Cometriq

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 

 

COMETRIQ 20 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One hard capsule contains cabozantinib (S)-malate equivalent to 20 mg cabozantinib.  

For the full list of excipients, see section 6.1. 

 

 
3. PHARMACEUTICAL FORM 

 

Hard capsule. 

The hard capsules are grey with “XL184 20mg” printed in black on the body of the capsule. The capsule 

contains an off-white to white powder. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

COMETRIQ is indicated for the treatment of adult patients with progressive, unresectable locally advanced 

or metastatic medullary thyroid carcinoma. 

 

For patients in whom rearranged during transfection (RET) mutation status is not known or is negative, a 

possible lower benefit should be taken into account before individual treatment decision (see important 

information in sections 4.4 and 5.1). 

 
4.2 Posology and method of administration 

 

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

medicinal products.  

 

Posology 

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

should not be used interchangeably (see section 5.2).  

The recommended dose of COMETRIQ is 140 mg once daily, taken as one 80 mg orange capsule and three 

20 mg grey capsules. Treatment should continue until the patient is no longer clinically benefiting from 

therapy or until unacceptable toxicity occurs. 

 

It should be expected that a majority of patients treated with COMETRIQ will require one or more dose 

adjustments (reduction and/or interruption) due to toxicity. Patients should therefore be closely monitored 

during the first eight weeks of therapy (see section 4.4). 

 

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

of COMETRIQ therapy. When dose reduction is necessary, it is recommended to reduce to 100 mg daily, 

taken as one 80 mg orange capsule and one 20 mg grey capsule, and then to 60 mg daily, taken as three 

20 mg grey capsules.  

 

Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable 

grade 2 toxicities.  



 

3 

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

 

As most events can 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), and gastrointestinal (GI) events (abdominal or mouth pain, 

mucosal inflammation, constipation, diarrhoea, vomiting).  

 

The occurrence of some serious adverse reactions (like GI fistula) might be dependent on the cumulative 

dose and might present in a later stage of treatment. 

 

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

 

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. 

 

Elderly patients 

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

However, a trend in increased rate of SAEs has been observed in subjects aged 75 years and older. 

 

Race 

There is little experience with cabozantinib in non-White patients.  

 

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. 

 

Hepatic impairment 

In patients with mild or moderate hepatic impairment the recommended dose of cabozantinib is 60 mg once 

daily. Close monitoring of overall safety is recommended in these patients (see section 5.2) as dose 

adjustment or interruption may be required. Cabozantinib is not recommended for use in patients with severe 

hepatic impairment as safety and efficacy have not been established in this population. 

 

Patients with cardiac impairment 

There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made. 

 

Paediatric population 

The safety and efficacy of cabozantinib in children aged <18 years have not yet been established. No data are 

available. 

 

Method of administration 

COMETRIQ is for oral use. The capsules should be swallowed whole and not opened. Patients should be 

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

 

4.3 Contraindications 

 

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

 



 

4 

4.4 Special warnings and precautions for use 

 

Dose reductions and dose interruptions occurred in 79% and 72%, respectively, of cabozantinib-treated 

patients in the pivotal clinical study. Two dose reductions were required in 41% of patients. The median time 

to first dose reduction was 43 days, and to first dose interruption was 33 days. Close monitoring of patients is 

therefore recommended during the first eight weeks of therapy (see section 4.2). 

 

Perforations, fistulas, and intra-abdominal abscesses  

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, and intra-abdominal abscesses have 

been observed with cabozantinib. Patients who have had recent radiotherapy, have inflammatory bowel 

disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, or diverticulitis), have tumour infiltration of 

trachea, bronchi, or oesophagus, have complications from prior GI surgery (particularly when associated 

with delayed or incomplete healing), or have complications from prior radiation therapy to the thoracic 

cavity (including mediastinum) should be carefully evaluated before initiating cabozantinib therapy and 

subsequently they should be monitored closely for symptoms of perforations and fistulas. Non-GI fistula 
should be ruled out as appropriate in cases of onset of mucositis after start of therapy. Cabozantinib should 

be discontinued in patients who experience a GI perforation or a GI or non-GI fistula. 

 

Thromboembolic events 

Events of venous thromboembolism, including pulmonary embolism and events of 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. Cabozantinib should be 

discontinued in patients who develop an acute myocardial infarction or any other clinically significant 

arterial thromboembolic complication. 

 

Haemorrhage 

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have evidence of 

involvement of the trachea or bronchi by tumour or a history of haemoptysis prior to treatment initiation 

should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be 

administered to patients with serious haemorrhage or recent haemoptysis. 

 

Aneurysms and artery dissections 

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. 

 

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 section 4.2). 

 

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 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 

Hypertension has been observed 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. 

 



 

5 

Osteonecrosis 

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  

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. 

 

Posterior reversible encephalopathy syndrome 

Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. PRES should be 

considered in any patient presenting with symptoms suggestive of the diagnosis, including seizures, 

headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be 

discontinued in patients with PRES. 

 

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. Concomitant treatment with strong CYP3A4 

inhibitors, which may increase cabozantinib plasma concentrations, should be used with caution. 

 

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. 
 

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. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Effect of other medicinal products on cabozantinib 

 



 

6 

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.  

 

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. 

 



 

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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. 

 

4.8 Undesirable effects 

 

Summary of safety profile 

The most common serious adverse reactions associated with cabozantinib are pneumonia, mucosal 
inflammation, hypocalcaemia, dysphagia, dehydration, pulmonary embolism, and hypertension. The most 

frequent adverse reactions of any grade (experienced by at least 20% of patients) included diarrhoea, PPES, 

weight decreased, decreased appetite, nausea, fatigue, dysgeusia, hair colour changes, hypertension, 

stomatitis, constipation, vomiting, mucosal inflammation, asthenia, and dysphonia. 

 

The most common laboratory abnormalities were increased aspartate aminotransferase (AST), increased 

alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), lymphopenia, hypocalcaemia, 

neutropenia, thrombocytopenia, hypophosphataemia, hyperbilirubinemia, hypomagnesaemia, and 

hypokalaemia. 

 

Tabulated list of adverse reactions 

Adverse reactions are listed in Table 1 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. 

 

  



 

8 

Table 1: Adverse reactions reported with cabozantinib 

 

MedDRA 

System Organ 

Class 

Very Common  

(1/10) 

Common  

(1/100 to <1/10) 

Uncommon  

(1/1,000 to <1/100) 

Not Known 

Infections and 

infestations 

 abscess* (including 

visceral, skin, tooth),  

pneumonia, 

folliculitis,  

fungal infection 

(including skin, oral, 

genital) 

aspergilloma  

Endocrine 

disorders 

 hypothyroidism   

Metabolism and 

nutrition 

disorders 

decreased appetite, 

hypocalcaemiac, 

hypokalaemiac, 

hypomagnesaemiac 

dehydration*, 

hypoalbuminaemiac,  

hyperbilirubinaemiad,  

hypophosphataemiac  

  

Psychiatric 

disorders 

 anxiety, depression, 

confusional state 

abnormal dreams, 

delirium 

 

Nervous system 

disorders 

dysgeusia, headache, 

dizziness 

cerebrovascular 

accident*, peripheral 

neuropathy, 

paraesthesia, ageusia, 

tremor 

ataxia, disturbance in 

attention, hepatic 

encephalopathy, loss 

of consciousness, 

speech disorder, 

posterior reversible 

encephalopathy 

syndrome*  

 

Eye disorders  vision blurred  cataract, 

conjunctivitis 

 

Ear and 

labyrinth 

disorders 

 ear pain, tinnitus hypoacusis  

Cardiac 

disorders 

 atrial fibrillation angina pectoris, 

supraventricular 

tachycardia 

myocardial 

infarction 

Vascular 

disorders 

hypertension*f  hypotensiong,  

deep vein 

thrombosis*,  

venous thrombosis*, 

arterial thrombosis*, 

pallor,  

peripheral coldness 

 aneurysms and 

artery 

dissections 



 

9 

MedDRA 

System Organ 

Class 

Very Common  

(1/10) 

Common  

(1/100 to <1/10) 

Uncommon  

(1/1,000 to <1/100) 

