4.1. Therapeutic indications

Renal cell carcinoma (RCC)

Cabozantinib Ipsen is indicated as monotherapy for advanced renal cell carcinoma

- as first-line treatment of adult patients with intermediate or poor risk (see section 5.1),

- in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy (see section 5.1).

Cabozantinib Ipsen, in combination with nivolumab, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1).

Hepatocellular carcinoma (HCC)

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

Differentiated thyroid carcinoma (DTC)

Cabozantinib Ipsen is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy.

Neuroendocrine Tumours (NET)

Cabozantinib Ipsen is indicated for the treatment of adult patients with unresectable or metastatic, well differentiated extra-pancreatic (epNET) and pancreatic (pNET) neuroendocrine tumours who have progressed following at least one prior systemic therapy other than somatostatin analogues.

4.2. Posology and method of administration

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

Posology

Cabozantinib Ipsen tablets and cabozantinib capsules are not bioequivalent and should not be used interchangeably (see section 5.2).

Cabozantinib Ipsen as monotherapy

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

Cabozantinib Ipsen in combination with nivolumab in first-line advanced RCC

The recommended dose of Cabozantinib Ipsen is 40 mg once daily in combination with nivolumab solution for infusion administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks, or with nivolumab solution for injection administered subcutaneously at either 600 mg every 2 weeks or 1200 mg every 4 weeks. The treatment should continue until disease progression or unacceptable toxicity. Nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression (see the Summary of Product Characteristics (SmPC) for posology of nivolumab).

Treatment modification

Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction (see Table 1). When dose reduction is necessary in monotherapy, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.

When Cabozantinib Ipsen is administered in combination with nivolumab, it is recommended to reduce the dose to 20 mg of Cabozantinib Ipsen once daily, and then to 20 mg every other day (refer to the nivolumab SmPC for recommended treatment modification for nivolumab).

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 Cabozantinib Ipsen 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 the treatment.

Liver enzymes elevations for RCC patients treated with Cabozantinib Ipsen in combination with nivolumab

ALT or AST > 3 times ULN but ≤10 times ULN without concurrent total bilirubin ≥ 2 times ULN

Interrupt Cabozantinib Ipsen and nivolumab until these adverse reactions resolves to Grade≤1

Corticosteroid therapy may be considered if immune-mediated reaction is suspected (refer to nivolumab SmPC).

Re-initiate with a single medicine or sequential re-initiating with both medicines after recovery may be considered. If re-initiating with nivolumab, refer to nivolumab SmPC.

ALT or AST > 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN

Permanently discontinue Cabozantinib Ipsen and nivolumab.

Corticosteroid therapy may be considered if immune-mediated reaction is suspected (refer to nivolumab SmPC).

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

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

Race

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

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 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).

Cardiac impairment

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

Paediatric population

The safety and efficacy of cabozantinib in children and adolescents aged <18 years have not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Cabozantinib Ipsen 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 Cabozantinib Ipsen.

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

Management of suspected adverse reactions may require temporary interruption or dose reduction of cabozantinib therapy (see section 4.2):

Dose reductions and dose interruptions due to an adverse event (AE) occurred in 46-67% and 70-84%, respectively, of cabozantinib-treated patients in the pivotal monotherapy clinical trials in RCC (METEOR, CABOSUN), HCC (CELESTIAL), DTC (COSMIC-311) and NET (CABINET). Two dose reductions were required in 9.4%-33% of patients. The median time to first dose reduction was 38-106 days and to first dose interruption was 28-68 days.

When cabozantinib is given in combination with nivolumab in first-line advanced RCC, dose reduction and dose interruption of cabozantinib due to an AE occurred in 54.1% and 73.4% of patients in the clinical trial (CA2099ER). Two dose reductions were required in 9.4% of patients. The median time to first dose reduction was 106 days, and to first dose interruption was 68 days.

Hepatotoxicity

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

When cabozantinib is given in combination with nivolumab, higher frequencies of Grades 3 and 4 ALT and AST elevations have been reported relative to cabozantinib monotherapy in patients with advanced RCC (see section 4.8). Liver enzymes should be monitored before initiation of and periodically throughout treatment. Medical management guidelines for both medicines should be followed (see section 4.2 and refer to the SmPC for nivolumab).

