Cabometyx

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 
 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 20 mg film-coated tablets 

CABOMETYX 40 mg film-coated tablets 

CABOMETYX 60 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

CABOMETYX 20 mg film-coated tablets 

Each film-coated tablet contains cabozantinib (S)-malate equivalent to 20 mg cabozantinib.  

 

Excipients with known effect 

Each film-coated tablet contains 15.54 mg lactose. 

 

CABOMETYX 40 mg film-coated tablets 

Each film-coated tablet contains cabozantinib (S)-malate equivalent to 40 mg cabozantinib. 

 

Excipients with known effect 

Each film-coated tablet contains 31.07 mg lactose. 

 

CABOMETYX 60 mg film-coated tablets 

Each film-coated tablet contains cabozantinib (S)-malate equivalent to 60 mg cabozantinib. 

 

Excipients with known effect 

Each film-coated tablet contains 46.61 mg lactose 

 

For the full list of excipients, see section 6.1. 

 

 
3. PHARMACEUTICAL FORM 

 

Film-coated tablet. 

 

CABOMETYX 20 mg film-coated tablets 

The tablets are yellow round with no score, and debossed with “XL” on one side and “20” on the 

other side of the tablet. 

 

CABOMETYX 40 mg film-coated tablets 

The tablets are yellow triangle shaped with no score, and debossed with “XL” on one side and “40” 

on the other side of the tablet. 

 

CABOMETYX 60 mg film-coated tablets 

The tablets are yellow oval shaped with no score, and debossed with “XL” on one side and “60” on 

the other side of the tablet. 

 

 



3 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Renal Cell Carcinoma (RCC) 

 

CABOMETYX is indicated for the treatment of advanced renal cell carcinoma (RCC): 

- in treatment-naïve adults with intermediate or poor risk (see section 5.1) 

- in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy 

Hepatocellular Carcinoma (HCC) 

CABOMETYX is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in 

adults who have previously been treated with sorafenib. 

 
4.2 Posology and method of administration 

 

Therapy with CABOMETYX should be initiated by a physician experienced in the administration of 

anticancer medicinal products.  

 

Posology 

CABOMETYX (cabozantinib) tablets and COMETRIQ (cabozantinib) capsules are not bioequivalent 

and should not be used interchangeably (see section 5.2). If a patient must switch from cabozantinib 

capsules to cabozantinib tablets, the patient should continue at a CABOMETYX dose not to exceed 

60 mg or the current COMETRIQ dose (whichever is lower). 

 

For RCC and HCC, the recommended dose of CABOMETYX is 60 mg once daily. Treatment should 

continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity 

occurs. 

 

Management of suspected adverse drug reactions may require temporary treatment interruption and/or 

dose reduction of CABOMETYX therapy (see Table 1). When dose reduction is necessary, it is 

recommended to reduce to 40 mg daily, and then to 20 mg daily. Dose interruptions are recommended 

for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities. Dose 

reductions are recommended for events that, if persistent, could become serious or intolerable. 

 

If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the 

next dose. 

 



4 

Table 1: Recommended CABOMETYX dose modifications for adverse reactions 

Adverse reaction and severity  Treatment Modification 

Grade 1 and Grade 2 adverse 

reactions which are tolerable and 

easily managed 

Dose adjustment is usually not required.  

Add supportive care as indicated.  

Grade 2 adverse reactions which are 

intolerable and cannot be managed 

with a dose reduction or supportive 

care 

Interrupt treatment until the adverse reaction resolves to 

Grade ≤1.  

Add supportive care as indicated. 

Consider re-initiating at a reduced dose.  

Grade 3 adverse reactions (except 

clinically nonrelevant laboratory 

abnormalities) 

Interrupt treatment until the adverse reaction resolves to 

Grade ≤1.  

Add supportive care as indicated. 

Re-initiate at a reduced dose. 

Grade 4 adverse reactions (except 

clinically nonrelevant laboratory 

abnormalities) 

Interrupt treatment.  

Institute appropriate medical care. 

If adverse reaction resolves to Grade ≤1, re-initiate at a 

reduced dose. 

If adverse reaction does not resolve, permanently 

discontinue CABOMETYX. 

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology 

Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4)  

 

Concomitant medicinal products 

Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, 

and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be 

avoided (see sections 4.4 and 4.5). 

 

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or 

inhibit CYP3A4 should be considered. 

 

Special populations 

 

Elderly patients 

No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended.  

 

Race 

No dose adjustment is necessary based on ethnicity (see section 5.2)  

 

Patients with renal impairment  

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. 

 

Patients with hepatic impairment 

In patients with mild hepatic impairment no dose adjustment is required. 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 (see sections 4.4 



5 

and 5.2).There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so 

cabozantinib is not recommended for use in these patients (see section 5.2). 

 

Patients with cardiac impairment 

There are limited data in patients with cardiac impairment. No specific dosing recommendations can 

be made. 

 

Paediatric population 

The safety and efficacy of cabozantinib in children and adolescents aged <18 years have not yet been 

established. No data are available. 

 

Method of administration 

CABOMETYX is for oral use. The tablets should be swallowed whole and not crushed. Patients 

should be instructed to not eat anything for at least 2 hours before through 1 hour after taking 

CABOMETYX. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 

4.4 Special warnings and precautions for use 

 

As most events 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. 

Events 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 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). 

 

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.  

 

Hepatic effects  

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). 

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 



6 

hepatic encephalopathy with cabozantinib treatment. Cabometyx is not recommended for use in 

patients with severe hepatic impairment (Child-Pugh C) as cabozantinib has not been studied in this 

population and exposure might be increased in these patients. 

 

Hepatic encephalopathy 

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. 

 

Perforations and fistulas  

Serious gastrointestinal (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. 

 

Gastrointestinal (GI) disorders  

Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most 

commonly reported GI adverse reactions (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). 

 

Thromboembolic events 

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. 

 

Haemorrhage 

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. 

 

Aneurysms and artery dissections 



7 

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. 

 

Thrombocytopenia 

In the HCC study (CELESTIAL), 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 

Wound complications have been observed with cabozantinib. Cabozantinib treatment should be 

stopped at least 28 days prior to scheduled surgery, including dental surgery, 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 

Hypertension has been observed with cabozantinib. Blood pressure should be well-controlled prior to 

initiating cabozantinib. During treatment with cabozantinib, all patients should be monitored for 

hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent 

hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. 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. 

 

Palmar-plantar erythrodysaesthesia syndrome  

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 

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. 