Not Known 

Respiratory, 

thoracic, and 

mediastinal 

disorders 

dysphonia, 

oropharyngeal pain 
non-gastrointestinal 

fistula* (including 

tracheal, 

pneumomediastinum, 

tracheo-

oesophageal), 

pulmonary 

embolism*, 

respiratory tract 

haemorrhage* 

(including 

pulmonary, 

bronchial, tracheal), 

pneumonia aspiration 

atelectasis, 

pharyngeal oedema, 

pneumonitis 

 

Gastrointestinal 

disorders 

diarrhoea*, nausea*, 

stomatitis, 

constipation, 

vomiting*,  

abdominal paine, 

dyspepsia, 

dysphagia, 

glossodynia 

gastrointestinal 

perforation*,  

gastrointestinal 

fistula*, 

gastrointestinal 

haemorrhage*, 

pancreatitis, 

haemorrhoids,  

anal fissure,  

anal inflammation, 

cheilitis 

oesophagitis  

Hepatobiliary 

disorders 

 cholelithiasis   

Skin and 

subcutaneous 

tissue disorders 

palmar-plantar 

erythrodysaesthesia 

syndrome*, hair 

colour changes, rash, 

dry skin, alopecia, 

erythema 

hyperkeratosis, acne, 

blister, hair growth 

abnormal, skin 

exfoliation, skin 

hypopigmentation  

skin ulcer, 

telangiectasia 

 

Musculoskeletal 

and connective 

tissue disorders 

arthralgia, muscle 

spasms,  

pain in extremity 

musculoskeletal 

chest pain, 

osteonecrosis of jaw* 

rhabdomyolysis  

Renal and 

urinary 

disorders 

 proteinuria*, dysuria, 

haematuria 

renal failure acute  

Reproductive 

system and 

breast disorders 

  amenorrhoea,  

vaginal haemorrhage 

 

General 

disorders and 

administration 

site conditions 

fatigue, mucosal 

inflammation, 

asthenia 

impaired wound 

healing*, chills, face 

oedema  

cyst, facial pain, 

localised oedema  

 



 

10 

MedDRA 

System Organ 

Class 

Very Common  

(1/10) 

Common  

(1/100 to <1/10) 

Uncommon  

(1/1,000 to <1/100) 

Not Known 

Investigations weight decreased, 

serum ALT, AST, 

and ALP increased,  

blood LDH 

increased, blood 

TSH increased*d, 

thrombocytopeniaa 

blood creatinine 

phosphokinase 

increased, 

lymphopeniaa, 

neutropeniaa 

activated partial 

thromboplastin time 

shortened,  

eosinophil count 

increasedb,  

platelet count 

increasedb 

 

 

*See section 4.8 Description of selected adverse reactions for further characterisation.  

The following terms have been combined to derive appropriate frequency categorisation: 
a Lowered haematology parameters: Lymphopenia and lymphocyte count decreased; Neutropenia and neutrophil count 

decreased; Thrombocytopenia and platelet count decreased. 
bElevated haematology parameters: Eosinophil count increased and eosinophilia; Platelet count increased and 

thrombocytosis  
c Lowered biochemistry parameters: Hypoalbuminaemia and blood albumin decreased; Hypocalcaemia and blood 

calcium decreased; Hypokalaemia and blood potassium decreased; Hypomagnesaemia and blood magnesium decreased; 

Hypohosphataemia and blood phosphorus decreased.  
d Elevated biochemistry parameters: Hyperbilirubinaemia and blood bilirubin increased; Hypothyroidism and blood 

thyroid stimulating hormone increased. 
e Abdominal pain, abdominal discomfort, abdominal pain upper and abdominal pain lower 
f Hypertension and blood pressure increased. 
g Hypotension and blood pressure decreased. 

 

Description of selected adverse reactions 

A thyroid stimulating hormone (TSH) value above normal after first dose was observed in 57% of patients 

on cabozantinib versus 19% of patients on placebo (regardless of baseline values). Ninety-two percent of 

patients on the cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormones prior to 

first dose. 

 

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 cancer patients (see section 4.4). This effect was not associated with a change in cardiac 

wave form morphology or new rhythms. No cabozantinib-treated subjects had a QTcF >500 ms. 

 

Please refer to section 4.4 for recommendations about the monitoring and management of the following 

adverse events: perforations, fistulas, and intra-abdominal abscesses; thromboembolic events; haemorrhage; 

aneurysms and artery dissections; gastrointestinal disorders; wound complications; hypertension; 

osteonecrosis; palmar-plantar erythrodysaesthesia syndrome; proteinuria; and posterior reversible 

encephalopathy syndrome. 

 

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. 

 

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. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

11 

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 remodelling, 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 RET, the GAS6 receptor (AXL), 

the stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3). 

 

Pharmacodynamic effects 

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

in a broad range of preclinical tumour models. 

 

Efficacy with cabozantinib was observed in medullary thyroid cancer patients with wild-type or mutant RET. 

 

Clinical data in medullary thyroid cancer 

A multi-center, randomised double-blind study comparing cabozantinib (N = 219) with placebo (N = 111) 

was conducted in patients with unresectable locally advanced or metastatic MTC and documented 

radiographic disease progression within 14 months prior to study entry. The primary objective was to 

compare progression-free survival (PFS) in patients receiving cabozantinib versus patients receiving placebo. 

The secondary objectives were to compare overall response rate (ORR) and overall survival (OS). 

Centralized, independent, blinded review of the imaging data was used in the assessment of PFS and ORR. 

Patients were treated until disease progression or unacceptable toxicity. 

 

The result of the PFS analysis, based on the central review RECIST assessment, demonstrated a statistically 

significant difference in the duration of PFS with cabozantinib versus placebo: the median duration was 

11.2 months for subjects in the cabozantinib arm versus 4.0 months for subjects in the placebo arm (stratified 

Hazard Ratio [HR] = 0.28; 95% CI: 0.19, 0.40; p<0.0001; Figure 1). The PFS results were consistent across 

all baseline and demographic subgroups evaluated, including prior therapy with tyrosine kinase inhibitors 

(which may have consisted of agents targeting pathways associated with anti-angiogenesis), RET mutational 

status (including subjects documented not to have RET mutations), prior anticancer or radiotherapy status, or 

the existence of bone metastases. 

 

The ORR was 27.9% and 0% for subjects in the cabozantinib arm and placebo arm, respectively (p<0.0001; 

Table 2). The median duration of objective responses was 14.6 months (95% CI: 11.1, 17.5) for subjects in 

the cabozantinib arm.  
 



 

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Figure 1: Kaplan Meier curve of progression free survival 

 

 
 

Number of subjects at risk 

Month 0 3 6 9 12 15 18 21 

Cometriq 219 121 78 55 31 12 2 1 

Placebo 111 35 11 6 3 2 0 0 

 

The final analysis of OS was conducted after 218 events (deaths) occurred and shows a trend for an increase 

in median survival of 5.5 months in the cabozantinib arm: median (months) 26.6 cabozantinib vs. 

21.1 placebo (HR = 0.85 [95% CI: 0.64, 1.12], p = 0.2409). 

 

Figure 2: Kaplan-Meier curve of overall survival 

 

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

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

 

 

 

Months 

 
 

0 12 24 
0.0 

0.2 

0.4 

0.6 

0.8 

1.0 Placebo (n=111) 

Cometriq (n=219) 

P
ro

b
a
b

il
it

y
  

Cometriq (n=219) 

Placebo (n=111) 

Months 

P
ro

b
a
b

il
it

y
 



 

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Table 2: Summary of key efficacy findings 

 

 Cabozantinib Placebo 

Median progression-free survival  

11.2 months 4.0 months 

HR: 0.28 (0.19, 0.40) 

p <0.0001 

Median overall survival  

26.6 months 21.1 months 

HR: 0.85 (0.64, 1.12) 

p = 0.2409 

Overall response ratea (95% CI) 

27.9% 

(21.9%, 34.5%) 

0% 

p <0.0001 

Duration of response; median (95% CI) 
14.6 months 

(11.1, 17.5) 

N/A 

Disease control rate b (95% CI) 
55.3% 

 (48.3%, 62.2%) 

13.5% 

(7.6%, 21.6%) 

Calcitonin responsea 
47%  

(49/104)c 

3%  

(1/40) c 

CEA responsea 
33%  

(47/143) c 

2%  

(1/55)c 
a Response = CR + PR 
b Disease Control Rate = SD+ ORR 
c Includes patients who were evaluable for response 

 

RET mutation status 

Of the 215 subjects with sufficient data to determine mutational status, 78.6% (n=169) were classified as 

RET mutation positive (126 of which were positive for the M918T mutation), and 21.4% (n=46) were 

classified as RET mutation negative. For an additional 115 subjects the RET mutational status could not be 

determined or was unclear. All three subgroups showed increased PFS in the cabozantinib arm compared to 

the placebo arm (HRs of 0.23, 0.53, and 0.30 for RET mutation positive, negative, and unknown subgroups, 

respectively). The objective response rates measured in these subgroups were generally consistent with the 

PFS results, with the RET mutation positive, negative, and unknown subgroups showing tumour response 

rates of 32%, 22%, and 25%, respectively. 

