance of P-gp inhibition by cabozantinib is unknown; however, P-gp inhibition is expected to increase temsirolimus (and active metabolite, sirolimus) exposure. Additionally, temsirolimus is a CYP3A4 substrate and cabozantinib is a weak CYP3A4 inhibitor in vitro. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of P-gp inhibitors or weak CYP3A4 inhibitors. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively.
    Teniposide: (Moderate) Monitor for an increase in teniposide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of teniposide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and teniposide is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir alafenamide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir alafenamide is a substrate of P-gp; the clinical relevance of this finding is unknown. When tenofovir alafenamide is administered in combination with cobicistat, other inhibitors of P-gp or BCRP are not expected to further increase tenofovir alafenamide concentrations. Cabozantinib is also a CYP3A4 and Multidrug Resistance Protein 2 (MRP2) substrate, while tenofovir alafenamide is an MRP2 inhibitor and weak CYP3A4 inhibitor in vitro. The effect of tenofovir alafenamide on CYP3A4 is not expected to be clinically relevant; MRP2 inhibition may result in increased plasma concentrations of cabozantinib, but the clinical relevance is unknown.
    Tenofovir, PMPA: (Moderate) Monitor for an increase in tenofovir, PMPA-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering cabozantinib. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C8, CYP2C9, CYP2C19, and CYP3A4; cabozantinib is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Testosterone: (Moderate) Monitor for an increase in testosterone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of testosterone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and testosterone is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Thiopental: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and thiopental is necessary. Cabozantinib is primarily metabolized by CYP3A4 and thiopental is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Ticagrelor: (Moderate) Monitor for an increase in ticagrelor-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ticagrelor may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ticagrelor is a substrate of P-gp; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while ticagrelor is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Tipranavir: (Severe) Tipranavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use tipranavir concomitantly with cabozantinib. Tipranavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and tipranavir is a substrate of P-gp. The clinical relevance of this finding is unknown; however, plasma concentrations of tipranavir may be increased.
    Tolvaptan: (Moderate) Monitor for an increase in tolvaptan-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tolvaptan may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tolvaptan is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Trabectedin: (Minor) Use caution if coadministration of trabectedin and cabozantinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, cabozantinib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Trandolapril; Verapamil: (Moderate) Monitor for an increase in cabozantinib- and verapamil-related adverse events if concomitant use of cabozantinib and verapamil is necessary. Cabozantinib is primarily metabolized by CYP3A4 and verapamil is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and verapamil is a substrate of P-gp; plasma concentrations of verapamil may be increased. However, the clinical relevance of this finding is unknown.
    Treprostinil: (Minor) Although pharmacokinetic drug interaction studies have not been conducted, coadministration of treprostinil and cabozantinib, a cytochrome P450 (CYP) 2C8 enzyme inhibitor, may result in increased treprostinil exposure. Human pharmacokinetic studies with oral treprostinil indicate that coadministration of gemfibrozil, another CYP2C8 inhibitor, results in increased exposure to treprostinil. The manufacturer of oral treprostinil recommends a reduction in the starting dose of oral treprostinil when coadministered with gemfibrozil. The clinical significance of this interaction with orally inhaled or parenteral treprostinil and other CYP2C8 inhibitors is unknown.
    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.
    Umeclidinium: (Moderate) Monitor for an increase in umeclidinium-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of umeclidinium may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and umeclidinium is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown.
    Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of umeclidinium may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and umeclidinium is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. (Moderate) Monitor for an increase in vilanterol-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vilanterol may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both umeclidinium and vilanterol are substrates of P-gp in vitro; the clinical relevance of this finding is unknown.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and cabozantinib. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; cabozantinib is a CYP3A4 and P-gp inhibitor and a P-gp substrate. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering cabozantinib at least 6 hours before venetoclax. If cabozantinib is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Verapamil: (Moderate) Monitor for an increase in cabozantinib- and verapamil-related adverse events if concomitant use of cabozantinib and verapamil is necessary. Cabozantinib is primarily metabolized by CYP3A4 and verapamil is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and verapamil is a substrate of P-gp; plasma concentrations of verapamil may be increased. However, the clinical relevance of this finding is unknown.
    Vinblastine: (Moderate) Monitor for an increase in vinblastine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vinblastine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and vinblastine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Vincristine Liposomal: (Moderate) Monitor for an increase in vincristine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vincristine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and vincristine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Vincristine: (Moderate) Monitor for an increase in vincristine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vincristine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and vincristine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Vinorelbine: (Moderate) Monitor for an increase in vinorelbine-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of vinorelbine may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and vinorelbine is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and cabozantinib. Vorapaxar is a CYP3A4 substrate. Cabozantinib inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with cabozantinib. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with voriconazole is necessary. Cabozantinib is primarily metabolized by CYP3A4 and voriconazole is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, fetal harm may occur if cabozantinib is administered during pregnancy based on animal studies. Females of reproductive potential should avoid becoming pregnant during cabozantinib therapy. Women who become pregnant while receiving cabozantinib should be apprised of the potential hazard to the fetus. Toxicities reported in pregnant rats included loss of pregnancy (at Cometriq exposures less than 1% and Cabometyx less than 0.12-fold those achieved with recommended dosing), delayed fetal ossifications, and skeletal variations (at Cometriq exposures less than 0.03% and Cabometyx less than 0.04-fold those achieved with recommended dosing). Visceral malformations, reduced spleen size, and missing lung lobe were reported in pregnant rabbits who received cabozantinib doses (3 mg/kg) that achieved about 11% Cometriq exposure and 1.1-fold Cabometyx exposure at the recommended human doses.