 

Reversible posterior leukoencephalopathy syndrome  

Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as 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 RPLS. 

 

 

Prolongation of 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.  

 

Biochemical laboratory test abnormalities 

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including 

hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). 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. 



8 

Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in 

case of persistent or recurrent significant abnormalities (see Table 1). 

 

CYP3A4 inducers and 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. 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). 

 

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 (see section 4.5). 
 

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 (see section 4.5). 

 

Excipient related warnings 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 

glucose-galactose malabsorption should not take this medicine. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Effect of other medicinal products on cabozantinib 

 

CYP3A4 inhibitors and inducers 

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.  

 

Gastric pH modifying agents 

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. 

 

MRP2 inhibitors 

In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of 

MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.  

 



9 

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 (see section 

5.2). The clinical significance of these potential interactions is unknown. 

 

Effect of cabozantinib on other medicinal products 

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. 

Because of high plasma protein binding levels of cabozantinib (section 5.2) a plasma protein 

displacement interaction with warfarin may be possible. In case of such combination, INR values 

should be monitored. 

 

P-glycoprotein substrates  

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. 

 

4.6 Fertility, pregnancy and lactation 

 

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 (see section 4.5). 

 

Pregnancy 

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. 

 

Breast-feeding 

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. 

 

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 (see section 5.3). Both men and women should 

be advised to seek advice and consider fertility preservation before treatment. 

 

4.7 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. 

 



10 

4.8 Undesirable effects 

 

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. 

 

 

Tabulated list of adverse reactions 

Adverse reactions are listed in Table 2 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. 

 

 

  



11 

Table 2: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with 

cabozantinib 

 

MedDRA 

System Organ 

Class 

Very Common  Common  Uncommon  Not Known 

Infections and 

infestations 

 abscess   

Blood and 

lymphatic 

disorders 

anaemia thrombocytopenia, 

neutropenia 

lymphopenia  

Endocrine 

disorders 

hypothyroidism    

Metabolism and 

nutrition 

disorders 

decreased appetite, 

hypomagnesaemia, 

hypokalaemia 

dehydration, 

hypoalbuminaemia, 

hypophosphataemia, 

hyponatraemia, 

hypocalcaemia, 

hyperkalaemia, 

hyperbilirubinemia 

hyperglycaemia, 

hypoglycaemia 

  

Nervous system 

disorders 

dysgeusia, 

headache, dizziness 

peripheral sensory 

neuropathy 

convulsion cerebrovascul

ar accident 

Ear and 

labyrinth 

disorders 

 tinnitus   

Cardiac 

disorders 

   myocardial 

infarction 

Vascular 

disorders 

hypertension, 

haemorrhage 

venous thrombosis 

arterial thrombosis 

 

 Aneurysms 

and artery 

dissections 

Respiratory, 

thoracic, and 

mediastinal 

disorders 

dysphonia, 

dyspnoea, cough 

pulmonary embolism   

Gastrointestinal 

disorders 

diarrhoea, nausea, 

vomiting, 

stomatitis, 

constipation, 

abdominal pain, 

dyspepsia, upper 

abdominal pain  

gastrointestinal 

perforation, fistula, 

gastroesophageal 

reflux disease, 

haemorrhoids, oral 

pain, dry mouth 

pancreatitis, 

glossodynia 

 



12 

MedDRA 

System Organ 

Class 

Very Common  Common  Uncommon  Not Known 

Hepatobiliary 

disorders 

 Hepatic 

encephalopathy 

hepatitis 

cholestatic 

 

Skin and 

subcutaneous 

tissue disorders 

palmar-plantar 

erythrodysaesthesia 

syndrome, rash 

pruritus, alopecia, 

dry skin, dermatitis 

acneiform, hair 

colour change 

  

Musculoskeletal 

and connective 

tissue disorders 

pain in extremity muscle spasms, 

arthralgia 

osteonecrosis of 

the jaw 

 

Renal and 

urinary 

disorders 

 proteinuria   

General 

disorders and 

administration 

site conditions 

fatigue, mucosal 

inflammation, 

asthenia, peripheral 

oedema 

   

Investigations weight decreased, 

serum ALT 

increased, AST 

increased 

blood ALP 

increased, GGT 

increased, blood 

creatinine increased, 

amylase increased, 

lipase increased, 

blood cholesterol 

increased, white 

blood cell count 

decreased 

blood 

triglycerides 

increased 

 

Injury, 

poisoning and 

procedural 

complications  

  wound 

complications 

 

 

 

Description of selected adverse reactions 

Data for the following reactions are based on patients who received Cabometyx 60 mg 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 (section 5.1).  

 

 

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. 



13 

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%). 

 

Reporting of suspected adverse reactions 

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. 

 

4.9 Overdose 

 

There is no specific treatment for cabozantinib overdose and possible symptoms of overdose have not 

been established. 

 



14 

In the event of suspected overdose, cabozantinib should be withheld and supportive care instituted. 

Metabolic clinical laboratory parameters should be monitored at least weekly or as deemed clinically 

appropriate to assess any possible changing trends. Adverse reactions associated with overdose are to 

be treated symptomatically. 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE26. 

 

Mechanism of action 

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in 

tumour growth and angiogenesis, pathologic bone remodeling, drug resistance, and metastatic 

progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of 

kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and 

VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine 

kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor 

receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.    

 

Pharmacodynamic effects 

Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited 

metastasis in a broad range of preclinical tumour models. 

 

Cardiac electrophysiology 

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 – 15 ms on Day 29 

(but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg qd) was 
observed in a controlled clinical study in medullary thyroid cancer patients. This effect was not 

associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated 

subjects in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated subjects in the 
RCC or HCC studies (at a dose of 60  mg). 
 

Clinical efficacy and safety 

 

Clinical data in renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-

targeted therapy  

The safety and efficacy of CABOMETYX for the treatment of renal cell carcinoma following prior 

vascular endothelial growth factor (VEGF)-targeted therapy were evaluated in a randomized, open-
label, multicenter Phase 3 study (METEOR). Patients (N=658) with advanced RCC with a clear cell 

component who had previously received at least 1 prior VEGF receptor tyrosine kinase inhibitor 

(VEGFR TKI) were randomized (1:1) to receive CABOMETYX (N=330) or everolimus (N=328). 

