Regorafenib (Tablets) Instructions for Use

ATC Code

L01EX05 (Regorafenib)

Active Substance

Regorafenib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; other protein kinase inhibitors

Pharmacological Action

Antitumor agent. Regorafenib is an inhibitor of numerous protein kinases, including kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAF^v600E), metastasis (VEGFR3, PDGFR, FGFR), as well as in the antitumor immune response (CSF1R).

In particular, Regorafenib inhibits the mutant KIT kinase, a key oncogenic factor in the development of gastrointestinal stromal tumors. Due to this, Regorafenib blocks the proliferation of tumor cells.

Preclinical studies have shown that Regorafenib has a pronounced antitumor effect on a wide range of tumor models, including colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. The effect of regorafenib may be associated with its antiangiogenic and antiproliferative effects.

Furthermore, Regorafenib reduces the level of tumor-associated macrophages and shows antimetastatic action in vivo. The main metabolites of the drug in the human body (M-2 and M-5) are comparable in efficacy to regorafenib in in vitro and in vivo models.

Pharmacokinetics

After oral administration, the mean relative bioavailability of regorafenib is 69-83%. The mean C_max in plasma is about 2.5 mg/L approximately 3-4 hours after a single oral dose of regorafenib 160 mg.

The highest concentration of regorafenib and its main pharmacologically active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is achieved after a low-fat breakfast compared to intake after a high-fat breakfast or fasting. Compared to fasting, regorafenib exposure increased by 48% when taken after a high-fat breakfast and by 36% when taken after a low-fat breakfast.

Compared to fasting, exposure to metabolites M-2 and M-5 is higher when regorafenib is taken after a low-fat breakfast and lower when taken after a high-fat breakfast.

The concentration-time curve shows multiple peaks for both regorafenib and its main circulating metabolites within 24 hours of dose administration, which is associated with enterohepatic recirculation. The binding of regorafenib to plasma proteins in vitro is high and amounts to 99.5%.

Metabolism of regorafenib occurs mainly in the liver by oxidation mediated by the CYP3A4 isoenzyme, as well as by glucuronidation mediated by UGT1A9. Two main and six minor metabolites of regorafenib are detected in plasma.

The main circulating plasma metabolites of regorafenib, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), have pharmacological activity and at steady state have concentrations similar to that of regorafenib.

In vitro binding of M-2 and M-5 to blood proteins is higher than that of regorafenib and amounts to 99.8% and 99.95% respectively. Metabolites can be reduced and hydrolyzed by the gastrointestinal microflora, with possible reabsorption of the unconjugated active substance and its metabolites (enterohepatic recirculation).

The T_1/2 of regorafenib and its metabolite M-2 from plasma ranges from 20 to 30 hours after oral administration. The mean T_1/2 of metabolite M-5 is about 60 hours (40-100 hours).

Approximately 90% of a radiolabeled dose of regorafenib is excreted within 12 days after its administration, with 71% excreted via the intestine (47% as unchanged substance and 24% as metabolites) and about 19% via the kidneys as glucuronides. At steady state, renal excretion of glucuronides decreases and is less than 10%. The parent compound found in feces may be a product of gastrointestinal cleavage of glucuronides, or a product of reduction of metabolite M-2 (N-oxide), or residual unabsorbed drug.

Systemic exposure of regorafenib at steady state increases proportionally with dose up to 60 mg and less than proportionally at doses above 60 mg. Accumulation of the active substance at steady state is approximately 2 times the plasma concentration, which corresponds to T_1/2 and the frequency of drug administration.

Since the liver is important in the elimination of regorafenib, its effect may be enhanced in patients with severe hepatic impairment.

In patients with mild, moderate, or severe renal impairment, the exposure of regorafenib and its metabolites M-2 and M-5 at steady state was the same as in patients with normal renal function. In patients with severe renal impairment, the steady-state exposure of regorafenib was the same as in patients with normal renal function, while the exposure of M-2 and M-5 decreased by approximately 30%. The pharmacokinetics of regorafenib in patients with end-stage renal disease have not been studied.

Indications

Metastatic colorectal cancer in patients who have previously received or are not candidates for fluoropyrimidine-based chemotherapy, anti-vascular endothelial growth factor (VEGF) therapy, and anti-epidermal growth factor receptor (EGFR) therapy.

Unresectable or metastatic gastrointestinal stromal tumors in patients with disease progression on imatinib and sunitinib therapy or intolerance to such treatment.

Hepatocellular carcinoma in patients who have previously been treated with sorafenib.

ICD codes

Dosage Regimen

Tablets

For oral administration.

