This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

CABOMETYX 20 mg film-coated tablets

CABOMETYX 40 mg film-coated tablets

CABOMETYX 60 mg film-coated tablets

2. Qualitative and quantitative composition

CABOMETYX 20 mg film-coated tablets

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

Excipients with known effect

Each film-coated tablet contains 15.54 mg lactose.

CABOMETYX 40 mg film-coated tablets

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

Excipients with known effect

Each film-coated tablet contains 31.07 mg lactose.

CABOMETYX 60 mg film-coated tablets

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

Excipients with known effect

Each film-coated tablet contains 46.61 mg lactose

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

CABOMETYX 20 mg film-coated tablets

The tablets are yellow round with no score and debossed with “XL” on one side and “20” on the other side of the tablet.

CABOMETYX 40 mg film-coated tablets

The tablets are yellow triangle shaped with no score and debossed with “XL” on one side and “40” on the other side of the tablet.

CABOMETYX 60 mg film-coated tablets

The tablets are yellow oval shaped with no score and debossed with “XL” on one side and “60” on the other side of the tablet.

4. Clinical particulars
4.1 Therapeutic indications

Renal Cell Carcinoma (RCC)

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

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

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

Hepatocellular Carcinoma (HCC)

CABOMETYX is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.

4.2 Posology and method of administration

Therapy with CABOMETYX should be initiated by a physician experienced in the administration of anticancer medicinal products.

Posology

CABOMETYX (cabozantinib) tablets and COMETRIQ (cabozantinib) capsules are not bioequivalent and should not be used interchangeably (see section 5.2). If a patient must switch from cabozantinib capsules to cabozantinib tablets, the patient should continue at a CABOMETYX dose not to exceed 60 mg or the current COMETRIQ dose (whichever is lower).

For RCC and HCC, the recommended dose of CABOMETYX is 60 mg once daily. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction of CABOMETYX therapy (see Table 1). When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily. Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities. Dose reductions are recommended for events that, if persistent, could become serious or intolerable.

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

Table 1: Recommended CABOMETYX dose modifications for adverse reactions

Adverse reaction and severity

Treatment Modification

Grade 1 and Grade 2 adverse reactions which are tolerable and easily managed

Dose adjustment is usually not required.

Add supportive care as indicated.

Grade 2 adverse reactions which are intolerable and cannot be managed with a dose reduction or supportive care

Interrupt treatment until the adverse reaction resolves to Grade ≤1.

Add supportive care as indicated.

Consider re-initiating at a reduced dose.

Grade 3 adverse reactions (except clinically nonrelevant laboratory abnormalities)

Interrupt treatment until the adverse reaction resolves to Grade ≤1.

Add supportive care as indicated.

Re-initiate at a reduced dose.

Grade 4 adverse reactions (except clinically nonrelevant laboratory abnormalities)

Interrupt treatment.

Institute appropriate medical care.

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

If adverse reaction does not resolve, permanently discontinue CABOMETYX.

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4)

Concomitant medicinal products

Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be avoided (see sections 4.4 and 4.5).

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.

Special populations

Elderly patients

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

Race

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

Patients with renal impairment

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

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

Patients with hepatic impairment

In patients with mild hepatic impairment no dose adjustment is required. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dosing recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2). There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so cabozantinib is not recommended for use in these patients (see section 5.2).

Patients with cardiac impairment

There 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 and adolescents aged <18 years have not yet been established. No data are available.

Method of administration

CABOMETYX is for oral use. The tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before, through 1 hour after, taking CABOMETYX.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

As most events occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting).

In renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy, dose reductions and dose interruptions due to an AE occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial (METEOR). Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption was 38 days.

In treatment-naïve renal cell carcinoma, dose reductions and dose interruptions occurred in 46% and 73%, respectively, of cabozantinib-treated patients in the clinical trial (CABOSUN).

In hepatocellular carcinoma following prior systemic therapy, dose reductions and dose interruptions occurred in 62% and 84%, respectively, of cabozantinib-treated patients in the clinical trial (CELESTIAL). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 38 days, and to first dose interruption was 28 days. Closer monitoring is advised in patients with mild or moderate hepatic impairment.