 

Further genetic analysis showed that a small proportion of patients harboured somatic tumour mutations in 

HRAS, KRAS, or NRAS. These patients (n=16) showed significant prolongation of PFS (HR of 0.15) and an 

objective response rate of 31%. RET mutation negative patients with no evidence of RAS mutation (n=33) 

showed a decreased PFS benefit on cabozantinib (HR of 0.87) and a lower response rate of 18% compared to 

other mutational subgroups. 

 

A significant improvement in OS was observed in the subgroup of RET M918T mutation positive patients 

(n=81/219 cabozantinib arm): 44.3 months in the cabozantinib arm vs. 18.9 months in the placebo arm 

(HR = 0.60, p = 0.0255). There was no improvement in OS for the RET M918T negative and unknown 

subgroups. 

 



 

14 

Figure 3: Kaplan-Meier analysis of OS among subjects with a RET M918T mutation 

 

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

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

 

 

Paediatric population 

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

cabozantinib in one or more subsets of the paediatric population in the treatment of malignant solid tumours 

(see section 4.2 for information on paediatric use). 

 

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that 

further evidence on this medicinal product is awaited. 

The European Medicines Agency will review new information on this medicinal product at least every year 

and this SmPC will be updated as necessary 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 2 to 

5 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. AUC were similar 

between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations (<10% difference). 

 

Distribution 

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

pharmacokinetic (PK) model, the volume of distribution (V/F) is approximately 349 L (SE: ± 2.73%). 

Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function. 

 

Cometriq (n=81) 

Placebo (n=45) 

P
ro

b
a
b

il
it

y
 

Months 



 

15 

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. 

 

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 

The plasma terminal half-life of cabozantinib in single dose studies in healthy volunteers is approximately 

120 hours. Mean clearance (CL/F) at steady-state in cancer patients was estimated to be 4.4 L/hr in a 

population PK analysis. 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 

Results from a study in patients with renal impairment indicate that 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. Patients with severe renal impairment have not been 

studied. 

 

Hepatic impairment 

Results from a study in patients with hepatic impairment indicate that exposure (AUC0-inf) increased by 81% 

and 63% in subjects with mild and moderate hepatic impairment, respectively (90% CI for AUC0-inf: 

121.44% to 270.34% for mild and 107.37% to 246.67% for moderate). Patients with severe hepatic 

impairment have not been studied. 

 

Race 

No data are available to determine a difference in PK 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. Cabozantinib was not carcinogenic in the rasH2 mouse 

model at a slightly higher exposure than the intended human therapeutic exposure.  



 

16 

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

observe 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 pediatric 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 bile duct hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, 

while effects on bone parameters and liver pigmentation were sustained. Evaluations in juvenile rats 

(comparable to a <2 year old pediatric population) have not been performed. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule content 

Microcrystalline cellulose 

Croscarmellose sodium 

Sodium starch glycolate 

Silica colloidal anhydrous 

Stearic acid 

 

Capsule shell 

Gelatin 

Black iron oxide (E172) 

Titanium dioxide (E171) 

 

Printing ink 

Shellac 

Black iron oxide (E172) 

Propylene glycol 

 

6.2 Incompatibilities 

 

Not applicable.  

 

6.3 Shelf life 

 

3 years. 

 

6.4 Special precautions for storage 

 

Do not store above 25 ºC. 

 

Store in the original package in order to protect from moisture. 

 

6.5 Nature and contents of container  

 

PVC/PE/PCTFE-Al blisters with foil backing, sealed into a secondary heat-sealed card packaging.  

 

Blister cards containing: 



 

17 

21 x 20 mg capsules (60 mg/day dose for a 7-day supply) 

 

28 day pack containing: 

84 capsules (4 blister cards of 21 x 20 mg) (60 mg/day dose for a 28 day supply) 

 

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)  

 

EU/1/13/890/001 21 x 20 mg capsules (60 mg/day dose for a 7-day supply) 

EU/1/13/890/004 84 capsules (4 blister cards of 21 x 20 mg) (60 mg/day dose for a 28 day supply) 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation:  21 March 2014 

Date of latest renewal: 21 February 2020 

 

 

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. 

 

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


 

18 

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 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib.  

For the full list of excipients, see section 6.1. 

 

 
3. PHARMACEUTICAL FORM 

 

Hard capsule. 

 

The hard capsules are grey with “XL184 20mg” printed in black on the body of the capsule. The capsule 

contains an off-white to white powder. 

 

The hard capsules are orange with “XL184 80mg” printed in black on the body of the capsule. The capsule 

contains an off-white to white powder. 

 

 

4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 

 

COMETRIQ is indicated for the treatment of adult patients with progressive, unresectable locally advanced 

or metastatic medullary thyroid carcinoma. 

 

For patients in whom rearranged during transfection (RET) mutation status is not known or is negative, a 

possible lower benefit should be taken into account before individual treatment decision (see important 

information in sections 4.4 and 5.1). 

 

4.2 Posology and method of administration 

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

medicinal products.  

 

Posology 

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

should not be used interchangeably (see section 5.2).  

The recommended dose of COMETRIQ is 140 mg once daily, taken as one 80 mg orange capsule and three 

20 mg grey capsules. Treatment should continue until the patient is no longer clinically benefiting from 

therapy or until unacceptable toxicity occurs. 

 

It should be expected that a majority of patients treated with COMETRIQ will require one or more dose 

adjustments (reduction and/or interruption) due to toxicity. Patients should therefore be closely monitored 

during the first eight weeks of therapy (see section 4.4). 

 



 

19 

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

of COMETRIQ therapy. When dose reduction is necessary, it is recommended to reduce to 100 mg daily, 

taken as one 80 mg orange capsule and one 20 mg grey capsule, and then to 60 mg daily, taken as three 

20 mg grey capsules.  
 
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. 

 

As most events can 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), and gastrointestinal (GI) events (abdominal or mouth pain, 

mucosal inflammation, constipation, diarrhoea, vomiting).  

 

The occurrence of some serious adverse reactions (like GI fistula) might be dependent on the cumulative 

dose and might present in a later stage of treatment. 

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

 

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. 

 

Elderly patients 

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

However, a trend in increased rate of SAEs has been observed in subjects aged 75 years and older. 

 

Race 

There is little experience with cabozantinib in non-White patients.  

 

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. 

 

Hepatic impairment 

In patients with mild or moderate hepatic impairment the recommended dose of cabozantinib is 60 mg once 

daily. Close monitoring of overall safety is recommended in these patients (see section 5.2) as dose 

adjustment or interruption may be required. Cabozantinib is not recommended for use in patients with severe 

hepatic impairment as safety and efficacy have not been established in this population. 

 

Patients with cardiac impairment 

There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made. 

 

Paediatric population 

The safety and efficacy of cabozantinib in children aged <18 years have not yet been established. No data are 

available. 

 

Method of administration 

COMETRIQ is for oral use. The capsules should be swallowed whole and not opened. Patients should be 

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



 

20 

 

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 

 

Dose reductions and dose interruptions occurred in 79% and 72%, respectively, of cabozantinib-treated 

patients in the pivotal clinical study. Two dose reductions were required in 41% of patients. The median time 

to first dose reduction was 43 days, and to first dose interruption was 33 days. Close monitoring of patients is 

therefore recommended during the first eight weeks of therapy (see section 4.2). 

 

Perforations, fistulas, and intra-abdominal abscesses  

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, and intra-abdominal abscesses have 

been observed with cabozantinib. Patients who have had recent radiotherapy, have inflammatory bowel 

disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, or diverticulitis), have tumour infiltration of 

trachea, bronchi, or oesophagus, have complications from prior GI surgery (particularly when associated 

with delayed or incomplete healing), or have complications from prior radiation therapy to the thoracic 

cavity (including mediastinum) should be carefully evaluated before initiating cabozantinib therapy and 

subsequently they should be monitored closely for symptoms of perforations and fistulas. Non-GI fistula 
should be ruled out as appropriate in cases of onset of mucositis after start of therapy. Cabozantinib should 

be discontinued in patients who experience a GI perforation or a GI or non-GI fistula. 

