Cabozantinib (Monograph)

Brand name: Cometriq
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA class: AN900
Chemical name: N′-[4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide
Molecular formula: C₂₈H₂₄FN₃O₅C₂₈H₂₄FN₃O₅•C₄H₆O₅
CAS number: 849217-68-1

Medically reviewed by Drugs.com on Jul 22, 2022. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.

Uses for Cabozantinib

Medullary Thyroid Cancer

Cometriq: Treatment of progressive, metastatic medullary thyroid cancer. Efficacy determined based on improved progression-free survival. Guidelines generally support the use of tyrosine kinase inhibitors, including cabozantinib, in the first-line treatment of progressive and metastatic medullary thyroid cancer.

Designated an orphan drug by the US FDA for this use.

Differentiated Thyroid Cancer

Cabometyx: Treatment of locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following VEGFR-targeted therapy in adult and pediatric patients ≥12 years of age who are refractory to or ineligible for radioactive iodine (iodine-131). Guidelines state that tyrosine kinase inhibitors should be considered in patients with metastatic radioactive iodine-refractory DTC that is rapidly progressive, symptomatic, and/or imminently threatening and not amenable to control with other approaches.

Renal Cell Carcinoma

Cabometyx: Single-agent for the treatment of patients with advanced renal cell carcinoma (RCC); first-line treatment in combination with nivolumab. Guidelines generally support the use of tyrosine kinase inhibitors, including cabozantinib, in patients with treatment-naive and treatment-experienced advanced RCC.

Hepatocellular Carcinoma

Cabometyx: Treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. Guidelines generally support second-line use of another tyrosine kinase inhibitor, including cabozantinib, in patients with HCC treated with sorafenib or lenvatinib in the first-line setting.

Designated an orphan drug by the US FDA for the treatment of patients with HCC.

Cabozantinib Dosage and Administration

General

Pretreatment Screening

• Assess for recent history of hemorrhage, including hemoptysis, hematemesis, or melena; do not use in patients with a history of these events.

• Blood pressure should be adequately controlled prior to initiating therapy. Do not initiate in patients with uncontrolled hypertension.

• Perform oral examination prior to initiating therapy.

• Verify pregnancy status of females of reproductive potential prior to initiation of therapy.

• The manufacturer of Cabometyx also recommends assessing for signs of thyroid dysfunction prior to the initiation of Cabometyx.

Patient Monitoring

• Monitor for signs and symptoms of GI perforation/fistula, including abscess and sepsis.

• Monitor blood pressure regularly during therapy.

• Perform oral examination periodically during therapy.

• Assess urine protein regularly during therapy.

• Monitor for hemorrhage.

• Monitor for arterial or venous thromboembolic events.

• The manufacturer of Cabometyx also recommends monitoring for signs and symptoms of thyroid dysfunction during Cabometyx therapy. Perform thyroid function testing and manage thyroid dysfunction as clinically indicated.

• The manufacturer of Cabometyx also recommends monitoring and correcting serum calcium levels as clinically indicated during Cabometyx therapy.

Other General Considerations

• Withhold cabozantinib ≥3 weeks prior to elective surgery, and for ≥2 weeks following major surgery and until adequate wound healing has occurred.

• Withhold cabozantinib ≥3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible.

• Maintain good oral hygiene during therapy.

• Clinicians should consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with cabozantinib tablets. When used in combination with nivolumab, the usual cautions, precautions, and contraindications associated with nivolumab must be considered in addition to those associated with cabozantinib tablets.

Administration

Oral Administration

Cabozantinib S-malate is administered orally as capsules (Cometriq) or tablets (Cabometyx).

Cometriq capsules: Administer orally once daily. Do not administer with food; do not eat for ≥2 hours before and ≥1 hour after taking cabozantinib capsules. Swallow capsules whole with a full glass (at least 240 mL) of water; do not open or crush capsules.

Cabometyx tablets: Administer orally once daily. The drug should not be administered with food; patients should not eat for ≥2 hours before and ≥1 hour after taking cabozantinib tablets. Cabozantinib tablets should be swallowed whole; the tablets should not be crushed.

If a dose of cabozantinib is missed, do not take the missed dose within 12 hours of the next dose.

Dosage

Available as cabozantinib S-malate; dosage expressed in terms of cabozantinib.

Cometriq capsules and Cabometyx tablets are not interchangeable.