Hepatic effects

Abnormalities of liver function tests (increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with cabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of cabozantinib treatment and to monitor closely during treatment. For patients with worsening of liver function tests considered related to cabozantinib treatment (i.e. where no alternative cause is evident), the dose modification advice in Table 1 should be followed (see section 4.2).

Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. Cabometyx is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as cabozantinib has not been studied in this population and exposure might be increased in these patients.

Hepatic encephalopathy

In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm. Cabozantinib has been associated with diarrhoea, vomiting, decreased appetite and electrolyte abnormalities. In HCC patients with compromised livers, these non-hepatic effects may be precipitating factors for the development of hepatic encephalopathy. Patients should be monitored for signs and symptoms of hepatic encephalopathy.

Perforations and fistulas

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients who have inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses and sepsis. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.

Gastrointestinal (GI) disorders

Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most commonly reported GI adverse reactions (see section 4.8). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see Table 1).

Thromboembolic events

Events of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism, sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. In the HCC study (CELESTIAL), portal vein thrombosis was observed with cabozantinib, including one fatal event. Patients with a history of portal vein invasion appeared to be at higher risk of developing portal vein thrombosis. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant thromboembolic complication.

Haemorrhage

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage.

In the HCC study (CELESTIAL), fatal haemorrhagic events were reported at a higher incidence with cabozantinib than placebo. Predisposing risk factors for severe haemorrhage in the advanced HCC population may include tumour invasion of major blood vessels and the presence of underlying liver cirrhosis resulting in oesophageal varices, portal hypertension, and thrombocytopenia. The CELESTIAL study excluded patients with concomitant anticoagulation treatment or antiplatelet agents. Subjects with untreated, or incompletely treated, varices with bleeding or high risk for bleeding were also excluded from this study.

Thrombocytopenia

In the HCC study (CELESTIAL), thrombocytopenia and decreased platelets were reported. Platelet levels should be monitored during cabozantinib treatment and the dose modified according to the severity of the thrombocytopenia (see Table 1).

Wound complications

Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.

Hypertension

Hypertension has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. During treatment with cabozantinib, all patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.

Palmar-plantar erythrodysaesthesia syndrome

Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.

Proteinuria

Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with RPLS.

Prolongation of QT interval

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

Biochemical laboratory test abnormalities

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). It is recommended to monitor biochemical parameters during cabozantinib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Cases of hepatic encephalopathy in HCC patients can be attributed to the development of electrolyte disturbances. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant abnormalities (see Table 1).

CYP3A4 inducers and inhibitors

Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see sections 4.2 and 4.5).

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib (see section 4.5).

MRP2 inhibitors

Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution (see section 4.5).

Excipient related warnings

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on cabozantinib

CYP3A4 inhibitors and inducers

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

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

Gastric pH modifying agents

Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.

MRP2 inhibitors

In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.

Bile salt-sequestering agents

Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure (see section 5.2). The clinical significance of these potential interactions is unknown.

Effect of cabozantinib on other medicinal products

The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended.

Because of high plasma protein binding levels of cabozantinib (section 5.2) a plasma protein displacement interaction with warfarin may be possible. In case of such combination, INR values should be monitored.

P-glycoprotein substrates

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as “effective methods of contraception”, they should be used together with another method, such as a barrier method (see section 4.5).

Pregnancy

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects (see section 5.3). The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.

Breast-feeding

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

Fertility

There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib (see section 5.3). Both men and women should be advised to seek advice and consider fertility preservation before treatment.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

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

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

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

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

Tabulated list of adverse reactions

Adverse reactions are listed in Table 2 according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100; not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

MedDRA System Organ Class

Very Common

Common

Uncommon

Not Known

Infections and infestations

abscess

Blood and lymphatic disorders

anaemia

thrombocytopenia, neutropenia,

lymphopenia

Endocrine disorders

hypothyroidism

Metabolism and nutrition disorders

decreased appetite, hypomagnesaemia, hypokalaemia.

