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Medullary Thyroid Cancer

Indicated for treatment of progressive, metastatic medullary thyroid cancer

140 mg PO qDay on empty stomach (see Administration)

Pharmacology

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

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

Distribution

Protein Bound: ≥99.7%

Vd: 349 L

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

Total body clearance: 4.4 L/hr

Excretion: 54% feces, 27% urine

Dosage Modifications

CYP3A4 inhibitors

        Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole)

         If strong CYP3A4 inhibitor required, decrease cabozantinib dose by 40 mg/day; resume previous dose 2-3 days after strong CYP3A4 inhibitor discontinued

CYP3A4 inducers

         Avoid coadministration of strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s wort)

         If strong CYP3A4 inducer required, increase dose by 40 mg/day; resume previous dose 2-3 days after strong CYP3A4 inducer discontinued

Hepatic impairment

         Moderate-to-severe: Not recommended

Withhold dose

         Withhold dose for Grade 4 hematologic adverse reactions, ≥Grade 3 nonhematologic adverse reactions, or intolerable Grade 2 adverse reactions

         Upon resolution, reduce dose as follows:

         -if previous daily dose 140 mg, resume at 100 mg/day

         -if previous daily dose 100 mg, resume at 60 mg/day

         -if previous daily dose 60 mg, resume at 60 mg if tolerated, otherwise, discontinue

Permanently discontinue

         Development of visceral perforation or fistula formation

         Severe hemorrhage

         Serious arterial thromboembolic event (eg, myocardial infarction, cerebral infarction)

         Nephrotic syndrome

         Malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management

         Osteonecrosis of the jaw

         Reversible posterior leukoencephalopathy syndrome

Administration

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

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

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)

Adverse Effects

>10%

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%; ≥Grade 3, 13%)

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%)

Dysphagia (13%)

Muscle spasms (12%)

Dyspepsia (11%)

Erythema (11%)

1-10%

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%)

eripheral neuropathy (5%)

Non-GI fistula (4%)

GI perforation (3%)

Arterial thromboembolism (2%)

Proteinuria (2%)

GI fistula (1%)

Osteonecrosis of the jaw (1%)

<1%

Reversible posterior leukoencephalopathy syndrome (RPLS)

Pregnancy & Lactation

Pregnancy Category: D; based on its mechanism of action, can cause fetal harm when administered to pregnant women

Lactation: Unknown whether distributed in breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Black Box Warnings

Perforations and fistulas

         GI perforations occurred in 3% and fistula formation in 1%

         Non-GI fistulas (eg, tracheal, esophageal) reported in 4%

         Discontinue if perforation or fistula formation occurs

Hemorrhage

         Severe, sometimes fatal, hemorrhage including hemoptysis and GI hemorrhage occurred in 3%

         Monitor for signs and symptoms of bleeding

         Do not administer with severe hemorrhage

Cautions

GI perforations and fistulas reported (see Black Box Warnings)

Serious and sometimes fatal hemorrhage reported (see Black Box Warnings)

Thromboembolic events reported

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

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

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

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

Proteinuria may occur

Reversible posterior leukoencephalopathy syndrome (RPLS) reported (rare)

Avoid coadministration with strong CYP3A4 inhibitors or inducers

Not recommended with moderate-to-severe hepatic impairment