 

Thromboembolic events 

Events of venous thromboembolism, including pulmonary embolism and events of 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. Cabozantinib should be 

discontinued in patients who develop an acute myocardial infarction or any other clinically significant 

arterial thromboembolic complication. 

 

Haemorrhage 

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have evidence of 

involvement of the trachea or bronchi by tumour or a history of haemoptysis prior to treatment initiation 

should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be 

administered to patients with serious haemorrhage or recent haemoptysis. 

 

Aneurysms and artery dissections 

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. 

 

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 section 4.2). 

 

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 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 



 

21 

Hypertension has been observed 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. 

 

Osteonecrosis 

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  

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. 

 

Posterior reversible encephalopathy syndrome 

Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. PRES should be 

considered in any patient presenting with symptoms suggestive of the diagnosis, including seizures, 

headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be 

discontinued in patients with PRES. 

 

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. Concomitant treatment with strong CYP3A4 

inhibitors, which may increase cabozantinib plasma concentrations, should be used with caution. 

 

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. 

 

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. 

 



 

22 

 

 

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.  

 

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). 

 



 

23 

 

 

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. 

 

4.8 Undesirable effects 

 

Summary of safety profile 

The most common serious adverse reactions associated with cabozantinib are pneumonia, mucosal 
inflammation, hypocalcaemia, dysphagia, dehydration, pulmonary embolism, and hypertension. The most 

frequent adverse reactions of any grade (experienced by at least 20% of patients) included diarrhoea, PPES, 

weight decreased, decreased appetite, nausea, fatigue, dysgeusia, hair colour changes, hypertension, 

stomatitis, constipation, vomiting, mucosal inflammation, asthenia, and dysphonia. 

 

The most common laboratory abnormalities were increased aspartate aminotransferase (AST), increased 

alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), lymphopenia, hypocalcaemia, 

neutropenia, thrombocytopenia, hypophosphataemia, hyperbilirubinemia, hypomagnesaemia, and 

hypokalaemia. 

 

Tabulated list of adverse reactions 

Adverse reactions are listed in Table 1 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. 

 

  



 

24 

Table 1: Adverse reactions reported with cabozantinib 

 

MedDRA 

System Organ 

Class 

Very Common  

(1/10) 

Common  

(1/100 to <1/10) 

Uncommon  

(1/1,000 to <1/100) 

Not Known 

Infections and 

infestations 

 abscess* (including 

visceral, skin, tooth),  

pneumonia, 

folliculitis,  

fungal infection 

(including skin, oral, 

genital) 

aspergilloma  

Endocrine 

disorders 

 hypothyroidism   

Metabolism and 

nutrition 

disorders 

decreased appetite, 

hypocalcaemiac, 

hypokalaemiac, 

hypomagnesaemiac 

dehydration*, 

hypoalbuminaemiac,  

hyperbilirubinaemiad,  

hypophosphataemiac 

  

Psychiatric 

disorders 

 anxiety, depression, 

confusional state 

abnormal dreams, 

delirium 

 

Nervous system 

disorders 

dysgeusia, headache, 

dizziness 

cerebrovascular 

accident*, peripheral 

neuropathy, 

paraesthesia, ageusia, 

tremor 

ataxia, disturbance in 

attention, hepatic 

encephalopathy, loss 

of consciousness, 

speech disorder, 

posterior reversible 

encephalopathy 

syndrome*  

 

Eye disorders  vision blurred  cataract, 

conjunctivitis 

 

Ear and 

labyrinth 

disorders 

 ear pain, tinnitus hypoacusis  

Cardiac 

disorders 

 atrial fibrillation angina pectoris, 

supraventricular 

tachycardia 

myocardial 

infarction 

Vascular 

disorders 

hypertension*f hypotensiong,  

deep vein 

thrombosis*,  

venous thrombosis*, 

arterial thrombosis*, 

pallor,  

peripheral coldness 

 aneurysms and 

artery 

dissections 

Respiratory, 

thoracic, and 

mediastinal 

disorders 

dysphonia, 

oropharyngeal pain 
non-gastrointestinal 

fistula* (including 

tracheal, 

pneumomediastinum, 

tracheo-

oesophageal), 

pulmonary 

embolism*, 

respiratory tract 

haemorrhage* 

(including 

atelectasis, 

pharyngeal oedema, 

pneumonitis 

 



 

25 

MedDRA 

System Organ 

Class 

Very Common  

(1/10) 

Common  

(1/100 to <1/10) 

Uncommon  

(1/1,000 to <1/100) 

Not Known 

pulmonary, 

bronchial, tracheal), 

pneumonia aspiration 

Gastrointestinal 

disorders 

diarrhoea*, nausea*, 

stomatitis, 

constipation, 

vomiting*,  

abdominal paine, 

dyspepsia, 

dysphagia, 

glossodynia 

gastrointestinal 

perforation*, 

gastrointestinal 

fistula*, 

gastrointestinal 

haemorrhage*, 

pancreatitis, 

haemorrhoids,  

anal fissure,  

anal inflammation, 

cheilitis 

oesophagitis  

Hepatobiliary 

disorders 

 cholelithiasis   

Skin and 

subcutaneous 

tissue disorders 

palmar-plantar 

erythrodysaesthesia 

syndrome*, hair 

colour changes, rash, 

dry skin, alopecia, 

erythema 

hyperkeratosis, acne, 

blister, hair growth 

abnormal, skin 

exfoliation, skin 

hypopigmentation  

skin ulcer, 

telangiectasia 

 

Musculoskeletal 

and connective 

tissue disorders 

arthralgia, muscle 

spasms,  

pain in extremity 

musculoskeletal 

chest pain, 

osteonecrosis of jaw* 

rhabdomyolysis  

Renal and 

urinary 

disorders 

 proteinuria*, dysuria, 

haematuria 

renal failure acute  

Reproductive 

system and 

breast disorders 

  amenorrhoea,  

vaginal haemorrhage 

 

General 

disorders and 

administration 

site conditions 

fatigue, mucosal 

inflammation, 

asthenia 

impaired wound 

healing*, chills, face 

oedema  

cyst, facial pain, 

localised oedema  

 

Investigations weight decreased, 

serum ALT, AST, 

and ALP increased,  

blood LDH 

increased, blood 

TSH increased*d, 

thrombocytopeniaa 

blood creatinine 

phosphokinase 

increased, 

lymphopeniaa, 

neutropeniaa 

activated partial 

thromboplastin time 

shortened,  

eosinophil count 

increasedb,  

platelet count 

increasedb 

 

 

*See section 4.8 Description of selected adverse reactions for further characterisation.  

The following terms have been combined to derive appropriate frequency categorisation: 
a Lowered haematology parameters: Lymphopenia and lymphocyte count decreased; Neutropenia and neutrophil count 

decreased; Thrombocytopenia and platelet count decreased. 
bElevated haematology parameters: Eosinophil count increased and eosinophilia; Platelet count increased and 

thrombocytosis  



 

26 

c Lowered biochemistry parameters: Hypoalbuminaemia and blood albumin decreased; Hypocalcaemia and blood 

calcium decreased; Hypokalaemia and blood potassium decreased; Hypomagnesaemia and blood magnesium decreased; 

Hypohosphataemia and blood phosphorus decreased.  
d Elevated biochemistry parameters: Hyperbilirubinaemia and blood bilirubin increased; Hypothyroidism and blood 

thyroid stimulating hormone increased. 
e Abdominal pain, abdominal discomfort, abdominal pain upper and abdominal pain lower 
f Hypertension and blood pressure increased. 
g Hypotension and blood pressure decreased. 

 

Description of selected adverse reactions 

A thyroid stimulating hormone (TSH) value above normal after first dose was observed in 57% of patients 

on cabozantinib versus 19% of patients on placebo (regardless of baseline values). Ninety-two percent of 

patients on the cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormones prior to 

first dose. 

 

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 cancer patients (see section 4.4). This effect was not associated with a change in cardiac 

wave form morphology or new rhythms. No cabozantinib-treated subjects had a QTcF >500 ms. 