    It is not known if cabozantinib or cabozantinib metabolites are excreted into human milk. Due to the potential for serious adverse reactions in the nursing infant, women should avoid breast-feeding during treatment and for 4 months after the last dose.

    MECHANISM OF ACTION

    Cabozantinib is an oral multi-tyrosine kinase inhibitor that works by blocking abnormal tyrosine kinase proteins (RET, MET, VEGFR-1, VEGFR-2, VEGFR-3, KIT, TRKB, FLT-3, AXL, TIE-2, ROS1, TYRO3, and MER) associated with the growth and development of medullary thyroid cancer (MTC) and renal cell carcinoma. Cabozantinib inhibits these receptor tyrosine kinases (RTK) that are responsible for the control of many cellular functions including cell migration, metabolism, proliferation, and differentiation, as well as maintenance of the tumor microenvironment. RTK mutations are common in MTC, occurring in 30 to 50% of sporadic cases and almost all of hereditary cases. The RET gene mutation activation is associated with a predisposition to certain cancers including MTC; increased levels of RTKs are also found in renal cell cancers. Cabozantinib inhibited MET and VEGFR-2 phosphorylation in vitro and in tumor models in vivo. In mouse models, cabozantinib led to decreased tumor and endothelial cell proliferation and increased apoptosis and inhibition of breast, lung, and glioma tumor growth.

    PHARMACOKINETICS

    Cabozantinib is administered orally. It is highly bound to human plasma proteins (>= 99.7%). The mean volume of distribution (Vd) was 349 L, the mean clearance was 4.4 L/hour, and the predicted effective half-life was 55 hours following oral doses of cabozantinib (Cometriq) 140 mg/day administered to 289 patients with solid tumors including medullary thyroid cancer in a pharmacokinetic analysis. The manufacturer of Cabometyx reports the Vd as 319 L, clearance as 2.2 L/hour, and terminal half-life as 99 hours. Following a single oral dose of 14C-cabozantinib given to healthy subjects, about 81% of the total radioactivity was recovered, with 54% of the radioactivity in the feces (43% as unchanged drug) and 21% of the radioactivity in the urine. Unchanged cabozantinib was not detectable in the urine following a 72 hour collection.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A1, CYP2C8, CYP2C9, CYP2C19, CYP3A4, P-gp, MRP2
    Cabozantinib is metabolized in the liver and is a substrate of CYP3A4 in vitro; inhibition of CYP3A4 reduced the formation of the oxidative metabolite by > 80%. While cabozantinib is also a CYP2C9 substrate, inhibition of CYP2C9 had a minimal effect on metabolite formation (< 20%). Cabozantinib is a CYP2C8 inhibitor in vitro; however, the interaction was not found to be relevant in a clinical study. Because of this, less sensitive substrates of other pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, CYP3A4) were not evaluated and a clinically relevant effect is considered unlikely. Cabozantinib induces CYP1A1 mRNA; however, the clinical significance of this interaction is unknown. It is also a MRP2 substrate and P-glycoprotein (P-gp) inhibitor, but the clinical significance of these findings is unknown.

    Oral Route

    Following a single cabozantinib oral dose, the median time to peak plasma concentration (Tmax) was 2 to 5 hours in 289 patients with solid tumors including medullary thyroid cancer in a pharmacokinetic analysis. Following repeat oral cabozantinib 140 mg/day dosing, steady state was achieved by day 15 and the AUC increased to 4 to 5 times the values achieved with single doses by day 19. When a single cabozantinib 140-mg dose was administered with a high-fat meal in healthy subjects, the Cmax and AUC values were increased by 41% and 57%, respectively. Therefore, cabozantinib should be taken on an empty stomach.
    The Cmax of the tablet formulation of cabozantinib (Cabometyx) was 19% higher compared to the capsule formulation (Cometriq) after a single 140-mg dose; the AUC was less than 10% different between dosage forms. Do not substitute Cabometyx tablets with Cometriq capsules.