Index of drugs

Treatment of adult patients with metastatic colorectal cancer (CRC), previously treated or not considering any other available treatment, i.e. fluoropyrimidine-based chemotherapy, treatment with an anti-VEGF drug or with an anti-EGFR drug. Treatment of adult patients with inoperable or metastatic gastrointestinal stromal tumors (GIST) who have experienced or undergone prior treatment with imatinib and sunitinib.

1 tabl powl. contains 40 mg regorafenib. 1 daily dose (160 mg) contains 2.427 mmol (or 55.8 mg) of sodium and 1.68 mg of lecithin (derived from soy).

An anti-cancer drug, a protein kinase inhibitor. Regorafenib strongly blocks many protein kinases, including kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2) and oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E) and those belonging to the microenvironment of the tumor (PDGFR, FGFR ). In preclinical studies, regorafenib has demonstrated strong antitumor activity in a broad spectrum of tumor models, including colorectal tumor models; this activity includes both anti-angiogenic and anti-proliferative effects of regorafenib. In addition, under conditionsin vivo regorafenib has anti-metastatic properties. Major human metabolites (M-2 and M-5) in modelsin vitro andin vivo they were similar in effectiveness to regorafenib alone. Regorafenib reaches the mean peak plasma concentration about 3-4 hours after oral administration. The concentration of regorafenib and its major metabolites (M-2 and M-5) was greatest after administration after a (light) low fat breakfast compared to a high fat breakfast or to an empty stomach. The level of binding of regorafenibin vitro with plasma proteins is high (99.5%). The degree of M-2 and M-5 bindingin vitro with proteins is higher (99.8% and 99.95% respectively). The M-2 and M-5 metabolites are weak substrates of the P-glycoprotein. Metabolite M-5 is a weak BCRP substrate. Regorafenib is metabolized mainly in the liver through oxidative metabolism mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. The major metabolites M-2 (N-oxide) and M-5 (N-oxide and N-demethyl) are pharmacologically active and have a similar concentration to regorafenib at steady-state. M-2 is further metabolised via CYP3A4-mediated oxidative metabolism as well as glucuronidation mediated by UGT1A9. The concentration of metabolites may be diminished or they may be hydrolyzed in the gastrointestinal tract by the bacterial flora, which enables reabsorption of the non-conjugated active substance and its metabolites (enterohepatic circulation). After oral administration, average T_0,5 regorafenib and its M-2 metabolite in plasma is about 20-30 h. Average T_0,5 metabolite M-5 is about 60 h (range 40-100 h). Approx. 71% of the dose is excreted in the faeces (47% of the starting substance, 24% in the form of metabolites), and about 19% of the dose - in the urine in the form of glucuronides. Urinary excretion of glucuronides decreases below 10% at steady-state.

Hypersensitivity to the active substance or to any of the excipients.

