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Stivarga (Regorafenib) - Warnings and Precautions

 
 



WARNINGS AND PRECAUTIONS

Hepatoxicity

Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1100 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver.

Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.

Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration ].

Hemorrhage

Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% in Stivarga-treated patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) of Stivarga-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts.

Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology].

Dermatological Toxicity

Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE) and rash frequently requiring dose modification. The overall incidence of HFSR (45% versus 7%) and the incidence of Grade 3 HFSR (17% versus 0) were increased in Stivarga-treated patients in Study 1. The overall incidence of rash (26% versus 4%) and the incidence of Grade 3 rash (6% versus <1%) were higher in Stivarga-treated patients in Study 1 [see Adverse Reactions ]. The onset of dermatologic toxicity occurred in the first cycle of treatment in most patients.

Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration]. Institute supportive measures for symptomatic relief.

Hypertension

Stivarga caused an increased incidence of hypertension (30% of Stivarga-treated patients vs. 8% of placebo-treated patients in Study 1) [see Adverse Reactions ]. Hypertensive crisis occurred in 0.18% of 1100 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients. Do not initiate Stivarga until blood pressure is adequately controlled.

Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration].

Cardiac Ischemia and Infarction

Stivarga increased the incidence of myocardial ischemia and infarction (1.2% for Stivarga-treated patients vs. 0.4% of placebo-treated patients) [see Adverse Reactions ].

Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS (also known as posterior reversible encephalopathy syndrome) occurred in one of 1100 Stivarga-treated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop RPLS.

Gastrointestinal Perforation or Fistula

Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with Stivarga across clinical trials. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula..

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, treatment with regorafenib should be stopped at least 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

Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions ]

Risk Summary

Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data

In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).

In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.

In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.

Nursing Mothers

It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established.

In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.

Geriatric Use

Of the total number of subjects in clinical studies of Stivarga, 39% were 65 and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Hepatic Impairment

No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology ( 12.3 )]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions ( 5.1 )].

Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been studied in this population.

Renal Impairment

No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology ]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

Females and Males of Reproductive Potential

Contraception

Use effective contraception during treatment and up to 2 months after completion of therapy.

Infertility

There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology].

Page last updated: 2012-09-27

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