 

Please refer to section 4.4 for recommendations about the monitoring and management of the following 

adverse events: perforations, fistulas, and intra-abdominal abscesses; thromboembolic events; haemorrhage; 

aneurysms and artery dissections; gastrointestinal disorders; wound complications; hypertension; 

osteonecrosis; palmar-plantar erythrodysaesthesia syndrome; proteinuria; and posterior reversible 

encephalopathy syndrome. 

 

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. 

 

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 remodelling, 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 RET, the GAS6 receptor (AXL), 

the stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3).    

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

27 

Pharmacodynamic effects 

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

in a broad range of preclinical tumour models. 

 

Efficacy with cabozantinib was observed in medullary thyroid cancer patients with wild-type or mutant RET. 

 

Clinical data in medullary thyroid cancer 

A multi-center, randomised double-blind study comparing cabozantinib (N = 219) with placebo (N = 111) 

was conducted in patients with unresectable locally advanced or metastatic MTC and documented 

radiographic disease progression within 14 months prior to study entry. The primary objective was to 

compare progression-free survival (PFS) in patients receiving cabozantinib versus patients receiving placebo. 

The secondary objectives were to compare overall response rate (ORR) and overall survival (OS). 

Centralized, independent, blinded review of the imaging data was used in the assessment of PFS and ORR. 

Patients were treated until disease progression or unacceptable toxicity. 

 

The result of the PFS analysis, based on the central review RECIST assessment, demonstrated a statistically 

significant difference in the duration of PFS with cabozantinib versus placebo: the median duration was 

11.2 months for subjects in the cabozantinib arm versus 4.0 months for subjects in the placebo arm (stratified 

Hazard Ratio [HR] = 0.28; 95% CI: 0.19, 0.40; p<0.0001; Figure 1). The PFS results were consistent across 

all baseline and demographic subgroups evaluated, including prior therapy with tyrosine kinase inhibitors 

(which may have consisted of agents targeting pathways associated with anti-angiogenesis), RET mutational 

status (including subjects documented not to have RET mutations), prior anticancer or radiotherapy status, or 

the existence of bone metastases. 

 

The ORR was 27.9% and 0% for subjects in the cabozantinib arm and placebo arm, respectively (p<0.0001; 

Table 2). The median duration of objective responses was 14.6 months (95% CI: 11.1, 17.5) for subjects in 

the cabozantinib arm.  
 

Figure 1: Kaplan Meier curve of progression free survival 

 

 

 

 

Number of subjects at risk 

Month 0 3 6 9 12 15 18 21 

Cometriq 219 121 78 55 31 12 2 1 

Placebo 111 35 11 6 3 2 0 0 

 

Months 

 
 

0 12 24 
0.0 

0.2 

0.4 

0.6 

0.8 

1.0 Placebo (n=111) 

Cometriq (n=219) 

P
ro

b
a
b

il
it

y
  



 

28 

The final analysis of OS was conducted after 218 events (deaths) occurred and shows a trend for an increase 

in median survival of 5.5 months in the cabozantinib arm: median (months) 26.6 cabozantinib vs. 

21.1 placebo (HR = 0.85 [95% CI: 0.64, 1.12], p = 0.2409). 

 

Figure 2: Kaplan-Meier curve of overall survival 

 

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

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

 

 

 

 

Table 2: Summary of key efficacy findings 

 

 Cabozantinib Placebo 

Median progression-free survival  

11.2 months 4.0 months 

HR: 0.28 (0.19, 0.40) 

p <0.0001 

Median overall survival  

26.6 months 21.1 months 

HR: 0.85 (0.64, 1.12) 

p = 0.2409 

Overall response ratea (95% CI) 

27.9% 

(21.9%, 34.5%) 

0% 

p <0.0001 

Duration of response; median (95% CI) 
14.6 months 

(11.1, 17.5) 

N/A 

Disease control rate b (95% CI) 
55.3% 

 (48.3%, 62.2%) 

13.5% 

(7.6%, 21.6%) 

Calcitonin responsea 
47%  

(49/104)c 

3%  

(1/40) c 

CEA responsea 
33%  

(47/143) c 

2%  

(1/55)c 
a Response = CR + PR 
b Disease Control Rate = SD+ ORR 
c Includes patients who were evaluable for response 

 

RET mutation status 

Of the 215 subjects with sufficient data to determine mutational status, 78.6% (n=169) were classified as 

RET mutation positive (126 of which were positive for the M918T mutation), and 21.4% (n=46) were 

classified as RET mutation negative. For an additional 115 subjects the RET mutational status could not be 

determined or was unclear. All three subgroups showed increased PFS in the cabozantinib arm compared to 

the placebo arm (HRs of 0.23, 0.53, and 0.30 for RET mutation positive, negative, and unknown subgroups, 

Cometriq (n=219) 

Placebo (n=111) 

Months 

P
ro

b
a
b

il
it

y
 



 

29 

respectively). The objective response rates measured in these subgroups were generally consistent with the 

PFS results, with the RET mutation positive, negative, and unknown subgroups showing tumour response 

rates of 32%, 22%, and 25%, respectively. 

 

Further genetic analysis showed that a small proportion of patients harboured somatic tumour mutations in 

HRAS, KRAS, or NRAS. These patients (n=16) showed significant prolongation of PFS (HR of 0.15) and an 

objective response rate of 31%. RET mutation negative patients with no evidence of RAS mutation (n=33) 

showed a decreased PFS benefit on cabozantinib (HR of 0.87) and a lower response rate of 18% compared to 

other mutational subgroups. 

 

A significant improvement in OS was observed in the subgroup of RET M918T mutation positive patients 

(n=81/219 cabozantinib arm): 44.3 months in the cabozantinib arm vs. 18.9 months in the placebo arm 

(HR = 0.60, p = 0.0255). There was no improvement in OS for the RET M918T negative and unknown 

subgroups. 

 

Figure 3: Kaplan-Meier analysis of OS among subjects with a RET M918T mutation 

 

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

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

 

 

Paediatric population 

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

cabozantinib in one or more subsets of the paediatric population in the treatment of malignant solid tumours 

(see section 4.2 for information on paediatric use). 

 

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that 

further evidence on this medicinal product is awaited. 

The European Medicines Agency will review new information on this medicinal product at least every year 

and this SmPC will be updated as necessary 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 2 to 

5 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.   

 

Cometriq (n=81) 

Placebo (n=45) 

P
ro

b
a
b

il
it

y
 

Months 



 

30 

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. AUC were similar 

between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations (<10% difference). 

 

Distribution 

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

pharmacokinetic (PK) model, the volume of distribution (V/F) is approximately 349 L (SE: ± 2.73%). 

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. 

 

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 

The plasma terminal half-life of cabozantinib in single dose studies in healthy volunteers is approximately 

120 hours. Mean clearance (CL/F) at steady-state in cancer patients was estimated to be 4.4 L/hr in a 

population PK analysis. 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 

Results from a study in patients with renal impairment indicate that 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. Patients with severe renal impairment have not been 

studied. 

 

Hepatic impairment 

Results from a study in patients with hepatic impairment indicate that exposure (AUC0-inf) increased by 81% 

and 63% in subjects with mild and moderate hepatic impairment, respectively (90% CI for AUC0-inf: 

121.44% to 270.34% for mild and 107.37% to 246.67% for moderate). Patients with severe hepatic 

impairment have not been studied. 

 

Race 

No data are available to determine a difference in PK 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: 



 

31 

 

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. 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 

observe 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 pediatric 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 bile duct hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, 

while effects on bone parameters and liver pigmentation were sustained. Evaluations in juvenile rats 

(comparable to a <2 year old pediatric population) have not been performed. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule content 

Microcrystalline cellulose 

Croscarmellose sodium 

Sodium starch glycolate 

Silica colloidal anhydrous 

Stearic acid 

 

Capsule shell 

Gelatin 

Black iron oxide (E172) (20 mg capsules only) 

Red iron oxide (E172) (80 mg capsules only) 

Titanium dioxide (E171) 

 

Printing ink 

Shellac 

Black iron oxide (E172) 

Propylene glycol 

 
6.2 Incompatibilities 

 

Not applicable.  



 

32 

 

6.3 Shelf life 

 

3 years. 

 

6.4 Special precautions for storage 

 

Do not store above 25 ºC. 

 

Store in the original package in order to protect from moisture. 

