Stevingra® (Stivarga®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRegoraphanibRegoraphanib
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  • Stevingra®
    pills inwards 
    Bayer Pharma AG     Germany
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    One tablet, film-coated, contains:

    Active substance: regorafenib - 40,00 mg.

    Excipients: microcrystalline cellulose - 100.00 mg, croscarmellose sodium - 154.00 mg, magnesium stearate - 3.60 mg, povidone-25 - 160.00 mg, silicon dioxide colloid - 2.40 mg.

    Film Sheath: fall off IITM 85G35294 pink (iron oxide red E172 - 0.0648 mg, iron oxide yellow E172 - 0.0732 mg, lecithin - 0.42 mg, macrogol /PEG 3350 - 1.482 mg, polyvinyl alcohol, partially hydrolyzed - 5.28 mg, talc - 2.40 mg, titanium dioxide E171- 2.28 mg) - 12.00 mg.

    Description:

    Oval tablets covered with a film shell, light pink in color, on one side the method of extrusion is applied "40", on the other side - "BAYER".

    Pharmacotherapeutic group:An antitumor preparation, a protein kinase inhibitor
    ATX: & nbsp

    L.01.X.E.21   Regoraphanib

    Pharmacodynamics:

    Mechanism of action

    Regoraphanib is an inhibitor of numerous protein kinases, including kinases involved in angiogenesis of the tumor (VEGFR1,-2,-3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAVv600E), as well as tumors included in the microenvironment (PDGFR, FGFR). In particular, regorafenib inhibits mutant kinase KIT, a key oncogenic factor in the development of stromal tumors of the gastrointestinal tract. Thereby regorafenib blocks the proliferation of tumor cells.In preclinical studies it was shown that regorafenib has a pronounced antitumor effect on a wide range of tumor models, including colorectal cancer and gastrointestinal stromal tumors. The effect of the drug is associated with its anti-angiogenic and antiproliferative effects. Besides, regorafenib shows antimetastatic action in vivo. The main metabolites of the drug in the human body (M-2 and M-5) in their effectiveness on models in vitro and in vivo are comparable with regoraphanib.

    Pharmacokinetics:

    Suction

    After taking the tablets regorafenib, its average relative bioavailability compared with the oral solution is 69-83%.

    The mean value of peak level of regorafenib in blood plasma (Cmax) is about 2.5 mg / L approximately 3-4 hours after a single oral dose of regoraphanib 160 mg (4 tablets of 40 mg).

    The highest concentration of regoraphanib and its major pharmacologically active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is achieved after taking breakfast with a low fat content compared with the reception after breakfast with high fat or fasting.Compared to fasting, the exposure of regorafenib is increased by 48% when taken after breakfast with a high fat content and by 36% when taken after breakfast with a low fat content. Compared to fasting, the exposure of metabolites M-2 and M-5 is higher when taking regorafenib after breakfast is low in fat and lower when taken after breakfast with a high fat content.

    Distribution

    The "concentration-time" curve shows several peaks for both regorafenib and its main circulating metabolites, within 24 hours after dosing, which is associated with hepatic intestinal recirculation of the drug. The association of regorafenib with plasma proteins in vitro high and is 99.5%.

    Metabolism

    Metabolism of regorafenib is mainly carried out in the liver by oxidation mediated by isoenzyme CYP3A4, as well as by glucuronation, mediated UGT1A9. Two main and six secondary metabolites of regoraphanib are detected in the plasma. The main metabolites of regorafenib M-2 circulating in the blood plasma (Noxide) and M-5 (Noxide and N-desmethyl) have pharmacological activity and in the equilibrium state have concentrations similar to the concentration of regoraphanib.

    In vitro the association of M-2 and M-5 with blood proteins is higher than that of regorafenib and is 99.8% and 99.95%, respectively.

    Metabolites can be restored and hydrolyzed by the microflora of the gastrointestinal tract, with the possibility of re-absorption of the unconjugated drug and its metabolites (hepatic-intestinal recirculation).

    Excretion

    The half-life of regorafenib and its metabolite M-2 from plasma is 20 to 30 hours after ingestion. The average half-life of metabolite M-5 is about 60 hours (40 - 100 hours).

    Approximately 90% of the dose of the radioactive drug is excreted within 12 days after its administration, with 71% being excreted through the intestine (47% as the starting compound and 24% in the form of metabolites) and about 19% by the kidneys in the form of glucuronides. In the equilibrium state, excretion of glucuronides by the kidneys decreases and is less than 10%. The initial compound found in fecal matter may be a product of gastrointestinal cleavage of glucuronides, or a metabolite recovery product of M-2 (Noxide), or the remainder of an unabsorbed preparation.

    Linearity/non-linearity

    The systemic effect of regorafenib at an equilibrium concentration increases in proportion to the dose at a dose of up to 60 mg or less in proportion with doses greater than 60 mg.

    Accumulation of the drug at an equilibrium concentration is approximately twice the concentration in the plasma, which corresponds to the half-life and the frequency of drug intake.

