Cabometyx · 4.4 Special warnings and precautions for use · 1

HOS-097783 · has-adverse-reaction-information · PDF-Seite 11

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 11 <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 decreased appetite, hypomagnesaemia, hypokalaemia, V

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HOS-097779 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 5

HOS-097778 · has-indication-information · PDF-Seite 3

Renal cell carcinoma (RCC) CABOMETYX 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). CABOMETYX, 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) CABOMETYX is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib. Differentiated thyroid carcinoma (DTC) CABOMETYX 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) CABOMETYX 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.

HOS-097781 · has-interaction-information · PDF-Seite 10

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 colestyramine 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 Pgp transport activities in a bidirectional assay sy

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HOS-097782 · has-pregnancy-information · PDF-Seite 10

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 10 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.

HOS-097780 · has-warning-information · PDF-Seite 6

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 instanc

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