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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Multi-tyrosine kinase inhibitor
    Used for certain types of thyroid cancer, advanced renal cell carcinoma, hepatocellular carcinoma
    Do not give cabozantinib for at least 3 weeks before elective surgery or for at least 2 weeks after major surgery and until adequate wound healing has occurred

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

    140 mg orally once daily on an empty stomach until disease progression or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with cabozantinib led to a significantly improved median progression-free survival time (11.2 months vs. 4 months) 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 3 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 locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy in patients who are radioactive iodine-refractory or ineligible.
    Oral dosage (Cabometyx [tablets] only; do not substitute with Cometriq [capsules])
    Adults

    60 mg PO once daily on an empty stomach until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, phase 3 clinical trial (COSMIC-311), patients who were at least 16 years of age with locally advanced or metastatic DTC that had progressed following prior VEGFR-targeted therapy and were radioactive iodine-refractory or ineligible were randomized to treatment with cabozantinib tablets or placebo until disease progression or unacceptable toxicity. After a median follow-up of 6.2 months, treatment with cabozantinib significantly improved the median progression-free survival (PFS) compared with placebo (not reached vs. 1.9 months); an updated analysis without formal statistical testing reported a PFS of 11 months for cabozantinib-treated patients compared with 1.9 months for those who received placebo. The overall response rate was 15% on patients treated with cabozantinib compared with 0% in those who received placebo.

    Children and Adolescents 12 years and older with BSA 1.2 m2 or higher

    60 mg PO once daily on an empty stomach until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use of cabozantinib tablets in pediatric patients 12 years and older with DTC is supported by well-controlled studies in adults with additional population pharmacokinetic data demonstrating similar exposure at the recommended dose in adults and pediatric patients 12 years and older. In a multicenter, randomized, phase 3 clinical trial (COSMIC-311), patients who were at least 16 years of age with locally advanced or metastatic DTC that had progressed following prior VEGFR-targeted therapy and were radioactive iodine-refractory or ineligible were randomized to treatment with cabozantinib tablets or placebo until disease progression or unacceptable toxicity. After a median follow-up of 6.2 months, treatment with cabozantinib significantly improved the median progression-free survival (PFS) compared with placebo (not reached vs. 1.9 months); an updated analysis without formal statistical testing reported a PFS of 11 months for cabozantinib-treated patients compared with 1.9 months for those who received placebo. The overall response rate was 15% on patients treated with cabozantinib compared with 0% in those who received placebo.

    Children and Adolescents 12 years and older with BSA less than 1.2 m2

    40 mg PO once daily on an empty stomach until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Use of cabozantinib tablets in pediatric patients 12 years and older with DTC is supported by well-controlled studies in adults with additional population pharmacokinetic data demonstrating similar exposure at the recommended dose in adults and pediatric patients 12 years and older. In a multicenter, randomized, phase 3 clinical trial (COSMIC-311), patients who were at least 16 years of age with locally advanced or metastatic DTC that had progressed following prior VEGFR-targeted therapy and were radioactive iodine-refractory or ineligible were randomized to treatment with cabozantinib tablets or placebo until disease progression or unacceptable toxicity. After a median follow-up of 6.2 months, treatment with cabozantinib significantly improved the median progression-free survival (PFS) compared with placebo (not reached vs. 1.9 months); an updated analysis without formal statistical testing reported a PFS of 11 months for cabozantinib-treated patients compared with 1.9 months for those who received placebo. The overall response rate was 15% on patients treated with cabozantinib compared with 0% in those who received placebo.

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

    60 mg by mouth once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. First-line treatment with cabozantinib significantly improved median progression free survival (PFS) over sunitinib in intermediate- or poor-risk patients with metastatic renal cell cancer in a multicenter, randomized, open-label, phase 2 clinical trial (8.6 months vs. 5.6 months). The secondary endpoint of ORR was also improved (46% vs. 18%); overall survival data were not mature (30.3 months vs. 21.8 months). Treatments were similarly tolerated.