 

6.5 Nature and contents of container  

 

PVC/PE/PCTFE-Al blisters with foil backing, sealed into a secondary heat-sealed card packaging.  

 

Blister cards containing either: 

7 x 20 mg and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply) 

21 x 20 mg and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply) 

 

28 day pack containing: 

56 capsules (4 blister cards of 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for a 28 day supply) 

112 capsules (4 blister cards of 21 x 20mg and 7 x 80 mg) (140 mg/day dose for a 28 day supply) 

 

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)  

 

EU/1/13/890/002 7 x 20 mg and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply) 

EU/1/13/890/003 21 x 20 mg and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply) 

EU/1/13/890/005 56 capsules (4 blister cards of 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for 28 day 

supply) 

EU/1/13/890/006 112 capsules (4 blister cards of 21 x 20mg and 7 x 80 mg) (140 mg/day dose for 28 

day supply) 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 21 March 2014 

Date of latest renewal: 21 February 2020 

 

 

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. 

 

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


 

33 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER 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 

 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 

THE CONDITIONAL MARKETING AUTHORISATION 

 

 



 

34 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Catalent UK Packaging Limited 

Lancaster Way, Wingates Industrial Park,  

Westboughton, Bolton,  

Lancashire, BL5 3XX,  

United Kingdom 

 

Or 

 

Catalent Germany Schorndorf GmbH 

Steinbeisstr. 1 und 2 

73614 Schorndorf 

Germany 

 

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 (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs 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. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT 

 

• Risk management plan (RMP) 

 

The marketing authorisation holder (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.  

 

 



 

35 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 

THE CONDITIONAL MARKETING AUTHORISATION  

 

This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) No 

726/2004, the MAH shall complete, within the stated timeframe, the following measures: 

 

Description Due date 

A dose-comparison study (XL-184-401) (140 mg vs 60 mg) in 112 patients with 

hereditary or sporadic medullary thyroid cancer. 

Patients with both sporadic and hereditary forms of MTC will be eligible for the 

study. Fresh tumour samples for tumour genetic analysis from the most recent 

metastatic site in patients enrolled in the dose-comparison study should be 

collected. 

Samples will undergo thorough evaluation for RET and RAS mutations. Tumour 

tissue samples initially will undergo histological evaluation, manual tumour 

enrichment, and DNA isolation. The resulting DNA samples will be evaluated for 

quality by a PCR-based amplification test, and by Sanger sequencing for RET 

M918T. A replacement sample will be requested if an original sample fails during 

the PCR quality or the Sanger sequencing tests. Next generation sequencing of 

RET exons 10, 11, and 13-16 will be performed, which covers the vast majority of 

known RET mutations. In addition, samples will be evaluated for mutations in RAS 

gene hotspots (HRAS, KRAS, and NRAS genes). 

PK assessments will be required for all subjects (both dose groups). Results will 

be used to evaluate the exposure to cabozantinib at the 60 and 140 mg dose levels 

and to further characterize the population PK models and exposure response 

relationships of cabozantinib and possible metabolites in this population.  

30 September 

2020  

 

  



 

36 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 

37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

  



 

38 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

BLISTER CARD, 60 mg dose 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

cabozantinib  

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsules 

20 mg 

60 mg Dose  

 

Pack for the 60 mg daily dose 

21 x 20 mg capsules (60 mg/day dose for a 7-day supply) 

Each 60 mg daily dose contains three grey 20 mg capsules. 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

Package leaflet inside pouch. 

 

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 

 

Dispensing instructions 

Take all capsules in one row each day without food (patients should fast for at least 2 hours before through 

1 hour after taking the capsules). Record date of first dose. 

 

1. Push in tab 
 

 
 



 

39 

2. Peel paper backing 
 

 
 

 

3. Push capsule through foil 
 

 
 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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/1/13/890/001 

 

13. BATCH NUMBER 

 

Lot  

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 



 

40 

 

COMETRIQ 20 mg 

60 mg/day dose  

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 



 

41 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF 28 DAY PACK, 60 mg dose (INCLUDING BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

cabozantinib 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

60 mg Dose 

 

28 day pack: 84 capsules (4 blister cards of 21 x 20 mg capsules) for the 60 mg daily dose for a 28 day 

supply. 

 

Each 60 mg daily dose contains a combination of three grey 20 mg capsules. 

 

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 

 

Refer to individual blister cards for dispensing instructions. 

 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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. 

 



 

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/1/13/890/004 84 capsules (4 blisters cards of 21 x 20 mg) (60 mg/day dose for 28 day supply) 

 

13. BATCH NUMBER 

 

Lot 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

COMETRIQ 20 mg 

60 mg/day dose 

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 

  



 

43 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BLISTER CARD OF 28 DAY PACK, 60 mg dose (WITHOUT BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

cabozantinib  

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsules 

20 mg 

60 mg Dose  

 

21 x 20 mg capsules (60 mg/day dose for a 7-day supply). Component of a 28 day pack, can’t be sold 

separately. 

 

Pack for the 60 mg daily dose 

Each 60 mg daily dose contains three grey 20 mg capsules. 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

Package leaflet inside pouch. 

 

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 

 

Dispensing instructions 

Take all capsules in one row each day without food (patients should fast for at least 2 hours before through 

1 hour after taking the capsules). Record date of first dose. 

 

1. Push in tab 
 

 
 



 

44 

2. Peel paper backing 
 

 
 

3. Push capsule through foil 
 

 
 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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/1/13/890/004 84 capsules (4 blisters cards of 21 x 20 mg) (60 mg/day dose for 28 day supply) 

 

13. BATCH NUMBER 

 

Lot  

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 



 

45 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

BLISTER CARD, 100 mg dose 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules  

cabozantinib  

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg of cabozantinib. 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsules 

20 mg and 80 mg 

100 mg Dose 

 

Pack for the 100 mg daily dose 

7 x 20 mg capsules and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply). 

Each 100 mg daily dose contains a combination of one grey 20 mg capsule and one orange 80 mg capsule. 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

Package leaflet inside pouch. 

 

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 

 

Dispensing instructions 

Take all capsules in one row each day without food (patients should fast for at least 2 hours before through 

1 hour after taking the capsules). Record date of first dose. 

 

1. Push in tab 
 

 
 

2. Peel paper backing 
 



 

46 

 
 

3. Push capsule through foil 
 

 
 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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/1/13/890/002 

 

13. BATCH NUMBER 

 

Lot  

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

COMETRIQ 20 mg 

COMETRIQ 80 mg 



 

47 

100 mg/day dose  

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 



 

48 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF 28 DAY PACK, 100 mg dose (INCLUDING BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules 

cabozantinib 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg of cabozantinib. 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

100 mg Dose 

 

28 day pack: 56 capsules (4 blister cards of 7 x 20 mg capsules and 7 x 80 mg capsules) for the 100 mg daily 

dose for a 28 day supply. 

 

Each 100 mg daily dose contains a combination of one grey 20 mg capsule and one orange 80 mg capsule. 

 

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 

 

Refer to individual blister cards for dispensing instructions. 

 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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. 



 

49 

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/1/13/890/005 56 capsules (4 blisters cards of 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for 28 day 

supply) 

 

13. BATCH NUMBER 

 

Lot 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

COMETRIQ 20 mg 

COMETRIQ 80 mg 

100 mg/day dose 

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 

  



 

50 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BLISTER CARD OF 28 DAY PACK, 100 mg dose (WITHOUT BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules  

cabozantinib  

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg of cabozantinib. 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsules 

20 mg and 80 mg 

100 mg Dose 

 

7 x 20 mg capsules and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply). Component of a 28 day 

pack, can’t be sold separately. 

 

Pack for the 100 mg daily dose 

Each 100 mg daily dose contains a combination of one grey 20 mg capsule and one orange 80 mg capsule. 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

Package leaflet inside pouch. 

 

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 

 

Dispensing instructions 

Take all capsules in one row each day without food (patients should fast for at least 2 hours before through 

1 hour after taking the capsules). Record date of first dose. 

 

1. Push in tab 
 

 
2. Peel paper backing 



 

51 

 

 
 

3. Push capsule through foil 
 

 
 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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/1/13/890/005 56 capsules (4 blisters cards of 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for 28 day 

supply) 

 

13. BATCH NUMBER 

 

Lot  

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 



 

52 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

BLISTER CARD 140 mg dose 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules  

cabozantinib  

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg of cabozantinib. 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsules 

20 mg and 80 mg 

140 mg Dose 

 

Pack for the 140 mg daily dose 

21 x 20 mg capsules and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply) 

Each 140 mg daily dose contains a combination of three grey 20 mg capsules and one orange 80 mg capsule. 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

Package leaflet inside pouch. 

