Stivarga

Last updated on RxList: 2/10/2021
Stivarga Side Effects Center

What Is Stivarga?

Stivarga (regorafenib) is a kinase inhibitor used to treat patients with metastatic colorectal cancer (CRC).

What Are Side Effects of Stivarga?

Common side effects of Stivarga include:

Stivarga can cause liver problems, which can be serious and sometimes fatal.

Dosage for Stivarga

The recommended dose for Stivarga is 160 mg, orally, once daily for the first 21 days of each 28-day cycle. Stivarga should be taken with a low-fat breakfast.

What Drugs, Substances, or Supplements Interact with Stivarga?

Stivarga may interact with grapefruit and grapefruit juice, bosentan, imatinib, nefazodone; St. John's wort, antibiotics, antifungals, heart medications, hepatitis C medications, HIV/AIDS medications, or seizure medications. Tell your doctor all medications and supplements you use.

Stivarga During Pregnancy and Breastfeeding

Stivarga is not recommended for use during pregnancy; it could harm a fetus. Use birth control to prevent pregnancy while you are receiving Stivarga, whether you are a man or a woman. Tell your doctor right away if a pregnancy occurs while either parent is taking Stivarga. Keep using birth control for at least 2 weeks after your treatment with Stivarga ends. It is unknown if Stivarga passes into breast milk or if it could harm a nursing baby. Consult your doctor before breastfeeding.

Additional Information

Our Stivarga (regorafenib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SLIDESHOW

Digestive Disorders: Common Misconceptions See Slideshow
Stivarga Consumer Information

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Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Regorafenib can cause serious or life-threatening liver problems. Call your doctor at once if you have nausea, vomiting, sleep problems, dark urine, or jaundice (yellowing of the skin or eyes).

Also call your doctor at once if you have:

  • headache, confusion, change in mental status;
  • vision changes;
  • a seizure;
  • pain, blisters, bleeding, or severe rash in the palms of your hands or the soles of your feet;
  • heart problems--chest pain, shortness of breath, feeling like you might pass out;
  • increased blood pressure--severe headache, blurred vision, pounding in your neck or ears;
  • perforation (a hole or tear) in your stomach or intestines--fever, chills, severe stomach pain or swelling, nausea, vomiting, increased thirst, decreased urination;
  • severe bleeding--bruising, nosebleeds, heavy menstrual periods or abnormal vaginal bleeding, blood in your urine, bloody or tarry stools, coughing up blood, or any bleeding that will not stop; or
  • signs of infection--fever, sore throat, feeling short of breath, cough with or without mucus, vaginal itching or discharge, pain or burning when you urinate, or redness and swelling anywhere in your body.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

  • diarrhea, nausea, stomach pain;
  • loss of appetite, weight loss;
  • increased blood pressure;
  • fever, infection;
  • abnormal liver function tests;
  • pain or redness in your mouth or throat, hoarse voice; or
  • feeling weak or tired.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Stivarga (Regorafenib Tablets)

QUESTION

What are risk factors for developing colon cancer? See Answer
Stivarga Professional Information

SIDE EFFECTS

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

  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Infections [see WARNINGS AND PRECAUTIONS]
  • Hemorrhage [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Perforation or Fistula [see WARNINGS AND PRECAUTIONS]
  • Dermatological Toxicity [see WARNINGS AND PRECAUTIONS]
  • Hypertension [see WARNINGS AND PRECAUTIONS]
  • Cardiac Ischemia and Infarction [see WARNINGS AND PRECAUTIONS]
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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 data described in the WARNINGS AND PRECAUTIONS section reflect exposure to STIVARGA in more than 4800 patients who were enrolled in four randomized, placebo-controlled trials (n=1142), an expanded access program (CONSIGN, n=2864), or single arm clinical trials (single agent or in combination with other agents). There were 4518 patients who received STIVARGA as a single agent; the distribution of underlying malignancies was 80% CRC, 4% GIST, 10% HCC, 6% other solid tumors; and 74% were White, 11% Asian, and 15% race not known. Among these 4518 patients, 83% received STIVARGA for at least 21 days and 20% received STIVARGA for 6 months or longer.

In randomized placebo-controlled trials (CORRECT, GRID, RESORCE and CONCUR), the most frequently observed adverse drug reactions (≥20%) in patients receiving STIVARGA are pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea.

Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (CORRECT) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer (CRC) 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 1.7 months (range 2 days, 10.8 months) 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. Adverse reactions that resulted in treatment discontinuation occurred 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 provides the incidence of adverse reactions (≥10%) in patients in CORRECT.

Table 1: Adverse drug reactions reported in ≥10% of patients treated with STIVARGA in CORRECT and reported more commonly than in patients receiving placeboa

Adverse ReactionsSTIVARGA
(N=500)
Placebo
(N=253)
GradeGrade
All
%
≥ 3
%
All
%
≥ 3
%
General disorders and administration site conditions
Asthenia/fatigue6415469
Pain599487
Fever282150
Metabolism and nutrition disorders
Decreased appetite and food intake475284
Skin and subcutaneous tissue disorders
HFSR/PPES451770
Rashb2664<1
Gastrointestinal disorders
Diarrhea438172
Mucositis33450
Investigations
Weight loss32<1100
Infections and infestations
Infectionc319176
Vascular disorders
Hypertension3088<1
Hemorrhagec2128<1
Respiratory, thoracic and mediastinal disorders
Dysphonia30060
Nervous system disorders
Headache10<170
a Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0 (NCI CTCAE v3.0).
b The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash.
cFatal outcomes observed.

Table 2 provides laboratory abnormalities observed in CORRECT.

Table 2: Laboratory test abnormalities reported in CORRECT

Laboratory ParameterSTIVARGA
(N=500a)
Placebo
(N=253a)
GradebGradeb
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Anemia79516630
Thrombocytopenia412<117<10
Neutropenia310000
  Lymphopenia5490354<1
Metabolism and nutrition disorders
Hypocalcemia591<11810
Hypokalemia26408<10
Hyponatremia30712240
Hypophosphatemia573111140
Hepatobiliary disorders
Hyperbilirubinemia451031753
Increased AST65514641
Increased ALT4551303<1
Renal and urinary disorders
Proteinuriac84206110
Investigations
Increased INRd244N/A172N/A
Increased Lipase46921932
Increased Amylase262<1172<1
a % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo).
b NCI CTCAE v3.0.
c Based on urine protein-creatinine ratio data.
d International normalized ratio: No Grade 4 denoted in NCI CTCAE, v3.0.

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (GRID) 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 5.7 months (range 1 day, 11.7 months) 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. 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 provides the incidence of adverse reactions (≥10%) in patients in GRID.

Table 3: Adverse reactions reported in ≥10% patients treated with STIVARGA in GRID and reported more commonly than in patients receiving placeboa

Adverse ReactionsSTIVARGA
(N=132)
Placebo
(N=66)
GradeGrade
All
%
≥ 3
%
All
%
≥ 3
%
Skin and subcutaneous tissue disorders
HFSR/PPE6722122
Rashb30730
Alopecia24220
General disorders and administration site conditions
Asthenia/Fatigue524392
Fever210112
Vascular disorders
Hypertension5928275
Hemorrhage11430
Gastrointestinal disorders
Pain6085514
Diarrhea47890
Mucositis40282
Nausea202122
Vomiting17<180
Respiratory, thoracic and mediastinal disorders
Dysphonia39090
Infections and infestations
Infectionc32550
Metabolism and nutrition disorders
Decreased appetite and food intake31<1213
Hypothyroidismd18060
Nervous system disorders
Headache16090
Investigations
Weight loss14080
Musculoskeletal and connective tissue disorders
Muscle spasms14030
a Adverse reactions graded according to NCI CTCAE v4.0.
bThe term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash.
cFatal outcomes observed.
d Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.

Table 4 provides laboratory abnormalities observed in GRID.

Table 4: Laboratory test abnormalities reported in GRID

Laboratory ParameterSTIVARGA
(N=132a)
Placebo
(N=66a)
GradebGradeb
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Thrombocytopenia1310202
Neutropenia16211230
Lymphopenia30802430
Metabolism and nutrition disorders
Hypocalcemia1720500
Hypokalemia2130300
Hypophosphatemia55202320
Hepatobiliary disorders
Hyperbilirubinemia33311220
Increased AST58314730
Increased ALT39413920
Renal and urinary disorders
Proteinuriac593-d533-d
Investigations
Increased Lipase1401500
a Percent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo).
b NCI CTCAE v4.0.
c Based on urine protein-creatinine ratio data.
d No Grade 4 denoted in NCI CTCAE v4.0.

