STIVARGA^® (regorafenib) safety profile in CORRECT

AEs reported in ≥10% of mCRC patients treated with STIVARGA and reported more commonly than in patients receiving placebo1^*

	STIVARGA (n=500)	Placebo (n=253)
AEs	All grades (%)	Grade ≥3 (%)	All grades (%)	Grade ≥3 (%)
General disorders and administration site conditions
Asthenia/fatigue	64%	15%	46%	9%
Pain	59%	9%	48%	7%
Fever	28%	2%	15%	0%
Metabolism and nutrition disorders
Decreased appetite and food intake	47%	5%	28%	4%
Skin and subcutaneous tissue disorders
HFSR/PPES	45%	17%	7%	0%
Rash^†	26%	6%	4%	<1%
Gastrointestinal disorders
Diarrhea	43%	8%	17%	2%
Mucositis	33%	4%	5%	0%
Investigations
Weight loss	32%	<1%	10%	0%
Infections and infestations
Infection^‡	31%	9%	17%	6%
Vascular disorders
Hypertension	30%	8%	8%	<1%
Hemorrhage^‡	21%	2%	8%	<1%
Respiratory, thoracic, and mediastinal disorders
Dysphonia	30%	0%	6%	0%
Nervous system disorders
Headache	10%	<1%	7%	0%

	STIVARGA (n=500)
AEs	All grades (%)	Grade ≥3 (%)
General disorders and administration site conditions
Asthenia/fatigue	64%	15%
Pain	59%	9%
Fever	28%	2%
Metabolism and nutrition disorders
Decreased appetite and food intake	47%	5%
Skin and subcutaneous tissue disorders
HFSR/PPES	45%	17%
Rash^†	26%	6%
Gastrointestinal disorders
Diarrhea	43%	8%
Mucositis	33%	4%
Investigations
Weight loss	32%	<1%
Infections and infestations
Infection^‡	31%	9%
Vascular disorders
Hypertension	30%	8%
Hemorrhage^‡	21%	2%
Respiratory, thoracic, and mediastinal disorders
Dysphonia	30%	0%
Nervous system disorders
Headache	10%	<1%

	Placebo (n=253)
AEs	All grades (%)	Grade ≥3 (%)
General disorders and administration site conditions
Asthenia/fatigue	46%	9%
Pain	48%	7%
Fever	15%	0%
Metabolism and nutrition disorders
Decreased appetite and food intake	28%	4%
Skin and subcutaneous tissue disorders
HFSR/PPES	7%	0%
Rash^†	4%	<1%
Gastrointestinal disorders
Diarrhea	17%	2%
Mucositis	5%	0%
Investigations
Weight loss	10%	0%
Infections and infestations
Infection^‡	17%	6%
Vascular disorders
Hypertension	8%	<1%
Hemorrhage^‡	8%	<1%
Respiratory, thoracic, and mediastinal disorders
Dysphonia	6%	0%
Nervous system disorders
Headache	7%	0%

AEs can occur at any time during the course of treatment. Monitoring is critical during the first cycle and throughout therapy2,3

Frequency of select treatment-related AEs ≥Grade 3 occurring in ≥5% of patients in either arm of CORRECT2, 4^§

HFSR

Fatigue

Diarrhea

Hypertension

Rash/Desquamation

Toxicity-related discontinuation

8.2% of STIVARGA patients discontinued treatment because of drug-related AEs vs 1.2% of placebo patients1
Skin toxicity (HFSR/PPE or rash) was the most common cause of permanent drug discontinuation1

Indications

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 RAS wild-type, an anti-EGFR therapy.

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.

STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Important Safety Information

WARNING: HEPATOTOXICITY

Severe and sometimes fatal hepatotoxicity has occurred in clinical trials.
Monitor hepatic function prior to and during treatment.
Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all 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 metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 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 upper limit of normal (ULN) or baseline values. 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.

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% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with 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 and monitor INR levels more frequently in patients receiving warfarin.

Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 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% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%). 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 depending on the severity and persistence of dermatologic toxicity.

Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). 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 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.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume 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 characteristics 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: Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing. Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.

Nursing Mothers: 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.

Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%).

For important risk and use information, please see the full Prescribing Information including the Boxed Warning.

You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For Bayer products, you can report these directly to Bayer by clicking here.

*Adverse reactions graded according to National Cancer Institute Common Terminology for Adverse Events version 3.0 (NCI CTCAE v3.0).

^†The term “rash” represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

^‡Fatal outcomes observed.

^§Per NCI CTCAE v3.0 category or term and worst grade. 2

AE, adverse event; CORRECT, COloRectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy; HFSR, hand-foot skin reaction; mCRC, metastatic colorectal cancer; PPES, palmar-plantar erythrodysesthesia syndrome.

References:

STIVARGA. Prescribing information. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; December 2020. Return to content
Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. Return to content
Grothey A, George S, van Cutsem E, et al. Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. Oncologist. 2014;19(6):669-680. Return to content
Grothey A, Van Cutsem E, Sobrero A, et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. Poster presented at: American Society of Clinical Oncology (ASCO) 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Poster 467. Return to content

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Last updated on July 2024

STIVARGA® (regorafenib) safety profile in CORRECT

Frequency of select treatment-related AEs ≥Grade 3 occurring in ≥5% of patients in either arm of CORRECT2, 4§