Regorafenib

Regorafenib
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

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Black Box Warning

WARNING: HEPATOTOXICITY See full prescribing information for complete Boxed Warning. Severe and sometimes fatal hepatotoxicity has been observed in clinical trials [see Warnings and Precautions (5.1)]. Monitor hepatic function prior to and during treatment [see Warnings and Precautions (5.1)]. Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence

Overview

Regorafenib is a antineoplastic that is FDA approved for the treatment of Colorectal Cancer, Gastrointestinal Stromal Tumors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, mucositis, dysphonia, infection, pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

1.1 Colorectal Cancer Stivarga® 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 KRAS wild type, an anti-EGFR therapy.

1.2 Gastrointestinal Stromal Tumors Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. 2.1 Recommended Dose 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. Continue treatment until disease progression or unacceptable toxicity.

Take Stivarga at the same time each day. Swallow tablet whole with a low-fat breakfast that contains less than 30% fat [see Clinical Pharmacology (12.3)]. Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skim milk (319 calories and 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories and 2 g fat). Do not take two doses of Stivarga on the same day to make up for a missed dose from the previous day.

2.2 Dose Modifications Interrupt Stivarga for the following:

NCI CTCAE Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR Symptomatic Grade 2 hypertension Any NCI CTCAE Grade 3 or 4 adverse reaction Reduce the dose of Stivarga to 120 mg:

For the first occurrence of Grade 2 HFSR of any duration After recovery of any Grade 3 or 4 adverse reaction For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity Reduce the dose of Stivarga to 80 mg:

For re-occurrence of Grade 2 HFSR at the 120 mg dose After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity) Discontinue Stivarga permanently for the following:

Failure to tolerate 80 mg dose Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN) Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Regorafenib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Regorafenib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Regorafenib in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Regorafenib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Regorafenib in pediatric patients.

Contraindications

There is limited information regarding Regorafenib Contraindications in the drug label.

Warnings

WARNING: HEPATOTOXICITY See full prescribing information for complete Boxed Warning. Severe and sometimes fatal hepatotoxicity has been observed in clinical trials [see Warnings and Precautions (5.1)]. Monitor hepatic function prior to and during treatment [see Warnings and Precautions (5.1)]. Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence

• 5.1 Hepatotoxicity

Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1200 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 in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [see Adverse Reactions (6.1)].

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 (2.2)].

5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 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 (12.3)].

5.3 Dermatological Toxicity Stivarga caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification.

The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)].

Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials.

Withhold Stivarga, reduce the dose, or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.

5.4 Hypertension Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2).

Do not initiate Stivarga unless 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 (2.2)].

5.5 Cardiac Ischemia and Infarction Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. 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.

5.6 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 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS.

5.7 Gastrointestinal Perforation or Fistula Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Stivarga-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.

5.8 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.

5.9 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

Adverse Reactions

Clinical Trials Experience

The following serious adverse reactions are discussed elsewhere in the labeling:

Hepatotoxicity [See Warnings and Precautions (5.1)] Hemorrhage [See Warnings and Precautions ( 5.2 )] Dermatological Toxicity [See Warnings and Precautions ( 5.3 )] Hypertension [See Warnings and Precautions (5.4)] Cardiac Ischemia and Infarction [See Warnings and Precautions ( 5.5 )] Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions ( 5.6 )] Gastrointestinal Perforation or Fistula [See Warnings and Precautions ( 5.7 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.

The most frequently observed adverse drug reactions (≥20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.

The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation.

6.1 Clinical Trials Experience Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga.

TABLE 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).

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This image is provided by the National Library of Medicine.

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated patients compared to 1.5% of patients who received placebo.

TABLE 3 compares the incidence of adverse reactions (≥10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).

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This image is provided by the National Library of Medicine.

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This image is provided by the National Library of Medicine.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Regorafenib in the drug label.

Drug Interactions

• 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib

Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)].

7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Stivarga with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole)

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

• 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.
Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Regorafenib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Regorafenib during labor and delivery.

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.

Geriatic Use

Of the 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age or and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Gender

There is no FDA guidance on the use of Regorafenib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Regorafenib with respect to specific racial populations.

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) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. 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). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

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.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Regorafenib in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Regorafenib in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Regorafenib in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Regorafenib in the drug label.

Overdosage

The highest dose of Stivarga studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization.

Pharmacology

There is limited information regarding Regorafenib Pharmacology in the drug label.

Mechanism of Action

• Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.

Structure

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Pharmacodynamics

There is limited information regarding Pharmacodynamics of Regorafenib in the drug label.

Pharmacokinetics

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.

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This image is provided by the National Library of Medicine.

File:Regorafenib01.png

This image is provided by the National Library of Medicine.

14.2 Gastrointestinal Stromal Tumors The efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).

The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator’s discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga.

A statistically significant improvement in PFS was demonstrated among patients treated with Stivarga compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.

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Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.

Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.

13.2 Animal Toxicology and/or Pharmacology In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposu

Clinical Studies

4.1 Colorectal Cancer The clinical efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus Best Supportive Care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast that contains less than 30% fat [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Treatment continued until disease progression or unacceptable toxicity.

In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.

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14.2 Gastrointestinal Stromal Tumors The efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).

The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.

Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator’s discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga.

A statistically significant improvement in PFS was demonstrated among patients treated with Stivarga compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.

File:Regorafenib01.png

This image is provided by the National Library of Medicine.

How Supplied

• Stivarga tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).

Storage

• Store Stivarga at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature].

Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening.

Discard any unused tablets 7 weeks after opening the bottle.Dispose of unused tablets in accordance with local requirements.

Images

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Patient Counseling Information

See FDA-Approved Patient Labeling (Patient Information).

Inform your patients of the following: Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider. Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding. Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling. Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out. Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration. Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery. Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga. Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib. Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day. Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes . Any remaining tablets should be discarded 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.

Precautions with Alcohol

• Alcohol-Regorafenib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• STIVARGA ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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