Pediatric Patients

Differentiated Thyroid Cancer

Oral

Cabometyx in pediatric patients ≥12 years of age and a BSA ≥1.2 m²: 60 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Cabometyx in pediatric patients ≥12 years of age and a BSA <1.2 m²: 40 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Withhold cabozantinib tablets (Cabometyx) if intolerable grade 2 adverse reactions, grade 3 or 4 adverse reactions, or osteonecrosis of the jaw (ONJ) occurs.

Upon resolution or improvement of the adverse effect (i.e., return to baseline or resolution to grade 1), the dosage should be reduced; however, in some cases, the drug should be permanently discontinued. (See Tables 1 and 2.)

If previously receiving lowest dosage, resume therapy at same dosage. If lowest dosage not tolerated, discontinue cabozantinib tablets.

If an adverse reaction occurs during therapy with cabozantinib tablets, modify dosage accordingly (see Table 2).

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Oral

Avoid concomitant use with drugs that are potent inhibitors of CYP3A4. If concomitant use cannot be avoided, reduce daily dosage of cabozantinib tablets (Cabometyx) by 20 mg (e.g., from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily, or from 20 mg daily to 20 mg every other day in pediatric patients with BSA <1.2 m²). If concomitant use of the potent CYP3A4 inhibitor is discontinued, return dosage of cabozantinib tablets to the dosage used prior to initiation of the potent CYP3A4 inhibitor 2–3 days following discontinuance of the potent CYP3A4 inhibitor.

Avoid concomitant use of potent CYP3A4 inducers in patients receiving cabozantinib tablets. Foods or dietary supplements (e.g., St. John's wort [Hypericum perforatum]) known to induce CYP3A4 activity should be avoided during therapy with the drug. If concomitant use of a potent CYP3A4 inducer cannot be avoided, increase daily dosage of cabozantinib tablets (Cabometyx) by 20 mg (e.g., from 60 mg to 80 mg daily, or from 40 mg to 60 mg daily) as tolerated. If concomitant use of the potent CYP3A4 inducer is discontinued, return dosage of cabozantinib tablets to the dosage used prior to initiation of the potent CYP3A4 inducer 2–3 days following discontinuance of the potent CYP3A4 inducer. Daily dosage of cabozantinib tablets should not exceed 80 mg.

Adults

Medullary Thyroid Cancer

Oral

Cometriq: 140 mg (one 80-mg and three 20-mg capsules) once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Differentiated Thyroid Cancer

Oral

Cabometyx in adults with BSA ≥1.2 m²: 60 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Renal Cell Carcinoma

Monotherapy

Oral

Cabometyx: 60 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Combination Therapy with Nivolumab

Oral

Cabometyx: 40 mg once daily. Administer in combination with nivolumab 240 mg every 2 weeks (as a 30-minute IV infusion) or 480 mg every 4 weeks (as a 30-minute IV infusion). Continue therapy for up to 2 years or until disease progression or unacceptable toxicity occurs.

Hepatocellular Carcinoma

Oral

Cabometyx: 60 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Cabometyx

Oral

Withhold cabozantinib tablets (Cabometyx) if intolerable grade 2 adverse reactions, grade 3 or 4 adverse reactions, or ONJ occur.

Upon resolution or improvement of the adverse effect (i.e., return to baseline or resolution to grade 1), the dosage should be reduced; however, in some cases, the drug should be permanently discontinued. (See Tables 2, 3, and 4.)

If previously receiving lowest dosage, resume therapy at same dosage. If lowest dosage not tolerated, discontinue cabozantinib tablets.

If an adverse reaction occurs during therapy with cabozantinib tablets, follow recommendations for dosage modification in pediatric patients (see Table 2).

If hepatotoxicity occurs when cabozantinib tablets (Cabometyx) are used in combination with nivolumab, the dosage of cabozantinib tablets should be reduced as described in Table 4. When used in combination with nivolumab, the recommended dosage modifications, usual cautions, precautions, and contraindications associated with nivolumab must be considered in addition to those associated with cabozantinib tablets.

