Leitlinien & Arzneimittelsicherheit

HOS-216322 · has-adverse-reaction-information · PDF-Seite 7

Summary of safety profile The most common serious adverse reactions associated with cabozantinib are pneumonia, mucosal inflammation, hypocalcaemia, dysphagia, dehydration, pulmonary embolism, and hypertension. The most frequent adverse reactions of any grade (experienced by at least 20% of patients) included diarrhoea, PPES, weight decreased, decreased appetite, nausea, fatigue, dysgeusia, hair colour changes, hypertension, stomatitis, constipation, vomiting, mucosal inflammation, asthenia, and dysphonia. The most common laboratory abnormalities were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), lymphopenia, hypocalcaemia, 7 neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia, hypomagnesaemia, and hypokalaemia. Tabulated list of adverse reactions Adverse reactions are listed in Table 1 according to MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 8 Table 1: Adverse reactions reported with cabozantinib Infections and infestations abscess* (including visceral, skin, tooth), pneumonia, folliculitis, fungal infection Common (including skin, oral, genital) Uncommon Aspergilloma Endocrine disorders Common Hypothyroidism Metabolism and nutrition disorders Very common decreased appetite, hypocalcaemiac, hypokalaemiac, hypomagnesaemiac Common dehydration*, hypoalbuminaemiac, hyperbilirubinaemiad, hypophosphatemiac Psychiatric disorders Common anxiety, depression, confusional state Uncommon abnormal dreams, delirium Nervous system disorders Very common dysgeusia, headache, dizziness Common cerebrovascular accident*, peripheral neuropathy, paraesthesia, ageusia, tremor ataxia, disturbance in attention, hepatic encephalopathy, loss of consciousness, Uncommon speech disorder, posterior reversible encephalopathy syndrome* Eye disorders Common vision blurred Uncommon

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HOS-216318 · has-contraindication-information · PDF-Seite 4

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

HOS-216317 · has-indication-information · PDF-Seite 2

COMETRIQ is indicated for the treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma. For patients in whom rearranged during transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision (see important information in section 5.1).

HOS-216320 · has-interaction-information · PDF-Seite 6

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. 6 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), b

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HOS-216321 · has-pregnancy-information · PDF-Seite 7

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.

HOS-216319 · has-warning-information · PDF-Seite 4

Dose reductions and dose interruptions occurred in 79% and 72%, respectively, of cabozantinib-treated patients in the pivotal clinical study. Two dose reductions were required in 41% of patients. The median time to first dose reduction was 43 days, and to first dose interruption was 33 days. Close monitoring of patients is therefore recommended during the first eight weeks of therapy (see section 4.2). 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 cabozantinb treatment (i.e., where no alternative cause is evident), the dose should be reduced or treatment interrupted following recommendations provided in section 4.2. Perforations, fistulas, and intra-abdominal abscesses Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, and intra-abdominal abscesses have been observed with cabozantinib. Patients who have had recent radiotherapy, have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, or diverticulitis), have tumour infiltration of trachea, bronchi, or oesophagus, have complications from prior GI surgery (particularly when associated with delayed or incomplete healing), or have complications from prior radiation therapy to the thoracic cavity (including mediastinum) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas. Non GI fistula should be ruled out as appropriate in cases of onset of mucositis after start of therapy. Cabozantinib should be discontinued in patients who experience a GI perforation or a GI or non-GI fistula. Thromboembolic events Events of venous thromboembolism, including pulmonary embolism and events of arterial thromboembolism, sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Haemorrhage Severe h

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