Stivarga · 4.1 Therapeutic indications · 1

HOS-096376 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC), 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular carcinoma (HCC). The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies. 9 The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage, gastrointestinal perforation and infection. The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are pain, hand foot skin reaction, asthenia/fatigue, diarrhoea, decreased appetite and food intake, hypertension and infection. Tabulated list of adverse reactions The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and not known (cannot be estimated from the available data). Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Table 3: Adverse drug reactions (ADRs) reported in clinical trials and postmarketing in patients treated with Stivarga System Organ Class Very common Common Uncommon Rare Not known (MedDRA) Infections and Infection infestations * Neoplasms Keratoacan- benign, thoma/ malignant and Squamous unspecified cell (including carcinoma of cysts and

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HOS-096372 · has-contraindication-information · PDF-Seite 5

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

HOS-096371 · has-indication-information · PDF-Seite 2

Stivarga is indicated as monotherapy for the treatment of adult patients with - metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy (see section 5.1) - unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib - hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

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Inhibitors of CYP3A4 and UGT1A9/inducers of CYP3A4 In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate glucuronosyl transferase UGT1A9. Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of approximately 33%, and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied. 7 Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic acid) during regorafenib treatment should be avoided, as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied. Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure of active metabolite M-2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John’s wort) may also increase metabolism of regorafenib. Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. UGT1A1 and UGT1A9 substrates In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state. Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted in an increase of approximately 44% in AUC of SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of approximately 28% was also observed. This indicates that co-administration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. Breast cancer resistance protein (BCRP) and P-glycoprotein substrat

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HOS-096375 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in males and females Women of childbearing potential must be informed that regorafenib may cause foetal harm. Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy. Pregnancy There are no data on the use of regorafenib in pregnant women. Based on its mechanism of action regorafenib is suspected to cause foetal harm when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Stivarga should not be used during pregnancy unless clearly necessary and after careful consideration of the benefits for the mother and the risk to the foetus. Breast-feeding It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib or its metabolites are excreted in milk. A risk to the breast-fed child cannot be excluded. Regorafenib could harm infant growth and development (see section 5.3). Breast-feeding must be discontinued during treatment with Stivarga. Fertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility (see section 5.3).

HOS-096373 · has-warning-information · PDF-Seite 5

Hepatic effects Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations (including hepatic failure and fatal outcomes) have been reported in a small proportion of patients (see section 4.8). In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga, compared with Caucasians (see section 4.2). It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated. Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor (see section 4.5). Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s syndrome. For patients with observed worsening of liver function tests considered related to treatment with Stivarga (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring advice in Table 2 should be followed (see section 4.2). Regorafenib is eliminated mainly via the hepatic route. Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population and exposure might be increased in these patients. Infections Stivarga has been associated with an increased incidence of infection events, some of which were fatal (see section 4.8). 5 In cases of worsening infection events, interruption of Stivarga treatment should be considered. Haemorrhage Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were fatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant med

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