Patients could have received other prior therapies, including cytokines, and antibodies targeting 

VEGF, the programmed death 1 (PD-1) receptor, or its ligands. Patients with treated brain metastases 

were allowed. Progression-free survival (PFS) was assessed by a blinded independent radiology 

review committee, and the primary analysis was conducted among the first 375 subjects randomized. 

Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumor 

assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter. 

 

The baseline demographic and disease characteristics were similar between the CABOMETYX and 

everolimus arms. The majority of the patients were male (75%), with a median age of 62 years. 

Seventy-one percent (71%) received only one prior VEGFR TKI; 41% of patients received sunitinib 

as their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Center criteria 

for prognostic risk category, 46% were favorable (0 risk factors), 42% were intermediate (1 risk 

factor), and 13% were poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more 



15 

organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone 

(22%). The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving 

CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus. 

 

A statistically significant improvement in PFS was demonstrated for CABOMETYX compared to 

everolimus (Figure 1 and Table 3). A planned interim analysis of OS was conducted at the time of the 

PFS analysis and did not reach the interim boundary for statistical significance (202 events, HR=0.68 

[0.51, 0.90], p=0.006). In a subsequent unplanned interim analysis of OS, a statistically significant 

improvement was demonstrated for patients randomized to CABOMETYX as compared with 

everolimus (320 events, median of 21.4 months vs. 16.5 months; HR=0.66 [0.53, 0.83], p=0.0003; 

Figure 2). Comparable results for OS were observed with a follow-up analysis (descriptive) at 430 

events. 

 

Exploratory analyses of PFS and OS in the ITT population have also shown consistent results in 

favour of CABOMETYX compared to everolimus across different subgroups according to age (<65 

vs. ≥65, sex, MSKCC risk group (favourable, intermediate, poor), ECOG status (0 vs. 1), time from 

diagnosis to randomisation (<1 year vs. ≥1 year), tumour MET status (high vs. low vs. unknown), 

bone metastases (absence vs. presence), visceral metastases (absence vs. presence), visceral and bone 

metastases (absence vs. presence), number of prior VEGFR-TKIs (1 vs. ≥2), duration of first VEGFR-

TKI (≤6 months vs. >6 months). 

 

Objective response rate findings are summarized in Table 4. 

 

Figure 1: Kaplan Meier curve for progression-free survival by independent radiology review 

committee, in RCC subjects following prior vascular endothelial growth factor (VEGF)-

targeted therapy (first 375 subjects randomized) (METEOR) 

M o n th s

P
r
o

b
a

b
il

it
y

 o
f 

P
r
o

g
r
e

s
s

io
n

-f
r
e

e
 S

u
r
v

iv
a

l

0 3 6 9 1 2 1 5 1 8

0 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1 .0

No. at Risk 
       CABOMETYX 187 152 92 68 20 6 2 

Everolimus 188 99 46 29 10 2 0 

 

  
 

  

P
ro

b
a
b

il
it

y
 o

f 
P

ro
g

re
s
s
io

n
-f

re
e
 S

u
rv

iv
a
l 

Months Number at risk: 

CABOMETYX 

Everolimus 

CABOMETYX 

Everolimus 



16 

Table 3: Summary of PFS findings by independent radiology review committee in RCC subjects 

following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR) 

 

 Primary PFS analysis Population Intent-To-Treat Population 

Endpoint CABOMETYX Everolimus CABOMETYX Everolimus 

 N = 187 N = 188 N = 330 N = 328 

Median PFS (95% 

CI), months 

7.4 (5.6, 9.1) 3.8 (3.7, 5.4) 7.4 (6.6, 9.1) 3.9 (3.7, 5.1) 

HR (95% CI), 

p-value1 

0.58 (0.45, 0.74), p<0.0001 0.51 (0.41, 0.62), p<0.0001 

1 stratified log-rank test 

 

Figure 2: Kaplan-Meier curve of overall survival in RCC subjects following prior vascular 

endothelial growth factor (VEGF)-targeted therapy (METEOR) 

M o n th s

P
r
o

b
a

b
il

it
y

 o
f 

O
v

e
r
a

ll
 S

u
r
v

iv
a

l

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0

0 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1 .0

C A B O M E T Y X

E v e ro lim u s

330 318 296 264 239 178 105 41 6 3 0

328 307 262 229 202 141 82 32 8 1 0

 
 

P
ro

b
a
b

il
it

y
 o

f 
O

v
e

ra
ll
 S

u
rv

iv
a
l 

Months Number at risk: 

CABOMETYX 

Everolimus 

CABOMETYX 

Everolimus 



17 

Table 4: Summary of ORR findings per independent radiology committee review (IRC) and 

investigator review, in RCC subjects following prior vascular endothelial growth factor 

(VEGF)-targeted therapy 

 

 Primary Analysis ORR Intent-

To-Treat Population (IRC) 

ORR per Investigator Review 

Intent-To-Treat Population 

Endpoint CABOMETYX Everolimus CABOMETYX Everolimus 

 N = 330 N = 328 N = 330 N = 328 

ORR (partial 

responses only) 

(95% CI) 

17% (13%, 22%) 3% (2%, 6%) 24% (19%, 29%) 4% (2%, 7%) 

p-value1 p<0.0001 p< 0.0001 

Partial Response 17% 3% 24% 4% 

Median time to 

First Response, 

months (95% CI) 

1.91 (1.6, 11.0) 2.14 (1.9, 9.2) 1.91 (1.3, 9.8) 3.50 (1.8, 5.6) 

Stable Disease as 

Best Response 

65% 62% 63% 63% 

Progressive Disease 

as Best Response 

12% 27% 9% 27% 

1 chi-squared test 

 

Clinical data in treatment-naïve renal cell carcinoma 

 

The safety and efficacy of CABOMETYX for the treatment of treatment-naïve renal cell carcinoma 

were evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N=157) with 

previously untreated, locally advanced or metastatic RCC with a clear cell component were randomized 

(1:1) to receive CABOMETYX (N=79) or sunitinib (N=78). Patients had to have intermediate or poor 

risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group 

categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no). 

Approximately 75% of patients had a nephrectomy prior to onset of treatment. 

For intermediate risk disease, one or two of the following risk factors were met, while for poor risk, 

three or more factors were met: time from diagnosis of RCC to systemic treatment < 1 year, Hgb < 

LLN, Corrected calcium > ULN, KPS < 80%, Neutrophil count > ULN and Platelet count > ULN. 

 

The primary endpoint was PFS. Secondary efficacy endpoints were objective response rate (ORR) and 

overall survival (OS). Tumor assessments were conducted every 12 weeks. 

