Stivarga

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Stivarga: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Stivarga

ATX code: L01XE21

Active ingredient: regorafenib (regorafenib)

Producer: Bayer Pharma, AG (Bayer Pharma, AG) (Germany)

Description and photo update: 2018-27-11

Stivarga is an anticancer drug, a protein kinase inhibitor.

Release form and composition

Dosage form - film-coated tablets: light pink, oval; embossing on one side - BAYER, on the other - "40" (28 tablets + 1 desiccant in a white opaque polyethylene bottle, sealed with a screw cap with a child-resistant safety lock, equipped with a sealing insert; in a cardboard box 1 or 3 bottles and instructions on the use of Stivarga).

Composition for 1 tablet:

active ingredient: regorafenib - 40 mg;
auxiliary ingredients: croscarmellose sodium - 154 mg, povidone-25 - 160 mg, magnesium stearate - 3.6 mg, colloidal silicon dioxide - 2.4 mg, MCC (microcrystalline cellulose) - 100 mg;
film shell: opadry II ^TM 85G35294 pink [iron oxide red (E172), iron oxide yellow (E172), macrogol / PEG 3350, lecithin, partially hydrolyzed polyvinyl alcohol, titanium dioxide (E171), talc] - 12 mg.

Pharmacological properties

Pharmacodynamics

The mechanism of action of regorafenib is based on its inhibitory action against numerous protein kinases, including those involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF and BRAF ^v600E), and also contained in the tumor microenvironment (PDGFR, FGFR).

For example, regorafenib inhibits the mutant kinase KIT, which is a key oncogenic factor in the development of stromal tumors of the gastrointestinal tract (GIT), thereby blocking the proliferation of tumor cells. According to the results of preclinical studies, it was found that regorafenib has a pronounced antitumor effect, demonstrated in a wide range of tumor models (including in gastrointestinal stromal tumors and colorectal cancer). The effect of Stivarga is due to its antiangiogenic and antiproliferative effects. In addition, regorafenib has shown antimetastatic effects in vivo. Its main metabolites M-2 and M-5 are comparable in their effectiveness in in vitro and in vivo models to regorafenib.

Pharmacokinetics

The main pharmacokinetic characteristics of Stivarga:

absorption: after taking regorafenib tablets, the average relative bioavailability compared to regorafenib in the form of oral solution is 69-83%. The average value of the maximum plasma concentration (C _max) regorafenib, approximately 2.5 mg / l, is achieved 3-4 hours after oral administration of a single dose of 160 mg (4 tablets of 40 mg). The highest level of regorafenib and its main metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which have pharmacological activity, is observed in the case of taking Stivarga after breakfast, containing a low amount of fat, compared with taking tablets after breakfast with a high fat content, or on an empty stomach. In comparison with taking the drug on an empty stomach, the exposure of regorafenib when taken after breakfast with a high fat content increases by 48%, when taken after breakfast with a low fat content - by 36%. When taking Stivarga after a low-fat breakfast, the exposure to the active metabolites of regorafenib (M-2 and M-5) is higher, and after a high-fat breakfast, it is lower.than when taken on an empty stomach;
distribution: on the pharmacokinetic curve "concentration - time" in regorafenib and its main metabolites after taking Stivarga for 24 hours, several peaks are distinguished, which is due to hepatic-intestinal recirculation of regorafenib. In vitro, the substance demonstrates a high connection with blood plasma proteins - at the level of 99.5%, the connection with blood proteins of its active metabolites M-2 and M-5 is higher and is 99.8% and 99.95%, respectively;
biotransformation: regorafenib is metabolized mainly in the liver by oxidation with the participation of the CYP3A4 isoenzyme, as well as through glucuronidation with the participation of the UGT1A9 enzyme to form two main and six secondary pharmacologically inactive metabolites. The pharmacological activity of the main circulating plasma metabolites of regorafenib (M-2 and M-5) and their stationary blood concentration (C _ss) are similar to those of regorafenib. Under the influence of the microflora of the gastrointestinal tract, metabolites are able to recover and undergo hydrolysis, after which reabsorption of the unconjugated drug and its metabolites is possible, the so-called. hepatic-intestinal recirculation;
excretion: after oral administration of Stivarga, the half-life (T _1/2) from the plasma of regorafenib and the active metabolite M-2 is 20-30 hours. For the metabolite M-5, this figure is approximately 60 hours (range from 40 to 100 hours). Up to 90% of the dose of the radioactively labeled drug is excreted within 12 days after administration: 71% is excreted through the intestine (as the initial compound - 47%, in the form of metabolites - 24%), about 19% is eliminated by the kidneys in the form of glucuronides. The excretion of glucuronides by the kidneys in the equilibrium state is reduced and is <10%. The parent compound found in feces may be the product of gastrointestinal degradation of glucuronides, the result of the reduction of the M-2 metabolite (N-oxide), or the remainder of an unabsorbed drug.