    After oral administration of regorafenib in a dose of 160 mg, its mean maximum concentration in the blood plasma (Cmax) in the equilibrium state reaches 3.9 mg / l (8.1 μmol). The ratio of the maximum and minimum concentrations of regorafenib in blood plasma is less than 2.

    For both metabolites M-2 and M-5, non-linear accumulation in the blood plasma is characteristic. After a single administration of regorafenib, the concentrations of metabolites M-2 and M-5 are much lower than those of the parent compound. In an equilibrium state, concentrations of M-2 and M-5 are comparable to the concentration of regoraphanib.

    Pharmacokinetics in different patient groups

    Patients with impaired hepatic function

    In patients with mild (Class A Child-Pugh classification) or moderate (Child-Pugh class B), the degree of hepatic insufficiency, the pharmacokinetic parameters of regoraphanib were the same as in patients with normal hepatic function. In patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) the pharmacokinetics of regoraphanib have not been studied.Since the liver is of great importance in the removal of regorafenib, in patients with severe impairment of liver function, the effect of the drug (see section "Special instructions").

    Patients from violation of function kidneys

    In patients with mild and moderate renal failure, the exposure of regorafenib and its metabolites M-2 and M-5 in equilibrium is the same as in patients with normal renal function. In patients with severe renal failure or terminal renal failure, the pharmacokinetics of regoraphanib have not been studied.

    Patients elderly age of

    The effect of age on the pharmacokinetics of regoraphanib in patients between 29 and 85 years of age was not detected.

    Floor

    There was no difference in the pharmacokinetics of regorafenib, depending on sex.

    Ethnicity

    There were no differences in the pharmacokinetic parameters of regoraphanib, depending on the ethnic group.

    Electrophysiology hearts/elongation QT

    In patients with cancer, no lengthening of the interval QT in the equilibrium state when taking regorafenib in a dose of 160 mg.

    Indications:
    • Metastatic colorectal cancer in patients who have already been or are not indicated by chemotherapy with fluoropyrimidine drugs, therapy directed against vascular endothelial growth factor (VEGF) and therapy directed against epidermal growth factor receptors (EGFR) with wild type KRAS;
    • Inoperable or metastatic gastrointestinal stromal tumors in patients with progression to therapy with imatinib and sunitinib or with intolerance to this type of treatment.
    Contraindications:
    • Hypersensitivity to regoraphanib or any other component in the formulation.
    • Children under 18 years old
    • Pregnancy and the period of breastfeeding (see the section "Application during pregnancy and during breastfeeding)
    • Severe hepatic insufficiency (class C according to Child-Pugh classification).
    • Severe degree of renal failure (clinical experience is not available).
    Carefully:

    It is necessary to take extra care when prescribing the drug in the following situations:

    • with violations of liver function of mild and moderate severity;
    • when there is a mutation KRAS in a tumor;
    • in the presence of risk factors for bleeding, as well as when combined with anticoagulants and other drugs that increase the risk of bleeding;
    • with ischemic heart disease.
    Pregnancy and lactation:

    Fertility

    There have been no special studies of the use of regorafenib to assess its effect on human fertility.

    In animal studies, male and female fertility declined.

    Women of reproductive age should be informed about the dangers of the preparation of Steveg® for the fetus. During treatment and for 8 weeks after treatment with Steiverg® women and men of reproductive age should apply reliable methods of contraception.

    Pregnancy

    Data on the use of the preparation of Steveg® in pregnant women are absent.

    Given the mechanism of action of regorafenib, possibly a negative effect of the drug Steveg® to the fetus. Animal studies have demonstrated the reproductive toxicity of regorafenib.

    Breastfeeding period

    It is not established whether the regorafenib and its metabolites with human milk.

    Studies in animals have shown that regorafenib and its metabolites are excreted in breast milk.

    Since the possibility of negative effects of regorafenib on the growth and development of young children can not be ruled out, breastfeeding should be stopped during the treatment with Steveng's®.

    Dosing and Administration:

    For oral administration.

    Stivag's preparation® should be appointed only by a doctor who has experience of antitumor therapy.

    The recommended daily dose of the preparation of Steveg® is 160 mg (4 tablets of 40 mg each). The drug is given once a day for 3 weeks. In the following week (the 4th week from the beginning of treatment), there should be a break in taking the drug. A period of 4 weeks from the start of admission is one course of treatment with the preparation of Steven®.

    Tablets are taken every day (once a day) at the same time after a meal containing a low (<30%) amount of fat (see section "Pharmacokinetics"). Tablets should be swallowed whole, washed down with water.

    If another medication is missed, the patient should take the pill on the same day as soon as he remembers it. Do not take a double dose of the drug for one day in order to compensate for a missed appointment.

    In the case of vomiting after taking the drug Steiverg® An additional tablet should not be taken.

    Treatment continues as long as the clinical efficacy of the drug persists or until its unacceptable toxic effect (see section "Special instructions").

