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Stivarga

Last reviewed on RxList: 5/5/2017
Stivarga Side Effects Center

Last reviewed on RxList 01/31/2017

Stivarga (regorafenib) is a kinase inhibitor used to treat patients with metastatic colorectal cancer (CRC). Common side effects of Stivarga include:

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

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. 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 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.

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.

Stivarga Consumer Information

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using regorafenib and call your doctor at once if you have:

  • fever, chills, flu symptoms, mouth sores, severe or ongoing vomiting or diarrhea;
  • feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
  • blood in your urine or stools, coughing up blood or vomit that looks like coffee grounds;
  • heavy menstrual periods or abnormal vaginal bleeding;
  • any bleeding that will not stop;
  • chest pain and severe dizziness, fainting, feeling short of breath;
  • headache, confusion, change in mental status, vision loss, seizure (convulsions);
  • upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • dangerously high blood pressure (blurred vision, buzzing in your ears, anxiety, uneven heartbeats);
  • rash, blisters, oozing, or severe pain in the palms of your hands or the soles of your feet;
  • any wound that won't heal; or
  • severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

  • diarrhea, stomach pain, weight loss;
  • 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)

Stivarga Professional Information

SIDE EFFECTS

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

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 Reactions STIVARGA
(N=500)
Placebo
(N=253)
Grade Grade
Alll
%
≥ 3
%
All
%
≥ 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
Rashb 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 c 31 9 17 6
Vascular disorders
Hypertension 30 8 8 < 1
Hemorrhage c 21 2 8 < 1
Respiratory, thoracic and mediastinal disorders
Dysphonia 30 0 6 0
Nervous system disorders
Headache 10 < 1 7 0
a Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0 (NCI CTCAE v3.0).
bThe term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash.
c Fatal outcomes observed.

Table 2 provides laboratory abnormalities observed in CORRECT.

Table 2: Laboratory test abnormalities reported in CORRECT

Laboratory Parameter STIVARGA
(N=500 a)
Placebo
(N=253 a)
Grade b Grade b
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Anemia 79 5 1 66 3 0
Thrombocytopenia 41 2 < 1 17 < 1 0
Neutropenia 3 1 0 0 0 0
Lymphopenia 54 9 0 35 4 < 1
Metabolism and nutrition disorders
Hypocalcemia 59 1 < 1 18 1 0
Hypokalemia 26 4 0 8 < 1 0
Hyponatremia 30 7 1 22 4 0
Hypophosphatemia 57 31 1 11 4 0
Hepatobiliary disorders
Hyperbilirubinemia 45 10 3 17 5 3
Increased AST 65 5 1 46 4 1
Increased ALT 45 5 1 30 3 < 1
Renal and urinary disorders
Proteinuriac 84 2 0 61 1 0
Investigations Increased INRd 24 4 N/A 17 2 N/A
Increased Lipase 46 9 2 19 3 2
Increased Amylase 26 2 < 1 17 2 < 1
a% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo).
bNCI CTCAE v3.0.
cBased 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 Reactions STIVARGA
(N=132)
Placebo
(N=66)
Grade Grade
All
%
≥ 3
%
All
%
≥ 3
%
Skin and subcutaneous tissue disorders
HFSR/PPE 67 22 12 2
Rash b 30 7 3 0
Alopecia 24 2 2 0
General disorders and administration site conditions
Asthenia/Fatigue 52 4 39 2
Fever 21 0 11 2
Vascular disorders
Hypertension 59 28 27 5
Hemorrhage 11 4 3 0
Gastrointestinal disorders
Pain 60 8 55 14
Diarrhea 47 8 9 0
Mucositis 40 2 8 2
Nausea 20 2 12 2
Vomiting 17 < 1 8 0
Respiratory, thoracic and mediastinal disorders
Dysphonia 39 0 9 0
Infections and infestations
Infection c 32 5 5 0
Metabolism and nutrition disorders
Decreased appetite and food intake 31 < 1 21 3
Hypothyroidism d 18 0 6 0
Nervous system disorders
Headache 16 0 9 0
Investigations
Weight loss 14 0 8 0
Musculoskeletal and connective tissue disorders
Muscle spasms 14 0 3 0
aAdverse reactions graded according to NCI CTCAE v4.0.
b The 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 Parameter STIVARGA
(N=132 a)
Placebo
(N=66 a)
Grade b Grade b
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Thrombocytopenia 13 1 0 2 0 2
Neutropenia 16 2 1 12 3 0
Lymphopenia 30 8 0 24 3 0
Metabolism and nutrition disorders
Hypocalcemia 17 2 0 5 0 0
Hypokalemia 21 3 0 3 0 0
Hypophosphatemia 55 20 2 3 2 0
Hepatobiliary disorders
Hyperbilirubinemia 33 3 1 12 2 0
Increased AST 58 3 1 47 3 0
Increased ALT 39 4 1 39 2 0
Renal and urinary disorders
Proteinuria c 59 3 -d 53 3 -d
Investigations Increased Lipase 14 0 1 5 0 0
aPercent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo).
bNCI CTCAE v4.0.
cBased on urine protein-creatinine ratio data.
dNo 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 Reactions STIVARGA
(N=374)
Placebo
(N=193)
Grade Grade
All
%
≥ 3
%
All
%
≥ 3
%
Skin and subcutaneous tissue disorders
HFSR/PPE 51 12 7 < 1
General disorders andadministration site conditions
Pain 55 9 44 8
Asthenia/Fatigue 42 10 33 5
Fever 20 0 7 0
Vascular disorders
Hypertension 31 15 6 5
Hemorrhage b 18 5 16 8
Gastrointestinal disorders
Diarrhea 41 3 15 0
Nausea 17 < 1 13 0
Vomiting 13 < 1 7 < 1
Mucositis 13 1 2 ≤ 1
Respiratory, thoracic and mediastinal disorders
Dysphonia 18 0 2 0
Infections and infestations
Infection b 31 8 18 6
Metabolism and nutrition disorders
Decreased appetite and food intake 31 3 15 2
Investigations
Weight loss 13 2 4 0
Musculoskeletal and connective tissue disorders
Muscle spasms 10 0 2 0
aAdverse 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 Parameter STIVARGA
(N=374 a)
Placebo
(N=193 a)
Grade b Grade b
All
%
3
%
4
%
All
%
3
%
4
%
Blood and lymphatic system disorders
Thrombocytopenia 63 5 < 1 50 0 0
Neutropenia 14 3 0 15 < 1 < 1
Lymphopenia 68 16 2 59 11 < 1
Metabolism and nutrition disorders
Hypocalcemia 23 < 1 0 10 0 0
Hypokalemia 31 4 < 1 9 2 0
Hypophosphatemia 70 32 2 31 7 0
Hepatobiliary disorders
Hyperbilirubinemia 78 13 3 55 11 5
Increased AST 93 16 2 84 17 3
Increased ALT 70 6 < 1 59 5 0
Renal and urinary disorders
Proteinuria c 51 17 -d 37 3 -d
Investigations
Increased INR 44 < 1 -d 35 2 -d
Increased Lipase 41 11 3 27 8 1
Increased Amylase 23 3 < 1 19 2 < 1
aPercent based on number of patients with post-baseline samples which may be less than 374 (regorafenib) or 193 (placebo).
bNCI CTCAE v4.0.
cBased 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

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

Related Resources for Stivarga

© 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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