cabozantinib (Rx)

Adverse effects are for all grades unless otherwise specified

>10% (Cometriq)

AST, ALT increased (86%)

Diarrhea (63%)

Hypertension, treatment-emergent (61%)

Increased TSH (57%)

Lymphopenia (53%)

ALP increased (52%)

Hypocalcemia (52%)

Stomatitis (51%)

Palmar-plantar erythrodysesthesia syndrome (50%)

Weight decreased (48%)

Appetite decreased (46%)

Nausea (43%)

Fatigue (41%)

Oral pain (36%)

Neutropenia (35%)

Thrombocytopenia (35%)

Dysgeusia (34%)

Hair color changes, depigmentation, graying (34%)

Hypertension (33%)

Hypophosphatemia (28%)

Constipation (27%)

Abdominal pain (27%)

Hypobilirubinemia (25%)

Vomiting (24%)

Asthenia (21%)

Dysphonia (20%)

Rash (19%)

Dry skin (19%)

Hypomagnesemia (19%)

Hypokalemia (18%)

Headache (18%)

Alopecia (16%)

Dizziness (14%)

Arthralgia (14%)

Palmar-plantar erythrodysesthesia syndrome, Grade 3 or 4 (13%)

Dysphagia (13%)

Muscle spasms (12%)

Dyspepsia (11%)

Erythema (11%)

>10% (Cabometyx)

Diarrhea (74%)

AST increased (74%)

ALT increased (68%)

Creatinine increased (58%)

Fatigue (56%)

Triglycerides increased (53%)

Nauseas (50%)

Hypophosphatemia (48%)

Decreased appetite (46%)

Palmar-plantar erythrodysesthesia syndrome (42%)

Hypertension (39%)

Hyperglycemia (37%)

Hypoalbuminemia (36%)

ALP increased (35%)

WBCs decreased (35%)

Vomiting (32%)

Hypomagnesemia (31%)

Weight decreased (31%)

ANC decreased (31%)

Hgb decreased (31%)

Hyponatremia (30%)

GGT increased (27%)

Constipation (25%)

Lymphocytes decreased (25%)

Platelets decreased (25%)

Dysgeusia (24%)

Abdominal pain (23%)

Rash (23%)

Stomatitis (22%)

Hypothyroidism (21%)

Dysphonia (20%)

Dyspnea (19%)

Mucosal inflammation (19%)

Asthenia (19%)

Cough (18%)

Anemia (17%)

Hypertension, Grade 3-4 (16%)

Muscle spasms (13%)

Dyspepsia (12%)

Proteinuria (12%)

Diarrhea (11%)

Dry skin, Grade 3-4 (11%)

Headache (11%)

Dizziness (11%)

Arthralgia (11%)

1-10% (Cometriq)

Hyponatremia (10%)

Hemorrhoids (9%)

Musculoskeletal chest pain (9%)

Anxiety (9%)

Paresthesia (7%)

Peripheral sensory neuropathy (7%)

Dehydration (7%)

Hyperkeratosis (7%)

Hypotension (7%)

Venous thromboembolism (6%)

Peripheral neuropathy (5%)

Non-GI fistula (4%)

GI perforation (3%)

Arterial thromboembolism (2%)

Proteinuria (2%)

GI fistula (1%)

Osteonecrosis of the jaw (1%)

1-10% (Cabometyx)

Fatigue, Grade 3-4 (9%)

Palmar-plantar erythrodysesthesia syndrome, Grade 3-4 (8%)

Hyponatremia, Grade 3-4 (8%)

Hypophosphatemia, Grade 3-4 (8%)

Hypomagnesemia, Grade 3-4 (7%)

Lymphocytes decreased, Grade 3-4 (7%)

Anemia, Grade 3-4 (5%)

GGT decreased, Grade 3-4 (5%)

Nausea, Grade 3-4 (4%)

Asthenia, Grade 3-4 (4%)

Abdominal pain, Grade 3-4 (4%)

Hgb decreased, Grade 3-4 (4%)

Triglycerides increased, Grade 3-4 (4%)

ALT increased, Grade 3-4 (3%)

AST increased, Grade 3-4 (3%)

Dyspnea, Grade 3-4 (3%)

Decreased appetite, Grade 3-4 (3%)

Proteinuria, Grade 3-4 (2%)

Vomiting, Grade 3-4 (2%)

Stomatitis, Grade 3-4 (2%)

ANC decreased, Grade 3-4 (2%)

ALP decreased, Grade 3-4 (2%)

Hypoalbuminemia, Grade 3-4 (2%)

