May 29, 2017
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Stivarga

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Stivarga




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hepatotoxicity

Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-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.

In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In the GRID study, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo [see ADVERSE REACTIONS].

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 and Use in Specific Populations].

Infections

STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs. 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials.The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. 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 STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% in STIVARGA-treated patients vs 0.2% in patients receiving placebo).

Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection [see DOSAGE AND ADMINISTRATION].

Hemorrhage

STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA and 9.5% in patients receiving placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or 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].

Gastrointestinal Perforation Or Fistula

Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as as single agent; this included eight fatal events.

Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and 0.2% of patients in placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatologic Toxicity

In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm and in 25.5% of patients in the placebo arm, including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES), and severe rash requiring dose modification.

In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53%) than in the placebo-treated patients (8%). Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% versus < 1%), Grade 3 rash (3% versus < 1%), serious adverse reactions of erythema multiforme ( < 0.1% vs. 0%) and Stevens-Johnson Syndrome ( < 0.1% vs. 0%) were also higher in STIVARGA-treated patients [see ADVERSE REACTIONS]. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%) [see Use in Specific Populations].

Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent.

Withhold STIVARGA, reduce the dose, or permanently discontinue STIVARGA depending on the severity and persistence of dermatologic toxicity [see DOSAGE AND ADMINISTRATION]. Institute supportive measures for symptomatic relief.

Hypertension

In randomized, placebo-controlled trials, hypertensive crisis occurred in 0.2% of patients in the regorafenib arms and in none of the patients in the placebo arms. STIVARGA caused an increased incidence of hypertension (30% versus 8% in CORRECT, 59% versus 27% in GRID, and 31% versus 6% in RESORCE) [see ADVERSE REACTIONS]. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials).

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].

Cardiac Ischemia And Infarction

STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% vs 0.2%) in randomized placebo-controlled trials [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

Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered mental function. Discontinue STIVARGA 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 STIVARGA can impair wound healing, discontinue treatment with STIVARGA at least 2 weeks prior to scheduled surgery. The decision to resume STIVARGA after surgery should be based on clinical judgment of adequate wound healing. Discontinue STIVARGA in patients with wound dehiscence.

Embryo-Fetal Toxicity

Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use 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. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose [see Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hepatotoxicity

Advise patients that they will need to undergo monitoring for liver damage and to report immediately any signs or symptoms of severe liver damage to their healthcare provider [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

Infections

Advise patients to contact their healthcare provider if they experience signs and symptoms of infection [see WARNINGS AND PRECAUTIONS].

Hemorrhage

Advise patients to contact their healthcare provider for unusual bleeding, bruising, or symptoms of bleeding, such as lightheadedness [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Perforation Or Fistula

Advise patients to contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, or dehydration [see WARNINGS AND PRECAUTIONS].

Dermatologic Toxicity

Advise patients to contact their healthcare provider if they experience skin changes including HFSR, rash, pain, blisters, bleeding, or swelling [see WARNINGS AND PRECAUTIONS].

Hypertension

Advise patients they will need to undergo blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see WARNINGS AND PRECAUTIONS].

Cardiac Ischemia And Infarction

Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, feel dizzy, or feel like passing out [see WARNINGS AND PRECAUTIONS].

Reversible Posterior Leukoencephalopathy Syndrome

Advise patients to contact their healthcare provider if they experience signs and symptoms of RPLS [see WARNINGS AND PRECAUTIONS].

Wound Healing Complications

Advise patients to contact their healthcare provider if they plan to undergo a surgical procedure or had recent surgery [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

Advise patients that regorafenib can cause fetal harm. Advise a pregnant woman of the potential risk to a fetus [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

Females And Males Of Reproductive Potential
  • Advise women of reproductive potential of the need for effective contraception during STIVARGA treatment and for 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her healthcare provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with STIVARGA [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].
  • Advise men of reproductive potential of the need for effective contraception during STIVARGA treatment and for 2 months after completion of treatment [see Use in Specific Populations].
Lactation

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 [see Use in Specific Populations].

Administration
  • Advise patients to swallow the STIVARGA tablet whole with water at the same time each day following a low-fat meal. Inform patients that the low-fat meal should contain less than 600 calories and less than 30% fat [see DOSAGE AND ADMINISTRATION].
  • Advise patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Discard any remaining tablets 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle [see HOW SUPPLIED].
Dosing Instructions

Advise patients to take STIVARGA after a low fat meal. Advise 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 [see DOSE AND ADMINISTRATION].

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Risk Summary

Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Administration of 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 [see Data]. Advise pregnant women of the potential hazard to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively.

Data

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. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and 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.

Lactation

Risk Summary

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. In rats, regorafenib and its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose.

Females And Males Of Reproductive Potential

Contraception

Females

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

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following the final dose of STIVARGA [see Nonclinical Toxicology].

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].

Pediatric Use

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

Animal Data

In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred 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 1142 STIVARGA-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among STIVARGA-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group.

Hepatic Impairment

No dose adjustment is recommended in patients with mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > ULN to ≤ 1.5 times ULN) or moderate (total bilirubin > 1.5 to ≤ 3 times ULN and any AST) hepatic impairment, [see CLINICAL PHARMACOLOGY]. Closely monitor patients with hepatic impairment for adverse reactions [see WARNINGS AND PRECAUTIONS].

STIVARGA is not recommended for use in patients with severe hepatic impairment (total bilirubin > 3x ULN) as STIVARGA has not been studied in this population.

Renal Impairment

No dose adjustment is recommended for patients with renal impairment. The pharmacokinetics of regorafenib have not been studied in patients who are on dialysis and there is no recommended dose for this patient population [see CLINICAL PHARMACOLOGY].

Race

Based on pooled data from three placebo-controlled trials (CORRECT, GRID and CONCUR), a higher incidence of HFSR and liver function test abnormalities occurred in Asian patients treated with STIVARGA as compared with Whites [see WARNINGS AND PRECAUTIONS]. No starting dose adjustment is necessary based on race.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/5/2017

Warnings
Precautions

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