    Correction of dose

    Individual tolerability and safety of treatment may require a temporary discontinuation of therapy and / or a reduction in the dose of Stivag®.

    Correction of the dose at each stage of dose reduction is 40 mg (1 tablet). The smallest recommended dose of the preparation of Steveg® is 80 mg per day. The maximum daily dose of 160 mg.

    Table 1. Recommendations for adjusting the dose of the drug Steveg® with the development of palmar-plantar erythrodysesthesia

    Degree of skin toxicity

    Episodes of skin toxicity

    Recommendations for adjusting the dose of the drug Steiverg®

    1st degree

    Any account

    Treatment with Steiverg® continue in the same dose and immediately begin supporting symptomatic therapy.

    2nd degree

    1st episode

    Reduce the dose of the drug Steiverg® on 40 mg (1 tablet) and immediately begin supporting therapy.

    In the absence of improvement within 7 days, suspend therapy with the drug Steiverg® until the skin toxicity is reduced to a degree of 0-1.

    Repeated increase in the dose of the drug is made on the recommendation of a doctor.

    Absence of decrease in intensity of skin symptoms within 7 days or 2nd episode

    Suspend therapy with Steiverg® until the skin toxicity is reduced to a degree of 0-1.

    When resuming therapy, reduce the dose of the drug Stevega® on 40 mg (1 tablet).

    Repeated increase in the dose of the drug is made on the recommendation of a doctor.

    3rd episode

    Suspend therapy with Steiverg® until the skin toxicity is reduced to a degree of 0-1.

    When resuming therapy, reduce the dose of the drug Stevega® on 40 mg (1 tablet).

    Repeated increase in the dose of the drug is made on the recommendation of a doctor.

    4th episode

    Therapy with Steiverg® should be discontinued.

    3rd degree

    1st episode

    Immediately begin maintenance therapy.

    Suspend therapy with Steiverg® for at least 7 days and until the skin toxicity is reduced to 0-1.

    When resuming therapy, reduce the dose of the drug Stevega® on 40 mg (1 tablet).

    Repeated increase in the dose of the drug is made on the recommendation of a doctor.

    2 nd episode

    Immediately begin maintenance therapy.

    Suspend therapy with Steiverg® for at least 7 days and until the skin toxicity is reduced to 0-1.

    When resuming therapy, reduce the dose of the drug Stevega® on 40 mg (1 tablet).

    3rd episode

    Therapy with Steiverg® should be discontinued.

    Table 2. Recommendations for the correction of the dose of the preparation Steveg® with worsening of biochemical parameters of liver function (see section "Special instructions")

    The increase in activity of alanine aminotransferase (ALT) and / or aspartate aminotransferase (ACT)

    Episodes

    Recommendations for adjusting the dose of the drug Steiverg®

    < 5 excess of the upper limit of the norm

    (maximally 2nd degree)

    Any account

    Treatment with Steiverg® continue.

    Perform a weekly monitoring of liver function until the degree of increase in transaminase activity returns to the baseline level or is <3 exceedances of the upper limit of the norm (1st degree).

    from> 5 to < 20 excess of the upper limit of the norm (3rd degree)

    1st episode

    Suspend therapy with Steiverg®. Perform weekly monitoring of liver function until the degree of increase in transaminase activity returns to the baseline level or reaches <3 excess of the upper limit of the norm.

    Therapy should be resumed if the expected benefit to the patient exceeds the risk of hepatotoxicity. Reduce the dose of the drug Steiverg® on 40 mg (1 tablet). Monitor weekly liver function for a minimum of 4 weeks.

    Repeat episode

    Therapy with Steiverg® should be discontinued.

    > 20 exceedances of the upper limit of the norm (4th degree)

    Any account

    Therapy with Steiverg® should be discontinued.

    > 3 excess of the upper limit of the norm (grade 2 or higher) with an excess of bilirubin> 2

    Any account

    Therapy with Steiverg® should be discontinued.

    Perform weekly monitoring of liver function to the state of resolution or until the liver function indicators return to the baseline level.

    An exception: patients with Gilbert's syndrome who have increased transaminase activity should receive therapy in accordance with the recommendations given above regarding the increased activity of alanine aminotransferase (ALT) and / oraspartate aminotransferase (AST).

    Special patient groups

    Patients with impaired hepatic function

    The liver is of great importance in the excretion of regoraphanib. There were no clinically significant differences in the effect of the preparation of Steveg® in patients with an average (class A Child-Pugh classification) and moderate (class B Child-Pugh classification), a violation of liver function in comparison with patients with normal liver function. Patients with moderate to moderate impairment of liver function do not need dose adjustment. It is recommended to monitor liver function against the background of therapy with the drug Steiverg® in this category of patients (see the sections "Pharmacokinetics", "Special instructions"). It is not recommended treatment with a preparation of Steiverg® patients with severe impaired liver function (class C according to the Child-Pugh classification), since the use of the drug in this category of patients has not been studied.

    Patients with impaired renal function

    In clinical studies, there were no significant differences in the safety and efficacy of Stivag's preparation® in patients with mild renal insufficiency (rSFR 60-89 ml / min / 1.73 m2) in comparison with patients with normal renal function.Limited data on pharmacokinetics did not reveal differences in exposure in patients with an average degree of renal failure (rSFR 30-59 mL / min / 1.73 m2). Patients with mild to moderate renal impairment should not be required to reduce their dose (see section "Pharmacokinetics"). Application of the preparation Steiverg® in patients with severe renal failure (rSKF <30 mL / min / 1.73 m2) has not been studied.

    Children

    Safety and efficacy of the administration of the drug Steiverg® in children and adolescents under 18 years is not established.

    Elderly patients

    In clinical studies, there were no significant differences in the safety and efficacy of Stivag's preparation® In elderly (65 years and older) patients in comparison with younger patients. Older patients do not need dose adjustment (see section "Pharmacokinetics").

    Floor

    In clinical studies, there were no significant differences in the safety and efficacy of Stivag's preparation® between male and female patients. Correction of dose of the drug depending on the patient's sex is not required (see section "Pharmacokinetics").

    Ethnicity

    In clinical studies, there were no significant differences in the safety and efficacy of Stivag's preparation® in patients of different ethnic groups. Adjusting the dose of the drug depending on the ethnicity of the patient is not required (see section "Pharmacokinetics").

    Side effects:

    General safety profile of the preparation of Steveg® is evaluated in clinical trials with more than 1,200 patients receiving therapy in placebo-controlled clinical trials III phase. This group included 500 patients with metastatic colorectal cancer and 132 patients with gastrointestinal stromal tumors.

    In clinical studies, the most frequent adverse reactions (> 30% of patients) had asthenia / fatigue, palmar-plantar erythrodysesthesia, diarrhea, decreased appetite and food intake, increased blood pressure, dysphonia, infection.

    The most serious adverse reactions with the use of the preparation of Steveg® there were liver lesions, bleeding, perforation of the gastrointestinal tract.

    The following undesirable phenomena noted with the use of the preparation of Steveorg® in the course of clinical trials, are distributed according to the frequency of occurrence in accordance with the following gradation: very often (>1/10), often (from >1/100 to <1/10), infrequently (from > 1/1000 to <1/100), rarely (from > 1/10000 to <1/1000). To classify and describe a specific reaction, its synonyms and associated states, the most appropriate term is used from the Medical Dictionary for Regulatory Activities (MedDRA).

    In each frequency group, undesirable phenomena are presented in order of decreasing importance.

    Violations of the blood and lymphatic system

    Often: thrombocytopenia, anemia.

    Often: leukopenia.

    Violations from the heart and blood vessels

    Often: bleeding *, increased blood pressure.

    Infrequently: myocardial infarction, myocardial ischemia, hypertensive crisis.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: dysphonia.

    Disturbances from the skin and subcutaneous tissues

    Often: palmar-plantar erythrodysesthesia, skin rash, alopecia.

    Often: dry skin, exfoliative dermatitis.

    Infrequently: defeat of nails, erythema multiforme.

    Rarely: Stevens-Johnson syndrome, toxic epidermal necrolysis.

    Disorders from the gastrointestinal tract

    Often: diarrhea, stomatitis, vomiting, nausea.

    Often: a taste disorder, dryness of the oral mucosa, gastroesophageal reflux, gastroenteritis.

    Infrequently: perforation of the gastrointestinal tract *, fistula of the gastrointestinal tract.

    Disturbances from the liver and bile ducts

    Often: hyperbilirubinemia.

    Often: increased activity of transaminases.

    Infrequently: severe liver dysfunction *#.

    Disturbances from the nervous system

    Often: headache.

    Often: tremor.

    Rarely: syndrome of posterior reversible encephalopathy.

    Disturbances from musculoskeletal and connective tissue

    Often: musculoskeletal rigidity.

    Disorders from the kidneys and urinary tract

    Often: proteinuria.

    Disorders from the endocrine system

    Often: hypothyroidism.

    Disorders from the metabolism and nutrition

    Often: decreased appetite and food intake.

    Often: hypokalemia, hypophosphatemia, hypocalcemia, hyponatremia, hypomagnesemia, hyperuricemia.

    Laboratory and instrumental data

    Often: decrease in body weight.

    Often: an increase in the activity of amylase and lipase, a deviation from the normal value of the international normalized ratio (INR).

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Rarely: keratoacanthoma / squamous cell carcinoma of the skin.

    Infectious and parasitic diseases

    Often: infection.

    General disorders and disorders at the site of administration

    Often: asthenia / general weakness, pain of different localization, fever, inflammation of the mucous membranes.

    * reported a lethal outcome as a result of an adverse reaction;

    # in accordance with the criteria of the International Working Group of Experts on drug damage to the liver.

    Liver disorders

    Heavy medicinal liver damage with a fatal outcome was observed in three patients from more than 1200 patients who participated in all clinical trials and received treatment with the preparation of Steveng® (0.25%). Two of these patients had metastases in the liver. Liver dysfunction in these patients began within the first two months of therapy and was characterized by damage to hepatocytes with an increase in activitytransaminase> 20 x VGN (upper limit of normal), accompanied by an increase in bilirubin concentration. As a result of liver biopsy, two patients showed necrosis of liver cells with an inflammatory infiltrate.

    Bleeding

    In two placebo-controlled studies III phase, the overall incidence of bleeding in patients treated with Steveng's®, was 19.3%. Most cases of bleeding had mild or moderate severity (1 st and 2 nd degree: 16.9%). The most frequently observed nasal bleeding (7.6%). Lethal outcomes in patients who received the drug Stevega®, were rare (0.6%) and were more often associated with respiratory, digestive and genito-urinary systems.

    Infections

    In two placebo-controlled studies III phase infectious diseases were more often observed in patients treated with the preparation of Steveng®, compared with patients receiving placebo (all degrees: 31.0% compared with 14.4%). More common infections in patients who received the drug Stevega®, had an easy or moderate degree of severity (1 st and 2 nd degree: 22.9%) and included infections of the urinary tract (6.8%), nasopharyngitis (4.2%), and candidiasis of the skin and mucous membranes and systemic mycosis (2.4%).There were no differences in the frequency of deaths due to the development of infection in patients who received the drug Steveg® (0.6%) and in patients receiving placebo (0.6%).

    Palmar-plantar erythrodysesthesia

    In a placebo-controlled study III phase, the total incidence of palmar-plantar erythrodysesthesia in patients with metastatic colorectal cancer who received the preparation of Steveng®, was 45.2% and in patients receiving placebo - 7.1%. In a placebo-controlled study III phase in patients with gastrointestinal stromal tumors, the total incidence of palmar-plantar erythrodysesthesia was 66.7% in patients treated with Steveng's®, and 15.2% in patients receiving placebo. In both studies, the majority of cases of palmar-plantar erythrodysesthesia in patients receiving the preparation of Steveng®, was noted during the first treatment cycle and had mild or moderate severity (1 st and 2 nd degree: 28.6% in patients with metastatic colorectal cancer and 44.7% in patients with gastrointestinal stromal tumors). Frequency of origin of palmar-plantarerythrodysesthesia of the third degree was 16.6% in patients with metastatic colorectal cancer and 22.0% in patients with gastrointestinal stromal tumors.

    Increased blood pressure

    In a placebo-controlled study III phase in patients with metastatic colorectal cancer, the overall incidence of elevated blood pressure was 30.4% in patients taking Steveng's drug®, and 7.9% in patients taking placebo. In a placebo-controlled study III phase in patients with gastrointestinal stromal tumors, the overall incidence of elevated blood pressure was 59.1% in patients treated with Steveng's®, and 27.3% in patients receiving placebo. In both studies, the majority of cases of increased blood pressure in patients who received the drug Steveg®, was recorded during the first treatment cycle. In this case, the cases of increase in blood pressure had mild and moderate severity (1 and 2 degrees: 22.8% in patients with metastatic colorectal cancer and 31.1% in patients with gastrointestinal stromal tumors).The frequency of cases of increase in arterial pressure of the 2nd degree was 7.6% (in patients with colorectal cancer) and 27.3% (in patients with gastrointestinal stromal tumors). One case of a 4-degree increase in arterial pressure in a patient with a gastrointestinal stromal tumor was recorded.

    Proteinuria

    In a placebo-controlled Phase III study among patients with metastatic colorectal cancer, the incidence of proteinuria associated with treatment was 7.4% in patients treated with Steveng's®, compared with 2.4% in patients taking placebo. After the development of proteinuria in 40.5% of patients from the Stevinga group® and 66.7% of patients in the placebo group did not return to baseline. In a placebo-controlled Phase III study among patients with gastrointestinal stromal tumors, the total incidence of proteinuria was 6.8% in patients receiving Steavrog®, compared with 1.5% in patients taking placebo.

    Violations from the heart and blood vessels

    In all the clinical trials conducted, adverse events in the form of cardiac arrhythmias (all degrees) were more frequently recorded (20.5% versus 10.4%) in patients treated with Steveng's®, at the age of 75 years or older (N= 78) than in patients receiving Stivag's treatment®, at the age of 75 years (N=995).

    Laboratory and instrumental data

    In two placebo-controlled Phase III studies, 26.1% of patients treated with Steveng's®, and in 15.1% of patients who received placebo, the thyroid-stimulating hormone (TSH) concentration was above the upper limit of the norm. The values ​​of TSH 4 times higher than the upper limit of the norm were recorded in 6.9% of patients who received Stevarga®, and in 0.7% of patients taking placebo. The concentration of free triiodothyronine (T3 free) less than the lower limit of normal was observed in 25.6% of patients receiving Steiverg therapy®, and in 20.9% of patients receiving a placebo. The concentration of free thyroxine (T4 free) was lower than the lower limit of normal in 8.0% of patients in the treatment group® and in 6.6% of patients in the placebo group. Overall, approximately 7% of patients receiving Stivag's therapy®, hypothyroidism has developed, requiring the use of hormone replacement therapy.