 

The baseline demographic and disease characteristics were similar between the CABOMETYX and 

sunitinib arms. The majority of the patients were male (78%) with a median age of 62 years. Patient 

distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥3 risk 

factors). Most patients (87%) had ECOG performance status of 0 or 1; 13% had an ECOG 

performance status of 2. Thirty-six percent (36%) of patients had bone metastases.  

 

A statistically significant improvement in PFS as retrospectively assessed by a blinded Independent 

Radiology Committee (IRC) was demonstrated for CABOMETYX compared to sunitinib (Figure 3 and 

Table 5). The results from the Investigator determined analysis and IRC-determined analysis of PFS 

were consistent.  

 

Patients with both positive and negative MET status showed a favourable effect with CABOMETYX 

compared to sunitinib, with greater activity in patients with a positive MET status compared to patients 

with a negative MET status (HR=0.32 (0.16, 0.63) vs 0.67 (0.37, 1.23)) respectively. 

 



18 

CABOMETYX treatment was associated with a trend for longer survival compared to sunitinib (Table 

5). The study was not powered for the OS analysis and the data are immature.  

 

 

Objective response rate (ORR) findings are summarized in Table 5. 

 

Figure 3: Kaplan Meier curve for progression-free survival by IRC in treatment-naïve RCC 

subjects  

  

0 3 6 9 12 15 18 21 24 27 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

 
  

P
ro

b
a
b

il
it

y
 o

f 
P

ro
g

re
s
s
io

n
-f

re
e
 S

u
rv

iv
a
l 

Months 
Number at risk: 

CABOMETYX 

Sunitinib 

CABOMETYX 

Sunitinib 



19 

Table 5: Efficacy results in treatment-naïve RCC subjects (ITT population, CABOSUN) 

 

 CABOMETYX 

(N=79) 

Sunitinib 

(N=78) 

Progression-free survival (PFS) by IRC a 

Median PFS in months (95% CI) 8.6 (6.2, 14.0) 5.3 (3.0, 8.2) 

HR (95% CI); stratified b,c 0.48 (0.32, 0.73) 

Two-sided log-rank p-value: 

stratified b 

p=0.0005 

Progression-free survival (PFS) by Investigator 

Median PFS in months (95% CI) 8.3 (6.5, 12.4) 5.4 (3.4, 8.2) 

HR (95% CI); stratified b,c 0.56 (0.37, 0.83) 

Two-sided log-rank p-value: 

stratified b 

p=0.0042 

Overall Survival 

Median OS in months (95% CI) 30.3 (14.6, NE) 21.0 (16.3, 27.0) 

HR (95% CI); stratified b,c 0.74 (0.47, 1.14) 

Objective Response Rate n (%) by IRC 

Complete responses 0 0 

Partial responses 16 (20) 7 (9) 

ORR (partial responses only) 16 (20) 7 (9) 

Stable disease 43 (54) 30 (38) 

Progressive Disease 14 (18)  23 (29) 

Objective Response Rate n (%) by Investigator 

Complete responses 1 (1) 0 

Partial responses 25 (32) 9 (12) 

ORR (partial responses only) 26 (33) 9 (12) 

Stable disease 34 (43) 29 (37) 

Progressive Disease 14 (18)  19 (24) 

 
a in accord with EU censoring  
b Stratification factors per IxRS comprise IMDC risk categories (intermediate risk, poor risk and bone metastasis (yes, no) 
c Estimated using the Cox proportional hazard model adjusted for stratification factors per IxRS. Hazard ratio < 1 indicates 

progression-free survival in favor of cabozantinib 

 

Clinical data in Hepatocellular Carcinoma 

The safety and efficacy of CABOMETYX were evaluated in a randomized, double-blind, placebo-

controlled Phase 3 study (CELESTIAL). Patients (N=707) with HCC not amenable to curative 

treatment and who had previously received sorafenib for advanced disease were randomized (2:1) to 

receive CABOMETYX (N=470) or placebo (N=237). Patients could have received one other prior 

systemic therapy for advanced disease in addition to sorafenib. Randomization was stratified by 

aetiology of disease (HBV [with or without HCV], HCV [without HBV], or other), geographic region 

(Asia, other regions) and by presence of extrahepatic spread of disease and/or macrovascular 

invasions (Yes, No). 

 

The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints were 

progression-free survival (PFS) and objective response rate (ORR), as assessed by the Investigator 

using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Tumour assessments were 

conducted every 8 weeks. Subjects continued blinded study treatment after radiological disease 

progression whilst they experienced clinical benefit or until the need for subsequent systemic or liver-



20 

directed local anticancer therapy. Crossover from placebo to cabozantinib was not allowed during the 

blinded treatment phase.   

The baseline demographic and disease characteristics were similar between the CABOMETYX and 

placebo arms and are shown below for all 707 randomised patients:  

Male: 82%  

Median age: 64 years.  

Caucasian: 56%, Asian: 34% 

ECOG performance status (PS) 0: 53% or ECOG PS 1: 47%.  

Child Pugh A: 99%, Child Pugh B: 1 %  

Aetiology for HCC included 38% hepatitis B virus (HBV), 21% hepatitis C virus (HCV),  40% other 

(neither HBV nor HCV).  

Presence of macroscopic vascular invasion and/ or extra-hepatic tumour spread:78%,  

Alfa-fetoprotein (AFP) levels ≥400 μg/L: 41%.  

Loco-regional transarterial embolisation or chemoinfusion procedures: 44% 

Radiotherapy prior to cabozantinib treatment: 37% 

Median duration of sorafenib treatment: 5.32 months 

Seventy-two percent (72%) of patients had received one and 28% had received 2 prior systemic 

therapy regimens for advanced disease.  

 

A statistically significant improvement in OS was demonstrated for CABOMETYX compared to 

placebo (Table 6 and Figure 4).  

PFS and ORR findings are summarized in Table 6. 

