Medical Editor: John P. Cunha, DO, FACOEP
Stivarga (regorafenib) is a kinase inhibitor used to treat patients with metastatic colorectal cancer (CRC). Common side effects of Stivarga include:
- weakness/fatigue,
- loss of appetite and decreased food intake,
- hand-foot skin reaction (HFSR),
- diarrhea,
- stomach pain,
- weight loss,
- infection,
- high blood pressure (hypertension),
- weakness,
- tiredness,
- voice changes or hoarseness, and
- swelling, pain, and redness of the lining of your mouth, throat, stomach, and bowel.
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.
Get emergency medical help if you have 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:
- severe headache, vision problems, confusion, thinking problems;
- a seizure;
- rash, blisters, or severe pain in the palms of your hands or the soles of your feet;
- heart problems--chest pain and severe dizziness, trouble breathing;
- increased blood pressure--severe headache, blurred vision, pounding in your neck or ears;
- liver problems--nausea, vomiting, sleep problems, dark urine, jaundice (yellowing of the skin or eyes);
- perforation (a hole or tear) in your stomach or intestines--fever with severe stomach pain or swelling, nausea, vomiting, increased thirst, decreased urination;
- severe bleeding--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 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, stomach pain, loss of appetite, weight loss;
- fever, infection;
- abnormal liver function tests;
- mouth or throat pain, 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)
SIDE EFFECTS
The following serious adverse reactions are discussed else where 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,RESORCEand 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 asasingle 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-footskin 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 placebo a
| Adverse Reaction | STIVARGA (N=500) |
Placebo (N=253) |
||
| Grade | Grade | |||
| All % |
≥ 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 |
| Rash b | 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). 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. 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). 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 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 |
|
a Adverse 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. c Fatal 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 |
|
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 days1-21 ofeach 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 PSof1. 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 and administration 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 |
|
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%), myocardialischemia (0.8%), gastrointestinal fistula (0.3%), and myocardialinfarction (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 |
|
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 post approval 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)