    Overdose:

    Symptoms

    In clinical trials, the maximum daily dose of the preparation of Steveg® was 220 mg.The most frequent adverse reactions at a given dose of the drug were unwanted reactions from the skin, dysphonia, diarrhea, inflammation of the mucous membranes, dryness of the oral mucosa, decreased appetite, increased blood pressure, general weakness.

    Treatment

    The specific antidote is not known.

    In case of an overdose® should stop and apply standard symptomatic therapy. The patient should be under the supervision of a doctor before stabilizing the condition.

    Interaction:

    Pharmacokinetic interactions

    Inductors CYP3A4 / inhibitors of CYP3A4 and UGT1A9

    In vitro it was shown that regorafenib is metabolized by cytochrome CYP3A4 and uridine phosphate-glucuronyltransferase UGT1A9.

    The use of ketoconazole (400 mg for 18 days), a strong inhibitor of isoenzyme CYP3A4, in combination with a single administration of regorafenib (160 mg on the fifth day) resulted in an increase in the mean exposure (AUC) of regorafenib by approximately 33% and a decrease in the average effect of its active metabolites, M-2 (Noxide) and M-5 (N-oxide and N-desmitted) by approximately 90%. It is not recommended to use the preparation of Steveg® together with strong inhibitors CYP3A4 (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole), since their effect on the effect of regorafenib in the stable state and its metabolites (M-2 and M-5) has not been studied.

    It is not recommended to use strong inhibitors UGT1A9 (eg, mefenamic acid, diflunizal and niflumic acid) during therapy with regoraphanib, since their effect on the exposure of regorafenib and its metabolites in the equilibrium state has not been studied.

    The use of rifampin (600 mg for 9 days), a strong inducer CYP3A4, in combination with a single administration of regoraphanib (160 mg on the seventh day) resulted in a decrease in the mean exposure (AUC) of regorafenib by approximately 50%, an increase in the average exposure of the active metabolite M-5 by 3-4 times, while there was no change in the exposure of the active metabolite M-2. Other strong inhibitors CYP3A4 (e.g., phenytoin, carbamazepine, phenobarbital) can increase the metabolism of regoraphanib. It is not recommended to use the preparation of Steveg® together with strong inducers CYP3A4 or to select medicines that do not affect CYP3A4 or induce it to a minimum.

    Substrates UGT1A1 and UGT1A9

    In vitro it was shown that regorafenib, as well as its active metabolite M-2, suppresses glucuronization under the action of UGT1A1 and UGT1A9, while the M-5 metabolite suppresses UGT1A1 only in concentrations that are reached in the equilibrium state in vivo.

    The use of regorafenib followed by a 5-day break before administration of irinotecan resulted in an increase in the average exposure (AUC) of SN-38, the substrate of UGT1A1 and the active metabolite of irinotecan by approximately 44%. There was also an increase in the mean exposure (AUC) of irinotecan by approximately 28%. These data show that the combined use of regorafenib can increase the systemic exposure of UGT1A1 and UGT1A9 substrates.

    Substrates protein resistance of breast cancer (BCRP) and P-glycoprotein

    In vitro it was shown that regorafenib (IC50 about 40-70 nmol) and its metabolites M-2 (IC50 390 nmol) and M-5 (IC50 150 nmol) are inhibitors of breast cancer resistance protein BCRP. Regoraphanib (IC50 about 2 μmol) and its metabolite M-2 (IC50 1.5 μmol) inhibit P-glycoprotein. Combined use with regorafenib can increase the concentration in the plasma of the accompanying substrates BCRP (eg, methotrexate) or P-glycoprotein substrates (eg, digoxin).

    P-glycoprotein inhibitors and BCRP/ stimulants of P-glycoprotein and BCRP

    Research in vitro show that metabolites of regorafenib M-2 and M-5 are substrates of Rgliprotein and BCRP. Inhibitors and stimulants BCRP and Rglikoproteina may interfere with the exposure of M-2 and M-5. The clinical significance of these results is unknown.

    Selective substrates of the CYP isoform

    In-vitro it was shown that regorafenib is a competitive inhibitor of cytochromes CYP2C8, CYP2C9, CYP2B6 in concentrations that are reached in vivo in a stable state (the maximum concentration in plasma is 8.1 μmol). In-vitro the inhibitory effect on CYP3A4 and CYP2C19 is less pronounced.

    A study was conducted to evaluate the effect of regorphenib at a dose of 160 mg for 14 days on the pharmacokinetics of marker substrates CYP2C8 (rosiglitazone), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP3A4 (midazolam).