    For the treatment of relapsed or refractory advanced renal cell cancer.
    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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label clinical trial of patients with advanced renal cell cancer 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). In the total study population, median overall survival (21.4 months vs. 16.5 months) and confirmed objective response rate (ORR) (17% vs. 3%) were also significantly improved in cabozantinib-treated patients (n = 330) compared with those who received everolimus (n = 328).

    For the first-line treatment of advanced renal cell cancer, in combination with nivolumab.
    Oral dosage (tablets only; do not substitute with cabozantinib capsules)
    Adults

    40 mg PO once daily without food until disease progression or unacceptable toxicity. Administer in combination with nivolumab 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. First-line treatment with nivolumab plus cabozantinib significantly improved median progression-free survival (16.6 months vs. 8.3 months) compared with sunitinib in a randomized, open-label study; the median overall survival was also significantly improved, with the lower end of the confidence interval not reached in the nivolumab plus cabozantinib arm compared with 22.6 months in the sunitinib arm. The objective response rate was 55.7% (complete response, [8%]) versus 27.1% (CR, 4.6%), respectively.

    For the treatment of hepatocellular cancer in patients who have been previously treated with sorafenib.
    Oral dosage (tablets only; do not substitute with cabozantinib capsules)
    Adults

    60 mg by mouth once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized phase 3 clinical trial, treatment with cabozantinib significantly improved median overall survival and median progression-free survival compared with placebo in patients with advanced hepatocellular cancer that progressed on or after sorafenib therapy. Patients in the cabozantinib arm experienced approximately twice as many serious adverse reactions compared with placebo.[63362] [60738]

    MAXIMUM DOSAGE

    Adults

    Cometriq: 140 mg/day PO.
    Cabometyx: 60 mg/day PO.

    Geriatric

    Cometriq: 140 mg/day PO.
    Cabometyx: 60 mg/day PO.

    Adolescents

    Cabometyx: BSA 1.2 m2 or higher, 60 mg PO; BSA less than 1.2 m2, 40 mg PO.

    Children

    Cabometyx, 12 years and older: BSA 1.2 m2 or higher, 60 mg PO; BSA less than 1.2 m2, 40 mg PO.
    Less than 12 years: 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): Use not recommended.[52506]
    Cabometyx tablets:
    Mild hepatic impairment (Child-Pugh class A): Specific guidelines for dosage adjustments in mild hepatic impairment are not available; it appears that no dosage adjustments are needed.
    Moderate hepatic impairment (Child-Pugh class B): Reduce the starting dose of cabozantinib 60 mg once daily to 40 mg once daily for adults and pediatric patients with a BSA of 1.2 m2 or higher. Reduce the starting dose of cabozantinib 40 mg once daily to 20 mg once daily for pediatric patients with a BSA less than 1.2 m2.
    Severe hepatic impairment (Child-Pugh class C): Use not recommended.[60738]
     
    Treatment-Related Hepatotoxicity:
    In combination with nivolumab (Cabometyx tablets):
    AST or ALT level of more than 3 to 10 times the ULN with concurrent total bilirubin level less than 2 times the ULN: Hold nivolumab and cabozantinib and consider the use of corticosteroid therapy. Upon recovery to grade 1 or less, consider rechallenge with one or both of nivolumab and cabozantinib.
    AST or ALT level more than 10 times the ULN or more than 3 times the ULN with concurrent total bilirubin level 2 times the ULN or more: Permanently discontinue nivolumab and cabozantinib; consider the use of corticosteroid therapy.

    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

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    Emetic Risk
    Moderate/High
    Administer routine antiemetic prophylaxis prior to treatment.

    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 perforations and fistulas, including abscess and sepsis. Permanently discontinue cabozantinib in patients who develop a GI perforation or grade 4 fistula.