 

  



21 

Table 6: Efficacy results in HCC (ITT population, CELESTIAL) 

 

 CABOMETYX 

(N=470) 

Placebo 

(N=237) 

Overall Survival 

Median OS (95% CI), months 10.2 (9.1, 12.0) 8.0 (6.8, 9.4) 

HR (95% CI)1,2 0.76 (0.63, 0.92) 

p-value1 p=0.0049 

 

 

Progression-free survival (PFS)3 

Median PFS in months (95% CI) 5.2 (4.0, 5.5) 1.9 (1.9, 1.9) 

HR (95% CI)1 0.44 (0.36, 0.52) 

p-value1 p<0.0001 

Kaplan-Meier landmark estimates of 

percent of subjects event-free at 3 

months 

 

% (95% CI) 67.0% (62.2%, 71.3%) 33.3% (27.1%, 39.7%) 

Objective Response Rate n (%)3 

Complete responses (CR) 0 0 

Partial responses (PR) 18 (4) 1 (0.4) 

ORR (CR+PR)) 18 (4) 1 (0.4) 

p-value1,4 p=0.0086 

Stable disease 282 (60) 78 (33) 

Progressive Disease 98 (21)  131 (55) 

 
1 2-sided stratified log-rank test with etiology of disease (HBV [with or without HCV], HCV [without 

HBV], or Other), geographic region (Asia, Other Regions), and presence of extrahepatic spread of 

disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data) 
2 estimated using the Cox proportional-hazard model 
3 as assessed by investigator per RECIST 1.1 
4 stratified Cochran-Mantel-Haenszel (CMH) test 

 



22 

Figure 4: Kaplan-Meier curve of overall survival (CELESTIAL) 

 
Figure 5: Kaplan Meier curve for progression-free survival (CELESTIAL) 

 
 

The incidence of systemic non-radiation and local liver-directed systemic non-protocol anticancer 

therapy (NPACT) was 26% in the cabozantinib arm and 33% in the placebo arm. Subjects receiving 

0 6 12 18 24 30 36 42

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months 

CABOMETYX 

Placebo 

P
ro

b
a
b

il
it

y
 o

f 
S

u
rv

iv
a
l 

P
ro

b
a
b

il
it

y
 o

f 
P

ro
g

re
s
s
io

n
-F

re
e
 S

u
rv

iv
a
l 

Months Number at risk: 

CABOMETYX 

Placebo 

CABOMETYX 

Placebo 

Number at risk: 

CABOMETYX 

Placebo 



23 

these therapies had to discontinue study treatment. An exploratory OS analysis censoring for the use 

of NPACT supported the primary analysis: the HR, adjusted for stratification factors (per IxRS), was 

0.66 (95% CI: 0.52, 0.84; stratified logrank p-value = 0.0005). The Kaplan- Meier estimates for 

median duration of OS were 11.1 months in the cabozantinib arm versus 6.9 months in the placebo 

arm, an estimated 4.2-month difference in the medians. 

 

Non-disease specific quality of life (QoL) was assessed using the EuroQoL EQ-5D-5L. A negative 

effect of Cabometyx versus placebo on the EQ-5D utility index score was observed during the first 

weeks of treatment. Only limited QoL data are available after this period. 

 

 

Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies with 

CABOMETYX in all subsets of the paediatric population in treatment of hepatocellular carcinoma, 

and kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell 

sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see 

section 4.2 for information on paediatric use).   

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached 

at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak 

approximately 24 hours after administration, which suggests that cabozantinib may undergo 

enterohepatic recirculation. 

 

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold 

mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady 

state is achieved by approximately Day 15.   

 

A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to 

fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is 

no information on the precise food-effect when taken 1 hour after administration of cabozantinib. 

 

Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations 

following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet 

formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ) was observed. A 

less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and 

capsule (COMETRIQ) formulations. 

 

Distribution 

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population-

pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was 

estimated to be 212 L. Protein binding was not altered in subjects with mild or moderately impaired 

renal or hepatic function. 

 

Biotransformation 

Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) 

greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy 

sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184-

N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition 

potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure. 

 



24 

Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 

inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalyzed human liver 

microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, 

CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A 

neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation 

(ie, a <20% reduction). 

 

Elimination 

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthy 

volunteers following oral administration of a range of doses from 20 to 140 mg, the plasma terminal 

half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was 

estimated to be 2.48 L/hr . Within a 48-day collection period after a single dose of 14C-cabozantinib in 

healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 

54% in faeces and 27% in urine.  

 

Pharmacokinetics in special patient populations 

 

Renal impairment 

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of 

geometric LS mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for 

subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 

171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 

140.11%), for subjects with moderate renal impairment compared to subjects with normal renal 

function.  Subjects with severe renal impairment have not been studied. 

 

Hepatic impairment 

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and 

cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma 

exposure was observed amongst subjects with normal liver function (n=1425) and mild hepatic 

impairment (n=558). There is limited data in patients with moderate hepatic impairment (n=15) as per 

NCI-ODWG (National Cancer Institute – Organ Dysfunction working Group) criteria. The 

pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment. 

 

 

Race 

A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based 

on race. 

 

5.3 Preclinical safety data 

 

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to 

clinical exposure levels and with possible relevance to clinical use were as follows: 

 

In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI 

tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed 

adverse effect level (NOAEL) for these findings were below human clinical exposure levels at 

intended therapeutic dose. 

 

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity 

assays. The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 

transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, cabozantinib-

related neoplastic findings consisted of an increased incidence of benign pheochromocytoma, alone or 

in combination with malignant pheochromocytoma/complex malignant pheochromocytoma of the 

adrenal medulla in both sexes at exposures well below the intended exposure in humans. The clinical 

relevance of the observed neoplastic lesions in rats is uncertain, but likely to be low. 



25 

Cabozantinib was not carcinogenic in the rasH2 mouse model at a slightly higher exposure than the 

intended human therapeutic exposure. 

 

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis 

was observed in male dogs at exposure levels below human clinical exposure levels at intended 

therapeutic dose.  

 

Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused 

postimplantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In 

rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing 

intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo-

foetal toxicity and teratogenic findings were below human clinical exposure levels at intended 

therapeutic dose.   

 

Juvenile rats (comparable to a >2 year- old paediatric population) administered cabozantinib showed 

increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive 

system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and 

density, liver pigmentation and lymph node lymphoid hyperplasia. Findings in uterus/ovaries and 

decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver 

pigmentation were sustained. Juvenile rats (correlating to a <2- year paediatric population) showed 

similar treatment-related findings but appeared to be more sensitive to cabozantinib-related toxicity at 

comparable dose levels. 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet content 

Microcrystalline cellulose 

Anhydrous lactose 

Hydroxypropyl cellulose 

Croscarmellose sodium 

Colloidal anhydrous silica 

Magnesium stearate 

 

Film-coating 

Hypromellose 2910 

Titanium dioxide (E171) 

Triacetin 

Iron oxide yellow (E172) 

 

6.2 Incompatibilities 

 

Not applicable.  