Cometriq

Oral

If grade 4 hematologic adverse effects, grade 3 or greater nonhematologic adverse effects, intolerable grade 2 adverse effects, or osteonecrosis of the jaw (ONJ) occurs, withhold cabozantinib capsules. Upon resolution or improvement of the adverse effect (i.e., return to baseline or resolution to grade 1), reduce dosage as follows: in patients previously receiving 140 mg daily, resume therapy at a dosage of 100 mg daily; in patients previously receiving 100 mg daily, resume therapy at a dosage of 60 mg daily; and in patients previously receiving 60 mg daily, resume therapy at a dosage of 60 mg daily, if tolerated. Otherwise, discontinue cabozantinib capsules.

Permanently discontinue cabozantinib capsules in patients who develop GI perforation or grade 4 fistula formation, severe hemorrhage, arterial (e.g., MI) or venous thromboembolic events, nephrotic syndrome, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, or reversible posterior leukoencephalopathy syndrome.

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Cabometyx

Oral

Avoid concomitant with drugs that are potent inhibitors of CYP3A4. If concomitant use cannot be avoided, reduce daily dosage of cabozantinib tablets by 20 mg (e.g., from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily). If concomitant use of the potent CYP3A4 inhibitor is discontinued, return dosage of cabozantinib tablets to the dosage used prior to initiation of the potent CYP3A4 inhibitor 2–3 days following discontinuance of the potent CYP3A4 inhibitor.

Avoid concomitant use of potent CYP3A4 inducers in patients receiving cabozantinib tablets. Foods or dietary supplements (e.g., St. John's wort [Hypericum perforatum]) known to induce CYP3A4 should be avoided during therapy with the drug. If concomitant use of a potent CYP3A4 inducer cannot be avoided, increase daily dosage of cabozantinib tablets by 20 mg (e.g., from 60 mg to 80 mg daily, or from 40 mg to 60 mg daily) as tolerated. If concomitant use of the potent CYP3A4 inducer is discontinued, return dosage of cabozantinib tablets to the dosage used prior to initiation of the potent CYP3A4 inducer 2–3 days following discontinuance of the potent CYP3A4 inducer. Daily dosage of cabozantinib tablets should not exceed 80 mg.

Cometriq

Oral

Avoid concomitant use of cabozantinib capsules with drugs that are potent inhibitors of CYP3A4. If concomitant use of a potent CYP3A4 inhibitor cannot be avoided, reduce daily dosage of cabozantinib capsules by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily). If concomitant use of the potent CYP3A4 inhibitor is discontinued, return dosage of cabozantinib capsules to the dosage used prior to initiation of the potent CYP3A4 inhibitor 2–3 days following discontinuance of the potent CYP3A4 inhibitor.

Avoid chronic concomitant use of potent inducers of CYP3A4 in patients receiving cabozantinib capsules. Foods or dietary supplements (e.g., St. John's wort [Hypericum perforatum]) that are known to induce CYP3A4 should not be ingested during therapy with the drug. If concomitant use of a potent CYP3A4 inducer cannot be avoided, increase daily dosage of cabozantinib capsules by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated. If concomitant use of the potent CYP3A4 inducer is discontinued, return dosage of cabozantinib capsules to the dosage used prior to initiation of the potent CYP3A4 inducer 2–3 days following discontinuance of the potent CYP3A4 inducer. Daily dosage of cabozantinib capsules should not exceed 180 mg.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment: Recommended initial dosage of cabozantinib capsules (Cometriq) is 80 mg.

Moderate hepatic impairment (Child-Pugh class B): Reduce initial dosage of cabozantinib tablets (Cabometyx) from 60 mg daily to 40 mg daily or, in pediatric patients with a BSA <1.2 m², from 40 mg daily to 20 mg daily.

Renal Impairment

No dosage adjustment necessary in patients with mild or moderate renal impairment. No experience in patients with severe renal impairment; no specific dosage recommendations at this time in such patients.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Cabozantinib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Perforations and Fistulas

GI perforations and fistulas, including serious and fatal cases, reported in 1–3 and 1% of patients receiving cabozantinib, respectively. Non-GI fistulas, including tracheal/esophageal, reported in 4% of patients receiving cabozantinib capsules (Cometriq); two cases (1%) were fatal.

Monitor patients for symptoms of perforations and fistulas. Permanently discontinue cabozantinib in patients who develop a GI perforation or fistula.