    Bleeding

    Severe bleeding has been reported with cabozantinib use; some cases were fatal. Discontinue cabozantinib at least 3 weeks prior to elective surgery. Monitor patients for signs and symptoms of bleeding. Do not use cabozantinib in patients who have a recent history of bleeding including hemoptysis, hematemesis, or melena. Permanently discontinue therapy in patients who develop grade 3 or 4 bleeding.[52506] [60738]

    Myocardial infarction, thromboembolism

    Serious arterial and venous thromboembolism has been reported with cabozantinib use; some cases were fatal. Permanently discontinue cabozantinib in patients who develop an acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention.[52506] [60738]

    Impaired wound healing, surgery

    Impaired wound healing has occurred in patients treated with cabozantinib. Discontinue cabozantinib at least 3 weeks prior to elective surgery; do not administer cabozantinib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming cabozantinib after resolution of wound healing complications has not been established.[52506] [60738]

    Hypertension

    Do not initiate cabozantinib therapy in patients with uncontrolled hypertension as treatment-emergent hypertension has occurred with cabozantinib use. Monitor blood pressure 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 for severe hypertension unable to be controlled with antihypertensive therapy and for hypertensive crisis.

    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 3 weeks before invasive dental work. Osteonecrosis of the jaw (ONJ) has been reported in cabozantinib-treated patients. If ONJ develops, hold cabozantinib therapy until it completely resolves and then resume treatment at a reduced dose.[52506] [60738]

    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; an interruption of therapy and dose reduction may be necessary for grade 2 or higher proteinuria. Permanently discontinue cabozantinib in patients who develop nephrotic syndrome.

    Diarrhea

    Severe diarrhea has been reported with cabozantinib treatment. Monitor patients and manage using antidiarrheals as indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.[60738]

    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.

    Hepatic disease, hepatotoxicity

    Avoid the use of cabozantinib in patients with severe hepatic disease (Child-Pugh C). Cabozantinib can cause elevated hepatic enzymes. Hepatotoxicity including grade 3 and 4 transaminitis is more common when cabozantinib is administered in combination with nivolumab compared to cabozantinib alone. Monitor hepatic function at baseline and periodically during treatment; consider more frequent monitoring when administered in combination with nivolumab. An interruption or discontinuation of therapy may be necessary; treatment with systemic corticosteroids may also be necessary when coadministered with nivolumab.

    Adrenal insufficiency

    Primary or secondary adrenal insufficiency can occur in patients treated with cabozantinib in combination with nivolumab. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency as clinically indicated. Both cabozantinib and nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.

    Thyroid disease

    Use cabozantinib with caution in patients with a history of thyroid disease. Thyroid dysfunction, primarily hypothyroidism, has been observed with cabozantinib treatment. Assess patients for signs of thyroid dysfunction at baseline as well as during treatment. Test thyroid function as clinically indicated and manage any thyroid dysfunction as appropriate.

    Hypocalcemia

    Hypocalcemia has been reported in patients treated with cabozantinib in clinical trials. Monitor blood calcium concentrations and replete as necessary during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of hypocalcemia.

    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, pregnancy testing, 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 of reproductive potential should avoid pregnancy and use effective contraception during and for at least 4 months after the last dose. These patients should undergo pregnancy testing prior to initiation of cabozantinib tablets. 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 less than0.1-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.[60738] [52506]