 

6.3 Shelf life 

 

3 years. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container  

 



26 

HDPE bottle with a polypropylene child-resistant closure and three silica gel dessicant canisters. Each 

bottle contains 30 film-coated tablets. 

 

6.6 Special precautions for disposal  

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

Cabometyx 20 mg film-coated tablets 

EU/1/16/1136/002 
 

Cabometyx 40 mg film-coated tablets 

EU/1/16/1136/004 
 

Cabometyx 60 mg film-coated tablets 

EU/1/16/1136/006 
 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 09 September 2016 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

  



27 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 



28 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Patheon France 

40 Boulevard de Champaret 

38300 Bourgoin-Jallieu 

FRANCE 

 

Or  

 

Tjoapack Netherlands B.V. 

Nieuwe Donk 9 

4879 AC Etten-Leur 

The Netherlands 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 

product within 6 months following authorisation.  

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached.  

 

  



29 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



30 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

  



31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 20 mg film-coated tablets 

cabozantinib  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains cabozantinib (S)-malate equivalent to 20 mg of cabozantinib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



32 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Any unused product or waste material should be disposed of in accordance with local requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1136/002 
 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

CABOMETYX 20 mg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

  



33 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 40 mg film-coated tablets 

cabozantinib  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains cabozantinib (S)-malate equivalent to 40 mg of cabozantinib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



34 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Any unused product or waste material should be disposed of in accordance with local requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1136/004 
 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

CABOMETYX 40 mg  

 

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 

  



35 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 60 mg film-coated tablets 

cabozantinib  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains cabozantinib (S)-malate equivalent to 60 mg of cabozantinib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Any unused product or waste material should be disposed of in accordance with local requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1136/006 
 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

CABOMETYX 60 mg  

 

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

  



37 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 20 mg film-coated tablets 

cabozantinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains cabozantinib (S)-malate equivalent to 20 mg cabozantinib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



38 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1136/002 
 

 

13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 



39 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 40 mg film-coated tablets 

cabozantinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains cabozantinib (S)-malate equivalent to 40 mg cabozantinib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



40 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1136/004 
 

 

13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 



41 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BOTTLE LABEL  

 

1. NAME OF THE MEDICINAL PRODUCT 

 

CABOMETYX 60 mg film-coated tablets 

cabozantinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains cabozantinib (S)-malate equivalent to 60 mg cabozantinib. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

30 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 



42 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1136/006 
 

 

13. BATCH NUMBER<, DONATION AND PRODUCT CODES> 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

  



43 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

  



44 

Package leaflet: Information for the patient 

 

CABOMETYX 20 mg film-coated tablets 

CABOMETYX 40 mg film-coated tablets 

CABOMETYX 60 mg film-coated tablets 

cabozantinib  

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

 

- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 

 

 

What is in this leaflet 

 

1. What CABOMETYX is and what it is used for  

2. What you need to know before you take CABOMETYX 

3. How to take CABOMETYX 

4. Possible side effects  

5. How to store CABOMETYX 

6. Contents of the pack and other information 

 

 

1. What CABOMETYX is and what it is used for 

 

What CABOMETYX is 

 

CABOMETYX is a cancer medicine that contains the active substance cabozantinib.  

It is used to treat: 

- advanced stages of a type of kidney cancer called renal cell carcinoma  
- liver cancer in adults who have been previously treated with a specific anticancer medicine 

(sorafenib).  

 

How CABOMETYX works 

 

CABOMETYX blocks the action of proteins called receptor tyrosine kinases (RTKs), which are 

involved in the growth of cells and the development of new blood vessels that supply them. These 

proteins can be present in high amounts in cancer cells, and by blocking their action CABOMETYX 

can slow down the rate at which the tumour grows and help to cut off the blood supply that the cancer 

needs.  

 

 

2. What you need to know before you take CABOMETYX 

 

Do not take CABOMETYX 



45 

 

- - if you are allergic to cabozantinib or any of the other ingredients of this medicine (listed in 
section 6). 

 

Warnings and precautions  

 

Talk to your doctor or pharmacist before taking CABOMETYX if you: 

 

-   have high blood pressure 

- have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear 
in a blood vessel wall 

-  have diarrhoea 

-  have a recent history of significant bleeding 

- have had surgery within the last month (or if surgical procedures are planned), including 

dental surgery 

- have inflammatory bowel disease (for example, Crohn’s disease or ulcerative colitis, 

diverticulitis, or appendicitis) 

- have a recent history of blood clot in the leg, stroke, or heart attack 

- have liver or kidney disease.  

 

Tell your doctor if any of these affect you.  

 

You may need treatment for them, or your doctor may decide to change your dose of CABOMETYX, 

or stop treatment altogether. See also section 4 “Possible side effects”. 

 

Children and adolescents 

 

CABOMETYX is not recommended for children or adolescents. The effects of CABOMETYX in 

people younger than 18 years old are not known. 

 

Other medicines and CABOMETYX 

 

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 

including medicines obtained without a prescription. This is because CABOMETYX can affect the 

way some other medicines work. Also, some medicines can affect the way CABOMETYX works. 

This could mean that your doctor needs to change the dose(s) that you take. You should tell your 

doctor about every medicine, but in particular if taking: 

 

- Medicines that treat fungal infections, such as itraconazole, ketoconazole, and posaconazole 
- Medicines used to treat bacterial infections (antibiotics) such as erythromycin, clarithromycin, 

and rifampicin 

- Allergy medicines such as fexofenadine and ranolazine 
- Medicines used to treat epilepsy or fits such as phenytoin, carbamazepine, and phenobarbital  
- Herbal preparations containing St. John’s Wort (Hypericum perforatum), sometimes used for 

treating depression or depression-related conditions such as anxiety 

- Medicines used to thin the blood, such as warfarin 
- Medicines to treat high blood pressure or other heart conditions, such as aliskiren, 

ambrisentan, dabigatran etexilate, digoxin, talinolol, and tolvaptan 

- Medicines for diabetes, such as saxagliptin and sitagliptin  
- Medicines used to treat gout, such as colchicine 
- Medicines used to treat HIV or AIDS, such as efavirenz, ritonavir, maraviroc and 

emtricitabine 

- Medicines used to prevent transplant rejection (ciclosporin) and ciclosporin-based regimens 
in rheumatoid arthritis and psoriasis 

 



46 

Oral contraceptives 

If you take CABOMETYX whilst using oral contraceptives, the oral contraceptives may be 

ineffective. You should also use a barrier contraceptive (e.g. condom or diaphragm) whilst taking 

CABOMETYX and for at least 4 months after treatment has finished. 

