Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Ipsen Pharma, 70 rue Balard, 75015 Paris, France
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
As most adverse reactions occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Adverse reactions that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting).
In renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy, dose reductions and dose interruptions due to an adverse event (AE) occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial (METEOR). Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption was 38 days.
In treatment-naïve renal cell carcinoma, dose reductions and dose interruptions occurred in 46% and 73%, respectively, of cabozantinib-treated patients in the clinical trial (CABOSUN).
When cabozantinib is given in combination with nivolumab in first-line advanced renal cell carcinoma, dose reduction and dose interruption of cabozantinib due to an AE occurred in 54.1% and 73.4% of patients in the clinical trial (CA2099ER). Two dose reductions were required in 9.4% of patients. The median time to first dose reduction was 106 days, and to first dose interruption was 68 days.
In hepatocellular carcinoma following prior systemic therapy, dose reductions and dose interruptions occurred in 62% and 84%, respectively, of cabozantinib-treated patients in the clinical trial (CELESTIAL). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 38 days, and to first dose interruption was 28 days. Closer monitoring is advised in patients with mild or moderate hepatic impairment.
In differentiated thyroid carcinoma, dose reductions and dose interruptions occurred in 67% and 71% respectively of cabozantinib treated patients in the clinical trial (COSMIC-311). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 57 days and to first dose interruption was 38.5 days.
Abnormalities of liver function tests (increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with cabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of cabozantinib treatment and to monitor closely during treatment. For patients with worsening of liver function tests considered related to cabozantinib treatment (i.e. where no alternative cause is evident), the dose modification advice in Table 1 should be followed (see section 4.2).
When cabozantinib is given in combination with nivolumab, higher frequencies of Grades 3 and 4 ALT and AST elevations have been reported relative to cabozantinib monotherapy in patients with advanced RCC (see section 4.8). Liver enzymes should be monitored before initiation of and periodically throughout treatment. Medical management guidelines for both medicines should be followed (see section 4.2 and refer to the SmPC for nivolumab).
Rare instances of vanishing bile duct syndrome have been reported. All cases have occurred in patients who have received immune checkpoint inhibitors, either before or concurrently with cabozantinib treatment.
Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. Cabozantinib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C, see section 4.2).
In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm. Cabozantinib has been associated with diarrhoea, vomiting, decreased appetite and electrolyte abnormalities. In HCC patients with compromised livers, these non-hepatic effects may be precipitating factors for the development of hepatic encephalopathy. Patients should be monitored for signs and symptoms of hepatic encephalopathy.
Serious GI perforations and fistulas, sometimes fatal, have been observed with cabozantinib. 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. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.
Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most commonly reported GI events (see section 4.8). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see Table 1).
Events of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism, sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events.
In the HCC study (CELESTIAL), portal vein thrombosis was observed with cabozantinib, including one fatal event. Patients with a history of portal vein invasion appeared to be at higher risk of developing portal vein thrombosis. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant thromboembolic complication.
Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage.
In the HCC study (CELESTIAL), fatal haemorrhagic events were reported at a higher incidence with cabozantinib than placebo. Predisposing risk factors for severe haemorrhage in the advanced HCC population may include tumour invasion of major blood vessels and the presence of underlying liver cirrhosis resulting in oesophageal varices, portal hypertension, and thrombocytopenia. The CELESTIAL study excluded patients with concomitant anticoagulation treatment or antiplatelet agents. Subjects with untreated, or incompletely treated, varices with bleeding or high risk for bleeding were also excluded from this study.
The study of cabozantinib in combination with nivolumab in first-line advanced RCC (CA2099ER) excluded patients with anticoagulants at therapeutic doses.
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.
In the HCC study (CELESTIAL) and in the DTC study (COSMIC-311), thrombocytopenia and decreased platelets were reported. Platelet levels should be monitored during cabozantinib treatment and the dose modified according to the severity of the thrombocytopenia (see Table 1).
Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery or invasive dental procedures, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.
Hypertension, including hypertensive crisis has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib.After cabozantinib initiation, blood pressure should be monitored early and regularly and treated as needed with appropriate antihypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib treatment should be interrupted until blood pressure is controlled, after which cabozantinib can be resumed at a reduced dose. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.
Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib therapy. Patients should be advised regarding oral hygiene practice. Cabozantinib treatment should be held at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ.
Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.
Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.
Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with PRES.
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.
Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of cabozantinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during cabozantinib treatment. Thyroid function should be 9 monitored periodically throughout treatment with cabozantinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice.
Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). Hypocalcaemia has been observed with cabozantinib at a higher frequency and/or increased severity (including Grade 3 and 4) in patients with thyroid cancer compared to patients with other cancers. It is recommended to monitor biochemical parameters during cabozantinib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Cases of hepatic encephalopathy in HCC patients can be attributed to the development of electrolyte disturbances. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant abnormalities (see Table 1).
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. 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 (see sections 4.2 and 4.5).
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 (see section 4.5).
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 (see section 4.5).
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.
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.
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.
Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.
In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.
Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure (see section 5.2). The clinical significance of these potential interactions is unknown.
The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended.
The effect of cabozantinib on the pharmacokinetics of warfarin has not been investigated. An interaction with warfarin may be possible. In case of such combination, INR values should be monitored.
Cabozantinib was an inhibitor (IC50 = 7.0 μM), but not a substrate, of 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.
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 (see section 4.5).
There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects (see section 5.3). 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.
There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib (see section 5.3). 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 pneumonia, abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia and 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, fatigue, nausea, decreased appetite, PPES, hypertension, weight decreased, vomiting, dysgeusia, constipation, and AST increased. 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, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain and thrombocytopenia.
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, decreased appetite, PPES, fatigue, nausea, hypertension and vomiting.
The most common serious adverse drug reactions in the DTC population (≥1% incidence) are diarrhoea, pleural effusion, pneumonia, pulmonary embolism, hypertension, anaemia, deep vein thrombosis, hypocalcemia, osteonecrosis of jaw, pain, palmar-plantar erythrodysaesthesia syndrome, vomiting and renal impairment. The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the DTC population included diarrhoea, PPES, hypertension, fatigue, decreased appetite, nausea, alanine aminotransferase increased, aspartate aminotransferase increased and hypocalcaemia.
Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in RCC, HCC and DTC (n=1128) or reported after post-marketing use of cabozantinib are listed in Table 2. The adverse reactions are listed by 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.
Table 2. Adverse drug reactions (ADRs) reported in clinical trials or after post-marketing use in patients treated with cabozantinib in monotherapy:
| Infections and infestations | |
| Common | abscess, pneumonia |
| Blood and lymphatic disorders | |
| Very common | anaemia, thrombocytopenia |
| Common | neutropenia, lymphopenia |
| Endocrine disorders | |
| Very common | hypothyroidism* |
| Metabolism and nutrition disorders | |
| Very common | decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia |
| Common | dehydration, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia, hyperglycaemia, hypoglycaemia |
| Nervous system disorders | |
| Very common | dysgeusia, headache, dizziness |
| Common | peripheral neuropathya |
| Uncommon | convulsion, cerebrovascular accident, posterior reversible encephalopathy syndrome |
| Ear and labyrinth disorders | |
| Common | tinnitus |
| Cardiac disorders | |
| Uncommon | acute myocardial infarction |
| Vascular disorders | |
| Very common | hypertension, haemorrhageb* |
| Common | venous thrombosisc |
| Uncommon | hypertensive crisis, arterial thrombosis, embolism arterial |
| Not known | aneurysms and artery dissections |
| Respiratory, thoracic, and mediastinal disorders | |
| Very common | dysphonia, dyspnoea, cough |
| Common | pulmonary embolism |
| Uncommon | pneumothorax |
| Gastrointestinal disorders | |
| Very common | diarrhoea*, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia |
| Common | gastrointestinal perforation*, pancreatitis, fistula*, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia |
| Uncommon | 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, hyperkeratosis, erythema |
| Not known | cutaneous vasculitis |
| 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 |
| Investigationsd | |
| 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, blood triglycerides increased |
| Injury, poisoning and procedural complications | |
| Uncommon | wound complicationse |
* See section 4.8 Description of selected adverse reactions for further characterisation.
a including polyneuropathy; peripheral neuropathy is mainly sensory
b Including epistaxis as the most commonly reported adverse reaction
c All venous thrombosis including deep vein thrombosis
d Based on reported adverse reactions
e Impaired healing, incision site complication and wound dehiscence
When cabozantinib is administered in combination with nivolumab, refer to the SmPC for nivolumab prior to initiation of treatment. For additional information on the safety profile of nivolumab monotherapy, please refer to the nivolumab SmPC.
In a dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every two weeks in RCC (n=320), with a minimum follow‑up of 16 months, the most common serious adverse drug reactions (≥1% incidence) are diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatremia, pyrexia, adrenal insufficiency, vomiting, dehydration.