Rare instances of vanishing bile duct syndrome have been reported. All cases have occurred in patients who have received immune checkpoint inhibitors, either before or concurrently with cabozantinib treatment.

Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. Cabozantinib is not recommended for use in patients with severe hepatic impairment (Child-Pugh C, see section 4.2).

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 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 events (see section 4.8). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see Table 1).

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.

In the CABINET study, the frequency of VTE was higher in the pNET cohort (19%) compared to epNET cohort (3.8%) in participants who received cabozantinib.

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.

The study of cabozantinib in combination with nivolumab in first-line advanced RCC (CA2099ER) excluded patients with anticoagulants at therapeutic doses.

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.

Thrombocytopenia

In the HCC study (CELESTIAL), in the DTC study (COSMIC-311) and in the NET study (CABINET), 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 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, including hypertensive crisis has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. After cabozantinib initiation, blood pressure should be monitored early and regularly and treated as needed with appropriate antihypertensive therapy. In the case of persistent hypertension despite use of anti‑hypertensives, the cabozantinib treatment should be interrupted until blood pressure is controlled, after which cabozantinib can be resumed at a reduced dose. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.

Cardiac Failure

Cabozantinib has been associated with an increased risk of cardiac failure. This risk may be exacerbated by common adverse drug reactions of cabozantinib (e.g. hypertension, hypothyroidism and arterial thrombotic events), which can lead to cardiac failure. Patients should be monitored for signs and symptoms of cardiac failure throughout treatment. These adverse events should be managed promptly, dose interruptions and/or adjustments should be considered if necessary (see section 4.2) and TKI therapy should be discontinued in patients who develop severe cardiac failure.

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. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with PRES.

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.

Thyroid dysfunction

Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of cabozantinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during cabozantinib treatment. Thyroid function should be monitored periodically throughout treatment with cabozantinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice.

Biochemical laboratory test abnormalities

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatraemia). Hypocalcaemia has been observed with cabozantinib at a higher frequency and/or increased severity (including Grade 3 and 4) in patients with thyroid cancer compared to patients with other cancers. It is recommended to monitor biochemical parameters during cabozantinib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Cases of hepatic encephalopathy in HCC patients can be attributed to the development of electrolyte disturbances. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant abnormalities (see Table 1).

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. cyclosporin, efavirenz, emtricitabine) should be approached with caution (see section 4.5).

Excipient

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

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.

The effect of cabozantinib on the pharmacokinetics of warfarin has not been investigated. An interaction with warfarin may be possible. In case of such combination, INR values should be monitored.

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

Cabozantinib as monotherapy

Summary of safety profile

The most common serious adverse drug reactions in the RCC population (≥1% incidence) are pneumonia, abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia and palmar-plantar erythrodysaesthesia syndrome (PPES).

The most common serious adverse drug reactions in the HCC population (≥1% incidence) are hepatic encephalopathy, asthenia, fatigue, PPES, diarrhoea, hyponatraemia, vomiting, abdominal pain and thrombocytopenia.

The most common serious adverse drug reactions in the DTC population (≥1% incidence) are diarrhoea, pleural effusion, pneumonia, pulmonary embolism, hypertension, anaemia, deep vein thrombosis, hypocalcaemia, osteonecrosis of jaw, pain, PPES, vomiting and renal impairment.

The most common serious adverse drug reactions in the NET population (≥1% incidence) are hypertension, fatigue, pulmonary embolism, vomiting, diarrhoea, nausea, and embolism.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC, HCC, DTC and NET populations were diarrhoea, fatigue, nausea, decreased appetite, PPES and hypertension.

Tabulated list of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with cabozantinib monotherapy in RCC, HCC, DTC and NET (n=1355) or reported after post-marketing use of cabozantinib are listed in Table 2. The adverse reactions are listed by MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse drug reactions (ADRs) reported in clinical trials or after post-marketing use in patients treated with cabozantinib in monotherapy

Infections and infestations

Common

Abscess, pneumonia

Blood and lymphatic disorders

Very common

anaemia, thrombocytopenia

Common

neutropenia, lymphopenia

Endocrine disorders

Very common

hypothyroidism*

Metabolism and nutrition disorders

Very common

decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia, hypocalcaemia

Common

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

Nervous system disorders

Very common

dysgeusia, headache, dizziness

Common

peripheral neuropathya

Uncommon

convulsion, cerebrovascular accident, posterior reversible encephalopathy syndrome