    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

    hypertension / Early / 8.0-28.0
    elevated hepatic enzymes / Delayed / 1.0-24.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 8.0-17.0
    lymphopenia / Delayed / 0-16.0
    diarrhea / Early / 7.0-16.0
    hypocalcemia / Delayed / 0-12.0
    fatigue / Early / 6.0-10.0
    hypophosphatemia / Delayed / 3.0-9.0
    hyponatremia / Delayed / 0-8.0
    thromboembolism / Delayed / 2.0-7.0
    asthenia / Delayed / 0-7.0
    hypomagnesemia / Delayed / 1.0-7.0
    neutropenia / Delayed / 2.0-7.0
    anorexia / Delayed / 3.0-6.0
    hypokalemia / Delayed / 0-6.0
    GI bleeding / Delayed / 0-5.0
    bleeding / Early / 3.0-5.0
    pulmonary embolism / Delayed / 2.0-5.0
    hypotension / Rapid / 0-5.0
    syncope / Early / 0-5.0
    weight loss / Delayed / 1.0-5.0
    anemia / Delayed / 2.5-5.0
    stomatitis / Delayed / 2.0-5.0
    oral ulceration / Delayed / 0-5.0
    nausea / Early / 1.0-4.0
    dysphagia / Delayed / 0-4.0
    abdominal pain / Early / 0-4.0
    back pain / Delayed / 0-4.0
    depression / Delayed / 0-4.0
    dehydration / Delayed / 0-4.0
    hypertriglyceridemia / Delayed / 0-4.0
    tracheoesophageal fistula / Delayed / 0-4.0
    renal failure (unspecified) / Delayed / 0-4.0
    skin ulcer / Delayed / 0-3.0
    proteinuria / Delayed / 0-3.0
    bone pain / Delayed / 0-3.0
    dyspnea / Early / 0-3.0
    GI perforation / Delayed / 0-3.0
    vomiting / Early / 0-2.0
    wound dehiscence / Delayed / 0-2.0
    rash / Early / 0-2.0
    hypoalbuminemia / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 0-2.0
    headache / Early / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    thrombocytopenia / Delayed / 0-2.0
    hyperamylasemia / Delayed / 0-2.0
    glossitis / Early / 0-2.0
    xerostomia / Early / 0-1.0
    constipation / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    erythema / Early / 0-1.0
    infection / Delayed / 0-1.0
    osteonecrosis / Delayed / 0-1.0
    nephrotic syndrome / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    dysphonia / Delayed / 0-1.0
    hyperkalemia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    leukoencephalopathy / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    hypothyroidism / Delayed / 0-1.0
    gastrointestinal fistula / Delayed / 0-1.0
    thrombosis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    hepatic failure / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    aortic dissection / Delayed / Incidence not known