Hemorrhage

Serious, sometimes fatal, hemorrhage, including hemoptysis and GI hemorrhage, reported. Incidence of grade 3 or greater adverse hemorrhagic events was higher in patients receiving cabozantinib capsules (Cometriq) compared with those receiving placebo (3 versus 1%, respectively). Grade 3 to 5 hemorrhagic events occurred in 5% of patients receiving cabozantinib tablets (Cabometyx) for the treatment of renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), or differentiated thyroid cancer (DTC).

Monitor patients for signs and symptoms of bleeding. Do not use in patients with severe hemorrhage or a recent history of hemorrhage, hemoptysis, hematemesis, or melena. Discontinue therapy prior to surgery or if grade 3 or 4 hemorrhage occurs.

Thromboembolic Events

Increased risk of thromboembolic events. Venous thromboembolism and arterial thromboembolism reported.

Permanently discontinue cabozantinib in patients who develop an acute MI or arterial or venous thromboembolic event that requires medical intervention.

Impaired Wound Healing

Wound-healing complications reported.

Discontinue cabozantinib ≥3 weeks prior to elective surgery, including invasive dental procedures. Resume therapy ≥2 weeks following major surgery based on clinical judgment of adequate wound healing. Safety of resuming cabozantinib after resolution of wound healing complications has not been established.

Hypertension

Increased incidence of treatment-induced hypertension. Stage 1 or 2 hypertension occurred in 61% of patients receiving cabozantinib capsules (Cometriq) compared with 30% of those receiving placebo in the phase 3 clinical study; none of the patients developed malignant hypertension. Hypertension reported in 37% of patients receiving cabozantinib tablets (Cabometyx); grade 3 or 4 hypertension occurred in 16% and <1% of patients, respectively.

Do not initiate cabozantinib in patients with uncontrolled hypertension. Monitor BP prior to initiation of and periodically during therapy. Withhold cabozantinib for hypertension not adequately controlled with medical management; when controlled, resume therapy at a reduced dosage. Permanently discontinue cabozantinib for hypertensive crisis, or persistent uncontrolled hypertension despite optimal medical management.

Osteonecrosis of the Jaw (ONJ)

ONJ reported. May manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or delayed healing of the mouth or jaw after dental surgery.

Perform an oral examination prior to initiation of and periodically during therapy. Advise patients to maintain good oral hygiene.

For invasive dental procedures, withhold cabozantinib for ≥3 weeks prior to scheduled surgery, if possible. If ONJ occurs, withhold until complete resolution of ONJ.

Resume cabozantinib tablets (Cabometyx) at a reduced dosage following resolution of ONJ.

Diarrhea

Diarrhea reported in 62–63% of patients receiving cabozantinib therapy; grade 3–4 diarrhea reported in 10–16% of patients.

Withhold cabozantinib until diarrhea improves to grade 1, and then resume the drug at a reduced dosage. When resuming cabozantinib capsules (Cometriq), reduce dosage only for intolerable grade 2 diarrhea, grade 3 diarrhea unresponsive to standard antidiarrheal therapy, or grade 4 diarrhea.

Palmar-plantar Erythrodysesthesia Syndrome

Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) reported in 45–50% of cabozantinib-treated patients, which was severe (grade 3 or greater) in 13% of patients. Hand-foot skin reaction with subungual splinter hemorrhages and hypertension reported in at least one patient.

If palmar-plantar erythrodysesthesia syndrome occurs, temporary interruption of cabozantinib and dosage reduction may be necessary.

Proteinuria

Proteinuria, including one patient with nephrotic syndrome, reported.

Regularly monitor urine protein during therapy. Permanently discontinue cabozantinib in patients who develop nephrotic syndrome. If proteinuria occurs, temporary interruption of cabozantinib and dosage reduction may be necessary.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS reported in one patient receiving cabozantinib.

Consider possible RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Magnetic resonance imaging (MRI) is necessary to confirm diagnosis. Permanently discontinue cabozantinib in patients who develop RPLS.

Hepatotoxicity

Higher frequency of grade 3 or 4 hepatotoxicity and elevated ALT/AST concentrations in patients receiving cabozantinib tablets (Cabometyx) in combination with nivolumab compared with cabozantinib alone.

Withhold cabozantinib tablets (Cabometyx) and resume at a reduced dosage based on severity. Monitor liver enzymes prior to and periodically during therapy; more frequent monitoring should be considered when cabozantinib is used in combination with nivolumab. For elevated liver enzymes, temporarily interrupt therapy with cabozantinib tablets (Cabometyx) and nivolumab and consider administration of systemic corticosteroids.