Upon reaching C _{ss, the} systemic effect of regorafenib when taking a dose not exceeding 60 mg (1.5 tablets) increases proportionally; when taking higher doses, this dependence is less proportional. Cumulation of the substance upon reaching C _{ss is} approximately 2 times higher than its plasma level, corresponding to T _1/2 and the frequency of taking Stivarga.

Taking regorafenib orally at a dose of 160 mg (4 tablets) provides an average C _ss in blood plasma of 3.9 mg / l (8.1 μmol). Plasma correlation of C _{max of} regorafenib and C _{min of} regorafenib is less than 2.

Both active metabolites (both M-2 and M-5) are characterized by non-linear cumulation in blood plasma. Due to a single dose of regorafenib, their concentrations are much lower than that of the parent compound. With prolonged use of C _ss metabolites and regorafenib are comparable.

Features of pharmacokinetic parameters for different groups of patients:

impaired hepatic function: mild to moderate hepatic impairment (classes A and B according to the Child-Pugh classification) - the pharmacokinetic parameters of regorafenib do not differ from those in patients with normal liver function. Severe liver failure (Child-Pugh class C) - Regorafenib pharmacokinetics have not been studied. Since the liver plays an important role in the excretion of regorafenib, the effects of Stivarga may be exacerbated in patients with severe liver dysfunction;
impaired renal function: mild to moderate renal failure - in equilibrium, the exposure of regorafenib and the exposure of its metabolites M-2 and M-5 do not differ from those in patients with normal renal function. Severe or end-stage renal failure - The pharmacokinetics of regorafenib have not been studied;
advanced age: in the age range of 29–85 years, no effect of the patient's age on the pharmacokinetics of Stivarga was found;
ethnicity, gender: there were no differences in the pharmacokinetics of regorafenib depending on the race and gender of the patient;
electrophysiological aspects of cardiac activity (lengthening of the QT interval): in cancer patients, lengthening of the QT interval in an equilibrium state was not revealed when taking Stivarga at a dose of 160 mg (4 tablets).

Indications for use

Stivarg is recommended for the treatment of metastatic colorectal cancer in patients who have already undergone or not indicated chemotherapy with fluoropyrimidine drugs. Stivarga is used for the treatment of vascular endothelial growth factor (VEGF) and treatment directed against epidermal growth factor receptors (EGFR).

The drug is prescribed for the treatment of inoperable or metastatic gastrointestinal stromal tumors when they progress during treatment with imatinib and sunitinib, or if the patient is intolerant to this type of therapy.

The administration of Stivarga is shown for hepatocellular carcinoma in patients who have already received sorafenib therapy.

Contraindications

Absolute:

hepatic insufficiency class C (severe) according to the Child-Pugh classification;
renal failure in the terminal stage (no experience of clinical use);
the period of pregnancy and breastfeeding (lactation);
children and adolescents under 18 years of age;
individual hypersensitivity to regorafenib, as well as to any other component in the drug.

Relative contraindications for which Stivarga should be used with caution:

hepatic impairment of classes A and B (mild and moderate) according to the Child-Pugh classification;
the presence of risk factors for bleeding, combined use with anticoagulants and other drugs that increase the risk of bleeding;
Ischemic heart disease (ischemic heart disease).

Stivarga, instructions for use: method and dosage

The tablets are intended for oral administration and should be swallowed whole and washed down with water.

Stivarga should only be prescribed by a physician experienced in anticancer therapy.

The duration of the course is 4 weeks and includes a 3-week period of taking the drug in the recommended daily dose of 160 mg (4 tablets of 40 mg) and a week break in taking Stivarga (at the 4th week from the start of treatment).

The tablets are taken daily at the same time at one time, after a meal containing a low (less than 30%) amount of fat.