    Moderate

    hemorrhoids / Delayed / 0-9.0
    peripheral neuropathy / Delayed / 0-7.0
    hepatitis / Delayed / 0-1.0
    confusion / Early / 0-1.0
    hemoptysis / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    osteomyelitis / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    hair discoloration / Delayed / 0-34.0
    dysgeusia / Early / 12.0-34.0
    xerosis / Delayed / 0-19.0
    alopecia / Delayed / 0-16.0
    dizziness / Early / 0-14.0
    anxiety / Delayed / 0-9.0
    hyperkeratosis / Delayed / 0-7.0
    paresthesias / Delayed / 0-7.0
    gastroesophageal reflux / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    dental pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Abacavir; Dolutegravir; Lamivudine: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with cabozantinib is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Abacavir; Lamivudine, 3TC: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Adefovir: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with adefovir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and adefovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Afatinib: (Moderate) If the concomitant use of cabozantinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cabozantinib. 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. Afatinib is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor 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 the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of cabozantinib and clarithromycin due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with clarithromycin 2 to 3 days after discontinuation of clarithromycin. Cabozantinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Apalutamide: (Major) Avoid coadministration of cabozantinib with apalutamide due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with apalutamide 2 to 3 days after discontinuation of apalutamide. Cabozantinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Atazanavir: (Major) Avoid concomitant use of cabozantinib and atazanavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with atazanavir 2 to 3 days after discontinuation of atazanavir. Cabozantinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Atazanavir; Cobicistat: (Major) Avoid concomitant use of cabozantinib and atazanavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with atazanavir 2 to 3 days after discontinuation of atazanavir. Cabozantinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of cabozantinib with phenobarbital due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with phenobarbital 2 to 3 days after discontinuation of phenobarbital. Cabozantinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking cabozantinib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and cabozantinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    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-glycoprotein (P-gp). Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Budesonide: (Minor) Monitor for an increase in budesonide-related adverse reactions if coadministration with cabozantinib is necessary. Budesonide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Budesonide; Formoterol: (Minor) Monitor for an increase in budesonide-related adverse reactions if coadministration with cabozantinib is necessary. Budesonide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Budesonide; Glycopyrrolate; Formoterol: (Minor) Monitor for an increase in budesonide-related adverse reactions if coadministration with cabozantinib is necessary. Budesonide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Avoid coadministration of cabozantinib with carbamazepine due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with carbamazepine 2 to 3 days after discontinuation of carbamazepine. Cabozantinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Carvedilol: (Minor) Monitor for an increase in carvedilol-related adverse reactions if coadministration with cabozantinib is necessary. Carvedilol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ceritinib: (Major) Avoid concomitant use of cabozantinib and ceritinib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ceritinib 2 to 3 days after discontinuation of ceritinib. Cabozantinib is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Chloramphenicol: (Major) Avoid concomitant use of cabozantinib and chloramphenicol due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with chloramphenicol 2 to 3 days after discontinuation of chloramphenicol. Cabozantinib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cidofovir: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with cidofovir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and cidofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Clarithromycin: (Major) Avoid concomitant use of cabozantinib and clarithromycin due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with clarithromycin 2 to 3 days after discontinuation of clarithromycin. Cabozantinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Cobicistat: (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Cobimetinib: (Minor) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with cabozantinib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Colchicine: (Minor) Monitor for an increase in colchicine-related adverse reactions if coadministration with cabozantinib is necessary. Colchicine is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Cyclosporine: (Minor) Monitor for an increase in cabozantinib- and cyclosporine-related adverse events if concomitant use of is necessary; consider closer monitoring of cyclosporine serum concentrations. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and cyclosporine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as cyclosporine; however, the clinical relevance of this finding is unknown.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with cabozantinib is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute 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 in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as dabigatran; however, the clinical relevance of this finding is unknown.
    Darunavir: (Major) Avoid concomitant use of cabozantinib and darunavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with darunavir 2 to 3 days after discontinuation of darunavir. Cabozantinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Darunavir; Cobicistat: (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Major) Avoid concomitant use of cabozantinib and darunavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with darunavir 2 to 3 days after discontinuation of darunavir. Cabozantinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Major) Avoid concomitant use of cabozantinib and darunavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with darunavir 2 to 3 days after discontinuation of darunavir. Cabozantinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Minor) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with cabozantinib is necessary. Dasabuvir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. (Minor) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of ombitasvir may be necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. (Minor) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of paritaprevir may be necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Delavirdine: (Major) Avoid concomitant use of cabozantinib and delavirdine due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with delavirdine 2 to 3 days after discontinuation of delavirdine. Cabozantinib is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Desogestrel; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Dexamethasone: (Minor) Monitor for an increase in