Chemical formula: C₂₈H₂₄FN₃O₅ Molecular mass: 501.514 g/mol PubChem compound: 25102847
Cabozantinib interacts in the following cases:
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.
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.
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.
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.
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.
Cabozantinib should be used with caution in patients with mild or moderate 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.
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.
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 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.
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 (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.
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.
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.
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.
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.
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.
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.
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.
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:
Common: abscess
Very Common: anaemia
Common: thrombocytopenia, neutropenia
Uncommon: lymphopenia
Very Common: hypothyroidism
Very Common: decreased appetite, hypomagnesaemia, hypokalaemia
Common: dehydration, hypoalbuminaemia, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia hyperglycaemia, hypoglycaemia
Very Common: dysgeusia, headache, dizziness
Common: peripheral sensory neuropathy
Uncommon: convulsion
Not Known: cerebrovascular accident
Common: tinnitus
Not Known: myocardial infarction
Very Common: hypertension, haemorrhage
Common: venous thrombosis, arterial thrombosis
Not Known: aneurysms and artery dissections
Very Common: dysphonia, dyspnoea, cough
Common: pulmonary embolism
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
Common: hepatic encephalopathy
Uncommon: hepatitis cholestatic
Very Common: palmar-plantar erythrodysaesthesia syndrome, rash
Common: pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change
Very Common: pain in extremity
Common: muscle spasms, arthralgia
Uncommon: osteonecrosis of the jaw
Common: proteinuria
Very Common: fatigue, mucosal inflammation, asthenia, peripheral oedema
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
Uncommon: wound complications
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.
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.
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).
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.
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.
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.
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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