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

Nervous system disorders

dysgeusia, headache, dizziness

peripheral sensory neuropathy

convulsion

cerebrovascular accident

Ear and labyrinth disorders

tinnitus

Cardiac disorders

myocardial infarction

Vascular disorders

Hypertension, haemorrhage

venous thrombosis

arterial thrombosis

Respiratory, thoracic, and mediastinal disorders

dysphonia, dyspnoea, cough

pulmonary embolism

Gastrointestinal disorders

diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, upper abdominal pain

gastrointestinal perforation, fistula, gastrooesophageal reflux disease, haemorrhoids, oral pain, dry mouth

pancreatitis, glossodynia

Hepatobiliary disorders

hepatic encephalopathy

hepatitis cholestatic

Skin and subcutaneous tissue disorders

palmar-plantar erythrodysaesthesia syndrome, rash

alopecia, dry skin, dermatitis acneiform, hair colour change

Musculoskeletal and connective tissue disorders

pain in extremity

muscle spasms, arthralgia

osteonecrosis of the jaw

Renal and urinary disorders

proteinuria

General disorders and administration site conditions

fatigue, mucosal inflammation, asthenia, peripheral oedema

Investigations

weight decreased, serum ALT increased, AST increased,

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

blood triglycerides increased

Injury, poisoning and procedural complications

wound complications

Description of selected adverse reactions

Data for the following reactions are based on patients who received Cabometyx 60 mg qd po in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC and in HCC following prior systemic therapy (section 5.1).

Gastrointestinal (GI) perforation

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

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

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

Hepatic encephalopathy

In the HCC study (CELESTIAL), hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonaemic encephalopathy) was reported in 5.6% of cabozantinib-treated patients (26/467); Grade 3-4 events in 2.8%, and one (0.2%) Grade 5 event. Median time to onset was 5.9 weeks.

No cases of hepatic encephalopathy were reported in the RCC studies (METEOR and CABOSUN)

Diarrhoea

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

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

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

Fistulas

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

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

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

Fatal fistulas have occurred in the cabozantinib clinical programme.

Haemorrhage

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

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

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Pharmacodynamic effects

Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Cardiac electrophysiology

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 – 15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg qd) was observed in a controlled clinical study in medullary thyroid cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated subjects in the RCC or HCC studies (at a dose of 60 mg).

Clinical efficacy and safety

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

The safety and efficacy of CABOMETYX for the treatment of renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy were evaluated in a randomized, open-label, multicentre Phase 3 study (METEOR). Patients (N=658) with advanced RCC with a clear cell component who had previously received at least 1 prior VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) were randomized (1:1) to receive CABOMETYX (N=330) or everolimus (N=328). Patients could have received other prior therapies, including cytokines, and antibodies targeting VEGF, the programmed death 1 (PD-1) receptor, or its ligands. Patients with treated brain metastases were allowed. Progression-free survival (PFS) was assessed by a blinded independent radiology review committee, and the primary analysis was conducted among the first 375 subjects randomized. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumour assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter.

The baseline demographic and disease characteristics were similar between the CABOMETYX and everolimus arms. The majority of the patients were male (75%), with a median age of 62 years. Seventy-one percent (71%) received only one prior VEGFR TKI; 41% of patients received sunitinib as their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Center criteria for prognostic risk category, 46% were favorable (0 risk factors), 42% were intermediate (1 risk factor), and 13% were poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%). The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus.

A statistically significant improvement in PFS was demonstrated for CABOMETYX compared to everolimus (Figure 1 and Table 3). A planned interim analysis of OS was conducted at the time of the PFS analysis and did not reach the interim boundary for statistical significance (202 events, HR=0.68 [0.51, 0.90], p=0.006). In a subsequent unplanned interim analysis of OS, a statistically significant improvement was demonstrated for patients randomized to CABOMETYX as compared with everolimus (320 events, median of 21.4 months vs. 16.5 months; HR=0.66 [0.53, 0.83], p=0.0003; Figure 2). Comparable results for OS were observed with a follow-up analysis (descriptive) at 430 events.

Exploratory analyses of PFS and OS in the ITT population have also shown consistent results in favour of CABOMETYX compared to everolimus across different subgroups according to age (<65 vs. ≥65, sex, MSKCC risk group (favourable, intermediate, poor), ECOG status (0 vs. 1), time from diagnosis to randomisation (<1 year vs. ≥1 year), tumour MET status (high vs. low vs. unknown), bone metastases (absence vs. presence), visceral metastases (absence vs. presence), visceral and bone metastases (absence vs. presence), number of prior VEGFR-TKIs (1 vs. ≥2), duration of first VEGFR-TKI (≤6 months vs. >6 months).