 

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 

 

Dispensing instructions 

Take all capsules in one row each day without food (patients should fast for at least 2 hours before through 

1 hour after taking the capsules). Record date of first dose. 

 

1. Push in tab 
 

 
 



 

53 

2. Peel paper backing 

 

 
 

3. Push capsule through foil 
 

 
 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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/1/13/890/003  

 

13. BATCH NUMBER 

 

Lot 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 



 

54 

COMETRIQ 20 mg 

COMETRIQ 80 mg 

140 mg/day dose  

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 



 

55 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF 28 DAY PACK, 140 mg dose (INCLUDING BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules 

cabozantinib 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg of cabozantinib. 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

140 mg Dose 

 

28 day pack: 112 capsules (4 blister cards of 21 x 20 mg capsules and 7 x 80 mg capsules) for the 140 mg 

daily dose for a 28 day supply. 

 

Each 140 mg daily dose contains a combination of three grey 20 mg capsules and one orange 80 mg capsule. 

 

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 

 

Refer to individual blister cards for dispensing instructions. 

 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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. 



 

56 

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/1/13/890/006 112 capsules (4 blisters cards of 21 x 20 mg and 7 x 80 mg) (140 mg/day dose for 28 

day supply) 

 

13. BATCH NUMBER 

 

Lot 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

COMETRIQ 20 mg 

COMETRIQ 80 mg 

140 mg/day dose 

 

17.  UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 

 

  



 

57 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

BLISTER CARD OF 28 DAY PACK, 140 mg dose (WITHOUT BLUE BOX) 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules  

cabozantinib  

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg of cabozantinib. 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsules 

20 mg and 80 mg 

140 mg Dose 

 

21 x 20 mg capsules and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply). Component of a 28 day 

pack, can’t be sold separately. 

 

Pack for the 140 mg daily dose 

Each 140 mg daily dose contains a combination of three grey 20 mg capsules and one orange 80 mg capsule. 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before use. 

Package leaflet inside pouch. 

 

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 

 

Dispensing instructions 

Take all capsules in one row each day without food (patients should fast for at least 2 hours before through 

1 hour after taking the capsules). Record date of first dose. 

 

1. Push in tab 
 

 
 



 

58 

2. Peel paper backing 
 

 
 

3. Push capsule through foil 
 

 
 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in the original package in order to protect from moisture. 

Do not store above 25°C. 

 

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/1/13/890/006 112 capsules (4 blisters cards of 21 x 20 mg and 7 x 80 mg) (140 mg/day dose for 28 

day supply) 

 

13. BATCH NUMBER 

 

Lot 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE  



 

59 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

60 

Package leaflet: Information for the patient 

 

COMETRIQ 20 mg hard capsules 

COMETRIQ 80 mg hard capsules 

cabozantinib (S)-malate 

 

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 COMETRIQ is and what it is used for  

2. What you need to know before you take COMETRIQ 

3. How to take COMETRIQ 

4. Possible side effects  

5. How to store COMETRIQ 

6. Contents of the pack and other information 

 

 

1. What COMETRIQ is and what it is used for 

 

What COMETRIQ is 

COMETRIQ is a cancer medicine that contains the active substance cabozantinib (S)-malate.  

It is a medicine used to treat medullary thyroid cancer, a rare type of thyroid cancer, that cannot be removed 

by surgery or that has spread to other parts of the body.  

 

How COMETRIQ works 

COMETRIQ 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 COMETRIQ can slow down the rate at which the 

tumour grows and help to cut off the blood supply that the cancer needs. 

COMETRIQ may slow or stop the growth of medullary thyroid cancer. It may help shrink tumours 

associated with this type of cancer. 

 

 

2. What you need to know before you take COMETRIQ 

 

Do not take COMETRIQ 

- 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 COMETRIQ if you: 

 



 

61 

-  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 coughing up blood or significant bleeding 

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

procedures 

- have had radiotherapy in the last 3 months 

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

- have been told that your cancer has spread to your airway or oesophagus 

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

- are taking medicines to control your heart rhythm, have a slow heart rate, have problems with your 

heart or have problems with the levels of calcium, potassium or magnesium in your blood 

- have severe 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 COMETRIQ, or stop treatment altogether. See also section 4 “Possible side effects”. 

 

You should also tell your dentist that you are taking COMETRIQ. It is important for you to practice good 

mouth care during treatment with COMETRIQ. 

 

Children and adolescents 

 

COMETRIQ is not recommended for children or adolescents. The effects of COMETRIQ in people younger 

than 18 years old are not known. 

 

Other medicines and COMETRIQ 

 

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 COMETRIQ can affect the way some other 

medicines work. Also, some medicines can affect the way COMETRIQ works. This could mean that your 

doctor needs to change the dose(s) that you take.  

 

- 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 
- Medicines to treat angina pectoris (chest pain owing to inadequate supply to the heart) such as 

ranolazine 

- Steroids used to reduce inflammation or treat a number of different diseases of the immune system 
- 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 and dabigatran etexilate 
- Medicines to treat high blood pressure or other heart conditions, such as aliskiren, ambrisentan, 

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 ritonavir, maraviroc and emtricitabine 
- Medicines used to treat viral infections such as efavirenz 
- Medicines used to prevent transplant rejection (cyclosporine) and cyclosporine-based regimens in 

rheumatoid arthritis and psoriasis 

 

Oral contraceptives 

If you take COMETRIQ whilst using oral contraceptives, the oral contraceptives may be ineffective. You 

should also use a barrier contraceptive (e.g. condom or diaphragm) whilst taking COMETRIQ and for at 

least 4 months after treatment has finished. 



 

62 

 

Taking COMETRIQ with food 

 

Avoid consuming grapefruit-containing products for as long as you are using this medicine, as it may 

increase the levels of COMETRIQ in your blood. 

 

Pregnancy, breast-feeding, and fertility  

 

Avoid becoming pregnant while being treated with COMETRIQ. 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 COMETRIQ. 

See section 2. 

 

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

treated with COMETRIQ.  

 

Talk to your doctor BEFORE taking COMETRIQ 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 COMETRIQ.  

 

Women taking COMETRIQ 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 COMETRIQ may make you 

feel tired or weak. 

 

3. How to take COMETRIQ 

 

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 

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

originally planned. Your doctor will determine if you need your dose adjusted, particularly during the first 

eight weeks of therapy with COMETRIQ. 

 

COMETRIQ should be taken once a day. Depending on the dose you were prescribed, the number of 

capsules to take are as follows: 

• 140 mg (1 orange 80 mg capsule and 3 grey 20 mg capsules)  

• 100 mg (1 orange 80 mg capsule and 1 grey 20 mg capsule) 

• 60 mg (3 grey 20 mg capsules)  
Your doctor will decide on the right dose for you. 

 

Your capsules will come in a blister card organised by prescribed dose. Each blister card has enough 

capsules to last for seven days (one week).  Your capsules are also available as a 28 day pack, which contains 

enough capsules to last for 28 days, in 4 blister cards with seven days of capsules on each card. 

 

Each day, take all the capsules across the row. More information on the blister cards including how many 

capsules you will take and how many capsules there are in total in each blister card are described below in 

section 6. To help you remember your doses, write the date when you took your first dose in the space next 

to the capsules. To remove the capsules for your dose: 

  



 

63 

 

1. Push in tab 
 

 

 

 

2. Peel paper backing 
 

 

 

 

3. Push capsule through foil 
 

 

 

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

COMETRIQ and for 1 hour after taking the medicine. Swallow the capsules one at a time with water. Do not 

open them. 

 

If you take more COMETRIQ than you should 

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

with the capsules and this leaflet straight away. 

 

If you forget to take COMETRIQ 

- 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 COMETRIQ 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, 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. 

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

• A wound that does not heal.  

• Vomiting or coughing up blood, which may be bright red or look like coffee grounds. 

• Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of 
heaviness in the jaw, or loosening of a tooth. These could be signs of bone damage in the jaw 

(osteonecrosis).  