dexamethasone-related adverse reactions if coadministration with cabozantinib is necessary. Dexamethasone is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Dextromethorphan; Quinidine: (Minor) Monitor for an increase in quinidine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of quinidine may be necessary. Quinidine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Digoxin: (Minor) Monitor for an increase in digoxin-related adverse reactions if coadministration with cabozantinib is necessary; monitor digoxin levels as clinically appropriate. Digoxin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Docetaxel: (Minor) Monitor for an increase in docetaxel-related adverse reactions if coadministration with cabozantinib is necessary. Docetaxel is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Dolutegravir: (Minor) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with cabozantinib is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Dolutegravir; Lamivudine: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with cabozantinib is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Dolutegravir; Rilpivirine: (Minor) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with cabozantinib is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Doxorubicin Liposomal: (Minor) Monitor for an increase in doxorubicin-related adverse reactions if coadministration with cabozantinib is necessary. Doxorubicin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Doxorubicin: (Minor) Monitor for an increase in doxorubicin-related adverse reactions if coadministration with cabozantinib is necessary. Doxorubicin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Drospirenone; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Efavirenz; Emtricitabine; Tenofovir: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Eletriptan: (Minor) 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Emtricitabine; Tenofovir disoproxil fumarate: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Enzalutamide: (Major) Avoid coadministration of cabozantinib with enzalutamide due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with enzalutamide 2 to 3 days after discontinuation of enzalutamide. Cabozantinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Erythromycin: (Minor) Monitor for an increase in erythromycin-related adverse reactions if coadministration with cabozantinib is necessary. Erythromycin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Erythromycin; Sulfisoxazole: (Minor) Monitor for an increase in erythromycin-related adverse reactions if coadministration with cabozantinib is necessary. Erythromycin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ethinyl Estradiol; Norelgestromin: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ethinyl Estradiol; Norgestrel: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Etonogestrel; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with cabozantinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Fosamprenavir: (Major) Avoid concomitant use of cabozantinib and fosamprenavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with fosamprenavir 2 to 3 days after discontinuation of fosamprenavir. Cabozantinib is a CYP3A substrate and fosamprenavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Fosphenytoin: (Major) Avoid coadministration of cabozantinib with fosphenytoin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with fosphenytoin 2 to 3 days after discontinuation of fosphenytoin. Cabozantinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Furosemide: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with furosemide is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and furosemide is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Glecaprevir; Pibrentasvir: (Minor) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with cabozantinib is necessary. Glecaprevir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. (Minor) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of pibrentasvir may be necessary. Pibrentasvir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Glyburide: (Minor) Monitor for an increase in glyburide-related adverse reactions, including hypoglycemia, if coadministration with cabozantinib is necessary. Glyburide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Glyburide; Metformin: (Minor) Monitor for an increase in glyburide-related adverse reactions, including hypoglycemia, if coadministration with cabozantinib is necessary. Glyburide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during cabozantinib treatment due to the risk of increased cabozantinib exposure and adverse reactions. Cabozantinib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
    Idelalisib: (Major) Avoid concomitant use of cabozantinib and idelalisib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with idelalisib 2 to 3 days after discontinuation of idelalisib. Cabozantinib is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Indinavir: (Major) Avoid concomitant use of cabozantinib and indinavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with indinavir 2 to 3 days after discontinuation of indinavir. Cabozantinib is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Irinotecan Liposomal: (Minor) Monitor for an increase in irinotecan-related adverse reactions if coadministration with cabozantinib is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Irinotecan: (Minor) Monitor for an increase in irinotecan-related adverse reactions if coadministration with cabozantinib is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of cabozantinib with rifampin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifampin 2 to 3 days after discontinuation of rifampin. Cabozantinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased single-dose cabozantinib exposure by 77%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of cabozantinib with rifampin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifampin 2 to 3 days after discontinuation of rifampin. Cabozantinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased single-dose cabozantinib exposure by 77%.
    Itraconazole: (Major) Avoid concomitant use of cabozantinib and itraconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with itraconazole 2 to 3 days after discontinuation of itraconazole. Cabozantinib is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Ketoconazole: (Major) Avoid concomitant use of cabozantinib and ketoconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ketoconazole 2 to 3 days after discontinuation of ketoconazole. Cabozantinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased cabozantinib exposure by 38%.
    Lamivudine, 3TC: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of cabozantinib and clarithromycin due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with clarithromycin 2 to 3 days after discontinuation of clarithromycin. Cabozantinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with cabozantinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with cabozantinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and cabozantinib is a P-gp inhibitor.
    Letermovir: (Moderate) Avoid coadministration of letermovir and cabozantinib in patients also receiving cyclosporine due to the risk of increased cabozantinib exposure; an interaction is not expected in patients taking letermovir and cabozantinib without cyclosporine. If concomitant use of cabozantinib with both letermovir and cyclosporine is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day); for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 100 mg/day or 100 mg/day to 60 mg/day). Resume the cabozantinib dose that was used prior to initiating treatment with letermovir and cyclosporine 2 to 3 days after discontinuation of either letermovir or cyclosporine. Cabozantinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased single-dose cabozantinib exposure by 38%.