 

Taking CABOMETYX with food 

 

You should not take CABOMETYX with food. You should not eat anything for at least 2 hours 

before taking CABOMETYX and for 1 hour after taking the medicine. Avoid consuming grapefruit-

containing products for as long as you are using this medicine, as they may increase the levels of 

CABOMETYX in your blood. 

 

Pregnancy, breast-feeding and fertility  

 

Avoid becoming pregnant while being treated with CABOMETYX. If you or your partner could 

become pregnant, use adequate contraception during treatment and for at least 4 months after 

treatment has finished. Talk to your doctor about which methods of contraception are appropriate 

while you are taking CABOMETYX (see also under Other medicines and CABOMETYX, above). 

 

Tell your doctor if you or your partner become pregnant or plan to become pregnant while you are 

being treated with CABOMETYX. 

 

Talk to your doctor BEFORE taking CABOMETYX if you or your partner are considering or 

planning to have a baby after your treatment has finished. There is a possibility your fertility could be 

affected by treatment with CABOMETYX.  

 

Women taking CABOMETYX should not breast-feed during treatment and for at least 4 months after 

treatment has finished, as cabozantinib and/or its metabolites may be excreted in breast milk and be 

harmful to your child. 

 

Driving and using machines 

 

Use caution when driving or using machines. Keep in mind that treatment with CABOMETYX may 

make you feel tired or weak and can affect your ability to drive or use machines. 

 

CABOMETYX contains lactose 

CABOMETYX contains lactose (a type of sugar). If you have been told by your doctor that you have 

an intolerance to some sugars, talk to your doctor before taking this medicine. 

 

 

3. How to take CABOMETYX 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

You should continue to take this medicine until your doctor decides to stop your treatment. If you get 

serious side effects, your doctor may decide to change your dose or stop treatment earlier than 

originally planned. Your doctor will tell you if you need your dose adjusted. 

 

CABOMETYX should be taken once a day. The usual dose is 60 mg, however your doctor will 

decide on the right dose for you. 

 

CABOMETYX should not be taken with food. You should not eat anything for at least 2 hours before 

taking CABOMETYX and for 1 hour after taking the medicine. Swallow the tablet with a full glass of 

water. Do not crush the tablets. 



47 

 

If you take more CABOMETYX than you should 

 

If you have taken more CABOMETYX than you have been instructed to, talk to a doctor or go to the 

hospital with the tablets and this leaflet straight away. 

 

If you forget to take CABOMETYX 

 

- If there are still 12 hours or more before your next dose is due, then take the missed dose as 

soon as you remember. Take the next dose at the normal time. 

- If your next dose is due in less than 12 hours, then do not take the dose that you have missed. 

Take your next dose at the normal time.  

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get 

side effects, your doctor may tell you to take CABOMETYX at a lower dose. Your doctor may also 

prescribe other medicines to help control your side effects. 

 

Tell your doctor straight away if you notice any of the following side effects – you may need 

urgent medical treatment: 

 

• Symptoms including pain in the abdomen, nausea (feeling sick), vomiting, constipation, or 
fever. These may be signs of a gastrointestinal perforation, a hole that develops in your 

stomach or intestine that could be life-threatening. 

• Severe or uncontrollable bleeding with symptoms such as: vomiting blood, black stolls, 
bloody urine, headache, coughing up blood. 

• Swelling, pain in your hands and feet, or shortness of breath. 

• A wound that does not heal.  

• Fits, headaches, confusion, or finding it difficult to concentrate. These may be signs of a 
condition called reversible posterior leukoencephalopathy syndrome (RPLS). RPLS is rare (it 

affects less than 1 in 1000 people). 

• Feeling drowsy, confused or loss of consciousness. This may be due to liver problems. 
 

 

Other side effects include: 

 

Very common side effects (may affect more than 1 in 10 people)  

 

• Stomach upset, including diarrhoea, nausea, vomiting, constipation, indigestion, abdominal 

pain,  

• Blisters, pain of the hands or soles of the feet, rash or redness of the skin 

• Decreased appetite, weight loss, altered sense of taste 

• Fatigue, weakness, headache, dizziness 

• Hypertension (increase in blood pressure) 

• Anaemia (low levels of red blood cells) 

• Redness, swelling or pain in the mouth or throat, Difficulty in speaking, hoarseness, cough 

• Changes in blood tests used to monitor general health and function of your organs (including 

the liver, and kidney), low levels of electrolytes (like magnesium, or potassium) 

• Shortness of breath 

• Reduced thyroid activity; symptoms can include: tiredness, weight gain, constipation, feeling 

cold and dry skin 

• Swelling in your legs and arms 



48 

 

Common side effects (may affect up to 1 in 10 people) 

 

• Abscess (collection of pus, with swelling and inflammation) 

• Dehydration 

• Ringing in ears 

• Blood clots in the veins, arteries and lungs 

• Low level of platelets and white blood cells 

• Low level of albumin in blood 

• Increased or decreased blood glucose level 

• Decrease in levels of; calcium, sodium and phosphate in the blood 

• Increase in level of potassium in the blood 

• Increase in the level of bilirubin in the blood (which may result in jaundice/yellow skin or 

eyes) 

• Increase in amylase levels in the blood 

• Increase in lipase levels in the blood 

• Increase in cholesterol levels in the blood 

• Numbness, tingling, burning sensation or pain in the limbs 

• A painful tear or abnormal connection of the tissues in your body 

• Gastro-oesophageal reflux disease (bringing up stomach acid) 

• Haemorrhoids (piles) 

• Dry mouth and pain in the mouth 

• Feeling drowsy, confused or loss of consciousness due to liver problems 

• Dry skin, severe itching of skin, acne 

• Alopecia (hair loss and thinning), hair colour change 

• Pain in arms, legs and joints, muscle spasms 
• Protein in urine (seen in tests) 

 

Uncommon side effects (may affect 1 in 100 people) 

 

• Fits  

• Low level of a type of white blood cell (lymphocytes) 

• A burning or stinging sensation of the tongue 

• Inflammation of the pancreas 

• Decrease in bile flow from the liver 

• Bone damage in the jaw 

• Increase in blood triglyceride levels in the blood 

• Wound complications 

 

Not known (proportion of people affected not known) 

 

• Stroke 

• Heart attack 

• An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 
(aneurysms and artery dissections) 

 

 

Reporting of side effects  

 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects, you can help provide more information on the safety 

of this medicine. 