Ear and labyrinth disorders

Common

tinnitus

Cardiac disorders

Uncommon

acute myocardial infarction, cardiac failure

Vascular disorders

Very common

hypertension, haemorrhageb*

Common

venous thrombosisc, hypotension, embolism

Uncommon

hypertensive crisis, arterial thrombosis, embolism arterial

Not known

aneurysms and artery dissections

Respiratory, thoracic, and mediastinal disorders

Very common

dysphonia, dyspnoea, cough

Common

pulmonary embolism, rhinitis allergic

Uncommon

pneumothorax

Gastrointestinal disorders

Very common

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

Common

gastrointestinal perforation* g, pancreatitis, fistula*, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia, flatulence

Uncommon

glossodynia

Hepatobiliary disorders

Common

hepatic encephalopathy*

Uncommon

hepatitis cholestatic

Skin and subcutaneous tissue disorders

Very common

palmar-plantar erythrodysaesthesia syndrome, rashf

Common

pruritus, alopecia, dry skin, hair colour change, hyperkeratosis, erythema

Not known

cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Very common

pain in extremity, arthralgia

Common

muscle spasms

Uncommon

osteonecrosis of the jaw

Renal and urinary disorders

Common

proteinuria

General disorders and administration site conditions

Very common

fatigue, mucosal inflammation, asthenia, peripheral oedema

Investigationsd

Very Common

weight decreased, serum ALT increased, AST increased, blood alkaline phosphatase increased

Common

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

Injury, poisoning and procedural complications

Uncommon

wound complicationse

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

a including polyneuropathy; peripheral neuropathy is mainly sensory

b Including epistaxis as the most commonly reported adverse reaction

cAll venous thrombosis including deep vein thrombosis

d Based on reported adverse reactions

e Impaired healing, incision site complication and wound dehiscence

f Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption.

g Fatal cases have been reported

Cabozantinib in combination with nivolumab in first-line advanced RCC

Summary of safety profile

When cabozantinib is administered in combination with nivolumab, refer to the SmPC for nivolumab prior to initiation of treatment. For additional information on the safety profile of nivolumab monotherapy, please refer to the nivolumab SmPC.

In a dataset of cabozantinib 40 mg once daily in combination with nivolumab 240 mg every two weeks in RCC (n =320), with a minimum follow‑up of 16 months, the most common serious adverse drug reactions (≥1% incidence) are diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatraemia, pyrexia, adrenal insufficiency, vomiting, dehydration.

The most frequent adverse reactions (≥25%) were diarrhoea, fatigue, palmar-plantar erythrodysaesthesia syndrome, stomatitis, musculoskeletal pain, hypertension, rash, hypothyroidism, decrease appetite, nausea, abdominal pain. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Tabulated list of adverse reactions

Adverse reactions identified in the clinical study of cabozantinib in combination with nivolumab are listed in Table 3, according to MedDRA System Organ Class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse reactions with cabozantinib in combination with nivolumab

Infections and infestations

Very Common

upper respiratory tract infection

Common

pneumonia

Blood and lymphatic system disorders

Common

eosinophilia

Immune system disorders

Common

hypersensitivity (including anaphylactic reaction)

Uncommon

infusion related hypersensitivity reaction

Endocrine disorders

Very common

hypothyroidism, hyperthyroidism

Common

adrenal insufficiency

Uncommon

hypophysitis, thyroiditis

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration

Nervous system disorders

Very common

dysgeusia, dizziness, headache

Common

peripheral neuropathy

Uncommon

encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome

Ear and labyrinth disorders

Common

tinnitus

Eye disorders

Common

dry eye, blurred vision

Uncommon

uveitis

Cardiac disorders

Common

atrial fibrillation, tachycardia

Uncommon

myocarditis

Vascular disorders

Very common

hypertension

Common

thrombosisa

Uncommon

embolism arterial

Respiratory, thoracic and mediastinal disorders

Very common

dysphonia, dyspnoea, cough

Common

pneumonitis, pulmonary embolism, epistaxis, pleural effusion

Uncommon

pneumothorax

Gastrointestinal disorders

Very common

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

Common

colitis, gastritis, oral pain, dry mouth, haemorrhoids

Uncommon

pancreatitis, small intestine perforationb, glossodynia

Hepatobiliary disorders

Common

hepatitis

Not known

vanishing bile duct syndromec

Skin and subcutaneous tissue disorders

Very common

palmar-plantar erythrodysaesthesia syndrome, rashd, pruritus

Common

alopecia, dry skin, erythema, hair colour change

Uncommon

psoriasis, urticaria

Not known

cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal paine, arthralgia, muscle spasm,