The most frequent adverse reactions (≥25%) were diarrhoea, fatigue, palmar-plantar erythrodysaesthesia syndrome, stomatitis, musculoskeletal pain, hypertension, rash, hypothyroidism, decrease appetite, nausea, abdominal pain. The majority of adverse reactions were mild to moderate (Grade 1 or 2).
Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab are listed in Table 3, 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.
Table 3. Adverse reactions with cabozantinib in combination with nivolumab:
| Infections and infestations | ||
| Very Common | upper respiratory tract infection | |
| Common | pneumonia | |
| Blood and lymphatic system disorders | ||
| Common | eosinophilia | |
| Immune system disorders | ||
| Common | hypersensitivity (including anaphylactic reaction) | |
| Uncommon | infusion related hypersensitivity reaction | |
| Endocrine disorders | ||
| Very common | hypothyroidism, hyperthyroidism | |
| Common | adrenal insufficiency | |
| Uncommon | hypophysitis, thyroiditis | |
| Metabolism and nutrition disorders | ||
| Very common | decreased appetite | |
| Common | dehydration | |
| Nervous system disorders | ||
| Very common | dysgeusia, dizziness, headache | |
| Common | peripheral neuropathy | |
| Uncommon | encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome | |
| Ear and labyrinth disorders | ||
| Common | tinnitus | |
| Eye disorders | ||
| Common | dry eye, blurred vision | |
| Uncommon | uveitis | |
| Cardiac disorders | ||
| Common | atrial fibrillation, tachycardia | |
| Uncommon | myocarditis | |
| Vascular disorders | ||
| Very common | hypertension | |
| Common | thrombosisa | |
| Uncommon | embolism arterial | |
| Respiratory, thoracic and mediastinal disorders | ||
| Very common | dysphonia, dyspnoea, cough | |
| Common | pneumonitis, pulmonary embolism, epistaxis, pleural effusion | |
| Uncommon | pneumothorax | |
| Gastrointestinal disorders | ||
| Very common | diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, dyspepsia | |
| Common | colitis, gastritis, oral pain, dry mouth, haemorrhoids | |
| Uncommon | pancreatitis, small intestine perforationb, glossodynia | |
| 2< Hepatobiliary disorders | ||
| Common | hepatitis | |
| Not known | vanishing bile duct syndromec | |
| Skin and subcutaneous tissue disorders | ||
| Very common | palmar-plantar erythrodysaesthesia syndrome, rashd, pruritus | |
| Common | alopecia, dry skin, erythema, hair colour change | |
| Uncommon | psoriasis, urticaria | |
| Not known | cutaneous vasculitis | |
| Musculoskeletal and connective tissue disorders | ||
| Very common | musculoskeletal paine, arthralgia, muscle spasm, | |
| Common | arthritis | |
| Uncommon | myopathy, osteonecrosis of the jaw, fistula | |
| Renal and urinary disorders | ||
| Very common | proteinuria | |
| Common | renal failure, acute kidney injury | |
| Uncommon | nephritis | |
| General disorders and administration site conditions | ||
| Very common | fatigue, pyrexia, oedema | |
| Common | pain, chest pain | |
| Investigationsf | ||
| Very common | increased ALT, increased AST, hypophosphataemia, hypocalcaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia, lymphopenia, increased alkaline phosphatase, increased lipase, increased amylase, thrombocytopaenia, increased creatinine, anaemia, leucopenia, hyperkalaemia, neutropenia, hypercalcaemia, hypoglycaemia, hypokalaemia, increased total bilirubin, hypermagnesaemia, hypernatraemia, weight decreased | |
| Common | blood cholesterol increased, hypertriglyceridaemia | |
Adverse reaction frequencies presented in Table 3 may not be fully attributable to cabozantinib alone but may contain contributions from the underlying disease or from nivolumab used in a combination.
a Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonary thrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein
thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb
b Fatal cases have been reported
c With prior or concomitant immune checkpoint inhibitor exposure
d Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption
e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain
f Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements with the exception of weight decreased, blood cholesterol increased and hypertriglyceridaemia
Data for the following reactions are based on patients who received CABOMETYX 60 mg orally once daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC, in HCC following prior systemic therapy and in DTC in patient refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy or in patients who received CABOMETYX 40 mg orally once daily in combination with nivolumab in first-line advanced RCC (section 5.1).
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.