Hepatocellular Carcinoma

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (RESORCE) in which patients with previously-treated HCC received either STIVARGA (n=374) 160 mg orally on days 1-21 of each 4 week treatment cycle or placebo (n=193). The median age was 63 years, 88% were men, 98% had Child-Pugh A cirrhosis, 66% had an ECOG performance status (PS) of 0 and 34% had PS of 1. The median duration of therapy was 3.5 months (range 1 day to 29.4 months) for patients receiving STIVARGA. Of the patients receiving STIVARGA, 33% were exposed to STIVARGA for greater than or equal to 6 months and 14% were exposed to STIVARGA for greater than or equal to 12 months. Dose interruptions for adverse events were required in 58.3% of patients receiving STIVARGA and 48% of patients had their dose reduced. The most common adverse reactions requiring dose modification (interruption or dose reduction) were HFSR/PPES (20.6%), blood bilirubin increase (5.9%), fatigue (5.1%) and diarrhea (5.3%). Adverse reactions that resulted in treatment discontinuation were reported in 10.4% of STIVARGA-treated patients compared to 3.6% of patients who received placebo; the most common adverse reactions requiring discontinuation of STIVARGA were HFSR/PPES (1.9%) and AST increased (1.6%).

Table 5 provides the incidence of adverse reactions (≥10%) in patients in RESORCE.

Table 5: Adverse reactions reported in ≥10% of patients treated with STIVARGA in RESORCE and reported more commonly than in patients receiving placeboa

Adverse ReactionsSTIVARGA
(N=374)
Placebo
(N=193)
GradeGrade
All
%
≥ 3
%
All
%
≥ 3
%
Skin and subcutaneous tissue disorders
HFSR/PPE51127<1
General disorders and administration site conditions
Pain559448
Asthenia/Fatigue4210335
Fever20070
Vascular disorders
Hypertension311565
Hemorrhageb185168
Gastrointestinal disorders
Diarrhea413150
Nausea17<1130
Vomiting13<17<1
Mucositis1312≤1
Respiratory, thoracic and mediastinal disorders
Dysphonia18020
Infections and infestations
Infectionb318186
Metabolism and nutrition disorders
Decreased appetite and food intake31240
Investigations
Weight loss13240
Musculoskeletal and connective tissue disorders
Muscle spasms10020
a Adverse reactions graded according to NCI CTCAE v4.0.
b Fatal outcomes observed.

Other clinically significant adverse reactions observed in less than 10% of STIVARGA-treated patients were: alopecia (7%), hypothyroidism (6.4%), pancreatitis (1.6%), exfoliative rash (1.3%), tremor (1.3%), erythema multiforme (0.8%), myocardial ischemia (0.8%), gastrointestinal fistula (0.3%), and myocardial infarction (0.3%).

Table 6 provides laboratory abnormalities observed in RESORCE.

Table 6: Laboratory test abnormalities reported in RESORCE

Laboratory ParameterSTIVARGA
(N=374a)
Placebo
(N=193a)
GradebGradeb
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Thrombocytopenia635<15000
Neutropenia143015<1<1
Lymphopenia681625911<1
Metabolism and nutrition disorders
Hypocalcemia23<101000
Hypokalemia314<1920
Hypophosphatemia703223170
Hepatobiliary disorders
Hyperbilirubinemia7813355115
Increased AST9316284173
Increased ALT706<15950
Renal and urinary disorders
Proteinuriac5117-d373-d
Investigations
Increased INR44<1-d352-d
Increased Lipase411132781
Increased Amylase233<1192<1
a Percent based on number of patients with post-baseline samples which may be less than 374 (regorafenib) or 193 (placebo).
b NCI CTCAE v4.0.
c Based on dipstick data.
d No Grade 4 denoted in NCI CTCAE v4.0.

Postmarketing Experience

The following adverse reaction has been identified during postapproval use of STIVARGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

  • hypersensitivity reaction
  • nephrotic syndrome
  • cardiac failure
  • arterial (including aortic) aneurysms, dissections, and rupture

Read the entire FDA prescribing information for Stivarga (Regorafenib Tablets)

© Stivarga Patient Information is supplied by Cerner Multum, Inc. and Stivarga Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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