Cabozantinib

Chemical formula: C₂₈H₂₄FN₃O₅  Molecular mass: 501.514 g/mol  PubChem compound: 25102847

Interactions

Cabozantinib interacts in the following cases:

MRP2 inhibitors

Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution.

Risk factors for QT prolongation, medicinal products that prolong the QT interval

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.

Strong CYP3A4 inhibitors

Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors.

Administration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) to healthy volunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinib exposure (AUC) by 38%. Therefore, co-administration of strong CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approached with caution.

Strong CYP3A4 inducers

Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided.

Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthy volunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinib exposure (AUC) by 77%. Chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John’s Wort [Hypericum perforatum]) with cabozantinib should therefore be avoided.

Mild or moderate renal impairment

Cabozantinib should be used with caution in patients with mild or moderate renal impairment.

Severe renal impairment

Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.

Moderate hepatic impairment

Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dosing recommendation can be provided. Close monitoring of overall safety is recommended in these patients.

Severe hepatic impairment

There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so cabozantinib is not recommended for use in these patients.

Bile salt-sequestering agents

Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown.

Fertility

There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib. Both men and women should be advised to seek advice and consider fertility preservation before treatment.

Patients who have inflammatory bowel disease, tumour infiltration in the GI tract, or complications from prior GI surgery

Patients who have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses and sepsis.

Hypertension, history of aneurysm

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating cabozantinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Pregnancy

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects. The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.

Nursing mothers

It is not known whether cabozantinib and/or its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as “effective methods of contraception”, they should be used together with another method, such as a barrier method.

Fertility

There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib. Both men and women should be advised to seek advice and consider fertility preservation before treatment.

Effects on ability to drive and use machines

Cabozantinib has minor influence on the ability to drive and use machines. Adverse reactions such as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be recommended when driving or operating machines.

Adverse reactions


Summary of safety profile

The most common serious adverse drug reactions in the RCC population (≥1% incidence) are diarrhoea, hypertension, dehydration, hyponatraemia, nausea, decreased appetite, embolism, fatigue, hypomagnesaemia, palmar-plantar erythrodysaesthesia syndrome (PPES).

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC population included diarrhoea, hypertension, fatigue, AST increased, ALT increased, nausea, decreased appetite, PPES, dysgeusia, platelet count decreased, stomatitis, anaemia, vomiting, weight decreased, dyspepsia, and constipation. Hypertension was observed more frequently in the treatment naïve RCC population (67%) compared to RCC patients following prior VEGF-targeted therapy (37%).

The most common serious adverse drug reactions in the HCC population (≥1% incidence) are hepatic encephalopathy, palmar-plantar erythrodysaesthesia syndrome, asthenia and diarrhoea.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, palmar-plantar erythrodysaesthesia syndrome, fatigue, decreased appetite hypertension and nausea.

List of adverse reactions

Adverse reactions are listed below according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse drug reactions (ADRs) reported in clinical trials in patients treated with cabozantinib:

Infections and infestations

Common: abscess

Blood and lymphatic disorders

Very Common: anaemia

Common: thrombocytopenia, neutropenia

Uncommon: lymphopenia

Endocrine disorders

Very Common: hypothyroidism

Metabolism and nutrition disorders

Very Common: decreased appetite, hypomagnesaemia, hypokalaemia

Common: dehydration, hypoalbuminaemia, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia hyperglycaemia, hypoglycaemia

Nervous system disorders

Very Common: dysgeusia, headache, dizziness

Common: peripheral sensory neuropathy

Uncommon: convulsion

Not Known: cerebrovascular accident

Ear and labyrinth disorders

Common: tinnitus

Cardiac disorders

Not Known: myocardial infarction

Vascular disorders

Very Common: hypertension, haemorrhage

Common: venous thrombosis, arterial thrombosis

Not Known: aneurysms and artery dissections

Respiratory, thoracic, and mediastinal disorders

Very Common: dysphonia, dyspnoea, cough

Common: pulmonary embolism

Gastrointestinal disorders

Very Common: diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, upper abdominal pain

