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

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

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

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.)

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Warnings

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

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

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 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

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

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 (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, 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

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

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.)

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

Specific Populations

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

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

Safety and efficacy not established.1

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

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

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

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

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