——Stivarga（regorafenib）获欧盟批准用于胃肠道间质瘤新适应症 2014年7月30日，拜耳公司（Bayer）研发的抗癌药Stivarga（regorafenib）获欧盟委员会（EC）批准，用于既往经2种酪氨酸激酶抑制剂【格列卫（Gleevec，通用名：imatinib，伊马替尼），索坦（Sutent，通用名：sunitinib，舒尼替尼）】治疗后病情恶化或不耐受的不可切除性或转移性胃肠道间质瘤（GIST）患者的治疗。 拜耳公司StivargaGIST新适应证的获批，是基于关键III期GRID研究的数据。数据显示，与安慰剂+最佳支持疗法（BSC）相比，Stivarga+BSC组合疗法使患者无进展生存期（PFS）取得了统计学意义的显著改善（4.8个月 vs 0.9个月，p＜0.0001）。 目前，Stivarga已获美国、欧盟、日本批准，用于转移性结直肠癌（mCRC）的治疗。同时，该药已获美国和日本批准用于治疗胃肠道间质瘤（GIST）。继诺华的格列卫（Gleevec）、辉瑞的索坦（Sutent），拜耳的Stivarga是FDA批准的第三个治疗胃肠道间质瘤（GIST）的药物。 胃肠道间质瘤（GIST）是癌细胞发生在胃肠道的一种肿瘤，患者多为老年人。GIST极具侵略性，目前依然是尚未满足的医疗需求，同时治疗的选择也很有限。相关临床研究表明，拜耳公司的Stivarga有望为经标准治疗后复发的患者提供一种重要的治疗方案。 Stivarga是一种口服多激酶抑制剂，在临床前研究中，regorafenib能够抑制数个促血管生成VEGF受体酪氨酸激酶，这些激酶在肿瘤的血管生成中发挥着重要作用。Stivarga由拜耳公司开发，由拜耳和Onyx制药联合推广。 Stivarga 40 mg film-coated tablets 1. Name of the medicinal product Stivarga 40 mg film-coated tablets. 2. Qualitative and quantitative composition Each film-coated tablet contains 40 mg of regorafenib. Excipients with known effect: Each daily dose of 160 mg contains 2.427 mmol (or 55.8 mg) of sodium (see section 4.4). Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya) (see section 4.4). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet. Light pink film-coated tablets, oval shaped with a length of 16 mm and a width of 7 mm marked with 'BAYER' on one side and '40' on the other side. 4. Clinical particulars 4.1 Therapeutic indications Stivarga is indicated 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 tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib. 4.2 Posology and method of administration Stivarga should be prescribed by physicians experienced in the administration of anticancer therapy. Posology The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy. This 4-week period is considered a treatment cycle. If a dose is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose. In case of vomiting after regorafenib administration, the patient should not take additional tablets. Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs (see section 4.4). Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limited data in patients with PS ≥2. Posology adjustments Dose interruptions and/or dose reductions may be required based on individual safety and tolerability. Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg. The maximum daily dose is 160 mg. For recommended dose modifications and measures in case of hand-foot skin reaction (HFSR) / palmar-plantar erythrodysesthesia syndrome see Table 1. Table 1: Recommended dose modifications and measures for HFSR Skin toxicity grade Occurrence Recommended dose modification and measures Grade 1 Any Maintain dose level and immediately institute supportive measures for symptomatic relief. Grade 2 1st occurrence Decrease dose by 40 mg (one tablet) and immediately institute supportive measures. If no improvement occurs despite dose reduction, interrupt therapy for a minimum of 7 days, until toxicity resolves to Grade 0-1. A dose re-escalation is permitted at the discretion of the physician. No improvement within 7 days or 2nd occurrence Interrupt therapy until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician. 3rd occurrence Interrupt therapy until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician. 4th occurrence Discontinue treatment with Stivarga permanently. Grade 3 1st occurrence Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician. 2nd occurrence Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). 3rd occurrence Discontinue treatment with Stivarga permanently. For recommended measures and dose modifications in case of worsening of liver function tests considered related to treatment with Stivarga see Table 2 (see also section 4.4). Table 2: Recommended measures and dose modifications in case of drug-related liver function test abnormalities Observed elevations of ALT and/or AST Occurrence Recommended measures and dose modification ≤5 times upper limit of normal (ULN) (maximum Grade 2) Any occurrence Continue Stivarga treatment. Monitor liver function weekly until transaminases return to <3 times ULN (Grade 1) or baseline. >5 times ULN ≤20 times ULN (Grade 3) 1st occurrence Interrupt Stivarga treatment. Monitor transaminases weekly until return to <3 times ULN or baseline. Restart: If the potential benefit outweighs the risk of hepatotoxicity, re-start Stivarga treatment, reduce dose by 40 mg (one tablet), and monitor liver function weekly for at least 4 weeks. Re-occurrence Discontinue treatment with Stivarga permanently. >20 times ULN (Grade 4) Any occurrence Discontinue treatment with Stivarga permanently. >3 times ULN (Grade 2 or higher) with concurrent bilirubin >2 times ULN Any occurrence Discontinue treatment with Stivarga permanently. Monitor liver function weekly until resolution or return to baseline. Exception: patients with Gilbert's syndrome who develop elevated transaminases should be managed as per the above outlined recommendations for the respective observed elevation of ALT and/or AST. Hepatic impairment Regorafenib is eliminated mainly via the hepatic route. In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose adjustment is required in patients with mild hepatic impairment. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 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. Renal impairment In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild renal impairment (estimated Glomerular Filtration Rate [eGFR] 60-89 mL/min/1.73m2) and patients with normal renal function. Limited pharmacokinetic data indicate no difference in exposure in patients with moderate renal impairment (eGFR 30-59 mL/min/1.73m2). No dose adjustment is required in patients with mild or moderate renal impairment (see also section 5.2). No clinical data are available in patients with severe renal impairment (eGFR <30 mL/min/1.73m2). Elderly population In clinical studies, no relevant differences in exposure, safety or efficacy were observed between elderly (aged 65 years and above) and younger patients (see also section 5.2). Gender In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male and female patients. No dose adjustment is necessary based on gender (see also section 5.2). Ethnic differences In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. A higher incidence of hand foot skin reaction (HFSR) / palmar-plantar erythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga compared with Caucasians. The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%). There is limited data on regorafenib in the black patient population. No dose adjustment is necessary based on ethnicity (see section 5.2). Paediatric population There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer. The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumors (GIST) have not been established. No data are available. Method of administration Stivarga is for oral use. Stivarga should be taken at the same time each day. The tablets should be swallowed whole with water after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat). 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 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 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 as 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. Patients with KRAS mutant tumours In patients with KRAS mutant tumours, a significant improvement in PFS was observed and a numerically lower effect on OS was documented (refer to section 5.1). In view of the substantial toxicity related to treatment, physicians are recommended to carefully evaluate benefits and risks when prescribing regorafenib in patients with KRAS mutant tumours. 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 medicinal products that increase the risk of bleeding. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be considered. Cardiac ischaemia and infarction Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (see section 4.8). Patients with unstable angina or new onset angina (within 3 months of starting Stivarga therapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded from the clinical studies. Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction, interruption of Stivarga is recommended until resolution. The decision to re-start Stivarga therapy should be based on careful consideration of the potential benefits and risks of the individual patient. Stivarga should be permanently discontinued if there is no resolution. Posterior reversible encephalopathy syndrome (PRES) PRES has been reported in association with Stivarga treatment (see section 4.8). Signs and symptoms of PRES include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES, discontinuation of Stivarga, along with control of hypertension and supportive medical management of other symptoms is recommended. Gastrointestinal perforation and fistula Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patients treated with Stivarga (see section 4.8). These events are also known to be common disease-related complications in patients with intra-abdominal malignancies. Discontinuation of Stivarga is recommended in patients developing gastrointestinal perforation or fistula. Arterial hypertension Stivarga has been associated with an increased incidence of arterial hypertension (see section 4.8). Blood pressure should be controlled prior to initiation of treatment with Stivarga. It is recommended to monitor blood pressure and to treat hypertension in accordance with standard medical practice. In cases of severe or persistent hypertension despite adequate medical management, treatment should be temporarily interrupted and/or the dose reduced at the discretion of the physician (see section 4.2). In case of hypertensive crisis, Stivarga should be discontinued. Wound healing complications As medicinal products with anti-angiogenic properties may suppress or interfere with wound healing, temporary interruption of Stivarga is recommended for precautionary reasons in patients undergoing major surgical procedures. The decision to resume treatment with Stivarga following major surgical intervention should be based on clinical judgment of adequate wound healing. Dermatological toxicity Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash represent the most frequently observed dermatological adverse reactions with Stivarga (see section 4.8). ). In clinical trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with Stivarga as compared with Caucasians (see section 4.2). Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use of keratolytic creams (e.g. urea-, salicylic acid-, or alpha hydroxyl acid-based creams applied sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see section 4.2). Biochemical and metabolic laboratory test abnormalities Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are generally of mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of Stivarga should be considered in case of persistent or recurrent significant abnormalities (see section 4.2). Important information about some of the ingredients Each daily dose of 160 mg contains 2.427 mmol (or 55.8 mg) of sodium. To be taken into consideration by patients on a controlled sodium diet. Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya). 4.5 Interaction with other medicinal products and other forms of interaction 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. 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 substrates In vitro data indicate that regorafenib, M-2 and M-5 are inhibitors of BCRP (IC50 values about 40 to 70 nanomolar [regorafenib], 390 nanomolar [M-2 metabolite] and 150 nanomolar [M-5 metabolite]) and that regorafenib and M-2 are inhibitors of P-glycoprotein (IC50 value of about 2 micromolar [regorafenib] and 1.5 micromolar [M-2 metabolite]) at concentrations which are achieved in vivo at steady state. Co-administration of regorafenib may increase the plasma concentrations of concomitant BCRP substrates, such as methotrexate, or P-glycoprotein substrates, such as digoxin. Inhibitors of P-glycoprotein and BCRP / Inducers of P-glycoprotein and BCRP In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-glycoprotein and BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere with the exposure of M-2 and M-5. The clinical significance of these findings is unknown. CYP isoform-selective substrates In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced. A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone) CYP2C9 (S-warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam). Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see also section 4.4). Antibiotics The concentration-time profile indicates that regorafenib and its metabolites may undergo enterohepatic circulation (see section 5.2). Co-administration of antibiotics that affect the flora of the gastrointestinal tract may interfere with the enterohepatic circulation of regorafenib and may result in a decreased regorafenib exposure. The clinical significance of these potential interactions is unknown, but may result in a decreased efficacy of regorafenib. Bile salt-sequestering agents Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation (see section 5.2). Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with regorafenib by forming insoluble complexes which may impact absorption (or reabsorption), thus resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown, but may result in a decreased efficacy of regorafenib. 4.6 Fertility, pregnancy and lactation 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). 4.7 Effects on ability to drive and use machines No studies on the effects of Stivarga on the ability to drive or use machines have been performed. If patients experience symptoms affecting their ability to concentrate and react during treatment with Stivarga, it is recommended that they do not drive or use machines until the effect subsides. 4.8 Undesirable effects Summary of the safety profile The overall safety profile of Stivarga is based on data from more than 1,200 treated patients in clinical trials including placebo-controlled phase III data for 500 patients with metastatic colorectal cancer (CRC) and 132 patients with gastrointestinal stromal tumours (GIST). The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage and gastrointestinal perforation. The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/fatigue, hand foot skin reaction, diarrhoea, decreased appetite and food intake, hypertension, dysphonia 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); and rare (≥1/10,000 to <1/1,000). Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Table 3: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with Stivarga System Organ Class (MedDRA)  Very common  Common  Uncommon  Rare Infections and infestations  Infection      Neoplasms benign, malignant and unspecified (including cysts and polyps)        Keratoacanthoma/Squamous cell carcinoma of the skin Blood and lymphatic system disorders  Thrombocytopenia Anaemia  Leucopenia  Immune system disorders      Hypersensitivity reaction   Endocrine disorders    Hypothyroidism    Metabolism and nutrition disorders  Decreased appetite and food intake  Hypokalaemia Hypophosphataemia Hypocalcaemia Hyponatraemia Hypomagnesaemia Hyperuricaemia      Nervous system disorders  Headache  Tremor    Posterior reversible encephalopathy syndrome (PRES) Cardiac disorders      Myocardial infarction Myocardial ischaemia Vascular disorders  Haemorrhage* Hypertension    Hypertensive crisis  Respiratory, thoracic and mediastinal disorders  Dysphonia   Gastrointestinal disorders  Diarrhoea Stomatitis Vomiting Nausea  Taste disorders Dry mouth Gastro-oesophageal reflux Gastroenteritis  Gastrointestinal perforation* Gastrointestinal fistula Hepatobiliary disorders  Hyperbilirubinaemia  Increase in transaminases  Severe liver injury*# Skin and subcutaneous tissue disorders  Hand-foot skin reaction** Rash Alopecia  Dry skin Exfoliative rash  Nail disorder Erythema multiforme  Stevens-Johnson syndrome Toxic epidermal necrolysis Musculoskeletal and connective tissue disorders    Musculoskeletal stiffness  Renal and urinary disorders    Proteinuria  General disorders and administration site conditions  Asthenia/fatigue Pain Fever Mucosal inflammation      Investigations  Weight loss  Increase in amylase * fatal cases have been reported ** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology # according to drug-induced liver injury (DILI) criteria of the international DILI expert working group Description of selected adverse reactions Severe drug-induced liver injury (DILI) with fatal outcome occurred in 3 patients out of more than 1,200 Stivarga-treated patients across all clinical trials (0.25%). Two of the patients had liver metastases. Liver dysfunction in these patients had an onset within the first 2 months of therapy, and was characterised by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. Liver biopsies in 2 patients revealed hepatocellular necrosis with inflammatory cell infiltration. In the two placebo-controlled phase III trials, the overall incidence of hemorrhage was 19.3% in patients treated with Stivarga. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 16.9%), most notably epistaxis (7.6%). Fatal events in patients treated with Stivarga were uncommon (0.6%), and involved the respiratory, gastrointestinal and genitourinary tracts. In the two placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 31.0% vs. 14.4%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 22.9%), and included urinary tract infections (6.8%), nasopharyngitis (4.2%) as well as mucocutaneous and systemic fungal infections (2.4%). No difference in fatal outcomes associated with infection between treatment groups was observed (0.6%, Stivarga arm vs. 0.6%, placebo arm) In the placebo-controlled metastatic CRC phase III trial, the overall incidence of hand-foot skin reaction was 45.2% in patients treated with Stivarga as compared to 7.1% in patients receiving placebo. In the placebo-controlled GIST phase III trial, the overall incidence of hand-foot skin reaction was 66.7% in patients treated with Stivarga as compared to 15.2% in patients receiving placebo. In both trials, most cases of hand-foot skin reaction in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 28.6%, CRC and 44.7%, GIST). The incidence of Grade 3 hand-foot skin reaction was 16.6% (CRC) and 22.0% (GIST). In both trials, the overall incidence of hand-foot skin reaction (78.4%, CRC and 88.2%, GIST) was higher in Stivarga-treated Asian patients compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 28.4% (CRC) and 23.5% (GIST) (see sections 4.2 and 4.4). In the placebo-controlled metastatic CRC phase III trial the overall incidence of hypertension was 30.4% in patients treated with Stivarga as compared to 7.9% in patients receiving placebo. In the placebo-controlled GIST phase III trial, the overall incidence of hypertension was 59.1% in patients treated with Stivarga as compared to 27.3% in patients receiving placebo. In both trials, most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 22.8%, CRC and 31.1%, GIST). The incidence of Grade 3 hypertension was 7.6% (CRC) and 27.3% (GIST). One case of Grade 4 hypertension was reported in the GIST trial. In the placebo-controlled phase III trial in patients with metastatic CRC, the overall incidence of treatment emergent proteinuria was 7.4% in patients treated with Stivarga as compared to 2.4% in patients receiving placebo . Of these events, 40.5% in the Stivarga arm and 66.7% in the placebo arm have been reported as not recovered / not resolved. In the placebo-controlled GIST phase III trial, the overall incidence of proteinuria was 6.8% in patients treated with Stivarga compared to 1.5% in patients receiving placebo. Across all clinical trials, cardiac disorder events (all grades) have been more often (20.5% vs. 10.4%) reported in Stivarga-treated patients aged 75 years or older (N=78) as compared to Stivarga-treated patients below 75 years (N=995). Laboratory test abnormalities Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 4, 4a and Table 5 (see also section 4.4). Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial in patients with metastatic CRC (CORRECT) Laboratory parameter (in % of samples investigated) Stivarga plus BSC§ (N=500) Placebo plus BSC§ (N=253) All Grades* Grade 3* Grade 4* All Grades* Grade 3* Grade 4* Blood and lymphatic system disorders             Haemoglobin decreased 78.5 4.7 0.6 66.3 2.8 0 Platelet count decreased 40.5 2.4 0.4 16.8 0.4 0 Neutrophil count decreased 2.8 0.6 0 0 0 0 Lymphocyte count decreased 54.1 9.3 0 34.4 3.2 0 Metabolism and nutrition disorders             Calcium decreased 59.3 1.0 0.2 18.3 1.2 0 Potassium decreased 25.7 4.3 0 8.3 0.4 0 Phosphate decreased 57.4 30.5 0.6 11.1 3.6 0 Hepatobiliary disorders             Bilirubin increased 44.6 9.6 2.6 17.1 5.2 3.2 AST increased 65.0 5.3 0.6 45.6 4.4 0.8 ALT increased 45.2 4.9 0.6 29.8 2.8 0.4 Renal and urinary disorders             Proteinuria 59.7 0.4 0 34.1 0.4 0 Investigations             INR increased** 23.7 4.2 -# 16.6 1.6 -# Lipase increased 46.0 9.4 2.0 18.7 2.8 1.6 Amylase increased 25.5 2.2 0.4 16.7 2.0 0.4 Best Supportive Care * Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 ** International normalized ratio # No Grade 4 denoted in CTCAE, Version 3.0 Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients enrolled. Table 4a: Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR) Laboratory parameter, (in % of samples investigated) Stivarga plus BSC§ (N=136) Placebo plus BSC§ (N=68) All Grades* Grade 3* Grade 4* All Grades* Grade 3* Grade 4* Bilirubin increased 66.7 7.4 4.4 32.8 4.5 0.0 AST increased 69.6 10.4 0.7 47.8 3.0 0.0 ALT increased 54.1 8.9 0.0 29.9 1.5 0.0 Best Supportive Care * Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 Table 5: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial (double-blind phase) in patients with GIST (GRID) Laboratory parameter, (in % of samples investigated) Stivarga plus BSC§ (N=132) Placebo plus BSC§ (N=66) All Grades* Grade 3* Grade 4* All Grades* Grade 3* Grade 4* Blood and lymphatic system disorders             Haemoglobin decreased 75.0 3.0 0 72.7 1.5 0 Platelet count decreased 12.9 0.8 