Common: gastrointestinal perforation, fistula, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth

Uncommon: pancreatitis, glossodynia

Hepatobiliary disorders

Common: hepatic encephalopathy

Uncommon: hepatitis cholestatic

Skin and subcutaneous tissue disorders

Very Common: palmar-plantar erythrodysaesthesia syndrome, rash

Common: pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change

Musculoskeletal and connective tissue disorders

Very Common: pain in extremity

Common: muscle spasms, arthralgia

Uncommon: osteonecrosis of the jaw

Renal and urinary disorders

Common: proteinuria

General disorders and administration site conditions

Very Common: fatigue, mucosal inflammation, asthenia, peripheral oedema

Investigations

Very Common: weight decreased, serum ALT increased, AST increased

Common: blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increased, white blood cell count decreased

Uncommon: blood triglycerides increased

Injury, poisoning and procedural complications

Uncommon: wound complications

Description of selected adverse reactions

Data for the following reactions are based on patients who received 60 mg cabozantinib qd po in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC and in HCC following prior systemic therapy.

Gastrointestinal (GI) perforation

In the study in RCC following prior VEGF-targeted therapy (METEOR), GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.

In the treatment-naïve RCC study (CABOSUN), GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.

In the HCC study (CELESTIAL), GI perforations were reported in 0.9% of cabozantinib-treated patients (4/467). All events were Grade 3 or 4. Median time to onset was 5.9 weeks.

Fatal perforations have occurred in the cabozantinib clinical program.

Hepatic encephalopathy

In the HCC study (CELESTIAL), hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonaemic encephalopathy) was reported in 5.6% of cabozantinib-treated patients (26/467); Grade 3-4 events in 2.8%, and one (0.2%) Grade 5 event. Median time to onset was 5.9 weeks. No cases of hepatic encephalopathy were reported in the RCC studies (METEOR and CABOSUN).

Diarrhoea

In the study in RCC following prior VEGF-targeted therapy (METEOR), diarrhoea was reported in 74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onset was 4.9 weeks.

In the treatment-naïve RCC study (CABOSUN), diarrhoea was reported in 73% of cabozantinib- treated patients (57/78);Grade 3-4 events in 10%..

In the HCC study (CELESTIAL), diarrhoea was reported in 54% of cabozantinib-treated patients (251/467); Grade 3-4 events in 9.9%. Median time to onset of all events was 4.1 weeks. Diarrhoea led to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and 5/467 (1%) of subjects, respectively.

Fistulas

In the study in RCC following prior VEGF-targeted therapy (METEOR), fistulas were reported in 1.2% (4/331) of cabozantinib-treated patients and included anal fistulas in 0.6% (2/331) cabozantinib-treated patients. One event was Grade 3; the remainder were Grade 2. Median time to onset was 30.3 weeks.

In the treatment-naïve RCC study (CABOSUN), no cases of fistulas were reported.

In the HCC study (CELESTIAL), fistulas were reported in 1.5% (7/467) of the HCC patients. Median time to onset was 14 weeks.

Fatal fistulas have occurred in the cabozantinib clinical program.

Haemorrhage

In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of severe haemorrhagic events (Grade ≥3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Median time to onset was 20.9 weeks.

In the treatment-naïve RCC study (CABOSUN), the incidence of severe haemorrhagic events (Grade ≥3) was 5.1% (4/78) in cabozantinib-treated RCC patients.

In the HCC study (CELESTIAL), the incidence of severe haemorrhagic events (Grade ≥3) was 7.3% in cabozantinib-treated patients (34/467). Median time to onset was 9.1 weeks.

Fatal haemorrhages have occurred in the cabozantinib clinical program.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

No case of RPLS was reported in the METEOR or CABOSUN or CELESTIAL studies, but RPLS has been reported rarely in other clinical studies (in 2/4872 subjects; 0.04%).

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