Objective response rate findings are summarized in Table 4.

Figure 1: Kaplan Meier curve for progression-free survival by independent radiology review committee, in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (first 375 subjects randomized (METEOR)

Table 3: Summary of PFS findings by independent radiology review committee in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR)

Primary PFS analysis Population

Intent-To-Treat Population

Endpoint

CABOMETYX

Everolimus

CABOMETYX

Everolimus

N = 187

N = 188

N = 330

N = 328

Median PFS (95% CI), months

7.4 (5.6, 9.1)

3.8 (3.7, 5.4)

7.4 (6.6, 9.1)

3.9 (3.7, 5.1)

HR (95% CI), p-value1

0.58 (0.45, 0.74), p<0.0001

0.51 (0.41, 0.62), p<0.0001

1 stratified log-rank test

Figure 2: Kaplan-Meier curve of overall survival in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy (METEOR)

Table 4: Summary of ORR findings per independent radiology committee review (IRC) and investigator review, in RCC subjects following prior vascular endothelial growth factor (VEGF)-targeted therapy

Primary Analysis ORR Intent-To-Treat Population (IRC)

ORR per Investigator Review Intent-To-Treat Population

Endpoint

CABOMETYX

Everolimus

CABOMETYX

Everolimus

N = 330

N = 328

N = 330

N = 328

ORR (partial responses only) (95% CI)

17% (13%, 22%)

3% (2%, 6%)

24% (19%, 29%)

4% (2%, 7%)

p-value1

p<0.0001

p< 0.0001

Partial Response

17%

3%

24%

4%

Median time to First Response, months (95% CI)

1.91 (1.6, 11.0)

2.14 (1.9, 9.2)

1.91 (1.3, 9.8)

3.50 (1.8, 5.6)

Stable Disease as Best Response

65%

62%

63%

63%

Progressive Disease as Best Response

12%

27%

9%

27%

1 chi-squared test

Clinical data in treatment-naïve renal cell carcinoma

The safety and efficacy of CABOMETYX for the treatment of treatment-naïve renal cell carcinoma were evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N=157) with previously untreated, locally advanced or metastatic RCC with a clear cell component were randomized (1:1) to receive CABOMETYX (N=79) or sunitinib (N=78). Patients had to have intermediate or poor risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no). Approximately 75% of patients had a nephrectomy prior to onset of treatment.

For intermediate risk disease, one or two of the following risk factors were met, while for poor risk, three or more factors were met: time from diagnosis of RCC to systemic treatment < 1 year, Hgb < LLN, Corrected calcium > ULN, KPS < 80%, Neutrophil count > ULN and Platelet count > ULN.

The primary endpoint was PFS. Secondary efficacy endpoints were objective response rate (ORR) and overall survival (OS). Tumor assessments were conducted every 12 weeks.

The baseline demographic and disease characteristics were similar between the CABOMETYX and sunitinib arms. The majority of the patients were male (78%) with a median age of 62 years. Patient distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥3 risk factors). Most patients (87%) had ECOG performance status of 0 or 1; 13% had an ECOG performance status of 2. Thirty-six percent (36%) of patients had bone metastases.

A statistically significant improvement in PFS as retrospectively assessed by a blinded Independent Radiology Committee (IRC) was demonstrated for CABOMETYX compared to sunitinib (Figure 3 and Table 5). The results from the Investigator determined analysis and IRC-determined analysis of PFS were consistent.

Patients with both positive and negative MET status showed a favourable effect with CABOMETYX compared to sunitinib, with greater activity in patients with a positive MET status compared to patients with a negative MET status (HR=0.32 (0.16, 0.63) vs 0.67 (0.37, 1.23)) respectively.

CABOMETYX treatment was associated with a trend for longer survival compared to sunitinib (Table 5). The study was not powered for the OS analysis and the data are immature.