Adrenal Insufficiency

Primary or secondary adrenal insufficiency reported in patients receiving cabozantinib tablets (Cabometyx) in combination with nivolumab. In clinical trials, management of adrenal insufficiency included systemic corticosteroids, temporary interruption of cabozantinib and nivolumab combination therapy, and/or hormone replacement therapy.

For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement therapy, as clinically indicated. Withhold cabozantinib (Cabometyx) and/or nivolumab therapy and resume cabozantinib (Cabometyx) at a reduced dosage depending on severity.

Thyroid Dysfunction

Thyroid dysfunction, primarily hypothyroidism, reported in patients receiving cabozantinib tablets (Cabometyx).

Assess patients for signs of thyroid dysfunction prior to initiation of cabozantinib (Cabometyx); monitor for signs and symptoms of thyroid dysfunction during treatment and manage as clinically indicated.

Hypocalcemia

Hypocalcemia reported in patients receiving cabozantinib tablets (Cabometyx).

Monitor serum calcium levels and replace calcium as necessary. Withhold cabozantinib (Cabometyx) therapy and resume at reduced dosage following recovery of hypocalcemia or permanently discontinue depending on severity.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic, fetotoxic, and teratogenic in animals.

Females of reproductive potential should be advised to use an effective method of contraception while receiving the drug and for ≥4 months after discontinuance of therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status prior to initiation of the drug in females of reproductive potential and advise such females to use effective contraceptive methods while receiving the drug and for 4 months after the last dose. Apprise patients of the potential hazard to the fetus if the drug is used during pregnancy.

Lactation

Not known whether cabozantinib or its metabolites are distributed into human milk. Effects of the drug on breast-fed infants or on the production of milk are unknown. Women should not breast-feed during therapy and for 4 months after the last dose.

Females and Males of Reproductive Potential

Females of reproductive potential should be advised to use an effective method of contraception while receiving cabozantinib and for ≥4 months after the last dose.

No data on the effect of cabozantinib on human fertility. Cabozantinib impaired male and female fertility in animal studies.

Pediatric Use

Safety and effectiveness of cabozantinib tablets (Cabometyx) for the treatment of differentiated thyroid cancer (DTC) established in pediatric patients aged ≥12 years; safety and effectiveness not established in patients <12 years of age.

Geriatric Use

Cometriq: Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults. Pharmacokinetics not affected by age in adults (20–86 years of age).

Cabometyx: No overall differences in safety or effectiveness were observed between patients ≥65 years of age and younger patients.

Hepatic Impairment

Mild to moderate hepatic impairment: Increased exposure to cabozantinib observed.

Severe (Child-Pugh class C) hepatic impairment: Not studied.

Cometriq: In patients with mild to moderate hepatic impairment, the recommended initial dosage of cabozantinib capsules (Cometriq) is 80 mg. Use not recommended in patients with severe hepatic impairment.

Cabometyx: In patients with moderate hepatic impairment (Child-Pugh class B), the initial dosage of cabozantinib tablets (Cabometyx) should be reduced from 60 mg daily to 40 mg daily or, in pediatric patients with a BSA <1.2 m², the initial dosage should be reduced from 40 mg daily to 20 mg daily. Avoid use in patients with severe hepatic impairment.

Renal Impairment

Severe renal impairment (eGFR <29 mL/minute per 1.73 m² as estimated by Modification of Diet in Renal Disease equation) or in those requiring dialysis: Not studied.

Dosage adjustment of cabozantinib not recommended in patients with mild or moderate renal impairment.

Common Adverse Effects

Cometriq (incidence ≥25%): Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), weight loss, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST concentrations, increased ALT concentrations, lymphopenia, increased alkaline phosphatase concentrations, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia.

Cabometyx (incidence ≥20%): Diarrhea, fatigue, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

Cabometyx in combination with nivolumab (incidence ≥20% ): Diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, upper respiratory tract infection.

Drug Interactions

Metabolized in liver by CYP3A4; substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced formation of N-oxide metabolite by >80%; inhibition of CYP2C9 had minimal effects on metabolite formation (i.e., <20% reduction). Inhibition of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 2E1 had no effect on metabolite formation.

In vitro, inhibitor of CYP2C8, but not an inhibitor of CYP isoenzymes 1A2 or 2D6.

Inducer of CYP1A1 messenger RNA (mRNA) in human hepatocyte incubations, but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 mRNA or isoenzyme-associated enzyme activities.

Inhibitor, but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system. In vitro, substrate of MRP2.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of cabozantinib). Avoid concomitant use if alternative therapy is available. If concomitant therapy cannot be avoided, reduce daily dosage of cabozantinib capsules (Cometriq) by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily) and the daily dosage of cabozantinib tablets (Cabometyx) by 20 mg (e.g., from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily, or from 20 mg daily to 20 mg every other day in pediatric patients with BSA <1.2 m²). If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib therapy (2–3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor.

Potent CYP3A4 inducers: Possible pharmacokinetic interaction (reduced systemic exposure of cabozantinib) with chronic concomitant use. Avoid chronic concomitant use if alternative therapy is available. If concomitant therapy cannot be avoided, increase daily dosage of cabozantinib capsules (Cometriq) by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated and the daily dosage of cabozantinib tablets (Cabometyx) by 20 mg (e.g., from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. If the potent CYP3A4 inducer is discontinued, resume cabozantinib therapy (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer. Do not exceed a cabozantinib capsule (Cometriq) daily dosage of 180 mg. Do not exceed a cabozantinib tablet (Cabometyx) daily dosage of 80 mg.

Do not ingest foods or dietary supplements known to inhibit or induce CYP isoenzymes, including CYP3A4.

Drugs Affected by Hepatic Microsomal Enzymes

Clinically relevant effects on exposure to CYP2C8 substrate drugs unlikely.

Drugs Affecting Multidrug Resistance Protein

MRP2 inhibitors may have the potential to increase plasma concentrations of cabozantinib. Monitor for increased cabozantinib toxicity.

Drugs Affected by the P-glycoprotein Transport System

Substrates of P-gp: Possible pharmacokinetic interaction (increased plasma concentrations of P-gp substrate).

Specific Drugs and Foods

Cabozantinib Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability not established.

Median time to peak plasma cabozantinib concentrations ranged from 2–5 hours after oral administration for Cometriq and 3–4 hours for Cabometyx.

Following a single 140-mg dose of cabozantinib capsules or tablets, peak plasma concentration of cabozantinib tablets was 19% higher compared with cabozantinib capsules; however, a <10% difference in AUC was observed between the tablet and capsule formulations.

Steady-state concentrations achieved in 15 days following administration of cabozantinib capsules (Cometriq).

Food

Administration of 140-mg dose with a high-fat meal increased cabozantinib (Cometriq) peak concentrations and AUC by 41 and 57%, respectively, relative to fasted conditions.

Special Populations

Results of a population pharmacokinetic analysis showed no clinically important differences in cabozantinib exposure between patients with normal liver function and those with mild hepatic impairment. In a pharmacokinetic study, cabozantinib exposure increased by 63% in patients with moderate hepatic impairment. Patients with severe hepatic impairment have not been studied.

Systemic exposure of cabozantinib (Cabometyx) in pediatric patients ≥12 years of age at the recommended dosage is expected to be comparable to the exposure in adults at a dosage of 60 mg once daily.

Distribution

Extent

Not known whether cabozantinib or its metabolites are distributed into human milk.

Plasma Protein Binding

≥99.7%.

Elimination

Metabolism

Metabolized in the liver by CYP3A4; substrate of CYP3A4 in vitro.

Elimination Route

Eliminated in feces (54%) and urine (27%).

Half-life

Cometriq: Approximately 55 hours.

Cabometyx: Approximately 99 hours.

Special Populations

Formal pharmacokinetic studies not conducted in patients with worse than moderate renal impairment (eGFR <29 mL/minute per 1.73 m²) or in those requiring dialysis. Mild to moderate renal impairment (Cl_cr ≥30 mL/minute) did not have a clinically important effect on clearance of cabozantinib in a population pharmacokinetic analysis.

No clinically significant differences in the mean cabozantinib exposure between subjects with normal liver function and those with mild hepatic impairment based on a population pharmacokinetic analysis.

In a dedicated pharmacokinetic study, AUC increased by 81% in patients with mild hepatic impairment and by 63% in patients with moderate hepatic impairment.

Not studied in patients with severe hepatic impairment.

Gender and race do not substantially affect clearance of cabozantinib.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted to 15–30°C).

