Cabozantinib

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); 2-3 hr (Cabometyx)

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

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

Steady-state achieved: Day 15

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)

Total body clearance: 4.4 L/hr (Cometriq); 2.2 L/hr (Cabometyx)

Excretion: 54% feces, 27% urine

Cabozantinib is a prescription medication used to treat a certain type of thyroid and kidney cancer that has spread to other parts of the body. Cabozantinib belongs to a group of drugs called tyrosine kinase inhibitors. It works by slowing or stopping the growth of cancer cells.

Cabozantinib comes as a capsule to take by mouth. It is usually taken once a day on an empty stomach. Patients should not eat for at least 2 hours before and at least 1 hour after taking cabozantinib.

Common side effects diarrhea, inflammation and sores in the mouth, decreased weight, and decreased appetite.

Cabozantinib may be found in some form under the following brand names:

• Cabometyx

• Cometriq

Breastfeeding mothers must discontinue nursing while receiving cabozantinib therapy.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

The recommended dose to treat thyroid cancer is 140 mg by mouth once daily.

The recommended dose to treat kidney cancer is 60 mg by mouth once daily. 

• Keep this medication in the container it came in, tightly closed, and out of reach of children.
• Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 12 hours away. Do not take extra medicine to make up the missed dose.

Grapefruit and grapefruit juice may interact with cabozantinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking cabozantinib.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Usual Adult Dose for Thyroid Cancer:

140 mg orally once a day

Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Comments:
-Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking this drug.
-Advise patients the capsule form of this drug cannot be substituted with the tablet form of this drug.

Use: Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Usual Adult Dose for Renal Cell Carcinoma:

60 mg orally once a day

Duration of therapy: Until patient no longer experiences clinical benefit or unacceptable toxicity occurs.

Comments:
-Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking this drug.
-Advise patients the tablet form of this drug cannot be substituted with the capsule form of this drug.

Use: Treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

Renal cell carcinoma, advanced (Cabometyx): Treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy

Thyroid cancer, medullary (Cometriq): Treatment of progressive, metastatic medullary thyroid cancer (MTC)

GI perforations occurred in 3% and fistula formation in 1% of cabozantinib-treated patients. Discontinue cabozantinib for perforation or for fistula formation.

Severe and sometimes fatal hemorrhage, including hemoptysis and GI hemorrhage, occurred in 3% of cabozantinib-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer cabozantinib to patients with severe hemorrhage.

Applies to cabozantinib: oral capsule, oral tablet

Cardiovascular

Very common (10% or more): Elevated blood pressure (up to 96%), hypertension (up to 61%)
Common (1% to 10%): Hypotension, venous thromboembolism, arterial thromboembolism, atrial fibrillation
Uncommon (0.1% to 1%): Angina pectoris, supraventricular tachycardia, shortened activated partial thromboplastin time
Frequency not reported: QT interval prolongation[Ref]

Hepatic

Very common (10% or more): Increased ALT (up to 86%), increased AST (up to 86%), increased alkaline phosphatase (up to 52%), hyperbilirubinemia (up to 25%)
Common (1% to 10%): Cholelithiasis
Uncommon (0.1% to 1%): Hepatic encephalopathy[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 63%), stomatitis (up to 51%), nausea (up to 43%), oral pain (up to 36%), constipation (up to 27%), abdominal pain (up to 27%), vomiting (up to 24%), dysphagia (up to 13%), dyspepsia (up to 11%), glossodynia
Common (1% to 10%): Hemorrhoids, GI perforation, GI fistula, GI hemorrhage, pancreatitis, anal fissure, anal inflammation, cheilitis
Uncommon (0.1% to 1%): Esophagitis[Ref]

Endocrine

Very common (10% or more): Increased blood thyroid stimulating hormone (up to 57%)
Common (1% to 10%): Hypothyroidism
Uncommon (0.1% to 1%): Amenorrhea[Ref]

Hematologic

Very common (10% or more): Lymphopenia (up to 53%), neutropenia (up to 35%), thrombocytopenia (up to 35%)
Uncommon (0.1% to 1%): Increased eosinophil count, increased platelet count[Ref]

Dermatologic

Very common (10% or more): Palmar-plantar erythrodysesthesia syndrome (up to 50%), hair color changes/depigmentation/graying (up to 34%), rash (up to 19%), dry skin (up to 19%), alopecia (up to 16%), erythema (up to 11%)
Common (1% to 10%): Hyperkeratosis, folliculitis, acne, blister, abnormal hair growth, skin exfoliation, skin hypopigmentation
Uncommon (0.1% to 1%): Skin ulcer, telangiectasia[Ref]

Metabolic

Very common (10% or more): Decreased weight (up to 48%), decreased appetite (up to 46%), hypocalcemia (up to 52%), hypophosphatemia (up to 28%), hypomagnesemia (up to 19%), hypokalemia (up to 18%), hyponatremia (up to 10%), increased blood lactate dehydrogenase, increased blood creatinine phosphokinase
Common (1% to 10%): Dehydration, hypoalbuminemia[Ref]

Other

Very common (10% or more): Fatigue (up to 41%), asthenia (up to 21%), mucosal inflammation
Common (1% to 10%): Abscess (including visceral, intra-abdominal, skin, tooth), fungal infection (including skin, oral, genital), ear pain, tinnitus, pallor, peripheral coldness, impaired wound healing/wound complications, chills, face edema
Uncommon (0.1% to 1%): Aspergilloma, hypoacusis, cyst, facial pain, localized edema
Frequency not reported: Hemorrhage[Ref]

Nervous system

Very common (10% or more): Dysgeusia (up to 34%), headache (up to 18%), dizziness (up to 14%)
Common (1% to 10%): Paresthesia, peripheral sensory neuropathy, peripheral neuropathy, ageusia, tremor
Uncommon (0.1% to 1%): Reversible posterior leukoencephalopathy syndrome, ataxia, attention disturbance, loss of consciousness, speech disorder, transient ischemic attack[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (up to 14%), muscle spasms (up to 12%)
Common (1% to 10%): Musculoskeletal chest pain, osteonecrosis of the jaw
Uncommon (0.1% to 1%): Rhabdomyolysis[Ref]

General

Patients should be closely monitored for the first 8 weeks as most adverse events have occurred early in the course of treatment.[Ref]

Genitourinary

Common (1% to 10%): Proteinuria, dysuria, hematuria
Uncommon (0.1% to 1%): Vaginal hemorrhage[Ref]

Ocular

Common (1% to 10%): Blurred vision
Uncommon (0.1% to 1%): Cataract, conjunctivitis[Ref]

Psychiatric

Common (1% to 10%): Anxiety, depression, confusional state
Uncommon (0.1% to 1%): Abnormal dreams, delirium[Ref]

Respiratory

Very common (10% or more): Dysphonia (up to 20%),oropharyngeal pain
Common (1% to 10%): Non-GI fistula (including tracheal, pneumomediastinum, tracheo-esophageal), pulmonary embolism, respiratory tract hemorrhage (including pulmonary, bronchial, tracheal), pneumonia, pneumonia aspiration
Uncommon (0.1% to 1%): Atelectasis, pharyngeal edema, pneumonitis[Ref]

Renal

Uncommon (0.1% to 1%): Acute renal failure[Ref]

Some side effects of cabozantinib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Capsule formulation (MTC):
-Mild to Moderate Hepatic Impairment: 80 mg orally once a day.
-Severe Hepatic Impairment: Not recommended.

Tablet formulation (RCC):
-Mild to Moderate Hepatic Impairment: 40 mg orally once a day.
-Severe Hepatic Impairment: Not recommended.