 



49 

 

5. How to store CABOMETYX 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the bottle label and carton after EXP. 

The expiry date refers to the last day of that month. 

 

This medicinal product does not require any special storage conditions. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What CABOMETYX contains  

 

The active substance is cabozantinib (S)-malate.  

 

CABOMETYX 20 mg film-coated tablets: Each tablet contains cabozantinib (S)-malate equivalent to 

20 mg of cabozantinib. 

CABOMETYX 40 mg film-coated tablets: Each tablet contains cabozantinib (S)-malate equivalent to 

40 mg of cabozantinib. 

CABOMETYX 60 mg film-coated tablets: Each tablet contains cabozantinib (S)-malate equivalent to 

60 mg of cabozantinib. 

 

The other ingredients are: 

 

- Tablet contents: microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, 

croscarmellose sodium, colloidal silicon dioxide anhydrous, magnesium stearate. (see section 

2 for lactose content) 

- Film coating: hypromellose, titanium dioxide (E171), triacetin, iron oxide yellow (E172) 

 

What CABOMETYX looks like and contents of the pack 

 

CABOMETYX 20 mg film-coated tablets are yellow, round with no score, and identified with “XL” 

on one side and “20” on the other side. 

CABOMETYX 40 mg film-coated tablets are yellow, triangle shaped with no score, and identified 

with “XL” on one side and “40” on the other side. 

CABOMETYX 60 mg film-coated tablets are yellow, oval shaped with no score, and identified with 

“XL” on one side and “60” on the other side. 

 

CABOMETYX tablets are available in packs containing one plastic bottle with 30 tablets.  

 

Marketing Authorisation Holder 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 



50 

Manufacturer 

 

Patheon France  

40 Boulevard de Champaret 

38300 Bourgoin Jallieu, France 

 

Or  

 

Tjoapack Netherlands B.V. 

Nieuwe Donk 9 

4879 AC Etten-Leur 

The Netherlands 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien, 

Luxembourg/Luxemburg 

Italia 

Ipsen NV Guldensporenpark 87 Ipsen SpA 

B-9820 Merelbeke  Via del Bosco Rinnovato n. 6 

België /Belgique/Belgien Milanofiori Nord Palazzo U7 

Tél/Tel: + 32 - 9 - 243 96 00 20090 Assago (Mi) 

 Tel: + 39 - 02 - 39 22 41 

  

България Latvija  

PharmaSwiss EOOD Ipsen Pharma representative office 

16, Troyanski Prohod Street, Kalnciema street 33-5 

Floor 3, Office 8, Lagera Riga  

1612 Sofia LV 1046 

Тел.: +359 2 8952 110 Tel: +371 67622233 

  

Česká republika Lietuva 

Ipsen Pharma, s.r.o.  

Olbrachtova 2006/9, 

140 00 Praha 4  

Ipsen Pharma SAS Lietuvos filialas  

T. Narbuto g. 5,  

08105 Vilnius 

Tel. +370 700 33305 
Tel: + 420 242 481 821 

 

Danmark, Norge, Suomi/Finland, 

Sverige, Ísland 

Magyarország 

Institut Produits Synthèse (IPSEN) AB 

Kista Science Tower  

Färögatan 33 

SE- 164 51 Kista  

Sverige/Ruotsi/Svíþjóð  

Tlf/Puh/Tel/Sími: +46 8 451 60 00 

Ipsen Pharma SAS Magyarországi Kereskedelmi 

Képviselet 

Árbóc utca 6. 

H- 1133 Budapest 

Tel.: +36-1-555-5930 

 

 

Deutschland, Österreich Nederland 

Ipsen Pharma GmbH  Ipsen Farmaceutica B.V.  

Einsteinstraße 174 Taurusavenue 33b 

D-81677 München 2132 LS Hoofddorp  

Tel.: +49 89 2620 432 89 Tel: + 31 (0) 23 554 1600 

  



51 

Eesti Polska 

Centralpharma Communications OÜ Ipsen Poland Sp. z o.o. Al. Jana Pawła II 29 

Selise 26-11, 00-867 Warszawa 

13522, Tallinn  Tel.: + 48 (0) 22 653 68 00 

Tel: +372 60 15 540  

  

Ελλάδα, Κύπρος, Malta Portugal 

Ipsen Μονοπρόσωπη EΠΕ 

Αγ. Δημητρίου 63 Άλιμος 

GR-17456 Αθήνα Ελλάδα 

Τηλ: + 30 - 210 - 984 3324 

Ipsen Portugal - Produtos Farmacêuticos S.A. 

Alameda Fernão Lopes, n° 16A – 1°B 

1495 - 190 Algés 

Portugal 

Tel: + 351 - 21 - 412 3550 

  

España România 

Ipsen Pharma, S.A. Ipsen Pharma România SRL 

Torre Realia, Plaza de Europa, 41-43  Sectorul 1, Strada Grigore  

08908 L‟Hospitalet de Llobregat  Alexandrescu nr. 59, Etaj 1 

Barcelona Bucureşti, 010623 

Tel: + 34 - 936 - 858 100 Tel: + 40 21 231 27 20 

  

France Slovenija   

Ipsen Pharma PharmaSwiss d.o.o.  

65 quai Georges Gorse Brodišče 32 

92100 Boulogne-Billancourt  SI-1236 Trzin   

France Tel: + 386 1 236 47 00  

Tél: + 33 1 58 33 50 00  

  

Hrvatska Slovenská republika 

PharmaSwiss d.o.o. Liek s.r.o. 

Strojarska 20, 10 000 Zagreb, Hviezdoslavova 19 

Hrvatska SK-90301 Senec 

Tel: +385 1 6311 833 Slovenská republika 

Fax: +385 1 6311 844 Tel: + 421 905 667 410 

  

Ireland United Kingdom 

Ipsen Pharmaceuticals Ltd.  Ipsen Ltd. 

Blanchardstown Industrial Park  190 Bath Road  

Blanchardstown Slough, Berkshire SL1 3XE 

IRL-Dublin 15 United Kingdom 

Tel: +353-1-809-8256 Tel: + 44  (0)1753 - 62 77 00 

 

This leaflet was last revised in  

 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET