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Cabozantinib S-malate

Class: Antineoplastic Agents
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
Brands: Cometriq

Warning(s)

  • Perforations and Fistulas
  • GI perforations and fistula formation reported in cabozantinib-treated patients.1 If a perforation or fistula develops, discontinue therapy permanently.1 (See Perforations and Fistulas under Cautions.)

  • Hemorrhage
  • Severe, sometimes fatal, hemorrhage, including hemoptysis and GI hemorrhage, reported.1 Monitor for signs and symptoms of bleeding.1 Do not use in patients with severe hemorrhage or a recent history of hemorrhage or hemoptysis; permanently discontinue therapy if severe hemorrhage occurs.1 (See Hemorrhage under Cautions.)

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.1 4 8 9 10

Uses for Cabozantinib S-malate

Medullary Thyroid Cancer

Treatment of progressive, metastatic medullary thyroid cancer (designated an orphan drug by FDA for this use).1 2 3 8 Efficacy determined based on improved progression-free survival.1 3

Slideshow: Prescription Drug Addiction - Are You at Risk?

Cabozantinib S-malate Dosage and Administration

General

Restricted Distribution

  • Obtain through a limited network of specialty pharmacies.5 Contact manufacturer at 855-253-3273 or consult the Cometriq website () for specific availability information.5

Administration

Oral Administration

Administer orally once daily.1 Do not administer with food; do not eat for ≥2 hours before and ≥1 hour after taking drug.1 (See Food under Pharmacokinetics.)

Swallow capsules whole with a full glass of water; do not open or crush capsules.1

If a dose of cabozantinib is missed, do not take the missed dose within 12 hours of the next dose.1 (See Advice to Patients.)

Dosage

Available as cabozantinib S-malate; dosage expressed in terms of cabozantinib.1

Adults

Medullary Thyroid Cancer
Oral

140 mg (one 80-mg and three 20-mg capsules) once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Manufacturer recommends reducing daily dosage by 40 mg if concomitant use of a potent CYP3A4 inhibitor is required (see Interactions).1

Manufacturer recommends increasing daily dosage by 40 mg, as tolerated, if concomitant use of a potent CYP3A4 inducer is required (see Interactions).1

Dosage Modification for Toxicity
Oral

If grade 4 hematologic adverse effects, grade 3 or greater nonhematologic adverse effects, or intolerable grade 2 adverse effects (as defined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) occur, withhold cabozantinib therapy.1 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 (one 80-mg and one 20-mg capsule); in patients previously receiving 100 mg daily, resume therapy at a dosage of 60 mg daily (three 20-mg capsules); and in patients previously receiving 60 mg daily, resume therapy at a dosage of 60 mg daily, if tolerated.1 Otherwise, discontinue cabozantinib.1

Permanently discontinue cabozantinib in patients who develop visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic events (e.g., MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, or reversible posterior leukoencephalopathy syndrome.1 (See Warnings/Precautions under Cautions.)

Special Populations

Hepatic Impairment

Not recommended in patients with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in patients with mild or moderate renal impairment.1 No experience in patients with severe renal impairment; no specific dosage recommendations at this time in such patients.1 (See Special Populations under Pharmacokinetics: Elimination.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Cabozantinib S-malate

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Perforations and Fistulas

GI perforations and fistulas reported in 3 and 1% of patients receiving cabozantinib, respectively; all were serious and one GI fistula was fatal (<1%).1 Non-GI fistulas, including tracheal/esophageal, reported in 4% of patients receiving the drug; two cases (1%) were fatal.1

Monitor patients for symptoms of perforations and fistulas.1 Permanently discontinue cabozantinib in patients who develop a visceral perforation or fistula.1

Hemorrhage

Serious, sometimes fatal, hemorrhage, including hemoptysis and GI hemorrhage, reported.1 Incidence of grade 3 or greater adverse hemorrhagic events was higher in patients receiving cabozantinib compared with those receiving placebo (3 versus 1%, respectively).1

Monitor patients for signs and symptoms of bleeding.1 Do not use in patients with severe hemorrhage or a recent history of hemorrhage or hemoptysis.1 Permanently discontinue therapy if severe hemorrhage occurs.1

Other Warnings and Precautions

Thromboembolic Events

Increased risk of thromboembolic events.1 Venous thromboembolism and arterial thromboembolism reported.1

Permanently discontinue cabozantinib in patients who develop an acute MI, cerebral infarction, or any other serious or clinically important arterial thromboembolic event.1

Wound-healing Complications

Wound-healing complications reported.1

Discontinue cabozantinib ≥28 days prior to scheduled surgery.1 Resume therapy following surgery based on clinical judgment of adequate wound healing.1 Withhold cabozantinib in patients with dehiscence or wound healing complications requiring medical intervention.1

Hypertension

Increased incidence of treatment-induced hypertension.1 Stage 1 or 2 hypertension occurred in 61% of patients receiving cabozantinib compared with 30% of those receiving placebo in the phase 3 clinical study; none of the patients developed malignant hypertension.1

Monitor BP prior to initiation of and periodically during therapy.1 Withhold cabozantinib for hypertension not adequately controlled with medical management; when controlled, resume therapy at a reduced dosage.1 Permanently discontinue cabozantinib for malignant hypertension, hypertensive crisis, or persistent uncontrolled hypertension despite optimal medical management.1

Osteonecrosis of the Jaw (ONJ)

ONJ reported.1 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.1

Perform an oral examination prior to initiation of and periodically during therapy.1 Advise patients to maintain good oral hygiene.1 (See Advice to Patients.)

For invasive dental procedures, withhold cabozantinib for ≥28 days prior to scheduled surgery, if possible.1 Permanently discontinue cabozantinib in patients who develop ONJ.1

Palmar-plantar Erythrodysesthesia Syndrome

Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) reported in 50% of cabozantinib-treated patients, which was severe (grade 3 or greater) in 13% of patients.1 Hand-foot skin reaction with subungual splinter hemorrhages and hypertension reported in at least one patient.11

Withhold cabozantinib in patients who develop intolerable grade 2 or grade 3–4 palmar-plantar erythrodysesthesia syndrome until improvement to grade 1, then resume cabozantinib at a reduced dosage.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Proteinuria

Proteinuria, including one patient with nephrotic syndrome, reported.1

Regularly monitor urine protein during therapy.1 Permanently discontinue cabozantinib in patients who develop nephrotic syndrome.1

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS reported in one cabozantinib-treated patient.1

Consider possible RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function.1 Magnetic resonance imaging (MRI) is necessary to confirm diagnosis.1 Permanently discontinue cabozantinib in patients who develop RPLS.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic, fetotoxic, and teratogenic in animals.1

Women of childbearing potential and men who are partners of such women should be advised to use an effective method of contraception while receiving the drug and for ≥4 months after discontinuance of therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Impairment of Fertility

No data on effect of cabozantinib on human fertility; the drug impaired male and female fertility in animals.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

Lactation

Not known whether cabozantinib or its metabolites are distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Pharmacokinetics not affected by age in adults (20–86 years of age).1

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.1 Limited data available in patients with serum bilirubin concentrations >1.5 times ULN.1

Safety and efficacy not established in patients with moderate or severe hepatic impairment; use not recommended in these patients.1

Renal Impairment

Formal pharmacokinetic studies not conducted in patients with renal impairment.1 (See Special Populations under Pharmacokinetics: Elimination.)

No dosage adjustment recommended in patients with mild or moderate renal impairment.1

No experience with cabozantinib in patients with severe renal impairment.1

Common Adverse Effects

Diarrhea,1 stomatitis,1 palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome),1 weight loss,1 decreased appetite,1 nausea,1 fatigue,1 oral pain,1 hair color changes,1 dysgeusia,1 hypertension,1 abdominal pain,1 constipation.1

Laboratory abnormalities: Increased AST concentrations,1 increased ALT concentrations,1 lymphopenia,1 increased alkaline phosphatase concentrations,1 hypocalcemia,1 neutropenia,1 thrombocytopenia,1 hypophosphatemia,1 hyperbilirubinemia.1

Interactions for Cabozantinib S-malate

Metabolized in liver by CYP3A4; substrate of CYP3A4 in vitro.1 4 Inhibition of CYP3A4 reduced formation of N-oxide metabolite by >80%; inhibition of CYP2C9 had minimal effects on metabolite formation (i.e., <20% reduction).1 Inhibition of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 2E1 had no effect on metabolite formation.1

Noncompetitive inhibitor of CYP2C8, a mixed-type inhibitor of CYP2C9 and CYP2C19, and a weak competitive inhibitor of CYP3A4 in human liver microsomal preparations.1 Unlikely to inhibit CYP isoenzymes 1A2, 2D6, or 3A4 to a clinically important degree.14

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.1

Inhibitor, but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of cabozantinib).1 Avoid concomitant use.1 If concomitant therapy cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily).1 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.1 (See Specific Drugs and Foods under Interactions.)

Potent CYP3A4 inducers: Possible pharmacokinetic interaction (reduced systemic exposure of cabozantinib) with chronic concomitant use.1 Avoid chronic concomitant use if alternative therapy is available.1 If concomitant therapy cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated.1 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.1 Do not exceed a cabozantinib daily dosage of 180 mg.1 (See Specific Drugs and Foods under Interactions.)

Do not ingest foods or nutritional supplements known to inhibit or induce CYP isoenzymes, including CYP3A4.1 (See Specific Drugs and Foods under Interactions.)

Drugs Affected by the P-glycoprotein Transport System

Substrates of P-gp: Possible pharmacokinetic interaction (increased plasma concentrations of P-gp substrate).1

Specific Drugs and Foods

Drug

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)

Potent CYP3A4 inhibitors: Possible increased cabozantinib exposure1

Ketoconazole (400 mg daily for 27 days) increased single-dose cabozantinib exposure by 38% in healthy individuals1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily)1

If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor 1

Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)

Possible reduced cabozantinib exposure 1

Rifampin (600 mg daily for 31 days) decreased cabozantinib (single dose) plasma exposure by 77% in healthy individuals1

Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available1

If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg1

If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer1

Antiretrovirals, HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased cabozantinib exposure1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily)1

If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor1

Carbamazepine

Possible reduced cabozantinib exposure 1

Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available1

If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a cabozantinib daily dosage of 180 mg1

If the potent CYP3A4 inducer is discontinued, resume cabozantinib dosage (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer1

Dexamethasone

Possible reduced cabozantinib exposure 1 14

Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available1 14

If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg1 14

If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer1 14

Grapefruit or grapefruit juice

Grapefruit products inhibit CYP, including CYP3A4; possible increased cabozantinib concentrations1 13

Avoid concomitant use1

Macrolides (clarithromycin, telithromycin)

Possible increased cabozantinib exposure1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily)1

If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor1

Nefazodone

Possible increased cabozantinib exposure1

Avoid concomitant use1

If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily)1

If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor1

Phenobarbital

Possible reduced cabozantinib exposure 1

Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available1

If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg1

If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer1

Phenytoin

Possible reduced cabozantinib exposure 1

Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available1

If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg1

If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer1

Rosiglitazone

No effect on rosiglitazone (a CYP2C8 substrate) peak plasma concentration and AUC; clinically important pharmacokinetic interaction unlikely1 12 14

St. John’s wort (Hypericum perforatum)

Possible reduced cabozantinib exposure1 14

Avoid concomitant use of potent CYP3A4 inducers if alternative therapy is available1 14

If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg1 14

If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2–3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer1 14

Cabozantinib S-malate Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability not established.4

Median time to peak plasma cabozantinib concentrations ranged from 2–5 hours after oral administration.1

Steady-state concentrations achieved in 15 days.1

Food

Administration of 140-mg dose with a high-fat meal increased cabozantinib peak concentrations and AUC by 41 and 57%, respectively, relative to fasted conditions.1 (See Administration under Dosage and Administration.)

Special Populations

Pharmacokinetics not studied in patients with hepatic impairment; limited data available in patients with serum bilirubin concentrations >1.5 times ULN.1

Pharmacokinetics not studied in pediatric patients.1

Pharmacokinetics in adults not affected by age (20–86 years of age).1

Distribution

Extent

Not known whether cabozantinib or its metabolites are distributed into human milk.1

Plasma Protein Binding

≥99.7%.1

Elimination

Metabolism

Metabolized in the liver by CYP3A4; substrate of CYP3A4 in vitro.1 4

Elimination Route

Eliminated in feces (54%) and urine (27%).1

Half-life

Approximately 55 hours.1 4

Special Populations

Formal pharmacokinetic studies not conducted in patients with renal impairment.1 Mild to moderate renal impairment (Clcr ≥30 mL/minute) did not have a clinically important effect on clearance of cabozantinib in a population pharmacokinetic analysis.1 No experience with cabozantinib in patients with severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Gender and race do not substantially affect clearance of cabozantinib.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple receptor tyrosine kinases (RTKs),1 4 8 9 10 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.1 6 7 9 10

  • 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).6 7 9

  • 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-2.1 9 10 These RTKs are involved in both normal cellular function and pathologic processes (e.g., oncogenesis, metastasis, tumor angiogenesis, maintenance of the tumor microenvironment).1

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 the drug.1 Importance of swallowing cabozantinib capsules whole with a full glass (at least 240 mL) of water and not to open or crush the capsules.1 Importance of avoiding grapefruit or grapefruit juice while taking the drug.1