When the next intake of Stivarga is missed, the pill must be taken on the same day, as soon as the patient remembers about it. You cannot take a double dose on one day in order to compensate for the missed dose of the drug.

If vomiting develops after taking the drug, do not take an additional Stivarga tablet.

It is recommended to continue treatment for as long as the clinical efficacy of the drug is maintained or until an unacceptable toxic effect develops.

The maximum therapeutic dose of regorafenib is 160 mg (4 tablets). Subjective tolerance and safety of therapy may require its temporary cessation and / or dose reduction of Stivarga. At each stage of dose adjustment, it is reduced by 40 mg (1 tablet), the lowest recommended daily dose is 80 mg.

In clinical studies, there were no significant differences in the safety and efficacy of regorafenib depending on the gender or ethnicity of the patient, therefore, dose adjustment of Stivarga taking into account these differences is not required.

Side effects

In placebo-controlled clinical trials assessing the general safety profile of Stivarga, more than 4.8 thousand patients who received treatment in phase III of the disease took part. The group included 636 patients with metastatic colorectal cancer, 132 with GIST (gastrointestinal stromal tumor) and 374 with hepatocellular carcinoma.

The most frequent undesirable effects (out of 100 patients in 30 cases or more) were asthenia, fatigue, palmar-plantar erythrodysesthesia, dysphonia, diarrhea, decreased appetite / food intake, increased blood pressure (BP), infectious lesions.

The most serious adverse reactions were liver damage, gastrointestinal perforation, and bleeding.

Adverse events from human systems and organs, listed below, were observed when using the drug Stivarga in clinical trials (distributed by frequency of registration in accordance with the following scale: very often - more than 0.1; often - 0.01-0.1; infrequently - 0.001-0.01; rarely - 0.0001-0.001):

blood and lymphatic system: very often - thrombocytopenia, anemia; often - leukopenia;
cardiovascular system: very often - bleeding ¹, an increase in blood pressure; infrequently - myocardial infarction, ischemic heart disease, hypertensive crisis;
respiratory system, organs of the chest and mediastinum: very often - dysphonia;
Gastrointestinal tract: very often - diarrhea, stomatitis, nausea / vomiting; often - ageusia (dysgeusia), dryness of the oral mucosa, gastroesophageal reflux, gastroenteritis; infrequently - perforation of the gastrointestinal tract ¹, fistulas of the stomach and intestines;
skin and subcutaneous tissue: very often - LPS (palmar-plantar syndrome), skin rashes, alopecia; often - increased dry skin, exfoliative dermatitis; infrequently - onychomycosis, erythema multiforme; rarely - Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis);
hepatobiliary system: very often - hyperbilirubinemia; often - increased activity of hepatic transaminases; infrequently - severe hepatic dysfunction ^{1 *};
nervous system: very often - cephalalgia (headache); often tremor; rarely - reversible posterior encephalopathy (syndrome);
kidneys and urinary tract: often - proteinuria;
musculoskeletal and connective tissue: often - muscle stiffness;
endocrine system: often - hypothyroidism;
metabolism and nutrition: very often - decreased appetite / food intake; often - hypophosphatemia, hypokalemia, hypocalcemia, hypomagnesemia, hyponatremia, hyperuricemia;
laboratory and instrumental research data: very often - a decrease in body weight; often - an increase in amylase and lipase activity, deviation of the international normalized ratio (MHO) from the norm;
benign, malignant, unspecified neoplasms (including cysts and polyps): rarely - keratoacanthoma of the skin, squamous cell carcinoma of the skin;
infections and infestations: very often - infectious lesions;
general disorders: very often - asthenia / general weakness, hyperthermia, pain of various localization, inflammation of the mucous membranes.

¹ Death has been reported as a result of an adverse reaction.

^** Meets the criteria of the International Expert Working Group on Medicinal Liver Damage.

According to clinical studies:

hepatic dysfunction: hepatic dysfunction in most episodes began within the first 2 months of treatment and was characterized by damage to hepatocytes with a simultaneous increase in the activity of hepatic transaminases, more than 20 times higher than ULN, and an increase in bilirubin levels. Severe liver damage with fatal outcome in patients of Japanese nationality who received Stivarga was observed more often than in patients of other nationalities (about 1.5% and less than 0.1%, respectively);
bleeding: according to the results of placebo-controlled phase III studies in patients treated with Stivarga, the total frequency of bleeding was 18.2%, in the placebo group - 9.5%. In most cases, bleeding was mild (1st) or moderate (2nd) severity - 15.2%. Most often, nosebleeds were noted - 6.1%. Deaths as a result of blood loss were rare - 0.7%, and were mainly associated with damage to the digestive, respiratory and genitourinary systems;
Infectious lesions: In Phase III placebo-controlled trials, patients treated with Stivarga were more likely to have infectious diseases than those in the placebo group (31.6% and 17.2%, respectively). Infections in the group receiving the drug were more often mild (1st) or moderate (2nd) severity - 23% (including urinary tract infections - 5.7%, nasopharyngitis - 4%, skin candidiasis / mucous membranes and systemic mycosis - 3.3%, pneumonia - 2.6%). The frequency of deaths due to the development of infection was more often observed in patients receiving Stivarga, and amounted to 1% versus 0.3% in the placebo group; they were associated, first of all, with an infectious lesion of the respiratory system;
LPS, or palmar-plantar erythrodysesthesia: according to the results of placebo-controlled phase III studies, the total incidence of LPS in patients with metastatic colorectal cancer who received Stivarga therapy was 51.4%, in the placebo group this figure was 6.5%. In gastrointestinal stromal tumors, the total incidence of LPS in patients treated with Stivarga was 66.7%, and in the placebo group - 15.2%. In hepatocellular carcinoma in the group receiving the drug, LPS was observed in 51.6%, in the placebo group - in 7.3%. Most cases of LPS in the group receiving the drug were observed during the first treatment cycle and were more often mild (1st) or moderate (2nd) severity: with metastatic colorectal cancer - 34.3%, with gastrointestinal stromal tumors - 44, 7%,with hepatocellular carcinoma - 39.3%. The incidence of grade 3 LPS in patients with metastatic colorectal cancer / gastrointestinal stromal tumors / hepatic cell carcinoma, respectively, was 17.1% / 22% / 12.3%;
increase in blood pressure: according to the results of placebo-controlled studies of phase III, the total frequency of cases of increased blood pressure in patients with metastatic colorectal cancer who took Stivarga was 29.6%, in subjects from the placebo group - 7.5%. With gastrointestinal stromal tumors, the overall incidence of increased blood pressure in patients receiving the drug was 60.6% versus 25.8% in the placebo group. In hepatocellular carcinoma, the overall incidence of increased blood pressure in patients receiving the drug was 31% versus 6.2% in the placebo group. Most of the cases of increased blood pressure in patients receiving Stivarga were registered during the first cycle of therapy and had mild (1st) and moderate (2nd) severity: in metastatic colorectal cancer - 20.9%, in gastrointestinal stromal tumors - 31.1%,with hepatocellular carcinoma - 15.8%. The increase in blood pressure of the 3rd degree was: with metastatic colorectal cancer - 8.7%, with gastrointestinal stromal tumors - 27.3%, with hepatocellular carcinoma - 15.2%. An increase in blood pressure of severe (4th) degree was recorded 1 time in a patient with a gastrointestinal stromal tumor;
Proteinuria: In phase III placebo-controlled trials, the cumulative incidence of treatment-related proteinuria among patients with metastatic colorectal cancer was 9.1% versus 1.9% in the placebo group. After the development of proteinuria in the group taking the drug, in 35.6% of patients, in the placebo group - in 54.5%, the state did not return to the initial values. In gastrointestinal stromal tumors, the overall incidence of proteinuria in patients receiving drug therapy was 6.8% compared with 1.5% in the placebo group;
cardiovascular pathologies: according to the results of all clinical studies, adverse reactions in the form of cardiac disorders (of all severity) during Stivarga therapy were more often recorded in patients aged 75 and older (N = 410) than in patients under the age of 75 years old (N = 4108) - 13.7% and 6.5%, respectively;
data from laboratory and instrumental studies: according to the results of two placebo-controlled phase III studies, the concentration of thyroid-stimulating hormone (TSH) was higher than the VGN in 34.6% of patients who received Stivarga and in 17.2% of patients in the placebo group. The TSH level exceeding VGN by 4 times was recorded in 6.5% of patients receiving the drug, and in 1.3% of subjects in the placebo group. The concentration of free triiodothyronine (free T3), which did not reach the lower limit of the norm, was observed in 29.2% of patients in the group receiving the drug, and in 20.4% of subjects in the placebo group. The concentration of free thyroxine (free T4), which did not reach the lower limit of the norm, was observed in 8.1% of patients in the group receiving the drug, and in 5.6% of subjects in the placebo group. In patients receiving Stivarga therapy, approximately 4,6% of cases developed hypothyroidism, requiring the appointment of hormone replacement therapy.

Overdose

In clinical trials, patients took Stivarga at a maximum daily dose of 220 mg. With such an overdose, the most common adverse effects were skin reactions, diarrhea, dysphonia, dryness of the oral mucosa, inflammation of the mucous membranes, decreased appetite, increased blood pressure, and general weakness.

For the treatment of an overdose of regorafenib, you should immediately stop taking Stivarga and begin standard symptomatic treatment, provided the patient is under medical supervision until the condition is stabilized.

The specific antidote for regorafenib is unknown.

special instructions

The daily dose of Stivarga (4 tablets - 160 g) contains sodium - 2.427 mmol (55.8 mg). This should be considered in patients on a low or salt-free diet and monitoring sodium intake.

The daily dose of Stivarga (4 tablets - 160 g) contains 1.68 mg of lecithin obtained from soy.

Tolerability of the drug in patients with hepatocellular carcinoma previously treated with sorafenib (in whom it was canceled due to toxicity or tolerance of only small doses of sorafenib less than 400 mg / day) was not determined, since the amount of data obtained in a key placebo-controlled study Phase III was not enough.

Effects on the liver

During Stivarga therapy, abnormalities in the parameters of biochemical tests of liver function [alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] were often recorded. Severe violations of liver function tests (3-4 degrees of severity) and clinically pronounced violations of hepatic function (including fatal) were observed in a small proportion of patients.

Before starting therapy, it is recommended to analyze the indicators of liver function (ALT, AST, bilirubin). Further, during the first two months of taking Stivarga, it is necessary to monitor the hepatic function at least once every 2 weeks, then at least once a month, if necessary, according to clinical indicators.

Because regorafenib is a uridine diphosphate glucuronyltransferase (UGT1A1) inhibitor, it can cause mild indirect (unconjugated) hyperbilirubinemia in patients with Gilbert's syndrome.

In case of deterioration of liver function indicators associated with Stivarga therapy (in the absence of other obvious reasons, for example, obstructive jaundice or the development of the underlying disease), a dose adjustment of the drug and monitoring of the patient's condition are required.

Infections

With Stivarga therapy, an increase in the frequency of infectious diseases is recorded in patients, some of which are fatal. The deterioration of the patient's condition against the background of the progression of the infection requires consideration of the question of stopping the course of treatment.

Bleeding

A clinically proven increase in the incidence of bleeding, some of which is fatal, has been associated with Stivarga's intake. Patients with risk factors for bleeding and, if necessary, the combined use of regorafenib with anticoagulants (warfarin, phenprocoumon) or other drugs that increase the risk of bleeding, require monitoring of coagulogram parameters, as well as a general blood test.

Before starting therapy, patients with cirrhosis of the liver need to undergo examination and follow-up treatment of varicose veins of the esophagus in accordance with the standard approach. The appearance of severe bleeding, in which emergency medical intervention is necessary, requires consideration of the issue of stopping the course.

Perforation and fistulas of the gastrointestinal tract

In patients receiving Stivarga, episodes of gastrointestinal tract perforation (up to death) and formation of gastrointestinal fistulas were recorded. These events are associated with the presence of tumors in the abdominal cavity.

In case of perforation of the gastrointestinal tract walls or fistula formation, Stivarga therapy should be discontinued.

IHD and myocardial infarction

Regorafenib increases the incidence of coronary artery disease and myocardial infarction.

Patients with unstable angina pectoris or the appearance of angina pectoris within 3 months before the start of the course, patients with recent myocardial infarction (from 6 months before the start of therapy) and heart failure from class II and higher according to the NYHA classification (New York cardiological association).

With ischemic heart disease, it is required to monitor the clinical signs and symptoms of myocardial ischemia, and if they occur, discontinue Stivarga therapy until the patient's condition is normalized. The doctor should make the decision to resume the course of administration after a careful assessment of the ratio of the benefits of taking the drug and the potential risks in each individual case. If the clinical manifestations of ischemia persist, therapy should not be resumed.

Reversible Posterior Encephalopathy Syndrome (PRES)

Cases of reversible posterior encephalopathy have been reported in patients treated with Stivarga. The symptoms of PRES syndrome are seizures, headache, changes in consciousness, visual impairment / cortical blindness, sometimes in combination with arterial hypertension. Confirmation of the diagnosis requires imaging of the brain.

If the PRES syndrome develops, drug treatment should be discontinued, the patient needs blood pressure control and maintenance therapy.

Increased blood pressure

Stivarga increases the frequency of increased blood pressure. Before and during administration of the drug, it is necessary to ensure regular monitoring of blood pressure and correction of its increase in accordance with the accepted standards of therapy.

With the development of severe / persistent arterial hypertension, showing resistance to adequate antihypertensive treatment, the doctor must temporarily interrupt the course and / or reduce the dose of regorafenib. The development of a hypertensive crisis requires the withdrawal of the drug Stivarga.

Wound healing disorders

If it is necessary to carry out major surgical interventions, it is recommended to temporarily discontinue therapy, since drugs with an antiangiogenic effect can suppress or complicate wound healing.

The decision to resume the course of anticancer therapy after surgery is recommended taking into account the clinical assessment of the adequacy of wound healing.

Dermal toxicity

Most often, when taking Stivarga, there are undesirable effects such as skin rash and palmar-plantar erythrodysesthesia. To prevent the development of toxic erythema of the palms and feet, it is necessary to control the formation of calluses and the use of special inserts for shoes and gloves for hands, which prevent pressure on the soles and palms. For the treatment of the disease, it is recommended to use keratolytic creams (for example, based on urea, salicylic acid or α-hydroxylic acid), which should be applied exclusively to the affected skin, as well as moisturizing creams in large quantities to relieve symptoms.

If necessary, the doctor may decide to temporarily stop treatment and / or reduce the dose of Stivarga. In severe or recurrent cases of skin reactions, the course is stopped.

Deviations in laboratory values

When using Stivarga, there was an increase in the frequency of electrolyte disturbances (including hypophosphatemia, hypocalcemia, hyponatremia and hypokalemia) and metabolic disorders (including an increase in TSH levels, increased amylase activity). Usually these deviations from the norm are mild or moderate in nature, not accompanied by clinical manifestations. If they occur, no dose adjustment or discontinuation of therapy is required.

During anticancer therapy with the use of Stivarga, it is recommended to monitor biochemical and metabolic parameters. If necessary, substitution therapy is used that meets the accepted standards of treatment. For persistent or recurrent disorders, the possibility of temporary interruption of treatment or dose reduction is considered. In special cases, drug therapy is completely stopped.

Systemic toxicity

In the course of experimental studies, according to the results of repeated administration of the dose of regorafenib to mice, rats and dogs, they had undesirable reactions mainly from the liver, kidneys, digestive tract, lymphatic / hematopoietic systems, thyroid gland, endocrine system, reproductive system, skin. A 26-week repeated dose toxicity study in rats showed a slight increase in the incidence of atrioventricular (AV) valve thickening. This may be due to the acceleration of the age-related physiological process. These reactions were observed in the case of systemic exposures within the range or below the range of the intended exposure in humans (when comparing the AUC - the total concentrations of the drug in the blood plasma during the entire observation period).

Changes in teeth and bones, as well as adverse effects on the reproductive system, were most pronounced in young and growing animals, indicating the potential risk of Stivarga in children and adolescents.

Teratogenicity and embryotoxicity

The effect of regorafenib on human fertility has not been specifically studied. But one should take into account the ability of the substance to have an adverse effect on the reproductive system of both men and women.

In studies in rats and dogs, repeated use of regorafenib at exposures lower than the intended therapeutic exposures in humans (comparison of AUC) revealed morphological changes in the testes, ovaries and uterus that were only partially reversible. In experiments on rabbits, in the case of exposure below the intended exposure in humans, the embryotoxic effect of the drug was recorded (when comparing the AUC). Mainly, pathologies of the formation of the heart, urinary system, large vessels / bones were found.

Influence on the ability to drive vehicles and complex mechanisms

When using Stivarga, undesirable reactions are possible that can affect the speed of psychomotor reactions and the ability to increase concentration. In this regard, it is recommended to avoid driving and other potentially hazardous activities until these symptoms disappear.

Application during pregnancy and lactation

It is important for women of reproductive age to inform about the dangerous effects of Stivarga on the fetus. During therapy and for 8 weeks after taking the drug, women and men of fertile age should use reliable contraception.

There are no data on the use of regorafenib in pregnant women, but given the mechanism of its action, we can assume a negative effect of the drug on the fetus. In animal studies, Stevarga has been found to be reproductively toxic.

It has not been established whether regorafenib, as well as its active metabolites, is excreted in human milk. In studies conducted on animals, it was found that regorafenib and its metabolites are excreted in breast milk. Since the possibility of a negative effect of regorafenib on the growth and development of children at an early age (from the neonatal period) cannot be ruled out, breastfeeding should be discontinued during Stivarga therapy.

No specific studies have been conducted with regorafenib to assess its effect on human fertility. In studies conducted in animals, there was a decrease in fertility in both males and females.

Pediatric use

Stivarga is not used in pediatrics, since its safety and efficacy for children and adolescents under the age of 18 have not been established.

With impaired renal function

According to clinical studies, it was found that the exposure of regorafenib and its pharmacologically active metabolites M-2 and M-5 in patients with renal insufficiency is similar to that in patients with normal renal function. Therefore, in patients with mild, moderate and severe renal failure, dose adjustment of regorafenib is not required.

Anticancer therapy with Stivarga is not recommended for patients with end-stage renal failure due to the lack of reliable data on the safety and effectiveness of its use.

For violations of liver function

The liver plays an important role in the excretion of regorafenib.

Reception of Stivarga in patients with mild or moderate impairment of hepatic function should be carried out under close supervision of the patient's condition.

In case of severe hepatic impairment, belonging to class C according to the Child-Pugh classification, the use of Stivarga is not recommended due to the lack of safety and efficacy studies in this category of patients, as well as a possible increase in the exposure of the drug.

Use in the elderly

Elderly patients do not need dose adjustment.

Drug interactions

CYP3A4 inducers / CYP3A4 and UGT1A9 inhibitors

In vitro studies have shown that the metabolism of regorafenib occurs with the participation of the cytochrome CYP3A4 and UGT1A9 enzymes. The use of a strong inhibitor of the CYP3A4 isoenzyme ketoconazole for 18 days at 400 mg in combination with a single dose on the 5th day of regorafenib at a dose of 160 mg led to an increase in the average effect (AUC) of regorafenib by about 33% and a decrease in the average effect of its active metabolites (M -2 and M-5) by about 90%. The combined use of Stivarga with strong inhibitors of the CYP3A4 isoenzyme, such as grapefruit juice, voriconazole, itraconazole, posaconazole, ketoconazole, telithromycin, clarithromycin, is not recommended, because their effect on the efficacy of regorafenib and its active metabolites in a stable state has not been studied.

It is not recommended to use strong inhibitors of UGT1A9, such as diflunisal, mefenamic and niflumic acids, simultaneously with regorafenib, since their effect on the exposure of regorafenib and its active metabolites in the equilibrium state has not been studied.

The use of a strong CYP3A4 inducer rifampin for 9 days at a dose of 600 mg in combination with a single dose on the 7th day of regorafenib at a dose of 160 mg caused a decrease in the average effect (AUC) of regorafenib by about 50%, an increase in the average effect of the active metabolite M-5 in 3-4 times, no change in the exposure of the M-2 metabolite was observed.

Other strong inducers of CYP3A4, such as carbamazepine, phenytoin, phenobarbital, are capable of increasing the metabolism of regorafenib; their combined use with Stivarga is not recommended. Drugs should be selected that do not affect CYP3A4 or induce it to a small extent.

Substrates UGT1A1 and UGT1A9

In vitro studies have shown that regorafenib, like its active metabolite M-2, inhibits glucuronidation by UGT1A1 and UGT1A9. In this case, the M-5 metabolite inhibits UGT1A1 exclusively in concentrations that are achieved in the equilibrium state in vivo.