0 1.5 0 1.5 Neutrophil count decreased 15.9 2.3 0 12.1 3.0 0 Lymphocyte count decreased 29.5 7.6 0 24.2 3.0 0 Metabolism and nutrition disorders             Calcium decreased 16.7 1.5 0 4.5 0 0 Potassium decreased 20.5 3.0 0 3.0 0 0 Phosphate decreased 54.5 19.7 1.5 3.1 1.5 0 Hepatobiliary disorders             Bilirubin increased 33.3 3.0 0.8 12.1 1.5 0 AST increased 58.3 3.0 0.8 47.0 3.0 0 ALT increased 39.4 3.8 0.8 39.4 1.5 0 Renal and urinary disorders             Proteinuria 38.5 1.5 - 39.0 1.7 - Investigations             INR increased** 9.3 1.6 - 12.5 4.7 - Lipase increased 14.4 0 0.8 4.6 0 0 Best Supportive Care * Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 ** International normalized ratio - No Grade 4 denoted in CTCAE, Version 4.0 In the two placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 26.1% of patients treated with Stivarga and in 15.1% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.9% of patients treated with Stivarga and in 0.7% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 25.6% of patients treated with Stivarga and in 20.9% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.0% of patients treated with Stivarga and 6.6% of patients receiving placebo. Overall approximately 7% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacement treatment. 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. 4.9 Overdose The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga should be discontinued immediately, with best supportive care initiated by a medical professional, and the patient should be observed until clinical stabilisation. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor; ATC Code: L01XE21 Mechanism of action and pharmacodynamic effects Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumors, and thereby blocks tumor cell proliferation. In preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal and gastrointestinal stromal tumour models which is mediated by its anti-angiogenic and anti-proliferative effects. In addition, regorafenib has shown anti-metastatic effects in vivo. Major human metabolites (M-2 and M-5) exhibited similar efficacies compared to regorafenib in in vitro and in vivo models. Clinical efficacy and safety Metastatic colorectal cancer (CRC) The clinical efficacy and safety of Stivarga have been evaluated in an international, multi-centre, randomised, double-blind, placebo-controlled phase III study (CORRECT) in patients with metastatic colorectal cancer who have progressed after failure of standard therapy. The primary efficacy endpoint was Overall Survival (OS). Secondary endpoints were Progression-Free Survival (PFS), objective tumour response rate and disease control rate. In total, 760 patients were randomised 2:1 to receive 160 mg regorafenib (4 tablets Stivarga each containing 40 mg regorafenib) orally once daily (N=505) plus Best Supportive Care (BSC) or matching placebo (N=255) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 147 mg. Patients continued therapy until disease progression or unacceptable toxicity. A pre-planned interim analysis for efficacy was performed when 432 deaths had occurred. The study was un-blinded after this planned interim analysis of OS had crossed the pre-specified efficacy boundary. Of the 760 randomised patients, the median age was 61 years, 61% were male, 78% were Caucasian, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. PS ≥2 was reported during Stivarga treatment in 11.4% of patients. The median treatment duration and daily dose, as well as the rate of dose modification and dose reduction were similar to those observed in patients with a reported PS ≥ 2 receiving placebo (8.3%). The majority of patients with PS ≥2 discontinued treatment for progressive disease. The primary site of disease was colon (65%), rectum (29%), or both (6%). A KRAS mutation was reported in 57% of patients at study entry. Most patients (52%) received 3 or fewer previous lines of treatment for metastatic disease. Therapies included treatment with fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if the patient was KRAS wild type, an anti-EGFR therapy. The addition of Stivarga to BSC resulted in significantly longer survival as compared to placebo plus BSC with a hazard ratio of 0.774 (p=0.005178 stratified log rank test) and a median OS of 6.4 months vs. 5.0 months [95% CI 0.636, 0.942] (see Table 6 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see Table 6). The response rate (complete response or partial response) was 1% and 0.4% for Stivarga and placebo treated patients, respectively (p=0.188432, 1-sided). The disease control rate (complete response or partial response or stable disease) was significantly higher in patients treated with Stivarga (41.0% vs. 14.9%, p<0.000001, 1 sided). Table 6: Efficacy results from the CORRECT study Efficacy parameter Hazard ratio* (95% CI) P-value (one-sided) Median (95% CI) Stivarga plus BSC§ (N=505) Placebo plus BSC§ (N=255) Overall Survival 0.774 (0.636, 0.942) 0.005178 6.4 months (5.9, 7.3) 5.0 months (4.4, 5.8) Progression Free Survival** 0.494 (0.419, 0.582) <0.000001 1.9 months (1.9, 2.1) 1.7 months (1.7, 1.7) Best Supportive Care * Hazard ratio < 1 favours Stivarga ** based on investigator's assessment of tumour response Figure 1: Kaplan-Meier curve of overall survival Subgroup analyses for overall survival and progression free survival according to age (<65; ≥65), gender, ECOG PS, primary site of disease, time from first diagnosis of metastatic disease, prior anticancer treatment, prior treatment lines for metastatic disease, and KRAS mutation showed a treatment effect favouring the regorafenib regimen over the placebo regimen. Subgroup analysis results by historical KRAS mutational status showed a treatment effect for OS in favour of regorafenib over placebo for patients with KRAS wild-type tumours whereas a numerically lower effect was reported in patients with KRAS mutant tumours; the treatment effect for PFS favouring regorafenib was observed regardless of KRAS mutational status. The hazard ratio (95% CI) of overall survival was 0.653 (0.476 to 0.895) for patients with KRAS wild-type tumours and 0.867 (0.670 to 1.123) for patients with KRAS mutant tumours, with no evidence of heterogeneity in treatment effect (non-significant interaction test). The hazard ratio (95% CI) of progression free survival was 0.475 (0.362 to 0.623) for patients with KRAS wild-type tumours and 0.525 (0.425 to 0.649) for patients with KRAS mutant tumours. A second phase III, international, multi-center, randomized, double blind, placebo-controlled study (CONCUR) evaluated the efficacy and safety of Stivarga in 204 pre-treated Asian patients (> 90% East Asian) with metastatic colorectal cancer who have progressed after failure of fluoropyrimidine-based chemotherapy. Only 59.5 % of patients enrolled in the CONCUR study were also previously treated with VEGF- or EGFR-targeted agents. The primary efficacy endpoint was OS. The addition of Stivarga to BSC resulted in a significantly longer survival, as compared to placebo plus BSC with a hazard ratio of 0.550 (p = 0.000159 stratified log rank test) and a median OS of 8.8 months vs. 6.3 months [95% CI 0.395, 0.765]. PFS was also significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.311, p<0.000001), median PFS 3.2 months with Stivarga vs. 1.9 months with placebo. The safety profile of Stivarga plus BSC in the CONCUR study was consistent with the safety profile observed in the CORRECT study. Gastrointestinal stromal tumours (GIST) The clinical efficacy and safety of Stivarga have been evaluated in an international, multi-center, randomized, double-blind, placebo-controlled phase III study (GRID) in patients with gastrointestinal stromal tumors (GIST) previously treated with 2 tyrosine kinase inhibitors (imatinib and sunitinib). The analysis of the primary efficacy endpoint Progression-Free Survival (PFS) was conducted after 144 PFS events (central blinded assessment). Secondary endpoints including Time To Progression (TTP) and Overall Survival (OS) (interim analysis) were also assessed. In total, 199 patients with GIST were randomized 2:1 to receive either 160 mg regorafenib plus Best Supportive Care (BSC; N=133) orally once daily or matching placebo plus BSC (N=66) for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 140 mg. Patients continued therapy until disease progression or unacceptable toxicity. Patients receiving placebo who experienced disease progression were offered open-label regorafenib (cross-over option). Patients receiving regorafenib who experienced disease progression and for whom in the investigator's opinion, treatment with regorafenib was providing clinical benefit, were offered the opportunity to continue open-label regorafenib. Of the 199 randomized patients, the mean age was 58 years, 64% were male, 68% were Caucasian, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. The overall median time since most recent progression or relapse to randomization was 6 weeks. Regorafenib plus BSC resulted in significantly longer PFS as compared to placebo plus BSC with a hazard ratio of 0.268 [95% CI 0.185, 0.388] and a median PFS of 4.8 months vs. 0.9 months (p < 0.000001). The relative risk of disease progression or death was reduced by approximately 73.2% in regorafenib-treated patients compared to placebo treated patients (see Table 7, Figure 2).The increase in PFS was consistent independent of age, sex, geographic region, prior lines of treatment, ECOG PS. TTP was significantly longer in the patients receiving regorafenib plus BSC than in patients receiving placebo plus BSC with a hazard ratio of 0.248 [95% CI 0.170, 0.364], and median TTP of 5.4 months versus 0.9 months (p<0.000001) (see Table 7). The HR for OS was 0.772 (95% CI, 0.423, 1.408; p = 0.199; median OS not reached in either arm); 85% of patients initially randomized to the placebo arm received post-progression treatment with regorafenib (see Table 7, Figure 3). Table 7: Efficacy Results from the GRID study Efficacy parameter Hazard Ratio* (95% CI) P-value (one-sided) Median (95% CI) Stivarga plus BSC§ (N=133) Placebo plus BSC§ (N=66) Progression-Free Survival 0.268 (0.185, 0.388) <0.000001 4.8 months (4.0, 5.7) 0.9 months (0.9, 1.1) Time To Progression 0.248 (0.170,0.364) <0.000001 5.4 months (4.1, 5.7) 0.9 months (0.9, 1.1) Overall Survival 0.772 (0.423, 1.408) 0.199 NR** NR** Best Supportive Care * Hazard ratio < 1 favors Stivarga ** NR: not reached Figure 2: Kaplan-Meier curves of Progression-Free Survival Figure 3: Kaplan-Meier curves of Overall Survival In addition, 56 placebo plus BSC patients received open-label Stivarga after cross-over following disease progression and a total of 41 Stivarga plus BSC patients continued Stivarga treatment after disease progression. The median secondary PFS (as measured by the investigator's assessment) were 5.0 and 4.5 months, respectively. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Stivarga in all subsets of the paediatric population in the treatment of adenocarcinoma of the colon and rectum (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Stivarga in one or more subsets of the paediatric population in the treatment of solid malignant tumours (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a single oral dose of 160 mg given as 4 tablets each containing 40 mg. Following single doses of 60 mg or 100 mg, the average relative bioavailability of tablets compared to an oral solution was 69% and 83%, respectively. The concentrations of regorafenib and its major pharmacologically active metabolites (M-2 and M-5) were highest when given after a low-fat (light) breakfast as compared to either a high-fat breakfast or fasting condition. The exposure for regorafenib was increased by 48% when administered with a high-fat breakfast, and 36% when administered with a low fat breakfast, compared to fasting. The exposure of metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is higher when regorafenib is given with a low fat breakfast as compared to fasting condition and lower when given with a high fat meal as compared to fasting condition. Distribution Plasma concentration-time profiles for regorafenib as well as for the major circulating metabolites showed multiple peaks across the 24-hour dosing interval, which are attributed to enterohepatic circulation. In vitro protein binding of regorafenib to human plasma proteins is high (99.5%). In vitro protein binding of M-2 and M-5 is higher (99.8% and 99.95%, respectively) than that of regorafenib. Metabolites M-2 and M-5 are weak substrates of P-gp. Metabolite M-5 is a weak BCRP-substrate. Biotransformation Regorafenib is metabolized primarily in the liver by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically active and have similar concentrations as regorafenib at steady state. M-2 is further metabolised by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowing reabsorption of the unconjugated active substance and metabolites (enterohepatic circulation). Elimination Following oral administration, mean elimination half-life for regorafenib and its metabolite M-2 in plasma ranges from 20 to 30 hours in different studies. The mean elimination half-life for the metabolite M-5 is approximately 60 hours (range from 40 to 100 hours). Approximately 90% of the radioactive dose was recovered within 12 days after administration, with about 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and about 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 10% under steady-state conditions. Parent compound found in faeces could be derived from intestinal degradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbed regorafenib. M-5 may be reduced to M-4 in the gastrointestinal tract by microbial flora, allowing reabsorption of M-4 (enterohepatic circulation). M-5 is finally excreted via M-4 as M-6 (carboxylic acid) in faeces. Linearity/non-linearity Systemic exposure of regorafenib at steady-state increases dose proportionally up to 60 mg and less than proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady state results in about a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life and dosing frequency. At steady state, regorafenib reaches mean peak plasma levels of about 3.9 mg/L (8.1 micromolar) after oral administration of 160 mg regorafenib and the peak-to-trough ratio of mean plasma concentrations is less than 2. Both metabolites, M-2 and M-5, exhibit non-linear accumulation, which might be caused by entero-hepatic recycling or saturation of the UGT1A9 pathway. Whereas plasma concentrations of M-2 and M-5 after a single dose of regorafenib are much lower than those of parent compound, steady-state plasma concentrations of M-2 and M-5 are comparable to those of regorafenib. Hepatic impairment The exposure of regorafenib and its metabolites M-2 and M-5 is comparable in patients with mild hepatic impairment (Child-PughA) and patients with normal hepatic function. Limited data in patients with moderate hepatic impairment (Child-Pugh B) indicate similar exposure as compared to patients with normal hepatic function after a single 100 mg dose of regorafenib. There are no data for patients with Child-Pugh C (severe) hepatic impairment. Regorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population. Renal impairment Available clinical data and physiology-based pharmacokinetic modelling indicate similar steady-state exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild and moderate renal impairment compared to patients with normal renal function. The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease. However, physiology-based pharmacokinetic modelling does not predict any relevant change in exposure in these patients. Elderly Age did not affect the regorafenib pharmacokinetics over the studied age range (29 – 85 years). Gender The pharmacokinetics of regorafenib is not influenced by gender. Ethnic differences The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is within the same range as seen in Caucasians. Cardiac electrophysiology/QT prolongation No QTc prolonging effects were observed after administration of 160 mg regorafenib at steady state in a dedicated QT study in male and female cancer patients. 5.3 Preclinical safety data Systemic toxicity After repeated dosing to mice, rats and dogs, adverse effects were observed in a number of organs, primarily in the kidneys, liver, digestive tract, thyroid gland, lympho-/haematopoietic system, endocrine system, reproductive system and skin. A slightly increased incidence of thickening of the atrioventricular valves of the heart was seen in the 26 week repeat-dose toxicity study in rats. This may be due to acceleration of an age-related physiological process. These effects occurred at systemic exposures in the range of or below the anticipated human exposure (based on AUC comparison). Alterations of teeth and bones and adverse effects in the reproductive system were more pronounced in young and growing animals as well as in juvenile rats and indicate a potential risk for children and adolescents. Reproductive and developmental toxicity Specific studies on fertility have not been performed. However, a potential of regorafenib to adversely affect male and female reproduction has to be considered based on morphological changes in the testes, ovaries, and the uterus observed after repeated dosing in rats and dogs at exposures below the anticipated human exposure (based on AUC comparison). The observed changes were only partially reversible. An effect of regorafenib on intrauterine development was shown in rabbits at exposures below the anticipated human exposure (based on AUC comparison). Main findings consisted of malformations of the urinary system, the heart and major vessels, and the skeleton. Genotoxicity and carcinogenicity There was no indication for a genotoxic potential of regorafenib tested in standard assays in vitro and in vivo in mice. Studies on the carcinogenic potential of regorafenib have not been performed. Environmental Risk Assessment (ERA) Environmental risk assessment studies have shown that regorafenib has the potential to be persistent, bioaccumulative and toxic to the environment and may pose a risk to the surface water and to the sediment compartment (see section 6.6). 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Cellulose microcrystalline Croscarmellose sodium Magnesium stearate Povidone (K-25) Silica, colloidal anhydrous Film coat Iron oxide red (E172) Iron oxide yellow (E172) Lecithin (derived from soya) Macrogol 3350 Polyvinyl alcohol, partially hydrolysed Talc Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. Once the bottle is opened the medicinal product has shown to be stable for 7 weeks. Thereafter, the medicinal product is to be discarded. 6.4 Special precautions for storage Store in the original package in order to protect from moisture. Keep the bottle tightly closed and keep the desiccant in the bottle. 6.5 Nature and contents of container White opaque HDPE bottle closed with a PP/PP (polypropylene) screw cap with sealing insert and a molecular sieve desiccant. Each bottle contains 28 film-coated tablets. Pack sizes Pack of 28 film-coated tablets. Pack of 84 (3 bottles of 28) film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bayer Pharma AG 13342 Berlin Germany 8. Marketing authorisation number(s) EU/1/13/858/001 EU/1/13/858/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 26 August 2013 10. Date of revision of the text 05 / 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 2013年-FDA批准Stivarga (瑞格菲尼)新适应症用于治疗晚期胃肠道间质瘤 胃肠道间质瘤是一类起源于胃肠道间叶组织的肿瘤，占消化道间叶肿瘤的大部分。 胃肠道间质瘤占胃肠道恶性肿瘤的1～3%，估计年发病率约为10－20/100万，多发于中老年患者，40岁以下患者少见，男女发病率无明显差异。 2013年2月25日，美国食品药品管理局（FDA）批准Stivarga (regorafenib，瑞格菲尼)新适应症，用于不能通过手术切除以及使用其它已上市药物治疗无效的晚期胃肠道间质瘤(GIST)患者治疗。 胃肠道间质瘤的癌症细胞在人体消化系统的胃肠道组织内形成。根据美国国家癌症中心的信息，美国每年估计有3300人到6000人的胃肠道间质瘤新病例，且大多数患者为老年人。 Stivarga是一种多激酶抑制剂，可以阻断几种促进肿瘤生长的酶。Stivarga新适应症的获批，可以使该产品用于胃肠道间质瘤不能通过手术切除或者肿瘤已扩散到身体其它部位的患者，也可用于FDA批准的其它两种药物格列卫（伊马替尼）及索坦治疗后不再有效的胃肠道间质瘤患者。 “Stivarga是FDA批准的第三个用于治疗胃肠道间质瘤的药物，” FDA药物评价和研究中心血液和肿瘤产品办公室主任Richard Pazdur医学博士说。“该产品给其它治疗药物无效的胃肠道间质瘤患者提供了一种新的治疗选择。” Stivarga是通过FDA优先审评程序获得批准的，通过优先审评程序，FDA可以在6个月内完成药物的审评，优先审评程序一般针对那些可能为当下没有令人满意替代疗法的疾病提供安全、有效治疗的药物，或者与已上市药物相比，能使疾病得到明显改进的药物。该药物因用于治疗罕有疾病而同时获得孤儿药资格。 Stivarga新适应症的安全性和有效性通过一项199名胃肠道间质瘤患者参与的临床试验得到评价，该199名患者的胃肠道间质瘤不能通过手术切除，并且使用格列卫或索坦治疗后病情仍有进展。试验中，患者被随机配给Stivarga或安慰剂。同时所有患者也接受最佳的支持治疗，包括对副作用及癌症症状的管理治疗。试验研究中，患者要等到癌症进展或者副作用无法接受时开始使用Stivarga或安慰剂。结果显示，接受Stivarga治疗的患者与接受安慰剂治疗的患者相比，肿瘤增长平均延期3.9个月。试验中，使用安慰剂的患者在其癌症进展后获得了转换成Stivarga治疗的机会。 Stivarga治疗患者常见的副作用有虚弱和乏力、手足综合征、腹泻、食欲不振、高血压、口腔溃疡、感染、声音或音调变化、疼痛、体重减轻、胃痛、皮疹、发烧及恶心。严重副作用发生率不到1%，包括肝损伤、严重出血、皮肤起水泡和脱皮、需要紧急处理的严重高血压、心脏病发作及肠道穿孔(洞)。 Stivarga于2012年9月获得批准用于结直肠癌治疗。Stivarga由新泽西州韦恩的拜耳制药上市销售。格列卫由新泽西州东汉诺威的诺华制药上市销售，索坦由纽约的辉瑞制药上市销售。 -------------------------------------------------- 产地国家: 德国 原产地英文商品名: Stivarga 40mg Tablet 84Tablets 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga  40毫克／片 84片/瓶（28片*3小瓶/盒） 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer Vital Germany -------------------------------------------------- 产地国家: 德国 原产地英文商品名: Stivarga 40mg Tablet 28 Tablets 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga  40毫克片  28片/盒 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer Vital Germany -------------------------------------------- 上市国家: 瑞士 原产地英文商品名: Stivarga 40mg/Tablet 84Tablets/box 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga 40毫克/片  84片/盒 中文参考药品译名: 瑞格非尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer (Schweiz) AG -------------------------------------------- 上市国家: 美国 原产地英文商品名: Stivarga 40mg/Tablet 84Tablets/box 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga 40毫克/片  84片/盒 中文参考药品译名: 瑞格非尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer --------------------------------------------- 上市国家: 日本 原产地英文商品名: Stivarga（スチバーガ錠）40mg/Tablet 28Tablets/box 原产地英文药品名: Regorafenib Hydrate 中文参考商品译名: Stivarga（スチバーガ錠）40毫克/片  28片/盒4（片×7） 中文参考药品译名: 瑞格非尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer --------------------------------------------------- 产地国家: 香港 原产地英文商品名: Stivarga 40mg Tablet 28 Tablets 原产地英文药品名: Regorafenib 中文参考商品译名: Stivarga 40毫克片 28片/盒 中文参考药品译名: 瑞格菲尼 生产厂家中文参考译名: 拜尔制药 生产厂家英文名: Bayer HK