    Levoketoconazole: (Major) Avoid concomitant use of cabozantinib and ketoconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ketoconazole 2 to 3 days after discontinuation of ketoconazole. Cabozantinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased cabozantinib exposure by 38%.
    Levonorgestrel; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Lonafarnib: (Major) Avoid concomitant use of cabozantinib and lonafarnib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with lonafarnib 2 to 3 days after discontinuation of lonafarnib. Cabozantinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Loperamide: (Minor) Monitor for an increase in loperamide-related adverse reactions, including decreased respirations and adverse cardiac events, if coadministration with cabozantinib is necessary. Loperamide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Coadministration of a single dose of loperamide with a single dose of other P-gp inhibitors increased loperamide plasma concentrations by 2 to 3-fold.
    Loperamide; Simethicone: (Minor) Monitor for an increase in loperamide-related adverse reactions, including decreased respirations and adverse cardiac events, if coadministration with cabozantinib is necessary. Loperamide is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Coadministration of a single dose of loperamide with a single dose of other P-gp inhibitors increased loperamide plasma concentrations by 2 to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of cabozantinib with lumacaftor; ivacaftor due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with lumacaftor; ivacaftor 2 to 3 days after discontinuation of lumacaftor; ivacaftor. Cabozantinib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of cabozantinib with lumacaftor; ivacaftor due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with lumacaftor; ivacaftor 2 to 3 days after discontinuation of lumacaftor; ivacaftor. Cabozantinib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Maraviroc: (Minor) Monitor for an increase in maraviroc-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of maraviroc may be necessary. Maraviroc is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Mefloquine: (Minor) Monitor for an increase in mefloquine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of mefloquine may be necessary. Mefloquine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Mephobarbital: (Major) Avoid coadministration of cabozantinib with mephobarbital due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with mephobarbital 2 to 3 days after discontinuation of mephobarbital. Cabozantinib is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Mifepristone: (Major) Avoid concomitant use of cabozantinib and mifepristone due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with mifepristone 2 to 3 days after discontinuation of mifepristone. Cabozantinib is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Mitotane: (Major) Avoid coadministration of cabozantinib with mitotane due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with mitotane 2 to 3 days after discontinuation of mitotane. Cabozantinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Morphine: (Minor) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with cabozantinib is necessary; a dose adjustment of morphine may be necessary. Morphine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Morphine; Naltrexone: (Minor) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with cabozantinib is necessary; a dose adjustment of morphine may be necessary. Morphine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Naldemedine: (Minor) Monitor for an increase in naldemedine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of naldemedine may be necessary. Naldemedine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with cabozantinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and cabozantinib is a P-gp inhibitor.
    Nefazodone: (Major) Avoid concomitant use of cabozantinib and nefazodone due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with nefazodone 2 to 3 days after discontinuation of nefazodone. Cabozantinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Nelfinavir: (Major) Avoid concomitant use of cabozantinib and nelfinavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with nelfinavir 2 to 3 days after discontinuation of nelfinavir. Cabozantinib is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Nevirapine: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Norethindrone; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Norgestimate; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Minor) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of ombitasvir may be necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. (Minor) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of paritaprevir may be necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of cabozantinib with rifabutin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifabutin 2 to 3 days after discontinuation of rifabutin. Cabozantinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer.
    Paclitaxel: (Minor) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of paclitaxel may be necessary. Paclitaxel is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Pazopanib: (Minor) Monitor for an increase in pazopanib-related adverse reactions if coadministration of with cabozantinib is necessary; a dose adjustment of pazopanib may be necessary. Pazopanib is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Phenobarbital: (Major) Avoid coadministration of cabozantinib with phenobarbital due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with phenobarbital 2 to 3 days after discontinuation of phenobarbital. Cabozantinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of cabozantinib with phenobarbital due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with phenobarbital 2 to 3 days after discontinuation of phenobarbital. Cabozantinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Phenytoin: (Major) Avoid coadministration of cabozantinib with phenytoin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with phenytoin 2 to 3 days after discontinuation of phenytoin. Cabozantinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Posaconazole: (Major) Avoid concomitant use of cabozantinib and posaconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with posaconazole 2 to 3 days after discontinuation of posaconazole. Cabozantinib is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Prednisone: (Minor) Monitor for an increase in prednisone-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of prednisone may be necessary. Prednisone is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Primidone: (Major) Avoid coadministration of cabozantinib with primidone due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with primidone 2 to 3 days after discontinuation of primidone. Cabozantinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Probenecid: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with probenecid is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and probenecid is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