Common

arthritis

Uncommon

myopathy, osteonecrosis of the jaw, fistula

Renal and urinary disorders

Very common

proteinuria

Common

renal failure, acute kidney injury

Uncommon

nephritis

General disorders and administration site conditions

Very common

fatigue, pyrexia, oedema

Common

pain, chest pain

Investigationsf

Very common

increased ALT, increased AST, hypophosphataemia, hypocalcaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia, lymphopenia, increased alkaline phosphatase, increased lipase, increased amylase, thrombocytopaenia, increased creatinine, anaemia, leucopenia, hyperkalaemia, neutropenia, hypercalcaemia, hypoglycaemia, hypokalaemia, increased total bilirubin, hypermagnesaemia, hypernatraemia, weight decreased

Common

blood cholesterol increased, hypertriglyceridaemia

Adverse reaction frequencies presented in Table 3 may not be fully attributable to cabozantinib alone but may contain contributions from the underlying disease or from nivolumab used in a combination.

a Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonary thrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb

b Fatal cases have been reported

c With prior or concomitant immune checkpoint inhibitor exposure

d Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic and drug eruption

e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain

f Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements with the exception of weight decreased, blood cholesterol increased and hypertriglyceridaemia

Description of selected adverse reactions

Data for the following reactions are based on patients who received Cabozantinib Ipsen 60 mg orally once daily as monotherapy in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC, in HCC following prior systemic therapy, in DTC in patient refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy, in progressive NET following prior systemic therapy or in patients who received Cabozantinib Ipsen 40 mg orally once daily in combination with nivolumab in first-line advanced RCC (section 5.1).

Gastrointestinal (GI) perforation (see section 4.4)

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

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

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

In the DTC study (COSMIC-311), GI perforation grade 4 was reported in one patient (0.6%) of cabozantinib-treated patients and occurred after 14 weeks of treatment.

In the NET study (CABINET), GI perforations were reported in 1.3% of cabozantinib-treated patients (3/227). Events were Grade 3, 4 and 5. Median time to onset was 21.6 weeks.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of GI perforations was 1.3% (4/320) treated patients. One event was grade 3, two events were grade 4 and one event was grade 5 (fatal).

Fatal perforations have occurred in the cabozantinib clinical program.

Hepatic encephalopathy (see section 4.4)

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.

In the NET study (CABINET), hepatic encephalopathy was reported in 0.9% of cabozantinib-treated patients (2/227); There was one Grade 3 event (0.4%) for which median time to onset was 14.3 weeks.

No cases of hepatic encephalopathy were reported in the RCC studies (METEOR, CABOSUN and CA2099ER) and in the DTC study (COSMIC-311).

Diarrhoea (see section 4.4)

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

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

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

In the DTC study (COSMIC-311), diarrhoea was reported in 62% of cabozantinib treated patients (105/170); Grade 3-4 events in 7.6%. Diarrhoea led to dose reduction and interruption in 24/170 (14%) and 36/170 (21%) of subjects respectively.

In the NET study (CABINET), diarrhoea was reported in 63% of cabozantinib treated patients (144/227); Grade 3 events in 8.4%, no Grade 4 events. Median time to onset of Grade 3 events was 5.1 weeks.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER), the incidence of diarrhoea was reported in 64.7% (207/320) of treated patients; Grade 3-4 events in 8.4% (27/320). Median time to onset of all events was 12.9 weeks. Dose delay or reduction occurred in 26.3% (84/320) and discontinuation in 2.2% (7/320) of patients with diarrhoea, respectively.

Fistulas (see section 4.4)

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

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

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

In the DTC study (COSMIC-311), fistulas (two anal and one pharyngeal fistula) were reported in 1.8% (3/170) of the cabozantinib treated patients.