    Pharmacokinetic data show that regorafenib can be used together with substrates CYP2C8, CYP2C9, CYP3A4 and CYP2C19. However, there is no clinically significant interaction between drugs.

    Antibiotics

    The concentration-time profile shows that regorafenib and its metabolites may undergo hepatic-intestinal circulation (see section "Pharmacokinetics"). The combined use of antibiotics that affect the flora of the gastrointestinal tract can disrupt the hepatic and intestinal circulation of regoraphanib and lead to a decrease in its exposure. The clinical significance of this interaction is not known, but may be a cause of a decrease in the effectiveness of regoraphanib.

    Complexing compounds of bile salts

    There is a possibility that regorafenib and its metabolites M2 and M5 can undergo hepatic circulation (see section "Pharmacokinetics"). Complexing compounds of bile salts, such as cholestyramine and cholestagel, can interact with regorafenib to form insoluble complexes that affect absorption (or reabsorption), potentially leading to a decrease in exposure. The clinical significance of these potential interactions is unknown, but may lead to a decrease in the efficacy of regoraphanib.

    Special instructions:

    Action on the liver

    In patients who received treatment with the drug Steiverg®, deviations of biochemical parameters of liver function (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were often recorded. A small part of the patients showed severe violations of liver function parameters (3-4 degrees of severity) and clinically significant violations of the liver (including fatal) (see section "Side effect").

    Before starting treatment with Steiverg® it is recommended to determine the indicators of liver function (AST, ALT, bilirubin). During the first two months of therapy, liver function should be monitored at least every 2 weeks, then at least 1 time per month, and also according to clinical indicators.

    Because the regorafenib is an inhibitor of uridine diphosphate glucuronyltransferase (UGT1A1), in patients with Gilbert's syndrome, the appearance of mild indirect (unconjugated) hyperbilirubinemia (see the section "Interaction with other drugs and other forms of interaction").

    If patients treated with Stivag's®, there is a worsening of liver function related to therapy (in the absence of an obvious alternative cause, for example, mechanical jaundice or progression of the underlying disease), the doctor should change the dose of the drug and monitor the patient's condition (see section "Method of administration and dose", Table 1).

    The liver is of great importance in the excretion of regoraphanib. When using Steiverg® In patients with mild and moderate impairment of liver function, careful monitoring of the patient's condition (see section "Method of administration and dose"). It is not recommended to use Steiverg® in patients with severe impairment of liver function (Child-Pugh class C), since the preparation of Steveg® It is not studied in this category of patients (it is possible to increase the exposure of the drug).

    Patients with tumors and mutations in the gene KRAS

    In patients with mutations in the gene KRAS There was a significant improvement in progression-free survival (PFS) and a numerically weaker effect on overall survival (OB) (see the section "Pharmacodynamics"). Taking into account the significant toxicity associated with therapy, doctors are advised to carefully evaluate the benefits and risks of prescribing regorafenib in patients with tumors with mutations in the gene KRAS

    Bleeding

    In patients who received the preparation of Steiverg®, there was an increase in the frequency of bleeding episodes, in some cases fatal (see section "Side effect"). In the presence of risk factors for bleeding, as well as with co-administration with anticoagulants (for example, warfarin, fenprokumone) or other drugs that increase the risk of bleeding, you should monitor the coagulogram and general blood count. If severe bleeding occurs that requires emergency medical intervention, consideration should be given to discontinuing treatment with Stivagg®.

    Myocardial ischemia and myocardial infarction

    When taking Steiverg's drug® there was an increase in the incidence of myocardial ischemia and myocardial infarction (see section "Side effect").

    Patients with unstable angina or the emergence of angina pectoris (within 3 months prior to the initiation of therapy with Steveng's®), recent myocardial infarction (6 months before initiation of therapy with Steveng's®) and patients with heart failure of grade 2 and higher according to the classification of the New York Heart Association were excluded from clinical studies.

    Patients with coronary heart disease should monitor the clinical signs and symptoms of myocardial ischemia. If you experience ischemia and / or myocardial infarction, you should discontinue therapy with Steiverg® before the normalization of the state. When deciding whether to resume therapy, the physician should assess the benefit-to-drug ratio with potential risk in each individual patient. If clinical manifestations of ischemia persist, treatment should not be resumed.

    Syndrome of reversible posterior encephalopathy.

    In patients who received the drug Steveg®, cases of development of reversible posterior encephalopathy (see section "Side effect"). Reversible posterior encephalopathy manifested itself in the form of convulsions, headache, altered consciousness, visual impairment or cortical blindness, sometimes in combination with hypertension.To confirm the diagnosis, patients should conduct a brain imaging. In the case of the development of reversible posterior encephalopathy, treatment with®, to monitor blood pressure and maintenance therapy.

    Perforation and fistula gastrointestinal tract

    In patients who received the drug Steveg®, cases of perforation of the gastrointestinal tract and formation of the fistula of the gastrointestinal tract (see section "Side effect"). These events were associated with tumors in the abdominal cavity. In the case of perforation of the gastrointestinal tract or the formation of fistula therapy with a preparation of Steveorg® should be discontinued.