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

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

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

CABOMETYX

(N=79)

Sunitinib

(N=78)

Progression-free survival (PFS) by IRC a

Median PFS in months (95% CI)

8.6 (6.2, 14.0)

5.3 (3.0, 8.2)

HR (95% CI); stratified b,c

0.48 (0.32, 0.73)

Two-sided log-rank p-value: stratified b

p=0.0005

Progression-free survival (PFS) by Investigator

Median PFS in months (95% CI)

8.3 (6.5, 12.4)

5.4 (3.4, 8.2)

HR (95% CI); stratified b,c

0.56 (0.37, 0.83)

Two-sided log-rank p-value: stratified b

p=0.0042

Overall Survival

Median OS in months (95% CI)

30.3 (14.6, NE)

21.0 (16.3, 27.0)

HR (95% CI); stratified b,c

0.74 (0.47, 1.14)

Objective Response Rate n (%) by IRC

Complete responses

0

0

Partial responses

16 (20)

7 (9)

ORR (partial responses only)

16 (20)

7 (9)

Stable disease

43 (54)

30 (38)

Progressive Disease

14 (18)

23 (29)

Objective Response Rate n (%) by Investigator

Complete responses

1 (1)

0

Partial responses

25 (32)

9 (12)

ORR (partial responses only)

26 (33)

9 (12)

Stable disease

34 (43)

29 (37)

Progressive Disease

14 (18)

19 (24)

a in accord with EU censoring

b Stratification factors per IxRS comprise IMDC risk categories (intermediate risk, poor risk and bone metastasis (yes, no)

c Estimated using the Cox proportional hazard model adjusted for stratification factors per IxRS. Hazard ratio < 1 indicates progression-free survival in favor of cabozantinib

Clinical data in Hepatocellular Carcinoma

The safety and efficacy of CABOMETYX were evaluated in a randomized, double-blind, placebo-controlled Phase 3 study (CELESTIAL). Patients (N=707) with HCC not amenable to curative treatment and who had previously received sorafenib for advanced disease were randomized (2:1) to receive CABOMETYX (N=470) or placebo (N=237). Patients could have received one other prior systemic therapy for advanced disease in addition to sorafenib. Randomization was stratified by aetiology of disease (HBV [with or without HCV], HCV [without HBV], or other), geographic region (Asia, other regions) and by presence of extrahepatic spread of disease and/or macrovascular invasions (Yes, No).

The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints were progression-free survival (PFS) and objective response rate (ORR), as assessed by the Investigator using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Tumour assessments were conducted every 8 weeks. Subjects continued blinded study treatment after radiological disease progression whilst they experienced clinical benefit or until the need for subsequent systemic or liver-directed local anticancer therapy. Crossover from placebo to cabozantinib was not allowed during the blinded treatment phase.

The baseline demographic and disease characteristics were similar between the CABOMETYX and placebo arms and are shown below for all 707 randomised patients:

Male: 82%

Median age: 64 years.

Caucasian: 56%, Asian: 34%

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

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

Aetiology for HCC included 38% hepatitis B virus (HBV), 21% hepatitis C virus (HCV), 40% other (neither HBV nor HCV).

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

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

Loco-regional transarterial embolisation or chemoinfusion procedures: 44%

Radiotherapy prior to cabozantinib treatment: 37%

Median duration of sorafenib treatment: 5.32 months

Seventy-two percent (72%) of patients had received one and 28% had received 2 prior systemic therapy regimens for advanced disease.

A statistically significant improvement in OS was demonstrated for CABOMETYX compared to placebo (Table 6 and Figure 4).

PFS and ORR findings are summarized in Table 6.

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

CABOMETYX

(N=470)

Placebo

(N=237)

Overall Survival

Median OS (95% CI), months

10.2 (9.1, 12.0)

8.0 (6.8, 9.4)

HR (95% CI)1,2

0.76 (0.63, 0.92)

p-value1

p=0.0049

Progression-free survival (PFS)3

Median PFS in months (95% CI)

5.2 (4.0, 5.5)

1.9 (1.9, 1.9)

HR (95% CI)1

0.44 (0.36, 0.52)

p-value1

p<0.0001

Kaplan-Meier landmark estimates of percent of subjects' event-free at 3 months

% (95% CI)

67.0% (62.2%, 71.3%)

33.3% (27.1%, 39.7%)

Objective Response Rate n (%)3

Complete responses (CR)