  • If a dose of is cabozantinib 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.1 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.1

  • Importance of informing patients that diarrhea often occurs and may be severe in some cases.1 Importance of contacting clinician if severe diarrhea occurs during therapy.1

  • Risk of palmar-plantar erythrodysesthesia syndrome.1 Importance of contacting clinician if progressive or intolerable rash occurs.1 Importance of advising patients to protect their skin to avoid subclinical vascular damage and subsequent adverse cutaneous effects that may interrupt ongoing therapy.11

  • Risk of mouth sores, oral pain, taste changes, nausea, or vomiting.1 Importance of contacting clinician if any of these symptoms are severe or prevent eating or drinking.1

  • Risk of weight loss, which may be substantial in some cases.1 Importance of informing clinician if substantial weight loss occurs.1

  • Risk of osteonecrosis of the jaw; symptoms may include jaw pain, toothache, or sores on the gums.1 Importance of advising patients that their clinician should examine their mouth before and during cabozantinib therapy.1 Importance of informing dentist about therapy with the drug.1 Importance of maintaining good oral hygiene during treatment.1

  • Importance of contacting clinician before any planned surgeries, including dental procedures.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential and men who are partners of such women that they must use an effective method of contraception while receiving cabozantinib and for ≥4 months after discontinuance of therapy.1 Importance of patients informing their clinicians if they or their partners become pregnant.1 If pregnancy occurs, apprise patient of potential hazard to the fetus.1 Importance of discontinuing nursing while receiving cabozantinib therapy.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hypertension, bleeding or wound disorders, hepatic impairment).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Distribution of cabozantinib S-malate is restricted. 5 (See Restricted Distribution under Dosage and Administration.)

Cabozantinib S-malate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

20 mg (of cabozantinib)

Cometriq

Exelixis

Kit

84 Capsules, Cabozantinib S-malate 20 mg (of cabozantinib) (Cometriq)

Cometriq 60 mg Daily Dose Blister Cards (available in a package containing 4 blister cards)

Exelixis

28 Capsules, Cabozantinib S-malate 20 mg (of cabozantinib) (Cometriq)

28 Capsules, Cabozantinib S-malate 80 mg (of cabozantinib) (Cometriq)

Cometriq 100 mg Daily Dose Blister Cards (available in a package containing 4 blister cards)

Exelixis

84 Capsules, Cabozantinib S-malate 20 mg (of cabozantinib) (Cometriq)

28 Capsules, Cabozantinib S-malate 80 mg (of cabozantinib) (Cometriq)

Cometriq 140 mg Daily Dose Blister Cards (available in a package containing 4 blister cards)

Exelixis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 31, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Exelixis, Inc. Cometriq (cabozantinib) capsules prescribing information. South San Francisco, CA; 2012 Nov.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website.

3. Schoffski P, Elisei R, and the EXAM Study Group. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol. 2012; 30 (May 20 Suppl): Abstract No. 5508.

4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 203756Orig1s000: Summary review. From FDA website.

5. Exelixis, Inc. Cometriq (cabozantinib) information for healthcare professionals. Accessed 2013 Apr 23. From Cometriq for healthcare professionals website.

6. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res. 2011; 2011:815826. [PubMed 21687607]

7. Giunti S, Antonelli A, Amorosi A et al. Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma. Int J Endocrinol. 2013; 2013:803171. [PubMed 23509459]

8. Kurzrock R, Sherman SI, Ball DW et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011; 29:2660-6. [PubMed 21606412]

9. Hart CD, De Boer RH. Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer. Onco Targets Ther. 2013; 6:1-7. [PubMed 23319867]

10. Nagilla M, Brown RL, Cohen EE. Cabozantinib for the treatment of advanced medullary thyroid cancer. Adv Ther. 2012; 29:925-34. [PubMed 23104465]

11. Cho YT, Chan CC. Cabozantinib-induced hand-foot skin reaction with subungual splinter hemorrhages and hypertension: a possible association with inhibition of the vascular endothelial growth factor signaling pathway. Eur J Dermatol. 2013; :. [PubMed 23518371]

12. Bowles DW, Kessler DW, Jimeno A. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib). Drugs of Today. 2011; 47:857-68. [PubMed 22146228]

13. Hanley MJ, Cancalon P, Widmer WW et al. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011; 7:267-86. [PubMed 21254874]

14. Exelixis, Inc., South San Francisco, CA: Personal communication.

15. GlaxoSmithKline. Votrient (pazopanib) tablets prescribing information. Research Triangle Park, NC: 2013 Feb.

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