The recommended dose is 160 mg once daily for 3 weeks. This is followed by a one-week break (the 4th week from the start of treatment). One treatment cycle is a period of 4 weeks from the start of administration.

Treatment is continued as long as clinical benefit persists or until unacceptable toxicity occurs.

Individual tolerance and safety of treatment may require temporary discontinuation of therapy and/or dose reduction.

Adverse Reactions

From the hematopoietic system: very common – thrombocytopenia, anemia; common – leukopenia.

From the immune system: uncommon – hypersensitivity reactions.

From the cardiovascular system: very common – bleeding, increased blood pressure; uncommon – myocardial infarction, myocardial ischemia, hypertensive crisis.

From the respiratory system: very common – dysphonia.

From the skin and subcutaneous tissues: very common – palmar-plantar erythrodysesthesia, skin rash; common – alopecia, dry skin, exfoliative dermatitis; uncommon – nail disorder, erythema multiforme; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the digestive system: very common – diarrhea, stomatitis, vomiting, nausea; common – taste disturbance, dry mouth, gastroesophageal reflux, gastroenteritis; uncommon – gastrointestinal perforation, gastrointestinal fistula, pancreatitis.

From the liver and biliary tract: very common – hyperbilirubinemia, increased transaminase activity; uncommon – severe hepatic impairment.

From the nervous system: common – headache, tremor; rare – posterior reversible encephalopathy syndrome.

From the musculoskeletal system: common – muscle spasms.

From the urinary system: common – proteinuria.

From the endocrine system: common – hypothyroidism.

From metabolism: very common – decreased appetite and food intake, weight loss; common – hypokalemia, hypophosphatemia, hypocalcemia, hyponatremia, hypomagnesemia, hyperuricemia, dehydration.

Laboratory data: common – increased amylase and lipase activity, deviation from normal INR value.

Benign, malignant and unspecified neoplasms (including cysts and polyps): rare – keratoacanthoma/squamous cell carcinoma of the skin.

Infectious and parasitic diseases: common – urinary tract infections, nasopharyngitis, skin and mucosal candidiasis, systemic mycosis, pneumonia.

General reactions: very common – asthenia/general weakness, pain of various localization, increased body temperature, mucosal inflammation.

Contraindications

Severe hepatic impairment (Child-Pugh class C); end-stage renal disease; concomitant use with strong CYP3A4 inhibitors and inducers; age under 18 years; pregnancy and lactation (breastfeeding); hypersensitivity to regorafenib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated for use in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Contraindicated for use in end-stage renal disease.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Use with caution in mild to moderate hepatic impairment; in the presence of risk factors for bleeding, as well as with concomitant use of anticoagulants and other drugs that increase the risk of bleeding; in coronary artery disease.

Before starting treatment with regorafenib, it is recommended to determine liver function parameters (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 indications.

Since Regorafenib is a UGT1A1 inhibitor, patients with Gilbert’s syndrome may develop mild indirect (unconjugated) hyperbilirubinemia.

If patients receiving regorafenib treatment experience therapy-related worsening of liver function parameters (in the absence of an obvious alternative cause, such as obstructive jaundice or progression of the underlying disease), the physician should adjust the dose of regorafenib and monitor the patient’s condition.

When used in patients with mild and moderate hepatic impairment, careful monitoring of the patient’s condition should be carried out. Use is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), as Regorafenib has not been studied in this category of patients (increased exposure is possible).

In cases of deterioration due to infection progression, the issue of temporarily discontinuing regorafenib treatment should be considered.

In the presence of risk factors for bleeding, as well as with concomitant prescription of anticoagulants (e.g., warfarin, phenprocoumon) or other medications that increase the risk of bleeding, coagulation parameters and complete blood count should be monitored. Before starting treatment with regorafenib in patients with liver cirrhosis, examination and subsequent treatment of esophageal varices should be performed according to the standard approach. If severe bleeding occurs requiring emergency medical intervention, discontinuation of regorafenib treatment should be considered.

In case of gastrointestinal perforation or fistula formation, regorafenib therapy should be discontinued.

In patients with coronary artery disease, clinical signs and symptoms of myocardial ischemia should be monitored. If myocardial ischemia and/or infarction occurs, regorafenib therapy should be discontinued until the condition normalizes. When deciding to resume therapy, the physician should assess the benefit-risk ratio of regorafenib for each individual patient. If clinical manifestations of ischemia persist, therapy should not be resumed.

In case of development of reversible posterior encephalopathy, treatment with regorafenib should be discontinued, blood pressure should be controlled, and supportive therapy should be provided.

Before starting and during treatment with regorafenib, blood pressure should be regularly monitored and its increase should be corrected in accordance with accepted treatment standards. 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 regorafenib. In case of a hypertensive crisis, regorafenib treatment should be discontinued.

In case of extensive surgical interventions, temporary discontinuation of regorafenib therapy is recommended, since drugs with antiangiogenic properties may suppress or impair wound healing. The decision to resume therapy after surgical interventions should be based on clinical assessment of the adequacy of wound healing.

To prevent the development of palmar-plantar erythrodysesthesia, callus formation should be controlled and special shoe inserts and gloves should be used to prevent pressure on the soles and palms. For the treatment of palmar-plantar erythrodysesthesia, keratolytic creams (e.g., creams based on urea, salicylic acid, or alpha-hydroxy acid, which should be applied only to the affected skin areas) and moisturizing creams in abundant amounts can be used to relieve symptoms. If necessary, treatment is temporarily discontinued and/or the dose of regorafenib is reduced, or in severe or recurrent cases of skin reactions, regorafenib therapy is discontinued.

Biochemical and metabolic parameters should be monitored. If necessary, replacement therapy is prescribed in accordance with accepted treatment standards. In cases of persistent or recurrent disorders, the possibility of temporary treatment discontinuation, dose reduction, or complete discontinuation of regorafenib therapy should be considered.

Effect on ability to drive vehicles and operate machinery

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).

Drug Interactions

Use of ketoconazole (400 mg for 18 days), a strong CYP3A4 isoenzyme inhibitor, in combination with a single dose of regorafenib (160 mg on the fifth day) led to an increase in the mean exposure (AUC) of regorafenib by approximately 33% and a decrease in the mean exposure of its active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) by approximately 90%. It is not recommended to use Regorafenib concomitantly with strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole), as their effect on the exposure of regorafenib at steady state and its metabolites (M-2 and M-5) has not been studied.

Use of rifampin (600 mg for 9 days), a strong CYP3A4 inducer, in combination with a single dose of regorafenib (160 mg on the seventh day) led to a decrease in the mean exposure (AUC) of regorafenib by approximately 50%, an increase in the mean exposure of the active metabolite M-5 by 3-4 times, with no change in the exposure of the active metabolite M-2. Other strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, and preparations containing St. John’s wort) may increase the metabolism of regorafenib. It is not recommended to use Regorafenib concomitantly with strong CYP3A4 inducers or to select medications that do not affect CYP3A4 or induce it to a minimal degree.

In vitro, it was shown that Regorafenib, as well as its active metabolite M-2, inhibits glucuronidation mediated by UGT1A1 and UGT1A9, while metabolite M-5 inhibits UGT1A1 only at concentrations achieved at steady state in vivo.

Use of regorafenib followed by a 5-day break before administration of irinotecan led to an increase in the mean exposure (AUC) of SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan, by approximately 44%. An increase in the mean exposure (AUC) of irinotecan by approximately 28% was also noted. These data indicate that combined use with regorafenib may increase the systemic exposure of UGT1A1 and UGT1A9 substrates.

Use of regorafenib (160 mg for 14 days) before a single dose of rosuvastatin (5 mg), which is a BCRP substrate, led to an increase in the mean exposure (AUC) of rosuvastatin by 3.8 times and an increase in its mean C_max in plasma by 4.6 times. Concomitant use with regorafenib may increase the plasma concentration of other BCRP substrates (e.g., methotrexate, fluvastatin, atorvastatin). It is recommended to monitor patients for signs and symptoms of increased exposure to BCRP substrates.

In vitro studies indicate that regorafenib metabolites M-2 and M-5 are substrates of P-glycoprotein and BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere with the exposure of M-2 and M-5. The clinical significance of these study results is unknown.

In vitro, Regorafenib has been shown to be a competitive inhibitor of cytochromes CYP2C8, CYP2C9, CYP2B6 at concentrations achieved in vivo at steady state (plasma C_max 8.1 µmol). In vitro inhibitory effect on CYP3A4 and CYP2C19 is less pronounced.

The combined use of regorafenib with neomycin does not affect the exposure of regorafenib but may disrupt its enterohepatic circulation. However, when comparing the pharmacological activity of regorafenib in vivo and in vitro, a decrease in the exposure of its active metabolites M-2 and M-5 by approximately 80% was shown. The clinical significance of the interaction with neomycin is unknown, but it may be a reason for reduced efficacy of regorafenib.

Bile acid sequestrant complexing agents, such as colestyramine and colestagel, may interact with regorafenib, forming insoluble complexes that affect absorption (or reabsorption), which could potentially lead to reduced exposure. The clinical significance of these potential interactions is unknown but may lead to reduced efficacy of regorafenib.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.