Before initiating treatment with the preparation, liver function tests (ALAT, AST and bilirubin) and close monitoring (at least once every 2 weeks) during the first 2 months of treatment are recommended. Then, periodic monitoring should be continued at least once a month and in case of clinical indications. Patients with Gilbert's syndrome may have mild, indirect hyperbilirubinaemia (related to unconjugated bilirubin). For patients with worsening liver function tests considered to be related to treatment with the preparation (ie if there is no evidence of another cause, such as extrahepatic cholestasis or disease progression), the dose and observation recommendations in the "Dosage" field should be followed. Close monitoring of safety is recommended in patients with mild or moderate hepatic impairment.The preparation is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) - studies. Patients with KRAS-positive tumors had a significant improvement in PFS, and a numerically smaller effect was noted for OS. Due to the significant toxicity associated with the treatment, doctors are advised to carefully assess the benefit-risk balance before prescribing regorafenib to patients with KRAS-carcinoma tumors. Due to the risk of hemorrhage, blood counts and clotting parameters should be monitored in patients with bleeding predisposing conditions and in patients treated with anticoagulants (eg Warfarin and fenprokumone) or other medicines that increase the risk of bleeding. In case of serious bleeding requiring urgent medical intervention, permanent discontinuation of the preparation should be considered. The use of the drug was associated with an increased incidence of ischemia and myocardial infarction. Patients with unstable angina or newly-occurring angina (within 3 months of starting treatment with the product), recent myocardial infarction (within 6 months of starting treatment with the product) and patients with NYHA class 2 or higher heart failure were excluded from clinical trials. Patients with a history of ischemic heart disease should be monitored for symptoms and clinical signs of myocardial ischemia. In patients who have had myocardial ischemia and / or heart attack, it is recommended to stop taking the medicine until the symptoms disappear. The decision to restart treatment with the preparation should be based on a careful consideration of the potential benefits and risks for a given patient. If the symptoms persist, the preparation should be permanently discontinued. Patients who have had a posterior reversible encephalopathy syndrome (PRES) are advised to discontinue treatment and to treat hypertension and supportive care for other symptoms. In patients who develop gastrointestinal perforation or fistula, it is recommended to discontinue treatment with the preparation. Blood pressure should be monitored before starting treatment. It is recommended to control blood pressure and treat hypertension in accordance with standard medical practice. In the case of severe or persistent hypertension, in spite of appropriate medical management, the treatment should be temporarily interrupted and / or reduced at the discretion of the physician. In the case of hypertensive crisis, treatment should be discontinued. Drugs with antiangiogenic properties can inhibit or interfere with wound healing - patients undergoing major surgery are advised to temporarily discontinue treatment with the product. The decision to resume treatment after major surgical intervention should be based on a clinical assessment of the correctness of wound healing. During the therapy, measures should be taken to prevent hand-foot syndrome (HFSR), which includes avoiding callous hair and the use of insoles and gloves to prevent pressure on the soles of the feet and hands. HFSR can be treated with keratolytic creams (eg creams containing urea, salicylic acid or hydroxy acids, sparingly used, only in affected areas) and moisturizing creams (used abundantly) for symptomatic treatment. Dose reduction and / or temporary discontinuation should be considered, and in severe or persistent cases permanent discontinuation. The use of the drug was associated with an increased incidence of electrolyte disturbances (including hypophosphataemia, hypocalcaemia, hyponatremia and hypokalemia) and metabolic (including increased thyroid stimulating hormone, lipase and amylase activity). These disorders are usually mild or moderate, are not associated with clinical symptoms and usually do not require discontinuation or reduction of the dose. It is recommended to monitor biochemical and metabolic parameters during treatment with the preparation and, if necessary, to implement appropriate substitution treatment in accordance with standard clinical practice. In the case of persistent or recurrent significant disorders, a dose reduction, discontinuation or permanent discontinuation should be considered. The use of the preparation in children and adolescents in metastatic colon cancer is not appropriate. The safety and efficacy of regorafenib in gastrointestinal stromal tumors (GISTs) in patients under 18 years have not been established.1 daily dose (160 mg) contains 2.427 mmol (or 55.8 mg) sodium, this should be taken into account in patients who control the sodium content of the diet. The product contains soya lecithin.

Based on the mechanism of action, it is assumed that regorafenib administered during pregnancy causes fetal harm. It should not be used during pregnancy unless clearly necessary and the benefits for the mother and the risk to the fetus have been carefully considered. Women of childbearing age and men should use effective contraception during treatment and up to 8 weeks after its completion. It is not known whether regorafenib or its metabolites are excreted in human milk. A danger for breastfed babies can not be excluded. Regorafenib may impair growth and development of infants. Breast-feeding should be discontinued during treatment. There are no data on the effects of the medicine on human fertility. The results of animal studies indicate that regorafenib can negatively affect male and female fertility.

Very common: infection (31%, mainly urinary tract infections, inflammation of the nose and throat, and fungal infections of mucous membranes and systemic), thrombocytopenia, anemia, decreased appetite and food intake, headache, haemorrhage (19.3%), hypertension (30.4%), dysphonia, diarrhea, stomatitis, vomiting, nausea, hyperbilirubinaemia, hand-foot syndrome - palmar plantar erythrodysaesthesia (45.2%), rash, alopecia, weakness / fatigue, pain, fever, inflammation mucous membranes, weight loss. Common: leukopenia, hypothyroidism, hypokalaemia, hypophosphatemia, hypocalcaemia, hyponatremia, hypomagnesaemia, hyperuricemia, tremor, taste disturbance, dry mouth, gastro-oesophageal reflux, gastroenteritis, transaminase elevation, dry skin, exfoliative rash, stiffness musculo-skeletal, proteinuria, increased amylase, increased lipase, abnormal INR. Uncommon: hypersensitivity reaction, myocardial infarction, myocardial ischemia, hypertensive crisis, gastrointestinal perforation, gastrointestinal fistula, severe liver damage, nail disorders, erythema multiforme. Rare: squamous cell carcinoma / squamous cell carcinoma, posterior reversible encephalopathy syndrome (PRES), Stevens-Johnson syndrome, toxic epidermal necrolysis.