• Seizures, headaches, confusion, or finding it difficult to concentrate. These may be signs of a 
condition called posterior reversible encephalopathy syndrome (PRES). PRES is uncommon (it 

affects less than 1 in 100 people). 

• Diarrhoea that is severe and does not seem to be settling. 
 

Other side effects include: 

 

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

 

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



 

64 

• Difficulty in swallowing 
• Blister, pain of the hands or soles of the feet, rash or redness of the skin, dry skin 

• Decreased appetite, weight loss, altered sense of taste 

• Fatigue, weakness, headache, dizziness 

• Hair colour changes (lightening), hair loss 

• Hypertension (increase in blood pressure) 
• Redness, swelling or pain in the mouth or throat, difficulty in speaking, hoarseness 

• Changes in blood tests used to monitor general health and the liver, low levels of electrolytes (like 

magnesium, calcium or potassium) 

• Low level of platelets 

• Joint pain, muscle spasms 

• Swollen lymph glands  

• Pain in the arms, hands, legs or feet 
 

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

 

• Anxiety, depression, confusion 

• Generalised pain, chest or muscle pain, ear pain, ringing in ears 

• Weakness or reduced sensation or tingling in the limbs  

• Chills, tremors  

• Dehydration  

• Inflammation of the abdomen or pancreas 

• Inflammation of the lips and corners of the mouth 

• Inflammation at the root of your hair, acne, blisters (on parts of your body other than the hands or 

feet) 

• Swelling in the face and in other parts of the body 

• Loss or change of taste 

• Hypotension (decrease in blood pressure) 

• Atrial fibrillation (a fast and erratic heartbeat) 

• Lightening of skin, flakey skin, unusual pale skin 

• Abnormal hair growth 

• Haemorrhoids 

• Pneumonia (lung infection) 

• Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of 

heaviness in the jaw, or loosening of a tooth 

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

and dry skin 

• Low level of white blood cells 

• Decrease in level of phosphate in the blood 

• Tear or hole or bleeding in your stomach or intestine, inflammation or tear of anus, bleeding in lungs 

or trachea (airway) 

• An abnormal connection of the tissue in your digestive system; symptoms can include severe or 

persistent stomach ache 

• Abnormal connection of the tissue in your trachea (airway), oesophagus, or lungs 

• Abscess (collection of pus, with swelling and inflammation) in the abdomen or pelvis area or in your 

teeth/gums  

• Blood clots in the blood vessels and the lungs 

• Stroke 

• Fungal infection that can be in the skin, mouth, or genitals 

• Wounds that have difficulties healing 

• Protein or blood in the urine, gallstones, painful urination 

• Blurred vision 

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

• Decrease in the levels of protein in your blood (albumin). 

 

 



 

65 

Uncommon side effects (may affect 1 in 100 people) 

 

• Inflammation of the oesophagus; symptoms can include heartburn, chest pain, feeling sick, altered 

taste, bloating, belching and indigestion 

• Infection and inflammation in the lung, collapse of lung 

• Skin ulcers, cysts, red spots on the face or thighs 

• Facial pain 

• Changes in test results that measure blood clotting or blood cells 

• Loss of coordination in your muscles, damage to skeletal muscles 

• Loss of attention, loss of consciousness, changes in speech, delirium, abnormal dreams 

•  

• Chest pain due to blockage in arteries, rapid heartbeat 

• Liver damage, kidney failure 

• Impaired hearing 

• Inflammation in the eye, cataracts 

• Stopping menstruation, vaginal bleeding 

• A condition called posterior reversible encephalopathy syndrome (PRES) which has symptoms such 

as seizures, headaches, confusion, or finding it difficult to concentrate 

 

Not Known (side effects with unknown frequency) 

• 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. 

 

 

5. How to store COMETRIQ 

 

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 blister card after EXP. The expiry date 

refers to the last day of that month. 

 

Do not store above 25ºC. Store in the original package in order to protect from moisture. 

 

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 COMETRIQ contains  

 

The active substance is cabozantinib (S)-malate.  

 

The COMETRIQ 20 mg hard capsules contain cabozantinib (S)-malate equivalent to 20 mg of cabozantinib. 

The COMETRIQ 80 mg hard capsules contain cabozantinib (S)-malate equivalent to 80 mg of cabozantinib. 

 

The other ingredients are: 

 

- Capsule contents: microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, silica 

colloidal anhydrous, and stearic acid  

- Capsule shell: gelatin, and titanium dioxide (E171) 



 

66 

- The 20 mg capsules also contain black iron oxide (E172) 

- The 80 mg capsules also contain red iron oxide (E172) 

- Printing ink: shellac glaze, black iron oxide (E172), and propylene glycol 

 

What COMETRIQ looks like and contents of the pack 

COMETRIQ 20 mg hard capsules are grey and have “XL184 20mg” printed on one side. 

COMETRIQ 80 mg hard capsules are orange and have “XL184 80mg” printed on one side. 

 

COMETRIQ hard capsules are packaged in blister cards organised by prescribed dose. Each blister card 

contains enough medicine for 7 days. Each row of the blister card contains the daily dose.  

 

The 60 mg daily dose blister card contains twenty-one 20 mg capsules as 7 daily doses in total.  Each 

daily dose is given in one row and contains three 20 mg capsules: 

 

 
three grey 20 mg  

 

The 100 mg daily dose blister card contains seven 80 mg capsules and seven 20 mg capsules as 

7 daily doses in total.  Each daily dose is provided in one row and contains one 80 mg capsule and 

one 20 mg capsule: 

 

 
 one orange 80 mg + one grey 20 mg  

 

The 140 mg daily dose blister card contains seven 80 mg capsules and twenty one 20 mg capsules as 

7 doses in total. Each daily dose is provided in one row and contains one 80 mg capsule and three 

20 mg capsules: 

 

 
 one orange 80 mg + three grey 20 mg 

 

COMETRIQ hard capsules are also available in 28 day packs: 

 84 capsules (4 blister cards of 21 x 20 mg) (60 mg/day dose) 

 56 capsules (4 blister cards of 7 x 20 mg and 7 x 80 mg) (100 mg/day dose) 

 112 capsules (4 blister cards of 21 x 20 mg and 7 x 80 mg) (140 mg/day dose) 

 

Each 28 day pack contains enough medicine for 28 days. 

 

Marketing Authorisation Holder 

 

Ipsen Pharma 

65 quai Georges Gorse 

92100 Boulogne-Billancourt  

France 

 

= 60 mg 

= 100 mg 

= 140 mg 



 

67 

Manufacturer 

 

Catalent UK Packaging Limited 

Lancaster Way 

Wingates Industrial Park 

Westhoughton 

Bolton 

Lancashire 

BL5 3XX 

United Kingdom 

 

Or 

 

Catalent Germany Schorndorf GmbH 

Steinbeisstr. 1 und 2 

73614 Schorndorf 

Germany 

 

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.  Ipsen Pharma SAS Lietuvos filialas  

Olbrachtova 2006/9, T. Narbuto 5, 

140 00 Praha 4 08105 Vilnius 

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

  

Danmark, Norge, Suomi/Finland, Sverige, Ísland Magyarország 

Institut Produits Synthèse (IPSEN) AB IPSEN Pharma Hungary Kft. 

Kista Science Tower  Váci út 33. IX. em. 

Färögatan 33 H-1134 Budapest 

SE- 164 51 Kista  Tel.: +36-1-555-5930 

Sverige/Ruotsi/Svíþjóð   

Tlf/Puh/Tel/Sími: +46 8 451 60 00  

  

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 

  

  

  



 

68 

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 Ipsen Portugal - Produtos Farmacêuticos S.A. 

Alameda Fernão Lopes, n° 16A-1°B 

Αγ. Δημητρίου 63 Άλιμος 1495 - 190 Algés 

GR-17456 Αθήνα Ελλάδα Portugal 

Τηλ: + 30 - 210 - 984 3324 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. Ipsen Pharma, organizačná zložka 

Strojarska 20, 10 000 Zagreb, Zámocká 3 

Hrvatska SK-811 01 Bratislava 

Tel: +385 1 6311 833 Slovenská republika 

Fax: +385 1 6311 844 Tel: + 420 242 481 821 

  

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  

 

This medicine has been given ‘conditional approval’. This means that there is more evidence to come about 

this medicine. 

The European Medicines Agency will review new information on this medicine at least every year and this 

leaflet will be updated as necessary. 

 

Other sources of information 

 

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

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

 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET