The drug Stivarga: side effects and phenomena, use of the drug

Stivarga is an antineoplastic drug used to treat colon cancer, liver carcinoma, and metastatic liver disease to other cancers, as well as to treat gastrointestinal stromal tumors.

The antitumor effect of this drug is based on the suppression of the action of several kinases that take part in the proliferation (division) of malignant cells, the growth of blood vessels and the creation of a tumor microenvironment.

Stivarga was officially approved by the FDA in 2012. It began to be used in EU countries in 2014, and in the CIS since 2016. The drug significantly increases overall life expectancy by 23% in patients with stage 4 colorectal cancer when standard therapy is ineffective, and also increases life time without progression. In this regard, this drug is considered as an optimal treatment option for patients for whom standard treatment methods have exhausted their resources. Before the advent of Stivarga, such patients received only symptomatic treatment.

Gastrointestinal stromal tumors (GIST) are malignant neoplasms that develop from the muscular lining of the gastrointestinal tract; they are classified as sarcomas. GISTs are extremely rare, but have a very aggressive course and poor prognosis. If a tumor is detected at an early stage, surgical treatment is indicated; however, unfortunately, 40% of patients develop a relapse and the tumor begins to metastasize. Standard first-line therapy involves the administration of imatinib, but 80% of patients who respond positively to therapy develop resistance and eventually progress.

Prescribing Stivarga in cases where other treatments have exhausted their potential reduces the risk of progression and death by 73%.

Compound
Release form
pharmachologic effect
Pharmacokinetics and pharmacodynamics
Indications for use
Contraindications to the use of Stivarg
Side effects
Methods of application
Special instructions when using the drug Stivarga
Compatibility of Stivarg with other drugs
Use of Stivarg during pregnancy and lactation
Overdose
Vehicle management

Release form

Stivarga comes in tablet form. Each tablet is made in the form of an oblong oval and is coated with a pale pink coating. It dissolves in the intestines, which provides protection against the adverse effects of gastric juice. The number 40 is engraved on one side of the tablet and BAYER on the other.

The tablets are packaged in opaque white plastic bottles with a screw cap. One bottle contains 28 tablets. Each bottle is placed in a blue and white cardboard box and is equipped with a paper insert containing instructions for using stivarga.

pharmachologic effect

Stivarga inhibits the action of various protein kinases, including those that are actively involved in the development and metastasis of malignant neoplasms:

Participating in the processes of angiogenesis - VERGFRI, TIE.
In the process of carcinogenesis - KIT, RET, BRAF, RAF.
During metastasis - PDGFR, FGFR.
Participating in providing antitumor immunity - CSF1R.

Pharmacokinetics and pharmacodynamics

Bioavailability

The bioavailability of Stivarga with the recommended method of administration is 69-83%, with the average concentration in the blood plasma achieved 3-4 hours after a single dose in a standard dosage of 160 mg (this is 4 tablets). The best absorption is observed when using Stivarga after a low-fat breakfast. At the same time, the exposure of both the main active substance and its metabolites increases.

It should be noted that the maximum concentration of the main active substance and its metabolites has daily fluctuations when used in the recommended regimen, which is associated with hepatic-intestinal recirculation.

Distribution in the body

After absorption, both the main active substance and its metabolites are tightly bound to plasma proteins. The binding of regorafenib and M-5 according to the results of laboratory studies is 99.5%, M-2 - 99.8%.

Metabolism

Metabolism is carried out by the liver through the isoenzymes CYP3A4 and UGT1A19. Several metabolites are determined in plasma, of which 2 major ones (M-2 and M-5) and 6 minor ones are distinguished. They have pharmacological activity and at steady state have similar concentrations to regorafenib. The concentration of metabolites can be reduced due to restoration by intestinal microflora, after which they can be reabsorbed (hepatic-intestinal recirculation).

Removal

The half-life of the main substance and its main metabolite M-2 is 20-30 hours. The half-life of minor metabolites and the M-5 metabolite is longer, taking about 60 hours, but can vary from 40 to 100 hours.

In general, 90% of the main active ingredient is eliminated within 12 days. The main route of elimination is through the intestines. Up to 70-71% of regorafenib is eliminated in this way. The remaining part is excreted by the kidneys.

Pharmacokinetics in hepatic dysfunction

The presence of mild to moderate liver failure did not give any significant deviations in the pharmacokinetics of the drug. The pharmacokinetics of Stivarg have not been studied in patients with severe deficiency (class C), and this treatment is not recommended for them. Given that the drug is mainly metabolized by the liver, its effect is expected to be enhanced in such patients.

Use in the elderly

In clinical trials, no pharmacokinetic changes were found. The study was conducted on patients from 29 to 85 years old.

Floor

No gender differences were found in the pharmacokinetics of Stivarga.

Ethnic characteristics

There were no differences in pharmacokinetics in patients of different races.

Stivarga (Regorafenib, Stivarga) tablets 40 mg 84 pcs - Instructions

Compound

The main active substance is regorafenib.
Other ingredients: microcrystalline cellulose, croscarmellose sodium, magnesium stearate, povidone (K-25), colloidal anhydrous silicon dioxide, red iron oxide (E172), yellow iron oxide (E172), lecithin (soy), macrogol 3350, polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide (E171).

Release form

The drug is in the form of tablets. Supplied in packs of 84 pieces each.

pharmachologic effect

Stivarga is an anticancer drug that is a protein kinase inhibitor.

The mechanism of action of the compound is based on the inhibition of endothelial kinases, structures that regulate many physiological processes in the cell. However, these enzymes, especially mutated ones, may also be responsible for cellular neoplasm, tumor growth, angiogenesis and metastasis, as well as the resistance of tumor cells to treatment. Inhibition of protein kinases leads to suppression of the growth of tumor changes and the process of angiogenesis.

Pharmacokinetics

The bioavailability of the substance ranges from 69% to 83%. The maximum concentration is achieved 3-4 hours after taking the drug. Optimal drug absorption was observed when the compound was taken after a light, low-fat meal.

The compound is more than 99% bound to plasma proteins, as are its metabolites. Regorafenib undergoes enterohepatic circulation.

The drug is transformed in the liver. The cytochrome p-450 isoform CYP3A4 and the enzyme UGT1A9 are involved in the metabolism of the compound. This metabolism produces the active metabolites regorafenib-M-2 and M-5. These substances are substrates for P-glycoprotein, while the parent compound is an inhibitor of this protein. The concentration of active metabolites may change as a result of their enterohepatic circulation and transformation in the intestinal lumen.

Regorafenib and its metabolites are inhibitors of UGT1A1 and UGT1A9.

The effect of the drug may be increased in people with severe liver impairment.

The substance and its metabolites are largely excreted in the feces (about 70%). The rest is excreted by the kidneys, mainly in the form of glucuronides. Regorafenib has a mean half-life of 28 hours, M-2 is 25 hours, and M-5 is approximately 51 hours.

Indications for use

Stivarga is a cancer medicine used in adults to treat:

hepatocellular carcinoma in patients previously treated with sorafenib;
metastatic or unresectable gastrointestinal stromal tumor in progression or in individuals who have not tolerated treatment with imatinib and sunitinib;
metastatic colorectal cancer.

Contraindications

A strict limitation is hypersensitivity to the constituent substances.

Side effects

The most common side effects of Stivarga (which can affect more than 3 in 10 people) are weakness, fatigue, loss of appetite and eating small meals, hand and foot syndrome (rash and numbness in the hands and soles), diarrhea, infections, high blood pressure (high blood pressure). pressure) and dysphonia (voice disorders).

The most serious side effects are severe liver damage, bleeding, and perforation of the digestive system (a hole in the intestinal wall).

Compatibility with other medications

Concomitant use is prohibited with:

ketoconazole, itraconazole, posaconazole and voriconazole;
mefenamic acid, diflunisal and niflumic acid;
rifampicin, clarithromycin, telithromycin;
phenytoin, carbamazepine, phenobarbital;
methotrexate;
rosuvastatin, fluvastatin, atorvastatin;
warfarin, phenprocoumon;
St. John's wort.

Application and dosage

Stivarga is taken orally, preferably after a light meal with a total fat content of about 30%. The drug is usually used for 3 weeks, followed by a week's break.

The amount of compound used depends on the response to treatment and the severity of side effects. The dose is titrated gradually.

The usual amount of medication administered to adults is 80 to 160 mg per day.

Due to the metabolism of Stivarga in the liver, the drug should not be prescribed to patients with severe liver failure.

Overdose

When taking too high doses of the drug, inflammation of the mucous membranes, dry mouth, dysphonia, decreased appetite, diarrhea, skin changes, fatigue and hypertension were observed.

special instructions

In case of perforation of the gastrointestinal tract or fistulas in it, it is recommended to stop using the drug. These effects were observed during treatment with the compound, but it is also known that patients with gastrointestinal tumors have a higher risk of developing severe gastrointestinal damage.

Serious infections, some fatal, have occurred during treatment. Patients should be protected from foci of infection, and in the event of infection, it is recommended to consider discontinuation of complex therapy.

Use during pregnancy and breastfeeding

Prescribing Stivarga to a pregnant woman is permitted if the benefits of therapy outweigh the risks to the embryo/fetus, but only after the expectant mother has accepted this risk.

The decision to use the drug during pregnancy is made by the doctor.

Because of the risk of serious side effects that may occur in a breastfed infant by a mother taking the medication, breastfeeding is not recommended during therapy and for at least two weeks after completion of therapy.

Impact on the ability to drive vehicles and operate machinery

Some side effects, such as tremors and dizziness, may impair your ability to drive and operate machines.

Terms of sale

As prescribed by the doctor.

Storage conditions

In a dry, cool place with limited access for children.

Indications for use

Metastatic form of colon cancer in patients against the background of ineffectiveness or tumor progression after therapy with fluoropyrimidines and targeted drugs. Stivarga can also be prescribed if there are contraindications to the above drugs.
An established diagnosis of GIST, including in an inoperable state, or in the presence of distant metastases when therapy with imatinib or sunitinib is ineffective, as well as in the presence of contraindications and intolerance to these drugs.
Liver carcinoma in patients with treatment failure with sorafenib.

Regorafenib

Regorafenib

(eng.
regorafenib
) is the international nonproprietary name (INN) of a new drug for the treatment of colorectal cancer, stromal tumors of the gastrointestinal tract and hepatocellular carcinoma. Regorafenib is an oral multikinase inhibitor that inhibits a number of receptor tyrosine kinases involved in the tumor formation of new blood vessels.

Regorafenib is a chemical substance

The empirical formula of regorafenib is C21H17ClF4N4O4. Chemical name 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate. Molecular weight 483 g/mol.

Stivarga (regorafenib) is a drug for the treatment of colorectal cancer and gastrointestinal stromal tumors

Regorafenib was approved for use in the United States in 2012 and in the European Union since 2014.
Trade name: Stivarga™. Also registered in Japan and many other countries. In Russia, the drug Stivarga received approval for use in 2016. Originally intended to treat patients with metastatic colorectal cancer, in 2013 the FDA expanded its use to treat patients with unresectable or metastatic gastrointestinal stromal tumors that have progressed or are intolerant to the other anticancer drugs imatinib and sunitinib. Regorafenib significantly increases overall survival in patients with metastatic colorectal cancer after progression on standard therapy and reduces the risk of death by 23%. The study also showed statistically significant improvements in progression-free survival and disease control rates, which allows us to consider regorafenib as a new optimal treatment option for patients who have developed resistance during previous systemic therapy regimens (Ter-Ovanesov M.D.). .

On the website gastroscan.ru in the “Literature” section there is a subsection “Diseases of the stomach and duodenum”, which contains, among other things, medical publications on oncological diseases of the stomach.

Indications for use of Stivarga

In Russia, the drug Stivarga is indicated for:

metastatic colorectal cancer in patients who have already received or are not eligible for fluoropyrimidine chemotherapy, anti-vascular endothelial growth factor (VEGF) therapy, and anti-epidermal growth factor receptor (EGFR) therapy in wild-type KRAS
inoperable or metastatic stromal tumors of the gastrointestinal tract in patients with progression on therapy with imatinib and sunitinib or intolerance to the latter

Stivarga (regorafenib) is a drug for the treatment of hepatocellular carcinoma

On April 27, 2022, the FDA approved Stivarga (regorafenib) to also treat patients with hepatocellular carcinoma (liver cancer) who were previously treated with sorafenib.
This is the first FDA-approved treatment for liver cancer in nearly a decade. According to the US National Cancer Institute, in 2022, approximately 40,710 people will be diagnosed with liver cancer, and approximately 28,920 people will die from these diseases. Hepatocellular carcinoma occurs in the liver and is the most common form of liver cancer.

The safety and effectiveness of Stivarga for the treatment of hepatocellular carcinoma was studied in a randomized trial of 573 patients with hepatocellular carcinoma whose tumors progressed after receiving sorafenib. The median overall survival of patients taking Stivarga was 10.6 months, compared with 7.8 months for patients taking placebo. Median progression-free survival for patients treated with Stivarga was 3.1 months, compared with 1.5 months for patients treated with placebo. The overall response rate for patients taking Stivarga was 11 percent, compared with 4 percent for patients taking placebo.

Side effects of Stivarga (regorafenib)

Common side effects of Stivarga include gastrointestinal and abdominal pain, dermatological reactions in the extremities, fatigue, diarrhea, decreased appetite, high blood pressure (hypertension), difficulty speaking (dysphonia), high levels of bilirubin in the blood (hyperbilirubinemia), fever, inflammation of the mucous membranes membranes (mucositis), weight loss, rash and nausea.
Stivarga therapy is associated with serious risks, including liver damage (hepatotoxicity), infections, severe bleeding and gastrointestinal perforation or fistula, dermatologic toxicity, hypertension, cardiac ischemia and infarction, temporary brain swelling (reversible posterior leukoencephalopathy syndrome), and healing complications. wound

Use of Stivarga (regorafenib) in pregnant and breastfeeding mothers

FDA Fetal Risk Category for Pregnant Women with Regorafenib is D (there is evidence of a risk of adverse drug effects on the human fetus, but the potential benefits associated with the drug in pregnant women may justify its use despite the risk).
The decision to stop breastfeeding or stop taking the drug should be made taking into account the importance of the drug to the mother. It is currently unknown whether regorafenib is excreted into human breast milk, but there is evidence that it is excreted into milk in animals. The effects on breastfeeding infants whose mothers take regorafenib are unknown.

general information

According to ATC, regorafenib is classified in the group “L01 Antitumor drugs”, subgroup “L01XE Protein kinase inhibitors”, code - L01XE21.
Women and men taking regorafenib should use effective contraception during and for two months after the last dose.

Regorafenib (Stivarga) is a prescription (Rx) drug. Manufacturer (distributor) - Bayer.

Instructions for using Stivagra for professionals and patients. For use in the USA (pdf, in English): Stivagra (regorafenib) tablets, for oral use. Full Prescribing Information. Bayer HealthCare Pharmaceuticals Inc. August 2013

Regorafenib has contraindications, side effects and application features; consultation with a specialist is necessary.

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Contraindications to the use of Stivarg

Severe liver damage with the development of Child-Pugh class C liver failure. Although clinical trials have not been conducted in this category of patients, it is expected that the drug will increase its toxic effect in them.
End-stage renal failure. In clinical trials in patients with all forms of renal failure (except end-stage), no pharmacokinetic changes in regorafenib were observed. In patients with severe renal failure, an increase in the concentration of major metabolites by 30% was noted. No studies have been conducted in patients with end-stage renal failure.
The need for simultaneous use of incompatible drugs, for example, strong CYP3A4 inhibitors. In this case, treatment with Stivarga is recommended to be suspended.
Age under 18 years. There have been no clinical trials of the effectiveness of the drugs on children, so this drug is not prescribed to them.
Individual intolerance to the active substance regorafenib.

Stivarga is prescribed with caution in the following cases:

Mild and moderate liver failure. In this case, more frequent monitoring of laboratory parameters of liver function is required.
Presence of a KRAS mutation.
High risk of bleeding. For example, patients with diagnosed coagulopathies or patients forced to take anticoagulants and antiplatelet agents.
Presence of coronary heart disease.

Stivarga, 40 mg, film-coated tablets, 84 pcs.

Effect on the liver

In patients treated with Stivarga®, abnormalities in the values of biochemical indicators of liver function (ALT, AST and bilirubin) were often recorded. A small proportion of patients experienced severe impairment of liver function tests (grade 3–4) and clinically significant impairment of liver function (including death) (see “Side effects”).

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

Because regorafenib is an inhibitor of UDP-GT (UGTEA1)

, in patients with Gilbert's syndrome, mild indirect (unconjugated) hyperbilirubinemia may occur (see “Interaction”). If patients receiving treatment with Stivarga experience treatment-related deterioration in liver function tests (in the absence of a clear alternative cause, such as obstructive jaundice or progression of the underlying disease), the physician should adjust the dose of the drug and monitor the patient's condition (see "Method" applications and doses”, table 1).

The liver is important in the elimination of regorafenib. When using Stivarga® in patients with mild to moderate liver dysfunction, the patient's condition should be carefully monitored (see "Dosage and Administration"). The use of Stivarga® in patients with severe liver dysfunction (class C according to the Child-Pugh classification) is not recommended, since it has not been studied in this category of patients (increased drug exposure is possible).

Patients with tumors and mutations in the KRAS

In patients with mutations in the KRAS

There was a significant improvement in progression-free survival (PFS) and a numerically weaker effect on overall survival (OS) was reported (see Pharmacodynamics).
Given the significant toxicity associated with therapy, clinicians are advised to carefully evaluate the benefits and risks when prescribing regorafenib to patients with tumors that have mutations in the KRAS
.

Bleeding

In patients receiving Stivarga®, an increase in the frequency of bleeding episodes, in some cases fatal, was reported (see “Side Effects”). In the presence of risk factors for bleeding, as well as when co-prescribed with anticoagulants (for example, warfarin, phenprocoumon) or other drugs that increase the risk of bleeding, coagulogram and general blood test parameters should be monitored. If severe bleeding requiring emergency medical attention occurs, discontinuation of treatment with Stivarga should be considered.

Myocardial ischemia and myocardial infarction

When taking the drug Stivarga®, an increase in the incidence of myocardial ischemia and myocardial infarction was observed (see “Side effects”).

Patients with unstable angina or new onset of angina (within 3 months prior to initiation of Stivarga® therapy), recent myocardial infarction (within 6 months prior to initiation of Stivarga® therapy), and patients with New York Heart Association class 2 or higher heart failure associations were excluded from clinical studies.

Patients with coronary artery disease should be monitored for clinical signs and symptoms of myocardial ischemia. If ischemia and/or myocardial infarction occurs, therapy with Stivarga should be discontinued until the condition normalizes. When deciding whether to restart therapy, the physician must evaluate the balance between the benefits of taking the drug and the potential risks for each individual patient. If clinical manifestations of ischemia persist, therapy should not be resumed.

Reversible posterior encephalopathy syndrome

Cases of reversible posterior encephalopathy have been reported in patients receiving Stivarga® (see “Side Effects”). Reversible posterior encephalopathy manifested as seizures, headache, changes in consciousness, visual disturbances or cortical blindness, sometimes in combination with arterial hypertension. To confirm the diagnosis, patients should undergo brain imaging. If reversible posterior encephalopathy develops, treatment with Stivarga should be discontinued and blood pressure should be monitored and supportive care administered.

Perforation and fistula of the gastrointestinal tract

Cases of gastrointestinal perforation and gastrointestinal fistula formation have been reported in patients receiving Stivarga® (see “Side Effects”). These events were associated with tumors in the abdominal cavity. In the event of gastrointestinal perforation or fistula formation, therapy with Stivarga should be discontinued.

Increased blood pressure

During therapy with Stivarga®, an increase in the frequency of increased blood pressure was recorded (see “Side effects”). Before starting and during treatment with Stivarga®, blood pressure should be regularly monitored and its increase should be corrected in accordance with accepted standards of treatment. In cases of severe or persistent arterial hypertension that is resistant to adequate antihypertensive therapy, the physician should temporarily interrupt therapy and/or reduce the dose of the drug (see “Dosage and Administration”). If a hypertensive crisis develops, treatment with Stivarga should be discontinued.

Wound healing disorders

In case of major surgical procedures, it is recommended to temporarily discontinue therapy with Stivarga®, since drugs with antiangiogenic properties may suppress or impair wound healing. The decision to restart therapy after surgery should be based on clinical assessment of the adequacy of wound healing.

Skin toxicity

The most common adverse reactions when taking Stivarga® were palmoplantar erythrodysesthesia and rash (see “Side Effects”). To prevent the development of palmoplantar erythrodysesthesia, callus formation should be monitored and special shoe inserts and gloves should be used to prevent pressure on the soles and palms. To treat palmoplantar erythrodysesthesia, keratolytic creams (such as urea, salicylic acid, or alpha hydroxyl acid creams, which should be applied only to the affected areas of the skin) and moisturizers in generous amounts can be used to relieve symptoms. If necessary, temporarily stop treatment and/or reduce the dose of Stivarga® or in severe or recurring cases of skin reactions, discontinue therapy with Stivarga® (see "Dosage and Administration").

Deviations in laboratory values

An increase in the incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcemia, hyponatremia and hypokalemia) and metabolic disorders (including increased TSH concentrations, increased amylase activity) has been reported with the use of Stivarga®. Deviations from the norm were usually mild or moderate in nature and were not accompanied by clinical manifestations. If electrolyte disturbances or metabolic disturbances occur, dose adjustment or discontinuation of therapy is not required. During therapy with Stivarga®, it is recommended to monitor biochemical and metabolic parameters. If necessary, replacement therapy is prescribed in accordance with accepted standards of treatment. In cases of persistent or recurrent disorders, temporary discontinuation of treatment or dose reduction, or complete discontinuation of therapy with Stivarga® should be considered (see Dosage and Administration).

Information about some ingredients

A daily dose of 160 g of regorafenib contains 2.427 mmol (or 55.8 mg) sodium. Patients on a sodium-controlled diet should be aware of this.

A daily dose of 160 g of regorafenib contains 1.68 mg of lecithin (derived from soy).

Systemic toxicity

Following repeated dosing, adverse reactions in a number of organs were observed in mice, rats and dogs, most notably the kidney, liver, digestive tract, thyroid, lymphatic/hematopoietic system, endocrine system, reproductive system and skin. In a 26-week repeated-dose toxicity study in rats, a slight increase in the incidence of thickening of the AV heart valves was observed. The reason for this phenomenon may be the acceleration of the age-related physiological process. These reactions were observed at systemic exposures at or below the expected human exposure range (based on AUC comparisons).

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

Teratogenicity and embryotoxicity

Specific studies on the effects of regorafenib on fertility have not been conducted. The potential for regorafenib to cause adverse effects on the reproductive system in men and women should be taken into account. In a study in rats and dogs, morphological changes in the testes, ovaries and uterus were observed after repeated administration of regorafenib at exposures below the estimated human exposure (AUC comparison). The observed changes were only partially reversible. In a study in rabbits, embryotoxicity (AUC comparison) was observed at exposures below the estimated human exposure. Basically, disturbances in the formation of the urinary system, heart and large vessels, and bones were found.

Influence on the ability to drive vehicles and machinery.

Special studies have not been conducted, however, if adverse events occur that may affect these abilities, it is recommended to avoid driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions (until these symptoms disappear).

Side effects

The safety of the drug was assessed in more than 1,200 patients in randomized, placebo-controlled trials. The study group included 500 patients with stage 4 colorectal cancer and 132 patients with GIST.

Depending on the frequency of occurrence, the following side effects were recorded:

Very common side effects (>1/10)

Inhibition of hematopoietic function, which leads to thrombocytopenia (bleeding) and anemia.
Arterial hypertension.
Dysphonia is a voice disorder.
Hand-foot syndrome, which is characterized by one of the following symptoms: tingling or burning in the fingers and toes, dryness, flaking, cracking of the skin, scaling and callus formation, hyperemia (mild or pronounced redness), swelling of the skin, blistering.
Skin rash.
Diarrhea.
Nausea and vomiting.
Phenomena of stomatitis.
Headache.
Decreased appetite, even to the point of refusing to eat, severe weight loss.
Changes in laboratory parameters - increased levels of bilirubin and liver transaminases.
Asthenic phenomena (weakness, loss of strength).
Pain of various localizations.
Increased body temperature not associated with infectious complications.

Frequent complications (>1/100-<1/10)

Hair loss.
Dry skin and mucous membranes.
Exfoliative dermatitis.
Change in taste perception.
Phenomena of gastroenteritis.
Heartburn, gastroesophageal reflux.
Cramps, muscle spasms.
Headache.
Tremor of the limbs.
Changes in laboratory parameters - the appearance of protein in the urine, a decrease in the level of thyroid hormones (hypothyroidism). Decrease in the level of electrolytes (K, Na, CL), P, magnesium, increase in INR, lipase and amylase activity.
Infectious complications of the urinary system, local and general fungal infections - candidiasis of the skin and mucous membranes.
On the part of the immune system - leukopenia with a decrease in the body's immune defense.

Uncommon complications (>1/1000-<1/100)

Hypersensitivity reactions, including anaphylaxis.
Ischemic lesions of the heart muscle.
Hypertensive crisis.
Nail damage.
Erythema multiforme.
Ulcers and perforations of the stomach and intestines, formation of fistulas.
Pancreatitis.
Development of severe liver dysfunction.

Rare complications (1/10000-1/1000)

Stephen-Jones syndrome is a serious condition caused by the toxic and allergic effects of the drug. It manifests itself as general malaise, fever, redness of the skin, which progresses to the death of skin cells and mucous membranes with the formation of blisters, crusts and cracks.
Posterior reversible encephalopathy syndrome. It manifests itself as headache, confusion, blurred vision and seizures in the presence of objective changes in the white matter of the posterior lobe of the brain. These changes are reversible if treatment is started in time and the action of the provoking factor is canceled.
The occurrence of secondary neoplasms, which can be both benign and malignant. These can be cysts, polyps, keratoacanthomas and squamous cell skin cancer.

Liver damage

There have been 3 reported deaths in patients treated with Stivarga. Two of them had metastatic liver disease. In all three, liver damage began to appear within the first two months of starting the drug and was accompanied by an increase in liver transaminases more than 20 times the upper limit of normal. An increase in bilirubin levels was also observed. As a result of the biopsy, necrosis of liver cells with an inflammatory infiltrate was revealed in two patients.

Bleeding

This complication was observed in 19.3% of cases. As a rule, these were nosebleeds of mild to moderate severity.

Infectious complications

Infectious complications were observed in 31% of patients. Mild or moderate manifestations were more common. The organs of the urinary system, nasopharyngitis, fungal infections of the mucous membranes and skin, as well as systemic mycoses were mainly affected. Infectious complications did not affect the mortality of patients.

Hand-foot syndrome

Hand-foot syndrome was observed in 45.2% of patients with colon cancer and in 66.7% of patients with GIST. In most cases, this complication developed during the first cycle of therapy and was of moderate or mild severity. Severe erythrodysesthesia was observed in 16.6% of patients with CRC and in 22% of patients with GIST.

Arterial hypertension

The overall incidence of hypertension during clinical trials was 30.4%. The complication more often developed in the first cycle of therapy, and patients with GIST suffered more. These were mostly mild hypertension, but one case of severe hypertension was reported.

Proteinuria

The presence of protein in the urine was observed in 7.4% of patients with CRC and in 6.8% of patients with GIST, while in 40.5% of such patients, after reducing the dose or discontinuing the drug, protein in the urine did not disappear.

Complications from the cardiovascular system

Complications from the cardiovascular system with the use of Stivarg were more often observed in patients over 75 years of age.

Hypothyroidism

An excess of TSH concentration was found in 26.1% of patients, of which 6.9% of patients had a 4-fold excess. A decrease in T3 was observed in 25.6% of patients, T4 in 8%. In 7% of cases, patients taking Stivarga required drug correction of hypothyroidism.

Fatalities with the use of Stivarga during clinical trials were rare (0.6%) and were associated with damage to the gastrointestinal tract (including the liver), lungs and kidneys.

The drug Stivarga (Regorafenib)

Stivarga is a modern drug successfully used by oncologists around the world. The findings suggest that this drug offers a chance even for patients for whom there are no other treatment options. Stivarga is taken under close medical supervision.

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Mechanism of action

The mechanism of action of the drug is associated with suppression of the activity of enzymes involved in the growth and spread of tumor tissue. Stivarga (regorafenib) belongs to the group of targeted drugs, since it acts specifically on pathologically altered tissue, practically without affecting healthy cells. This property allows you to minimize the frequency and severity of side effects.

Application protocol

Stivarga (Regorafenib) comes in tablet form and is intended for oral use. The standard dosage of the drug is 160 mg (or 4 tablets), which are taken once a day immediately after a meal containing less than 30% fat. Each treatment cycle includes 21 days of taking the drug, followed by a week-long break. When using Stivarga, you should strictly adhere to the administration regimen, taking the drug at the same time of day. The tablet must not be chewed.

Efficiency of use

Results from clinical trials of Stivarga demonstrated that its addition to the treatment protocol increased patient survival by 20%. In addition, while taking the drug, the frequency of responses to antitumor therapy increased almost 3 times compared to other treatment regimens.

Stivarga Contraindications:

allergic reactions to regorafenib, as well as any other components included in Stivarga;
pregnancy;
lactation.

Side effects:

manifestations of anemia, leukopenia and thrombocytopenia;
hypothyroidism;
loss of appetite;
metabolic disorders;
headache;
tremor of the limbs;
increased blood pressure, sometimes up to the development of a hypertensive crisis;
hemorrhages in the subcutaneous fat and mucous membranes;
voice change;
intestinal disorders;
inflammatory diseases of the oral mucosa;
nausea, sometimes vomiting;
disorders of taste sensitivity;
gastroesophageal reflux and heartburn;
inflammation of the mucous membranes of the stomach and small intestine;
hand-foot syndrome;
hair loss;
dry skin;
exfoliative rash on the skin;
lesions of the nail plates;
motor activity disorders;
the appearance of protein in the urine;
weight loss;
increasing weakness and fatigue;
increase in body temperature to subfebrile values.
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Stivarga Instructions for use

Interaction with other drugs

Under close medical supervision, Stivarga should be used in conjunction with compounds that belong to the pharmacological group of metabolites of the CYP3A4 enzyme.

Methods of application

The recommended dosage regimen for Stivarga is 160 mg once daily for 3 weeks. In the fourth week from the start of treatment, you need to take a break. Thus, one course of therapy with Stivarga is 4 weeks.

Treatment is continued in courses until it produces a clinical effect or unacceptable complications develop. In case of individual intolerance or the development of severe complications, the drug is temporarily discontinued or its dosage is reduced.

If the drug was missed, the recommended dose should be taken as soon as the patient remembers it, further treatment should be carried out according to the usual regimen. Do not take a double dose of medication on the same day to compensate for a missed dose.

Instructions for use STIVARGA®

Pharmacodynamics

Mechanism of action and pharmacodynamic effects

Regorafenib effectively blocks a variety of protein kinases, including kinases involved in angiogenesis (VEGFR1, -2, -3, TIE2), tumorigenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis formation (VEGFR3, PDGFR, FGFR) and activity immunity against tumors (CSF1R). In particular, regorafenib inhibits mutant KIT kinase, a key oncogenic factor in the development of gastrointestinal stromal tumors. Thanks to this, regorafenib blocks the proliferation of tumor cells. In preclinical studies, regorafenib demonstrated potent antitumor activity in a wide range of tumor models, including colorectal, gastrointestinal stromal, and hepatocellular tumor models. The effect of the drug is associated with its antiangiogenic and antiproliferative effects. In addition, regorafenib reduced levels of tumor-associated macrophages and showed antimetastatic effects in vivo

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The major metabolites of regorafenib in humans (M-2 and M-5)
show effects similar to regorafenib in vivo and in vitro

Clinical efficacy and safety

Metastatic colorectal cancer

The clinical efficacy and safety of Stivarga® was evaluated in an international, multicenter, randomized, double-blind, placebo-controlled, phase III trial (CORRECT) in patients with metastatic colorectal cancer who had disease progression after standard therapy.

The primary efficacy endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), tumor response rate, and disease control rate.

A total of 760 patients were randomized in a 2:1 ratio. Patients received either regorafenib 160 mg orally (4 Stivarga® tablets containing 40 mg regorafenib each) once daily (N=505) plus optimal supportive care (OST) (N=255), or placebo plus OSC, for 3-3 days. x weeks and a break of therapy of one week. The average daily dose of regorafenib was 147 mg.

Treatment was continued until disease progression or clinically unacceptable signs of toxicity occurred. A pre-planned interim efficacy analysis was conducted after 432 deaths were reported. The study was de-blinded after results from this planned interim OS analysis fell outside the predefined efficacy boundaries.

Among 760 patients with a mean age of 61 years, 61% were male, 78% were Caucasian, and all patients had an ECOG performance status score of 0 or 1 at baseline. During treatment with Stivarga®, a performance status score ≥ 2 was observed in 11.4% of patients. The mean treatment duration and daily dose, as well as the frequency of dose adjustments and dose reductions, were the same as in patients with OS ≥ 2 receiving placebo (8.3%). Most patients with OS ≥ 2 discontinued treatment due to disease progression.

The primary tumor location was the colon (65%), rectum (29%), or both (6%). At the time of inclusion in the study, KRAS mutations were observed in 57% of patients. Most patients (52%) had received 3 or fewer previous courses of anticancer therapy for metastatic disease. Treatment included fluoropyrimidine-based chemotherapy, treatment with vascular endothelial growth factor (VEGF) inhibitors, and, in the KRAS wild type, treatment with epidermal growth factor receptor (EGFR) inhibitors. The addition of Stivarga® to OPT showed a significant increase in survival compared with placebo plus OPT with a p value of 0.005178 according to the stratified log-rank test, relative risk (RR) of 0.774 (95% CI 0.636, 0.942) and median OS of 6.4 months compared to 5.0 months. PFS was significantly longer among patients treated with Stivarga plus OPT (HR: 0.494, p < 0.000001). The response rate (complete response or partial response) was 1% and 0.4% for patients receiving Stivarga® and placebo, respectively (p=0.188432). Disease control rates (complete response, partial response, or stable disease) were significantly higher for patients taking Stivarga® (41.0% vs. 14.9%, p < 0.000001). Subgroup analysis for overall survival and progression-free survival showed the effectiveness of regorafenib compared with placebo regardless of age (<65; ≥65), gender, ECOG status, primary site of disease, time from diagnosis to detection of metastases, previous antitumor therapy therapy, previous lines of therapy for metastatic cancer and mutations in the KRAS gene. Subgroup analysis by patient history of KRAS mutation status suggests that in patients with wild-type KRAS tumors, regorafenib had a beneficial effect on OS compared with placebo; with mutations in the KRAS gene, a low effect in numerical equivalent was observed; a positive effect on PFS in the regorafenib group was observed regardless of the status of mutations in the KRAS gene. The relative risk (95% CI) for overall survival was 0.653 (0.476 to 0.895) in patients with tumors containing wild-type KRAS gene and 0.867 (0.670 to 1.123) in patients who had tumors with mutations in the KRAS gene without any evidence of heterogeneity in the treatment effect (test for non-significant interactions). The relative risk (95% CI) for progression-free survival was 0.475 (0.362-0.623) in patients with tumors containing wild-type KRAS gene and 0.525 (0.425-0.649) in patients with tumors having mutations in the KRAS gene.

The clinical efficacy and safety of Stivarga® in patients of Mongoloid race were evaluated in an international, multicenter, randomized, double-blind, placebo-controlled Phase III trial (CONCUR) in 204 patients (> 90% from East Asia) with metastatic colorectal cancer. pretreated patients who experienced disease progression after fluoropyrimidine-based chemotherapy. Only 59.5% of patients enrolled in the CONCUR study had received prior VEGF and EGFR therapy. The primary efficacy endpoint was overall survival (OS). The addition of Stivarga® to OPT resulted in a significant increase in patient survival compared with the combination of placebo and OPT, the relative risk was 0.550 (p = 0.000159 by stratified log-rank test), and the median OS was 8.8 months and 6.3 months (95% CI 0.395 ; 0.765). PFS was significantly higher in patients treated with Stivarga® and OPT (HR: 0.311, p <0.000001), with a median PFS of 3.2 months with Stivarga® and 1.9 months with placebo. The safety profile of Stivarga plus OPT in the CONCUR study was comparable to the safety profile obtained in the CORRECT study.

Metastatic gastrointestinal stromal tumors (GIST)

The clinical efficacy and safety of Stivarga® in the treatment of patients with gastrointestinal stromal tumors (GIST) previously treated with two tyrosine kinase inhibitors (imatinib and sunitinib) was assessed in an international multicenter, randomized, double-blind, placebo-controlled phase III study. Analysis of the main outcome measure, progression-free survival (PFS), was carried out after registration of 144 cases of PFS. Secondary endpoints including time to disease progression (TDP) and overall survival (OS) were also assessed. A total of 199 patients with GIST were randomized in a 2:1 ratio to receive regorafenib 160 mg plus OPT or placebo plus OPT (N=66) orally once daily (N=133) for 3 weeks, followed by no dosing. lasting 1 week. The average daily dose of regorafenib was 140 mg. Treatment was continued until disease progression or clinically unacceptable signs of toxicity. In placebo-treated patients who experienced disease relapse, open-label regorafenib (crossover) was offered. Patients receiving regorafenib who experienced relapse of disease and who were judged by the investigator to be clinically benefiting from regorafenib therapy were able to continue receiving regorafenib in the open-label study.

Among 199 randomized patients with a mean age of 58 years, 64% were men, 68% were Caucasian, and all patients had an ECOG performance status (PS) score of 0 or 1 at baseline. The overall median time from last relapse or recurrence to randomization was 6 weeks. PFS was significantly higher among patients receiving regorafenib plus OPT than placebo plus OPT, with an HR of 0.268 [95% CI 0.185; 0.388] and median PFS of 4.8 months versus 0.9 months (p <0.000001). The relative risk of disease recurrence or death was reduced by approximately 73.2% in patients treated with regorafenib compared with patients treated with placebo. The increase in PFS was constant regardless of age, gender, geographic region, previous treatment, or OS according to the ECOG scale. TDP was significantly longer in patients receiving regorafenib plus OPT than in patients receiving placebo plus OPT, with an RR of 0.248 [95% CI 0.170; 0.364], and the mean TDP was 5.4 months versus 0.9 months (p < 0.000001).

The HR for OS was 0.772 (95% CI 0.423, 1.408; p = 0.199); 85% of patients initially randomized to placebo were treated with regorafenib after disease relapse.

In addition, 56 patients receiving placebo plus OPT in the open-label study were treated with Stivarga® after crossover due to disease relapse, and a total of 41 patients receiving Stivarga® plus OPT continued treatment with Stivarga® after disease relapse. Median secondary PFS (as measured by investigator assessment) was 5.0 and 4.5 months, respectively.

Hepatocellular carcinoma (RCC)

The clinical efficacy and safety of Stivarga® in the treatment of patients with RCC previously treated with sorafenib was assessed in an international multicenter, randomized, double-blind, placebo-controlled phase III trial (RESORCE). The primary efficacy endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), time to disease progression (TDP), tumor response rate, and disease control rate.

A total of 573 patients with RCC were randomized in a 2:1 ratio to receive regorafenib 160 mg plus OPT (N=379) or placebo plus OPT (N=194) orally once daily for 3 weeks, followed by no dosing. lasting 1 week. The average daily dose of regorafenib was 144 mg.

The study included patients who experienced disease progression after sorafenib therapy and patients with mild hepatic impairment (Child-Pugh class A). Patients who completely discontinued therapy due to sorafenib-related toxicity or who tolerated less than 400 mg of sorafenib once daily before discontinuation of therapy were excluded from the study. Randomization occurred within 10 weeks of discontinuation of sorafenib therapy. Patients continued taking Stivarga until radiological or clinical disease progression or evidence of unacceptable toxicity was observed. However, patients could continue treatment with Stivarga after progression was detected at the discretion of the investigator.

For all 573 randomized patients, the demographic and baseline disease characteristics presented below were comparable between the Stivarga and placebo treatment groups:

• Median age: 63 years

• Men: 88%

• Caucasian: 36%, Mongoloid: 41%

• OS on the ECOG scale: 0 points - 66%, 1 point - 34

• Liver failure: class A on the Child-Pugh scale - 98%, class B on the Child-Pugh scale - 2%

• Etiologies included hepatitis B (38%), hepatitis C (21%), non-alcoholic steatohepatitis ASH (7%)

• Absence of both macroscopic vascular invasion and extrahepatic tumor spread: 19%

• Liver cancer: stage B - 13% (according to BCLC - Barcelona classification of liver cancer), stage C - 87%

• Local-regional transarterial embolization or infusion chemotherapy: 61%

• Radiation therapy before regorafenib: 15%

• Median duration of treatment: 7.8 months

The addition of Stivarga® to OPT showed a statistically significant increase in survival compared with placebo plus OPT with an HR of 0.624 (95% CI 0.498, 0.7852), p=0.000017 by stratified log-rank test, and median overall survival of 10.6 months versus 7.8 months.

Special instructions when using the drug Stivarga

Before starting antitumor treatment, it is necessary to determine the level of liver enzymes and bilirubin. In the first 2 months, these indicators are monitored at least once every 2 weeks, then at least once a month. If there are clinical indications, tests are monitored more often.

If liver function tests worsen in patients due to Stivarga therapy, the dose of the drug is reduced and the patient is actively monitored. In this case, alternative causes of hepatic pathology should be excluded, for example, obstructive jaundice due to obstruction of the bile ducts by a tumor or stones, or progression of a malignant process (hepatic carcinoma, the occurrence of multiple metastases, etc.).

If treatment is carried out against the background of mild or moderate liver failure, the patient is subject to active monitoring with laboratory monitoring of liver function tests. Treatment is contraindicated against the background of severe liver failure, since the effect of the drug has not been studied in this cohort of patients. It is expected that they may experience an increase in exposure time to the active substance.

If there are risk factors for bleeding (thrombocytopenia, coagulopathy, the need to take anticoagulants or antiplatelet agents), it is necessary to monitor coagulogram parameters and platelet levels. If therapy is administered to patients with cirrhosis, they require preliminary treatment of dilated veins of the esophagus. If severe blood loss develops, discontinuation of the drug is necessary. Also, the drug is discontinued if there is perforation of the gastrointestinal tract.

When treating with Stivarga against the background of coronary artery disease, it is necessary to monitor the condition of the heart, in particular, monitor for signs of ischemia and infarction. If they develop, the drug is immediately discontinued, and treatment is continued after the patient’s condition has normalized. When resuming treatment, it is necessary to carefully weigh the benefit/risk ratio in a particular case. If signs of ischemia persist, resumption of antitumor treatment with this drug is not recommended.

Before starting and during treatment with Stivarga, blood pressure should be regularly monitored and, if necessary, hypertension adjusted according to accepted standards. If hypertension is severe and persistent and resistant to recommended treatment, it is necessary to temporarily stop taking Stivarg or reduce its dosage. If a hypertensive crisis develops, the drug is completely discontinued.

If symptoms of posterior encephalopathy develop, treatment with Stivarga is canceled and blood pressure is normalized and controlled; antitumor treatment is continued with maintenance therapy.

When planning extensive operations, it is necessary to discontinue Stivarg, since the drug has an antiangiogenic effect, which impairs the wound healing process. In addition, it increases the risk of bleeding during surgery and in the postoperative period. Antitumor treatment is resumed after wound healing.

With the development of hand-foot syndrome, it is recommended to use creams and drugs that have a keratolytic effect. They are applied only to the affected skin. It is also recommended to use moisturizers in unlimited quantities. They partially relieve symptoms. If necessary, antitumor treatment is temporarily suspended. In severe cases of the syndrome and the development of relapses, discontinuation of Stivarg is necessary.

In general, it is recommended to regularly monitor biochemical and metabolic parameters and, if necessary, prescribe corrective therapy according to accepted standards. If the disorders are recurrent and persistent, the use of Stivarga should be temporarily stopped or completely discontinued.

Stivarga®

Effect on the liver

Abnormalities in liver biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were frequently reported in patients treated with Stivarga®. A small proportion of patients experienced severe impairment of liver function tests (grade 3-4) and clinically significant impairment of liver function (including death) (see section “Side Effects”).

Since regorafenib is an inhibitor of uridine diphosphate glucuronyl transferase (UGT1A1), mild indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert's syndrome (see section "Interaction with other drugs and other forms of interaction").

If patients receiving treatment with Stivarga experience treatment-related deterioration in liver function tests (in the absence of a clear alternative cause, such as obstructive jaundice or progression of the underlying disease), the physician should adjust the dose of the drug and monitor the patient's condition (see section "Method of administration and dosage", table 1).

The liver is important in the elimination of regorafenib. When using Stivarga® in patients with mild to moderate liver dysfunction, the patient's condition should be carefully monitored (see section "Dosage and Administration"). The use of Stivarga® in patients with severe liver dysfunction (class C according to the Child-Pugh classification) is not recommended, since Stivarga® has not been studied in this category of patients (increased drug exposure is possible).

Patients with tumors and mutations in the KRAS gene

Patients with KRAS mutations experienced significant improvement in progression-free survival (PFS) and a numerically weaker effect on overall survival (OS) (see Pharmacodynamics). Given the significant toxicity associated with therapy, clinicians are advised to carefully evaluate the benefits and risks when prescribing regorafenib to patients with tumors harboring mutations in the KRAS gene.

Bleeding

In patients receiving Stivarga®, an increase in the frequency of bleeding episodes, in some cases with a fatal outcome, was reported (see section "Side effects"). In the presence of risk factors for bleeding, as well as when co-prescribed with anticoagulants (for example, warfarin, phenprocoumon) or other drugs that increase the risk of bleeding, coagulogram and general blood test parameters should be monitored. If severe bleeding requiring emergency medical attention occurs, discontinuation of treatment with Stivarga should be considered.

Myocardial ischemia and myocardial infarction

When taking the drug Stivarga®, an increase in the incidence of myocardial ischemia and myocardial infarction was observed (see section “Side effects”).

Patients with unstable angina or new-onset angina (within 3 months prior to initiation of Stivarga® therapy), recent myocardial infarction (within 6 months prior to initiation of Stivarga® therapy), and patients with New York Heart Association class 2 or higher heart failure were excluded from clinical trials.

Reversible posterior encephalopathy syndrome.

Cases of reversible posterior encephalopathy have been reported in patients receiving Stivarga® (see section "Side Effects"). Reversible posterior encephalopathy manifested as seizures, headache, changes in consciousness, visual disturbances or cortical blindness, sometimes in combination with arterial hypertension. To confirm the diagnosis, patients should undergo brain imaging. If reversible posterior encephalopathy develops, treatment with Stivarga should be discontinued and blood pressure should be monitored and supportive care administered.

Perforation and fistula of the gastrointestinal tract

Cases of gastrointestinal perforation and gastrointestinal fistula formation have been reported in patients receiving Stivarga® (see section "Side Effects"). These events were associated with tumors in the abdominal cavity. In the event of perforation of the gastrointestinal tract or formation of a fistula, therapy with Stivarga should be discontinued.