In the DTC study (COSMIC-311), GI perforation grade 4 was reported in one patient (0.6%) of cabozantinib-treated patients and occurred after 14 weeks of treatment. In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of GI perforations was 1.3% (4/320) treated patients. One event was grade 3, two events were grade 4 and one event was grade 5 (fatal).
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, CABOSUN and CA2099ER) and in the DTC study (COSMIC-311).
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 DTC study (COSMIC-311), diarrhoea was reported in 62% of cabozantinib treated patients (105/170); Grade 3-4 events in 7.6%. Diarrhoea led to dose reduction and interruption in 24/170 (14%) and 36/170 (21%) of subjects respectively.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER), the incidence of diarrhoea was reported in 64.7% (207/320) of treated patients; Grade 3-4 events in 8.4% (27/320). Median time to onset of all events was 12.9 weeks. Dose delay or reduction occurred in 26.3% (84/320) and discontinuation in 2.2% (7/320) of patients with diarrhoea, 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.
In the DTC study (COSMIC-311), fistulas (two anal and one pharyngeal fistula) were reported in 1.8 % (3/170) of the cabozantinib treated patients.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of fistula was reported in 0.9% (3/320) of treated patients and the severity was Grade 1.
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.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of ≥ Grade 3 haemorrhage was in 1.9% (6/320) of treated patients.
In the DTC study (COSMIC-311), the incidence of severe haemorrhagic events (grade ≥ 3) was 2.4% in cabozantinib-treated patients (4/170). Median time to onset was 80.5 days.
Fatal haemorrhages have occurred in the cabozantinib clinical program.
No case of PRES was reported in the METEOR, CABOSUN, CA2099ER or CELESTIAL studies, but PRES has been reported in one patient in the DTC study (COSMIC-311) and rarely in other clinical trials (in 2/4872 subjects; 0.04%).
In a clinical study of previously untreated patients with RCC receiving cabozantinib in combination with nivolumab, a higher incidence of Grades 3 and 4 ALT increased (10.1%) and AST increased (8.2%) were observed relative to cabozantinib monotherapy in patients with advanced RCC (ALT increased of 3.6% and AST increased of 3.3% in METEOR study). The median time to onset of grade > 2 increased ALT or AST was 10.1 weeks (range: 2 to 106.6 weeks; n=85). In patients with grade ≥ 2 increased ALT or AST, the elevations resolved to Grades 0-1in 91% with median time to resolution of 2.29 weeks (range: 0.4 to 108.1 weeks).
Among the 45 patients with Grade ≥2 increased ALT or AST who were rechallenged with either cabozantinib (n=10) or nivolumab (n=10) administered as a single agent or with both (n=25), recurrence of Grade ≥2 increased ALT or AST was observed in 4 patients receiving cabozantinib, in 3 patients receiving nivolumab and 8 patients receiving both cabozantinib and nivolumab.
In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of hypothyroidism was 21% (68/331).
In the treatment-naïve RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.
In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib-treated patients and Grade 3 events in 0.4% (2/467).
In the DTC study (COSMIC-311), the incidence of hypothyroidism was 2.4% (4/170), all grade 1-2, none requiring modification of treatment.
In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of hypothyroidism was 35.6% (114/320) of treated patients.
In study ADVL1211, a limited dose-escalation study of cabozantinib in paediatric and adolescent patients with recurrent or refractory solid tumors including CNS tumors, the following events: aspartate aminotransferase (AST) increased (very common, 76.9%), alanine aminotransferase (ALT) increased (very common, 71.8%), lymphocyte count decreased (very common, 48.7%), neutrophil count decreased (very common, 35.9%), and lipase increased (very common, 33.3%) were observed at a higher frequency in all subjects across all dose groups included in the safety population (N=39), compared to adults. The increased rates for these Preferred Terms (PTs) concern any grade as well as grade ¾ of these ADRs. The adverse events reported are in line qualitatively with the recognised safety profile for cabozantinib in adult populations. However, the small numbers of subjects preclude a conclusive assessment of trends and frequencies and further comparison with the recognised safety profile of cabozantinib.
In study ADVL1622 of cabozantinib in children and young adults with the following solid tumor strata: Ewing sarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), osteosarcoma, Wilms tumor and other rare solid tumors (nonstatistical cohort), the safety profile of cabozantinib treated children and young adults in all strata was comparable with that observed in adults treated with cabozantinib.
Physeal widening has been observed in children with open growth plates when treated with cabozantinib.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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