July 24, 2016
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Stivarga

"The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved t"...

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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 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; In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [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].

Hemorrhage

Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivargatreated 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].

Dermatologic Toxicity

Stivarga increased the incidence 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]. In both studies, a higher incidence of HFSR was observed in Asian patients treated with Stivarga (all grades: 78.4% in Study 1 and 88.2% in Study 2 and Grade 3: 28.4% in Study 1 and 23.5% in Study 2) [see Use In Specific Populations].

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]. Institute supportive measures for symptomatic relief.

Hypertension

Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see ADVERSE REACTIONS]. 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].

Cardiac Ischemia And Infarction

Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [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 1200 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.

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.

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 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. Discontinue regorafenib 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

See 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].

Hemorrhage

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

Dermatologic Toxicity

Advise patients to contact their healthcare provider if they experience skin changes associated with redness, 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].

Myocardial 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].

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].

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 with 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/Storage and Handling].
Missed dose

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.

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 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age 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]. 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].

Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), since 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) 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). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

Race

Based on pooled data from three placebo-controlled trials (Studies 1 and 2, and a study conducted in East Asia), 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: 6/28/2016

Warnings
Precautions

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