This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
Stivarga 40 mg film-coated tablets.
Each film-coated tablet contains 40 mg of regorafenib. Excipientswithknowneffect: 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.
Film-coated tablet. Light pink film-coated tablets, oval shaped with a length of 16 mm and a width of 7 mm embossed with 'BAYER' on one side and '40' on the other side.
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).
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.
| 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).
| 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) and since regorafenib has not been studied in patients with severe hepatic impairment (Child Pugh C), 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. There is only limited information for patients older than 75 years (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, safety or efficacy were observed between patients of different ethnic groups. No dose adjustment is necessary based on ethnicity (see section 5.2). There is limited data on regorafenib in patients of Black race.
Paediatric population
There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer.
Methodofadministration
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).
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hepaticeffects
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). 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.
PatientswithKRASmutanttumours
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.
Cardiacischaemiaandinfarction
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.
Posteriorreversibleencephalopathysyndrome(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.
Gastrointestinalperforationandfistula
Gastrointestinal perforation 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.
Arterialhypertension
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, treatment should be discontinued.
Woundhealingcomplications
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.
Dermatologicaltoxicity
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). 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).
Biochemicalandmetaboliclaboratorytestabnormalities
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).
Importantinformationaboutsomeoftheingredients
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).
InhibitorsofCYP3A4andUGT1A9/inducersofCYP3A4
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.
UGT1A1andUGT1A9substrates
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.
Breastcancerresistanceprotein(BCRP)andP-glycoproteinsubstrates
In vitro data indicate that regorafenib is an inhibitor of BCRP (IC50 values about 40-70 nanomolar) and P-glycoprotein (IC50 value of about 2 micromolar). Co-administration of regorafenib may increase the plasma concentrations of concomitant BCRP substrates, such as methotrexate, or P-glycoprotein substrates, such as digoxin.
CYPisoform-selectivesubstrates
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.
Bilesalt-sequesteringagents
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.
Womenofchildbearingpotential/Contraceptioninmalesandfemales
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).
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.
Summaryofthesafetyprofile
The overall safety profile of Stivarga is based on data from more than 1,100 cancer patients (all types of cancer) in clinical trials including 621 with metastatic CRC of whom 500 patients were treated in a placebo-controlled phase III trial. 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, decreased appetite and food intake, hand foot skin reaction, diarrhoea, weight loss, infection, hypertension and dysphonia.
Tabulatedlistofadversereactions
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 | ||
| Endocrine disorders | Hypothyroidism | |||
| Metabolism and nutrition disorders | Decreased appetite and food intake | Hypokalaemia Hypophosphataemi a 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 | Taste disorders Dry mouth Gastro-oesophagea l 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 | Dry skin Alopecia Nail disorder Exfoliative rash | Erythema multiforme | Stevens-Johnson syndrome Toxic epidermal necrolysis |
| System Organ Class (MedDRA) | Very common | Common | Uncommon | Rare |
| 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 Increase in lipase Abnormal International normalised ratio |
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
Descriptionofselectedadversereactions
Severe drug-induced liver injury (DILI) with fatal outcome occurred in 3 patients out of more than 1,100 Stivarga-treated patients across all clinical trials (0.3%). 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 placebo-controlled phase III trial in patients with metastatic CRC, the overall incidence of haemorrhage was 21.4% in patients treated with Stivarga as compared to 7.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 19.2%), most notably epistaxis (8.8%). Fatal events in patients treated with Stivarga were uncommon (0.8%), and involved the respiratory, gastrointestinal and genitourinary tracts. In the placebo-controlled phase III trial in patients with metastatic CRC, infections were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 30.8% vs. 17.0%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 22.0%), and included urinary tract infections (7.2%) as well as mucocutaneous and systemic fungal infections (6.6%). No difference in fatal outcomes associated with infection between treatment groups was observed (0.6%, Stivarga arm vs. 0.8%, placebo arm). In the placebo-controlled phase III trial in patients with metastatic CRC the overall incidence of hand-foot skin reactions was 45.2% in patients treated with Stivarga as compared to 7.1% in patients receiving placebo. Most cases of hand foot skin reactions were mild to moderate in severity (Grades 1 and 2: 28.6%) and most appeared during the first cycle of treatment with Stivarga. In the placebo-controlled metastatic CRC phase III trial the overall incidence of hypertension was 30.4% in patients treated with Stivarga and 7.9% in patients receiving placebo. 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%). The incidence of Grade 3 hypertension was 7.6%. 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.
Laboratorytestabnormalities
Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trial in patients with metastatic CRC are shown in Table 4 (see also section 4.4).
| Laboratory parameter (in % of samples | All | Stivarga plus BSC SS (N=500) Grade G | rade | All | Placebo plus BSC SS (N=253) Grade Grade | ||||
| investigated) Grades * | 3 * | 4 * | Grades * | 3 * | 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 Phosphate decreased | 25.7 57.4 | 4.3 30.5 | 0 0.6 | 8.3 11.1 | 0.4 3.6 | 0 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 | |||
SS
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
Overall, tests on thyroid-stimulating hormone (TSH) showed post baseline >ULN in 23.1% in the regorafenib and 13.3% in the placebo arm.
TSH post baseline >4 times ULN was reported in 4.0% in the regorafenib arm and in no patients in the placebo arm.
Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (< LLN) was reported in 20.8% in the regorafenib arm and 15.7% in the placebo arm.
Concentration of free thyroxin (FT4) post baseline
Reportingofsuspectedadversereactions
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 .
viathenationalreportingsystem
listedinAppendixV
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.
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor; ATC Code: L01XE21
Mechanismofactionandpharmacodynamiceffects
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 preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal tumour models which is mediated both 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 both in vitro and in vivo models.
Clinicalefficacyandsafety
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 5 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see Table 5). The response rate (complete response or partial response) was 1% and 0.4% for Stivarga and placebo treated patients, respectively. 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).
| Efficacy parameter | Hazard ratio * (95% CI) | P-value (one-sided) | Median (95% CI) | |
| Stivarga plus BSC (N=505) | Placebo plus BSC (N=255) | |||
| Median Overall | 0.774 | 0.005178 | 6.4 months | 5.0 months |
| Survival | (0.636, 0.942) | (5.9, 7.3) | (4.4, 5.8) | |
| Median | 0.494 | <0.000001 | 1.9 months | 1.7 months |
| Progression Free | (0.419, 0.582) | (1.9, 2.1) | (1.7, 1.7) | |
| Survival * * | ||||
Hazard ratio < 1 favours Stivarga
* * based on investigator's assessment of tumour response
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.
Paediatricpopulation
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).
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.
Hepaticimpairment
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.
Renalimpairment
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.
Ethnicdifferences
The exposure of regorafenib in various Asian populations (Chinese, Japanese, Korean) is within the same range as seen in Caucasians.
Cardiacelectrophysiology/QTprolongation
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.
Systemictoxicity
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 were observed in young and growing rats and indicate a potential risk for children and adolescents.
Reproductiveanddevelopmentaltoxicity
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.
Genotoxicityandcarcinogenicity
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.
Tabletcore
Cellulose microcrystalline Croscarmellose sodium Magnesium stearate Povidone (K-25) Silica, colloidal anhydrous
Filmcoat
Iron oxide red (E172) Iron oxide yellow (E172) Lecithin (derived from soya) Macrogol 3350 Polyvinyl alcohol, partially hydrolysed Talc Titanium dioxide (E171)
Not applicable.
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.
Store in the original package in order to protect from moisture. Keep the bottle tightly closed and keep the desiccant in the bottle.
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. Packsizes Pack of 28 film-coated tablets. Pack of 84 (3 bottles of 28) film-coated tablets. Not all pack sizes may be marketed.
The use of the compound regorafenib may result in a risk to the surface water and to the sediment compartment. Therefore Stivarga should not be disposed of via wastewater or household waste. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Bayer Pharma AG 13342 Berlin Germany
EU/1/13/858/001 EU/1/13/858/002
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.