    Probenecid; Colchicine: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with probenecid is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and probenecid is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in colchicine-related adverse reactions if coadministration with cabozantinib is necessary. Colchicine is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Quinidine: (Minor) Monitor for an increase in quinidine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of quinidine may be necessary. Quinidine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Quinine: (Minor) Monitor for an increase in quinine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of quinine may be necessary. Quinine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Ranolazine: (Minor) Monitor for an increase in ranolazine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral cabozantinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer cabozantinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral cabozantinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer cabozantinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor.
    Ribociclib: (Major) Avoid concomitant use of cabozantinib and ribociclib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ribociclib 2 to 3 days after discontinuation of ribociclib. Cabozantinib is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Ribociclib; Letrozole: (Major) Avoid concomitant use of cabozantinib and ribociclib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ribociclib 2 to 3 days after discontinuation of ribociclib. Cabozantinib is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Rifabutin: (Major) Avoid coadministration of cabozantinib with rifabutin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifabutin 2 to 3 days after discontinuation of rifabutin. Cabozantinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer.
    Rifampin: (Major) Avoid coadministration of cabozantinib with rifampin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifampin 2 to 3 days after discontinuation of rifampin. Cabozantinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased single-dose cabozantinib exposure by 77%.
    Rifapentine: (Major) Avoid coadministration of cabozantinib with rifapentine due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifapentine 2 to 3 days after discontinuation of rifapentine. Cabozantinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Rifaximin: (Moderate) Rifaximin is a substrate of P-gp and cabozantinib is a P-gp inhibitor. Coadministation may result in increased plasma concentrations of rifaximin; use caution. In patients with hepatic impairment, reduced drug metabolism may increase the effects of P-gp inhibition.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with cabozantinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and cabozantinib is a P-gp inhibitor.
    Ritonavir: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Romidepsin: (Minor) Monitor for an increase in romidepsin-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of romidepsin may be necessary. Romidepsin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Saquinavir: (Major) Avoid concomitant use of cabozantinib and saquinavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with saquinavir 2 to 3 days after discontinuation of saquinavir. Cabozantinib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with cabozantinib is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Silodosin: (Minor) Monitor for an increase in silodosin-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of silodosin may be necessary. Silodosin is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Simeprevir: (Minor) Monitor for an increase in simeprevir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of simeprevir may be necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Sirolimus: (Major) Avoid coadministration of sirolimus with cabozantinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and cabozantinib is a P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of cabozantinib with St. Johns Wort due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with St. Johns Wort 2 to 3 days after discontinuation of St. Johns Wort. Cabozantinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer, although the effect varies widely and is preparation-dependent. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with cabozantinib is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telithromycin: (Major) Avoid concomitant use of cabozantinib and telithromycin due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with telithromycin 2 to 3 days after discontinuation of telithromycin. Cabozantinib is a CYP3A substrate and telithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Temsirolimus: (Minor) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with cabozantinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Tenofovir Alafenamide: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Tenofovir, PMPA: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Ticagrelor: (Minor) Monitor for an increase in ticagrelor-related adverse reactions if coadministration with cabozantinib is necessary. Ticagrelor is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Tipranavir: (Major) Avoid concomitant use of cabozantinib and tipranavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with tipranavir 2 to 3 days after discontinuation of tipranavir. Cabozantinib is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Topotecan: (Major) Avoid coadministration of cabozantinib with oral topotecan due to increased topotecan exposure; cabozantinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp). Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Trandolapril; Verapamil: (Minor) Monitor for an increase in verapamil-related adverse reactions if coadministration with cabozantinib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Tucatinib: (Major) Avoid concomitant use of cabozantinib and tucatinib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with tucatinib 2 to 3 days after discontinuation of tucatinib. Cabozantinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with cabozantinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; cabozantinib is a P-gp inhibitor.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with cabozantinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of cabozantinib. Venetoclax is a P-glycoprotein (P-gp) substrate; cabozantinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Minor) Monitor for an increase in verapamil-related adverse reactions if coadministration with cabozantinib is necessary. Verapamil is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Vincristine Liposomal: (Moderate) Monitor for an increase in vincristine-related adverse reactions, including neurotoxicity and severe constipation, if coadministration of with cabozantinib is necessary. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as vincristine; however, the clinical relevance of this finding is unknown. The effect of concomitant use of P-gp inhibitors with vincristine has not been investigated, but it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Vincristine: (Moderate) Monitor for an increase in vincristine-related adverse reactions, including neurotoxicity and severe constipation, if coadministration of with cabozantinib is necessary. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as vincristine; however, the clinical relevance of this finding is unknown. The effect of concomitant use of P-gp inhibitors with vincristine has not been investigated, but it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Voriconazole: (Major) Avoid concomitant use of cabozantinib and voriconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with voriconazole 2 to 3 days after discontinuation of voriconazole. Cabozantinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.

    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% or more). 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 (less than 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.