0

0

Partial responses (PR)

18 (4)

1 (0.4)

ORR (CR+PR))

18 (4)

1 (0.4)

p-value1,4

p=0.0086

Stable disease

282 (60)

78 (33)

Progressive Disease

98 (21)

131 (55)

1 2-sided stratified log-rank test with etiology of disease (HBV [with or without HCV], HCV [without HBV], or Other), geographic region (Asia, Other Regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data)

2 estimated using the Cox proportional-hazard model

3 as assessed by investigator per RECIST 1.1

4 stratified Cochran-Mantel-Haenszel (CMH) test

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

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

The incidence of systemic non-radiation and local liver-directed systemic non-protocol anticancer therapy (NPACT) was 26% in the cabozantinib arm and 33% in the placebo arm. Subjects receiving these therapies had to discontinue study treatment. An exploratory OS analysis censoring for the use of NPACT supported the primary analysis: the HR, adjusted for stratification factors (per IxRS), was 0.66 (95% CI: 0.52, 0.84; stratified logrank p-value = 0.0005). The Kaplan- Meier estimates for median duration of OS were 11.1 months in the cabozantinib arm versus 6.9 months in the placebo arm, an estimated 4.2-month difference in the medians.

Non-disease specific quality of life (QoL) was assessed using the EuroQoL EQ-5D-5L. A negative effect of Cabometyx versus placebo on the EQ-5D utility index score was observed during the first weeks of treatment. Only limited QoL data are available after this period.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with CABOMETYX in all subsets of the paediatric population in treatment of hepatocellular carcinoma and kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.

A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.

Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ) was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations.

Distribution

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was estimated to be 212L.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

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 normal healthy volunteers following oral administration of a ramge of doses from 20 to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.48 L/hr. Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in special patient populations

Renal impairment

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of geometric LS mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. Subjects with severe renal impairment have not been studied.

Hepatic impairment

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma exposure was observed amongst subjects with normal liver function (n=1425) and mild hepatic impairment (n=558) .There is limited data in patients with moderate hepatic impairment, (n=15) as per NCI-ODWG (National Cancer Institute – Organ Dysfunction working Group) criteria. The pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment..

Race

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

5.3 Preclinical safety data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed adverse effect level (NOAEL) for these findings were below human clinical exposure levels at intended therapeutic dose.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays. The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, cabozantinib-related neoplastic findings consisted of an increased incidence of benign pheochromocytoma, alone or in combination with malignant pheochromocytoma/complex malignant pheochromocytoma of the adrenal medulla in both sexes at exposures well below the intended exposure in humans. The clinical relevance of the observed neoplastic lesions in rats is uncertain, but likely to be low.

Cabozantinib was not carcinogenic in the rasH2 mouse model at a slightly higher exposure than the intended human therapeutic exposure.

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis was observed in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.

Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused postimplantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo-foetal toxicity and teratogenic findings were below human clinical exposure levels at intended therapeutic dose.

Juvenile rats (comparable to a >2 year old paediatric population) administered cabozantinib showed increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and density, liver pigmentation and lymph node lymphoid hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. Juvenile rats (correlating to a <2 year paediatric population) showed similar treatment-related findings, but appeared to be more sensitive to cabozantinib-related toxicity at comparable dose levels.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet content

Microcrystalline cellulose

Anhydrous lactose

Hydroxypropyl cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Film-coating

Hypromellose 2910

Titanium dioxide (E171)

Triacetin

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PCTFE blister with push-through aluminum foil backing containing 7 film-coated tablets. Each carton contains 4 blisters with 28 film-coated tablets.

HDPE bottle with a polypropylene child-resistant closure and three silica gel dessicant canisters. Each bottle contains 30 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Ipsen Pharma

65 quai Georges Gorse

92100 Boulogne-Billancourt

France

8. Marketing authorisation number(s)

Cabometyx 20 mg film-coated tablets

EU/1/16/1136/001

EU/1/16/1136/002

Cabometyx 40 mg film-coated tablets

EU/1/16/1136/003

EU/1/16/1136/004

Cabometyx 60 mg film-coated tablets

EU/1/16/1136/005

EU/1/16/1136/006

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 9 September 2016

10. Date of revision of the text

12 November 2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.