Orally. Adults. The preparation should only be prescribed by doctors with experience in administering anti-cancer drugs. The recommended dose is 160 mg (4 tablets of 40 mg) once a day for three weeks, followed by one week without taking the medicine. This 4-week period is called the treatment cycle. If you miss a dose, take it as soon as you remember. You should not take 2 doses on the same day to make up for a forgotten dose. If vomiting occurs after administration of regorafenib, the patient should not take additional tablets. Treatment should be continued for as long as the benefits of treatment are observed or until unacceptable toxicity occurs. Patients with performance status (PS) 2 or higher were excluded from clinical trials. Available data on patients with PS ≥ 2 are limited.Dosage adjustment. Based on your individual patient's safety status and treatment tolerance, you may need to stop treatment and / or reduce the dose. Dose modifications should be done gradually after 40 mg (1 table). The lowest recommended daily dose is 80 mg. The largest daily dose is 160 mg.Recommended dose modifications and actions to be taken if a hand-foot syndrome (HFSR) occurs. 1st degree of the severity of skin toxicity - maintain the dose of the drug and take symptomatic relief immediately.2. degree of skin toxicity: 1. occurrence of changes - reduce the dose by 40 mg and immediately take symptomatic treatment, if there is no improvement despite the dose reduction, discontinue treatment for at least 7 days until the symptoms of toxicity have resolved to 0-1, re-increase of the dose is allowed at the doctor's discretion operator; no improvement within 7 days or 2nd occurrence of changes - discontinue treatment until resolution of toxicity to grade 0-1, resuming treatment, dose should be reduced by 40 mg, re-dose increase is acceptable at the discretion of the attending physician; 3.occurrence of changes - discontinue treatment until resolution of toxicity to Grade 0-1, resuming treatment, the dose should be reduced by 40 mg, re-dose increase is acceptable at the discretion of the attending physician; 4. occurrence of changes - cease permanent treatment with the preparation.3. severity of skin toxicity: 1. occurrence of changes - immediately take symptomatic treatment, discontinue treatment for at least 7 days until resolution of toxicity to grade 0-1, resuming treatment dose should be reduced by 40 mg, re-increase of the dose is acceptable at the discretion of the attending physician; 2. occurrence of changes - immediately take symptomatic treatment, discontinue treatment for at least 7 days until resolution of toxicity to grade 0-1, resuming treatment dose of the drug should be reduced by 40 mg; 3. occurrence of changes - stop permanent treatment with the preparation.Recommended action to take and dose modifications in case of abnormal liver function tests related to the drug. Increased ALT and / or AST activity ≤ 5 times ULN (maximum grade 2) - continue treatment with the product, monitor liver function every week for the return of transaminases to <3 times ULN (Grade 1) or to baseline.Increase in ALT and / or AST> 5 times ULN to ≤ 20 times ULN (grade 3): 1. occurrence of changes - discontinue treatment with the preparation, monitor the activity of aminotransferases every week to return to <3 times ULN or to baseline, if the potential benefits outweigh the risk of hepatotoxicity, restart treatment with the product, reduce the dose by 40 mg and monitor the activity every week liver for at least 4 weeks; re-occurrence of changes - stop permanent treatment with the preparation.Increased ALT and / or AST> 20 times ULN (Grade 4) - stop permanent treatment with the preparation.Increased ALT and / or AST> 3 times ULN (Grade 2 or higher) with concomitant bilirubin> 2 fold GGN - stop treatment permanently, monitor liver function weekly to relieve symptoms or to return to baseline values, exception: patients with Gilbert syndrome who have elevated aminotransferase levels should be treated according to the above recommendations for a given observed increase in ALT and / or AST. No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate and severe hepatic impairment (Child-Pugh B and C), close monitoring is recommended. It is not recommended for use in patients with severe hepatic impairment (Child-Pugh C). No dose adjustment is required in patients with mild or moderate renal impairment. There are no clinical data on patients with severe renal impairment (eGFR <30 ml / min / 1.73 m²). There were no significant differences in exposure, safety or efficacy in elderly patients (from 65 years of age) and in younger patients. There is no dose adjustment based on ethnicity; data on the use of regorafenib in black patients are limited.
The product should be taken at the same time every day. The tablets should be swallowed whole with a drink of water after a light meal containing less than 30% fat. An exemplary light (low-fat) meal may contain 1 serving of flakes (about 30 g), 1 cup of skim milk, 1 toast with jam, 1 glass of apple juice and 1 cup of coffee or tea (520 calories, 2 g of fat).