In the NET study (CABINET), fistulas (two anal and one biliary fistula) were reported in 1.3 % (3/227) of the cabozantinib treated patients. Anal fistula events were Grade 1 and 3, biliary fistula was Grade 2. Median time to onset was 19.3 weeks.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of fistula was reported in 0.9% (3/320) of treated patients and the severity was Grade 1.

Fatal fistulas have occurred in the cabozantinib clinical program

Haemorrhage (see section 4.4)

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

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

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

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of ≥ Grade 3 haemorrhage was in 1.9% (6/320) of treated patients.

In the DTC study (COSMIC-311), the incidence of severe haemorrhagic events (grade ≥ 3) was 2.4% in cabozantinib-treated patients (4/170). Median time to onset was 11.5 weeks.

In the NET study (CABINET), the incidence of severe haemorrhagic events (grade ≥ 3) was 1.8% in cabozantinib-treated patients (4/227). Median time to onset was 14.1 weeks.

Fatal haemorrhages have occurred in the cabozantinib clinical program.

Posterior reversible encephalopathy syndrome (PRES) (see section 4.4)

No case of PRES was reported in the METEOR, CABOSUN, CA2099ER or CELESTIAL studies, but PRES has been reported in one patient in the DTC study (COSMIC-311) and in one patient in the NET study (CABINET). PRES has been rarely reported in other clinical trials (in 2/4872 subjects; 0.04%).

Elevated liver enzymes when cabozantinib is combined with nivolumab in RCC

In a clinical study of previously untreated patients with RCC receiving cabozantinib in combination with nivolumab, a higher incidence of Grades 3 and 4 ALT increased (10.1%) and AST increased (8.2%) were observed relative to cabozantinib monotherapy in patients with advanced RCC (ALT increased of 3.6% and AST increased of 3.3% in METEOR study). The median time to onset of grade ≥ 2 increased ALT or AST was 10.1 weeks (range: 2 to 106.6 weeks; n=85). In patients with grade ≥ 2 increased ALT or AST, the elevations resolved to Grades 0-1in 91% with median time to resolution of 2.3 weeks (range: 0.4 to 108.1 weeks).

Among the 45 patients with Grade ≥2 increased ALT or AST who were rechallenged with either cabozantinib (n=10) or nivolumab (n=10) administered as a single agent or with both (n=25), recurrence of Grade ≥2 increased ALT or AST was observed in 4 patients receiving cabozantinib, in 3 patients receiving nivolumab and 8 patients receiving both cabozantinib and nivolumab.

Hypothyroidism

In the RCC study (METEOR), the incidence of hypothyroidism was 21% (68/331).

In the treatment-naïve RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.

In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib-treated patients and Grade 3 events in 0.4% (2/467).

In the DTC study (COSMIC-311), the incidence of hypothyroidism was 2.4% (4/170), all grade 1-2, none requiring modification of treatment.

In the NET study (CABINET), the incidence of hypothyroidism was 26% (59/227) in cabozantinib-treated patients, all grade 1-2.

In combination with nivolumab in advanced RCC in first-line treatment (CA2099ER) the incidence of hypothyroidism was 35.6% (114/320) of treated patients.

Paediatric population (see section 5.1)

In study ADVL1211, a limited dose-escalation study of cabozantinib in paediatric and adolescent patients with recurrent or refractory solid tumours including CNS tumours, the following events: aspartate aminotransferase (AST) increased (very common, 76.9%), alanine aminotransferase (ALT) increased (very common, 71.8%), lymphocyte count decreased (very common, 48.7%), neutrophil count decreased (very common, 35.9%), and lipase increased (very common, 33.3%) were observed at a higher frequency in all subjects across all dose groups included in the safety population (N=39), compared to adults. The increased rates for these Preferred Terms (PTs) concern any grade as well as grade 3/4 of these ADRs. The adverse events reported are in line qualitatively with the recognised safety profile for cabozantinib in adult populations. However, the small numbers of subjects preclude a conclusive assessment of trends and frequencies and further comparison with the recognised safety profile of cabozantinib.

In study ADVL1622 of cabozantinib in children and young adults with the following solid tumour strata: Ewing sarcoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), osteosarcoma, Wilms Tumour and other rare solid tumours (nonstatistical cohort), the safety profile of cabozantinib treated children and young adults in all strata was comparable with that observed in adults treated with cabozantinib.

Physeal widening has been observed in children with open growth plates when treated with cabozantinib.

Reporting 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 Website: 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.