The use of regorafenib followed by a break of 5 days before irinotecan led to an increase in the average effect (AUC) of SN-38-substrate UGT1A1 and the active metabolite of irinotecan by about 44%. There was also an increase in the AUC of irinotecan by approximately 28%. These indicators indicate that combined use with regorafenib is able to increase the systemic exposure of the UGT1A1 and UGT1A9 substrates.

Breast cancer resistance protein (BCRP) and P-glycoprotein substrates

The use of regorafenib for 14 days at a dose of 160 mg before a single dose of rosuvastatin, which is a substrate of BCRP, at a dose of 5 mg led to an increase in the average action (AUC) of rosuvastatin by 3.8 times and an increase in its average C _max (maximum plasma concentration) by 4, 6 times. Combined use with regorafenib can increase the plasma concentration of other BCRP substrates, such as atorvastatin, methotrexate, fluvastatin. If necessary, such a combined use of drugs requires monitoring the patient's condition to identify signs and symptoms of increased exposure to BCRP substrates.

In the course of clinical studies, it was found that regorafenib does not affect the pharmacokinetic parameters of digoxin, as a result of which it can be used in conjunction with P-glycoprotein substrates, such as digoxin. At the same time, there is no clinically significant mutual influence between them.

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

In vitro studies have shown that the active metabolites of regorafenib (M-2 and M-5) are substrates of P-glycoprotein and BCRP. In this regard, inhibitors and stimulants of BCRP and P-glycoprotein are able to interfere with the exposure of M-2 and M-5. At the moment, the clinical significance of the obtained research results is unknown.

Selective substrates of the CYP isoform

According to the results of in vitro studies, it was determined that regorafenib at concentrations achieved in vivo in a stable state (at C _max in plasma of 8.1 μmol) is a competitive inhibitor of cytochromes CYPs 2C8, 2C9, 2B6. Its in vitro inhibitory effect on CYP3A4 and CYP2C19 is much weaker.

The effect of regorafenib, when taken for 14 days at a dose of 160 mg, on the pharmacokinetics of marker substrates CYP2C9 (warfarin), CYP2C8 (rosiglitazone), CYP2C19 (omeprazole), CYP3A4 (midazolam) was studied. Based on the results, it was determined that Stivarga can be used simultaneously with CYPs 2C8, 2C9, 3A4 and 2C19 substrates. There were no clinically significant interactions between drugs.

Antibacterial drugs

Based on the concentration-time profile, it can be concluded that regorafenib and its metabolites are subject to hepatic-intestinal circulation.

When regorafenib is used together with neomycin, a poorly absorbed antimicrobial drug used to eradicate the gastrointestinal flora, the exposure of regorafenib does not change, but the antibiotic can affect its hepatic-intestinal circulation. When comparing the pharmacological activity of regorafenib both in vivo and in vitro, a decrease in the exposure of its active metabolites M-2 and M-5 by about 80% was found. The clinical significance of the interaction of neomycin with regorafenib is unknown, but it may be the reason for the decrease in the effectiveness of the latter.

The pharmacokinetic interaction of regorafenib with other antibiotics has not been studied.

Complexing compounds of bile salts

It is likely that regorafenib, like its active metabolites M-2 and M-5, is subject to hepatic-intestinal circulation. Bile salt complexing compounds such as cholestyramine and cholestagel can interact with regorafenib to form insoluble complexes that affect the absorption / reabsorption of the substance, which is likely to potentially reduce its exposure. The clinical significance of these potential interactions is unknown, but may decrease the effectiveness of regorafenib.

Analogs

Analogues of Stivarga are: Imatib, Imatinib-Teva, Kaprelsa, Ksalkori, Votrient, Sunitinib-native, etc.

Terms and conditions of storage

Store at temperatures up to 30 ° C in original packaging. Keep out of the reach of children.

After the first opening, the drug must be used within 7 weeks.

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Stivarg

The few reviews about Stivarg are mostly positive. They are mainly left by relatives of elderly people, in whom taking the drug helps to significantly improve the quality of life, relieve pain and inhibit the progress of the disease.

In some cases, it is indicated that therapy had to be discontinued due to such negative side reactions as skin rash, nausea, and a strong increase in blood pressure.

Price for Stivarga in pharmacies

The approximate price of Stivarga (film-coated tablets, 40 mg, in a package of 3 vials of 28 tablets) - 164,000-214,497 rubles.

Maria Kulkes Medical journalist About the author

Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!