Increased blood pressure

During therapy with Stivarga®, an increase in the incidence of increased blood pressure was recorded (see section "Side effects"). Before starting and during treatment with Stivarga®, blood pressure should be regularly monitored and its increase should be corrected in accordance with accepted standards of treatment. In cases of severe or persistent arterial hypertension that is resistant to adequate antihypertensive therapy, the physician should temporarily interrupt therapy and/or reduce the dose of the drug (see section "Dosage and Administration"). If a hypertensive crisis develops, treatment with Stivarga should be discontinued.

Wound healing disorders

Skin toxicity

The most common adverse reactions when taking Stivarga® were palmoplantar erythrodysesthesia and rash (see section "Side effects"). To prevent the development of palmoplantar erythrodysesthesia, callus formation should be monitored and special shoe inserts and gloves should be used to prevent pressure on the soles and palms. To treat palmoplantar erythrodysesthesia, keratolytic creams (such as urea, salicylic acid, or alpha hydroxyl acid creams, which should be applied only to the affected areas of the skin) and moisturizers in generous amounts can be used to relieve symptoms. If necessary, temporarily stop treatment and/or reduce the dose of Stivarga® or, in severe or recurring cases of skin reactions, discontinue therapy with Stivarga® (see section "Dosage and Administration").

Deviations in laboratory values

An increase in the incidence of electrolyte disturbances (including hypophosphatemia, hypocalcemia, hyponatremia and hypokalemia) and metabolic disorders (including increased concentrations of thyroid-stimulating hormone, increased amylase activity) has been reported with the use of Stivarga®. Deviations from the norm were usually mild or moderate in nature and were not accompanied by clinical manifestations. If electrolyte disturbances or metabolic disturbances occur, no dose adjustment or discontinuation of therapy is required. During therapy with Stivarga®, it is recommended to monitor biochemical and metabolic parameters. If necessary, replacement therapy is prescribed in accordance with accepted standards of treatment. In cases of persistent or recurrent disorders, temporary discontinuation of treatment or dose reduction, or complete discontinuation of therapy with Stivarga® should be considered (see section "Dosage and Administration").

Information about some ingredients

A daily dose of 160 g of regorafenib contains 2.427 mmol (or 55.8 mg) sodium. Patients on a sodium-controlled diet should be aware of this. A daily dose of 160 g of regorafenib contains 1.68 mg of lecithin (derived from soy).

Systemic toxicity

Following repeated dosing, adverse reactions in a number of organs were observed in mice, rats and dogs, most notably the kidney, liver, digestive tract, thyroid, lymphatic/hematopoietic system, endocrine system, reproductive system and skin. In a 26-week repeated-dose toxicity study in rats, a slight increase in the incidence of thickening of the atrioventricular heart valves was observed. The reason for this phenomenon may be the acceleration of the age-related physiological process. These reactions were observed at systemic exposures at or below the expected human exposure range (based on AUC comparisons).

Teratogenicity and embryotoxicity

In a study in rabbits, embryotoxicity (AUC comparison) was observed at exposures below the estimated human exposure. Mainly, disturbances in the formation of the urinary system, heart and large vessels, and bones were found.

Compatibility of Stivarg with other drugs

CYP3A4 inducers/CYP3A4 and UGT1A9 inhibitors

In laboratory studies, it was found that the metabolism of Stivarg is carried out using the cytochrome enzymes CYP3A4 and UGT1A9. Further study showed that when a single dose of Stivarg was used concomitantly with ketoconazole, an increase in the AUC of regorafenib was detected. At the same time, the AUC of its active metabolites decreased by 90%. In this regard, the use of Stivarg simultaneously with strong CYP3A4 inhibitors: clarithromycin, itraconazole, ketoconazole, etc. is contraindicated. Its simultaneous use with strong UGN1A9 inhibitors (mefenamic acid, niflumic acid, etc.) is also contraindicated.

A change in pharmacokinetics was also observed when combined with a single dose of Stivarg at the recommended dosage with rifampin (a strong CYP3A4 inducer). This combination caused a decrease in the AUC of regorafenib by half and an increase in the AUC of its active metabolites by 4 times. Interaction studies with other similar drugs have not been conducted, but a similar change in pharmacokinetics is expected, so their combined use is not recommended (phenytoin, carbamazepine, phenobarbital, etc.).

Substrates UGP1A1 and UGT1A9

Regorafenib and M-2 suppress the glucuronidation process, which occurs under the influence of UGP1A1 and UGT1A9, and M-5 suppresses the effect of UGT1A1 at equilibrium concentrations.

During trials, the use of Stivarga in combination with standard therapy for GIST resulted in an increase in the AUC of irinotecan metabolites by 44%, and an increase in the AUC of the main active ingredient irinotecan increased by 28%.

BCR and P-glycoprotein substrates

The combined use of Stivarg and Rosuvastin led to an increase in the AUC of Rosuvastin by 3.8 times. If simultaneous treatment with these drugs is necessary, it is imperative to monitor the condition of such patients in order to promptly identify symptoms of increased exposure to BCR substrates.

No clinically significant changes in the pharmacokinetics of Stivarg and P-glycoprotein substrates were detected, therefore their combined use is allowed.

Selective CYP substrates

No clinically significant changes in the metabolism of Stivarg and CYP substrates were detected, therefore their combined use with warfarin, omeprazole and other drugs is allowed.

Antibiotics

Clinical studies have been conducted on the interaction of Stivarg with neomycin. It was found that the exposure of regorafenib did not change, but a decrease in its active metabolites was found, which may lead to impaired enterohepatic circulation and a decrease in the antitumor effect. Interaction with other antibiotics has not been studied.

Use of Stivarg during pregnancy and lactation

Pregnancy

Stivarga's studies have shown toxic and mutagenic effects on the fetus when tested on laboratory animals, therefore its use is prohibited at all stages of pregnancy. Men and women in their reproductive years who are indicated for anticancer treatment with Stivarga should use reliable, reliable contraception during treatment and for 8 weeks after its completion.

Breast-feeding

Also, studies on laboratory animals have shown that both the main active ingredient of the drug Stivarga and its metabolites are excreted in milk. Considering that it is impossible to completely eliminate their toxic effect on the child, breastfeeding should be abandoned.

Fertility

No special studies have been conducted to evaluate the effect of Stivarga on human reproductive capabilities. However, tests on animals showed a decrease in reproductive properties in both females and males.

Overdose

With an overdose of the drug Stivarga, the following effects were noted:

Dermatological reactions.
Voice disorder.
Diarrhea.
Inflammatory reactions and dry mucous membranes.
Increased blood pressure.
Fatigue.

There is no antidote to Stivarga. If an overdose of the drug is suspected, its use is immediately stopped and symptomatic treatment is prescribed. The patient is actively monitored until his condition stabilizes.