    Increased blood pressure

    Against the background of therapy with the drug Steiverg® there was an increase in the frequency of increase in blood pressure (see section "Side effect"). Before and during treatment with Steiverg® should regularly monitor blood pressure and adjust its increase in accordance with accepted standards of treatment. In cases of severe or persistent arterial hypertension, resistant to adequate antihypertensive therapy, the doctor should temporarily interrupt therapy and / or reduce the dose of the drug (cm.section "Method of administration and dose"). In the case of hypertensive crisis, treatment with the drug Steveg® should be canceled.

    Wound healing disorders

    In the case of extensive surgical interventions, temporary discontinuation of therapy with Steveng's®, since drugs that have anti-angiogenic properties can suppress or worsen wound healing. The decision to resume therapy after surgery should be based on a clinical assessment of the adequacy of wound healing.

    Skin Toxicity

    The most frequent adverse reactions with the administration of Steiverg® palmar-plantar erythrodysesthesia and rash (see section "Side effect"). In order to prevent the development of palmar-plantar erythrodysesthesia, it is necessary to control the formation of calluses and use special liners for shoes and gloves to prevent pressure on the soles and palms. For the treatment of palmar-plantar erythrodysesthesia, keratolytic creams can be used (for example, creams based on urea, salicylic acid or alpha hydroxy acid,which should be applied only to the affected areas of the skin) and moisturizing creams in abundant amounts to alleviate the symptoms. If necessary, temporarily stop treatment and / or reduce the dose of the drug Steiverg® or, in severe or repetitive cases of skin reactions, therapy with Steiverg® terminate (see section "Method of administration and dose").

    Deviations of laboratory values

    When using Steiverg® an increase in the frequency of electrolyte disturbances (including hypophosphatemia, hypocalcemia, hyponatremia and hypokalemia) and metabolic disorders (including an increase in the thyroid-stimulating hormone concentration, an increase in amylase activity) have been reported. Deviations from the norm were usually mild or moderate and were not accompanied by clinical manifestations. In the event of electrolyte disturbances or metabolic disorders, dose adjustment or discontinuation of therapy is not required. During therapy with Steiverg® it is recommended to monitor biochemical and metabolic parameters. If necessary, prescribe substitution therapy in accordance with accepted treatment standards.In cases of persistent or recurrent disorders, consideration should be given to the temporary discontinuation of treatment or dose reduction, or the complete cessation of therapy with Steiverg® (see section "Method of administration and dose").

    Information on some ingredients

    The daily dose of regorafenib 160 g contains 2.427 mmol (or 55.8 mg) of sodium. This should pay attention to patients who follow a diet that controls sodium intake. The daily dose of regorafenib 160 g contains 1.68 mg of lecithin (obtained from soy).

    Systemic Toxicity

    After repeated administration of the dose, unwanted reactions from a number of organs, especially the kidneys, liver, digestive tract, thyroid, lymphatic / hematopoietic system, endocrine system, reproductive system and skin were observed in mice, rats and dogs. In a 26-week toxicity study with repeated doses, rats showed a slight increase in the incidence of thickening of the atrioventricular heart valves. The cause of this phenomenon can serve as the acceleration of the age-related physiological process. These reactions were observed at system exposures that are in the range or below the range of expected exposure in humans (based on a comparison AUC).

    Changes in teeth and bones, as well as undesirable phenomena in the reproductive system, were most pronounced in young and growing animals, as well as in young rats, indicating a potential risk to children and adolescents.

    Teratogenicity and embryotoxicity

    Special studies of the effect of regorafenib on fertility have not been conducted. The ability of regoraphanib to have an adverse effect on the reproductive system of men and women should be considered. In a study in rats and dogs after repeated use of regoraphanib at exposures below the estimated exposure in humans (when compared AUC), morphological changes were observed in the testes, ovaries and uterus. The observed changes were only partially reversible.

    In a study on rabbits with exposure below the estimated exposure, a person experienced embryotoxicity (by comparison AUC). Basically, violations of the formation of the urinary system, the heart and large vessels, bones were detected.

    Effect on the ability to drive transp. cf. and fur:

    Special studies have not been conducted, however, in the event of undesirable phenomena that may affect these abilities,it is advisable to avoid driving and other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions (until the disappearance of these symptoms).

    Form release / dosage:Tablets, film-coated, 40 mg.
    Packaging:

    For 28 tablets with a desiccant in an opaque white bottle of high-density polyethylene with a screw cap with a sealing insert and a device against opening the bottle by children. 1 or 3 bottles with instructions for use in a cardboard pack.

    Storage conditions:

    Store at a temperature not exceeding 30 °FROM.

    Keep in original packaging.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date stated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003405
    Date of registration:12.01.2016
    The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany
    Manufacturer: & nbsp
    Representation: & nbspBAYER, AOBAYER, AO
    Information update date: & nbsp28.03.2016
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