Hyperglycemia, Grade 3-4 (2%)

<1%

Reversible posterior leukoencephalopathy syndrome (RPLS)

Postmarketing Effects

Suprahepatic international normalized ratio and epistaxis (during concomitant use of warfarin)

Contraindications

None

Cautions

GI perforations and fistulas reported (see Black Box Warnings for Cometriq); monitor patients for symptoms of perforations and fistulas, including abscess and discontinue therapy in patients who experience a Grade 4 fistula or a GI perforation

Serious and fatal hemorrhage reported (see Black Box Warnings for Cometriq); do not administer Cabometyx to patients with risk for severe hemorrhage

Incidence of Grade 3 to 5 hemorrhagic events was 5% in treated patients in RCC and HCC studies

Thromboembolic events reported; discontinue if acute MI or any other arterial thromboembolic event develops

May impair wound healing; stop treatment at least 28 days prior to schedules surgery; withhold with dehiscence or wound healing complications requiring medical intervention

Osteonecrosis of the jaw reported (rare); discontinue at least 28 days prior to invasive dental procedures

Increases risk of treatment-emergent hypertension; discontinue for severe hypertension that cannot be controlled with antihypertensive therapy

Palmar-plantar erythrodysesthesia syndrome reported; withhold treatment if needed (see Dosage Modifications)

Proteinuria may occur

Fetal harm may occur when administered to a pregnant woman (see Pregnancy)

Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare)

Withhold therapy for at least 3 weeks prior to elective surgery; do not administer therapy for at least 2 weeks after major surgery and until adequate wound healing; the safety of resumption of therapy after resolution of wound healing complications not established

Diarrhea

• Cabometyx only
• Diarrhea occurred in 74% of patients treated with Cabometyx and in 28% of patients treated with everolimus
• Grade 3 diarrhea occurred in 11% of Cabometyx-treated patients and in 2% of everolimus-treated patients (see Dosage Modifications)

Drug interactions overview

• CYP3A4 inhibitors

  • Cometriq: Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%
  • Cabometyx: Coadministration with a strong CYP3A4 inhibitor increased the exposure of cabozantinib, which may increase the risk of exposure-related adverse reactions

• CYP3A4 inducers

  • Cometriq: Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%
  • Cabometyx: Coadministration with a strong CYP3A4 inducer decreased the exposure of cabozantinib, which may reduce efficacy

Pregnancy

Based on its mechanism of action, can cause fetal harm when administered to pregnant women

Verify pregnancy status of females of reproductive potential before initiation

Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the final dose

May impair male and female fertility

Lactation

Unknown whether distributed in breast milk

Because of potential for serious adverse reactions in a breastfed infant from cabozantinib, advise females of reproductive potential to not breastfeed during treatment and for 4 months after the final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways; these tyrosine kinases are involved in both normal cellular function and pathologic processes (eg, oncogenesis, metastasis, tumor angiogenesis, and maintenance of tumor microenvironment)

Absorption

Peak plasma time: 2-5 hr; (Cometriq); 3-4 hr (Cabometyx)

Steady-state achieved: Day 15

A 19% increase in the peak plasma concentration of the tablet formulation (Cabometyx) compared with the capsule formulation (Cometriq)

Effects of food

• High fat meal increases Cmax and AUC by 41% and 57% respectively compared to fasted conditions

Distribution

Protein Bound: ≥99.7%

Vd: 349 L (Cometriq); 319 L (Cabometyx)

Metabolism

Metabolized via hepatic CYP3A4

Metabolites: XL184 N-oxide

CYP3A4 substrate; CYP2C8 inhibitor (noncompetitive), CYP2C9 and CYP2C19 inhibitor (mixed), CYP3A4 (weak competitive); CYP1A1 inducer

P-gp transport inhibitor

Elimination

Half-life: 55 hr (Cometriq); 99 hr (Cabometyx)

Clearance: 4.4 L/hr (Cometriq); 2.2 L/hr (Cabometyx)

Excretion (Cabometyx): 54% feces, 27% urine

Oral Administration

Do not substitute Cabometyx tablets and Cometriq capsules for one another

Take on empty stomach, do not eat for at least 2 hr before or 1 hr after administration

Swallow capsule or tablet whole; do not chew or empty contents of capsule; do not crush tablet

Do not take a missed dose within 12 hr of the next dose

Do not ingest foods (eg, grapefruit, grapefruit juice) or nutritional supplements known to affect CYP3A4 substrates (eg, St. John’s wort)

Storage

Tablets or capsules: Store at room temperature (20-25°C [68-77°F])