Tablets

20–25°C (excursions permitted to 15–30°C).

Actions

• Inhibits multiple receptor tyrosine kinases (RTKs), which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.

• Various tyrosine kinases and pathways are abnormally activated in medullary thyroid carcinoma cells (e.g., rearranged during transfection [RET] proto-oncogene mutations are associated with development of hereditary medullary thyroid cancer).

• In vitro, inhibits activity of multiple RTKs, including RET; met proto-oncogene encoding hepatocyte growth factor (c-MET); vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3; stem cell factor receptor (c-Kit); tropomyosin receptor kinase B (trkB); fms-like tyrosine kinase 3 (Flt-3); AXL; and TIE-2. These RTKs are involved in both normal cellular function and pathologic processes (e.g., oncogenesis, metastasis, tumor angiogenesis, maintenance of the tumor microenvironment).

Advice to Patients

• Importance of informing patients that cabozantinib should not be taken with food; importance of instructing patients not to eat for ≥2 hours before and ≥1 hour after taking cabozantinib capsules or tablets. Importance of swallowing cabozantinib capsules whole with a full glass (at least 240 mL) of water and not to open or crush the capsules. Importance of swallowing cabozantinib tablets whole and not to crush the tablets. Importance of avoiding grapefruit or grapefruit juice while taking the drug.

• If a dose of cabozantinib is missed and it is ≥12 hours before the next scheduled dose, importance of taking the dose as soon as it is remembered, and taking the next dose at the regularly scheduled time. If a dose is missed and there are <12 hours before the next scheduled dose, importance of taking the next dose at the regularly scheduled time; the missed dose should not be replaced.

• Importance of informing patients that diarrhea often occurs and may be severe in some cases. Importance of contacting clinician if severe diarrhea occurs during therapy.

• Risk of palmar-plantar erythrodysesthesia syndrome. Importance of contacting clinician if progressive or intolerable rash occurs. Importance of advising patients to protect their skin to avoid subclinical vascular damage and subsequent adverse cutaneous effects that may interrupt ongoing therapy.

• Risk of mouth sores, oral pain, taste changes, nausea, or vomiting. Importance of contacting clinician if any of these symptoms are severe or prevent eating or drinking.

• Risk of weight loss, which may be substantial in some cases. Importance of informing clinician if substantial weight loss occurs.

• Risk of osteonecrosis of the jaw; symptoms may include jaw pain, toothache, or sores on the gums. Importance of advising patients that their clinician should examine their mouth before and during cabozantinib therapy. Importance of informing dentist about therapy with the drug. Importance of maintaining good oral hygiene during treatment.

• Risk of hypertension. Importance of informing clinician of signs or symptoms of elevated blood pressure and of regular monitoring.

• Risk of hemorrhage. Importance of informing clinician of any signs or symptoms of bleeding.

• Risk of thromboembolic events. Importance of advising patients to seek emergency medical care for signs or symptoms of blood clots, stroke, heart attack, or chest pain.

• Risk of GI perforation and development of fistulas. Importance of informing clinician of any abdominal tenderness or pain.

• Risk of adrenal insufficiency. Importance of informing clinician of extreme fatigue, dizziness, fainting, weakness, nausea, or vomiting.

• Risk of hypocalcemia. Importance of informing clinician of muscle stiffness, numbness, seizures, weight gain, and swelling of extremities.

• Risk of impaired wound healing. Importance of contacting clinician before any planned surgeries, including dental procedures, or if any recent surgery has occurred.

• Risk of fetal harm. Necessity of advising females of reproductive potential that they must use an effective method of contraception while receiving cabozantinib and for ≥4 months after discontinuance of therapy. Importance of patients informing their clinicians if they become pregnant. If pregnancy occurs, apprise patient of potential hazard to the fetus.

• Importance of discontinuing breast-feeding while receiving cabozantinib therapy and for at least 4 months after discontinuance of therapy.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hypertension, bleeding or wound disorders, hepatic impairment).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cabozantinib S-malate can only be obtained through a specialty pharmacy. Specific information regarding distribution of the drug is available by telephone at 855-253-3273 or at [Web]).

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Frequently asked questions

• How long do you take it for?
• What is the success rate of Cabometyx (cabozantinib)?
• Does Cabometyx (cabozantinib) cure cancer?
• What is the difference between Cabometyx and Cometriq?

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