Regorafenib Monohydrate

Uses

Colorectal Cancer: Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine, oxaliplatin-and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy ... Read more

Dosage

Regorafenib Monohydrate dosage

The recommended dose is 160 mg Regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Treatment should be continued until disease progression or unacceptable toxicity. Regorafenib should be taken at the same time each day and swallowed tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat. Two doses of Regorafenib should not be taken on the same day to make up for a missed dose from the previous day.Dose Modifications: If dose modifications are required, the dose should be reduced in 40 mg (one tablet) increments; the lowest recommended daily dose of Regorafenib is 80 mg daily. Or, as directed by the registered physicians.Pediatric Use: The safety and efficacy of Regorafenib in pediatric patients less than 18 years of age have not been established.

Side Effects

Hepatotoxicity Infections Hemorrhage Gastrointestinal Perforation or Fistula Dermatological Toxicity Hypertension Cardiac Ischemia and Infarction Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Precaution

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in Regorafenib- treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. Liver function tests (ALT, AST, and bilirubin) should be obtained before initiation of Regorafenib and monitored at least every two weeks during the first 2 months of treatment. Regorafenib should be temporarily held and then reduced or permanently discontinued depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.Infections: Regorafenib caused an increased risk of infections. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with Regorafenib (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% in Regorafenib- treated patients vs 0.2% in patients receiving placebo). Regorafenib should be withheld for Grade 3 or 4 infections, or worsening infection of any grade. Regorafenib should be resumed at the same dose following resolution of infection.Hemorrhage: Regorafenib caused an increased incidence of hemorrhage. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Regorafenib should be permanently discontinued in patients with severe or life-threatening hemorrhage. INR levels should be monitored more frequently in patients receiving Warfarin.Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with Regorafenib across all clinical trials of Regorafenib administered as a single agent; this included eight fatal events. Regorafenib should be permanently discontinued in patients who develop gastrointestinal perforation or fistula.Dermatologic Toxicity: A higher incidence of Hand-foot skin reaction (HFSR) was observed in Asian patients treated with Regorafenib (all grades: 72%; Grade 3: 18%). Regorafenib should be withheld, reduced the dose, or permanently discontinued Regorafenib depending on the severity and persistence of dermatologic toxicity. Supportive measures for symptomatic relief should be instituted.Hypertension: Regorafenib caused an increased incidence of hypertension (30% versus 8% in CORRECT, 59% versus 27% in GRID, and 31% versus 6% in RESORCE). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials). Regorafenib should not be initiated unless blood pressure is adequately controlled, monitored blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Regorafenib should be temporarily or permanently withheld for severe or uncontrolled hypertension.Cardiac Ischemia and Infarction: Regorafenib increased the incidence of myocardial ischemia and infarction (0.9%vs 0.2%) in randomized placebo-controlled trials. Regorafenib should be withheld in patients who develop new or acute onset cardiac ischemia or infarction. Regorafenib should be resumed only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Regorafenib- treated patients across all clinical trials. An evaluation for RPLS should be performed in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered mental function. Regorafenib should be discontinued in patients who develop RPLS.Wound Healing Complications: No formal studies of the effect of Regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as Regorafenib can impair wound healing, discontinue treatment with Regorafenib atleast 2 weeks prior to scheduled surgery. The decision to resume Regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence.Embryo-Fetal Toxicity: There are no available data on Regorafenib use in pregnant women. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Regorafenib and for 2 months after the final dose. Males with female partners of reproductive potential should be advised to use effective contraception during treatment with Regorafenib and for 2 months after the final dose.

Interaction

Effect of Strong CYP3A4 Inducers on Regorafenib: Co-administration of a strong CYP3A4 inducer with Regorafenib decreased the plasma concentrations of Regorafenib, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2 and may lead to decreased efficacy. Concomitant use of Regorafenib with strong CYP3A4 inducers (e.g. Rifampin, Phenytoin, Carbamazepine, Phenobarbital, and St. John’s Wort) should be avoided.Effect of Strong CYP3A4 Inhibitors on Regorafenib: Co-administration of a strong CYP3A4 inhibitor with Regorafenib increased the plasma concentrations of Regorafenib and decreased the plasma concentrations of the active metabolites M-2 and M-5 and may lead to increased toxicity. Concomitant use of Regorafenib with strong CYP3A4 inhibitors (e.g. Clarithromycin, Grapefruit juice, Itraconazole, Ketoconazole, Nefazodone, Posaconazole, Telithromycin, and Voriconazole) should be avoided.Effect of Regorafenib on Breast Cancer Resistance Protein (BCRP) Substrates: Co-administration of Regorafenib with a BCRP substrate increased the plasma concentrations of the BCRP substrate Patients should be monitored closely for signs and symptoms of exposure related toxicity to the BCRP substrate(e.g. Methotrexate, Fluvastatin, Atorvastatin). Concomitant BCRP substrate product information should be consulted when considering administration of such products together with Regorafenib.

Pregnancy & Breastfeeding use

There are no available data on Regorafenib use in pregnant women. Pregnant women should be advised of the potential hazard to a fetus. There are no data on the presence of Regorafenib or its metabolites in human milk, the effects of Regorafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants from Regorafenib, breastfeed should not be done during treatment with Regorafenib and for 2 weeks after the final dose.Female reproductive Potential: Effective contraception should be used during treatment and for 2 months after completion of therapy. Males reproductive Potential: Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment and for 2 months following the final dose of Regorafenib.Infertility: There are no data on the effect of Regorafenib on human fertility.

Contraindication

It is contraindicated in patients with known hypersensitivity to Regorafenib or any other components of this product.

Acute Overdose

The highest dose of Regorafenib studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for Regorafenib overdose. In the event of suspected overdose, Regorafenib should be interrupted, instituted supportive care, and observed until clinical stabilization.

Storage Condition

Store below 30°C in a cool and dry place, away from sunlight. Keep out of the reach of children.

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