Stivarga
FDA Approves Stivarga for Advanced Gastrointestinal Stromal Tumors »
"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
Stivarga Side Effects Center
Medical Editor: John P. Cunha, DO, FACOEP
Stivarga (regorafenib) is a kinase inhibitor used for the treatment of patients with metastatic colorectal cancer (CRC). Stivarga can cause liver problems, which can be serious and sometimes fatal. The most common side effects with Stivarga are weakness/fatigue, decreased appetite and food intake, hand-foot skin reaction (HFSR), diarrhea, inflammation of mucus membranes, weight loss, infection, high blood pressure (hypertension), and voice disorders.
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 Tasigna (nilotinib), Tegretol (carbamazepine), Dilantin (phenytoin), phenobarbital, Rifadin (rifampin/rifampicin), Mycobutin (rifabutin), and Decadron (dexamethasone) nefazodone, Sporanox (itraconazole), Reyataz (atazanavir), and Crixivan (indinavir). Stivarga can cause fetal harm when given to a pregnant woman. It is not known whether Stivarga is present in breast milk. Consult your doctor to discuss whether to discontinue nursing or to discontinue Stivarga.
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.
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Stivarga FDA Prescribing Information: Side Effects
(Adverse Reactions)
SIDE EFFECTS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Hepatotoxicity [See WARNINGS AND PRECAUTIONS]
- Hemorrhage [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]
- Gastrointestinal Perforation or Fistula [See WARNINGS AND PRECAUTIONS]
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 most frequently observed adverse drug reactions ( ≥ 20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.
The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation.
Clinical Trials Experience
Colorectal Cancer
The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic colorectal cancer 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 7.3 (range 0.3, 47.0) weeks 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. Drug-related adverse reactions that resulted in treatment discontinuation were reported 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 compares the incidence of adverse reactions ( ≥ 10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).
Table 1 :Adverse drug reactions ( ≥ 10%) reported in patients
treated with Stivarga in Study 1 and reported more commonly than in patients
receiving placebo
| Adverse Reactions | 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 | 29 | 3 | 21 | 2 |
| Fever | 28 | 2 | 15 | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite and food intake | 47 | 5 | 28 | 4 |
| Skin and subcutaneous tissue disorders | ||||
| HFSR/PPE | 45 | 17 | 7 | 0 |
| Rasha | 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 |
| Hemorrhageb | 21 | 2 | 8 | < 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Dysphonia | 30 | 0 | 6 | 0 |
| Nervous system disorders | ||||
| Headache | 10 | < 1 | 7 | 0 |
| aThe term rash represents reports of events of
drug eruption, rash, erythematous rash, generalized rash, macular rash,
maculo-papular rash, papular rash, and pruritic rash. bFatal outcomes observed. |
||||
Laboratory Abnormalities
Laboratory abnormalities observed in Study 1 are shown in Table 2.
Table 2 Laboratory test abnormalities reported in Study 1
| Laboratory Parameter | Stivarga (N=500a) |
Placebo (N=253a) |
||||
| Gradeb | Gradeb | |||||
| 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 | 34 | 3 | 0 |
| 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 Proteinuria | 60 | < 1 | 0 | 34 | < 1 | 0 |
| Investigations | ||||||
| Increased INRc | 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 Common Terminology Criteria for Adverse Events (CTCAE), v3.0. c International normalized ratio: No Grade 4 denoted in CTCAE, v3.0. |
||||||
Gastrointestinal Stromal Tumors
The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 2) 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 22.9 (range 0.1, 50.9) weeks 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. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivargatreated patients compared to 1.5% of patients who received placebo.
Table 3 compares the incidence of adverse reactions ( ≥ 10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).
Table 3 : Adverse reactions ( ≥ 10%)
reported in patients treated with Stivarga in Study 2 and reported more
commonly than in patients receiving placebo
| Adverse Reactions | Stivarga (N=132) |
Placebo (N=66) |
||
| Grade | Grade | |||
| All % | ≥ 3 % | All % | ≥ 3 % | |
| Skin and subcutaneous tissue disorders | ||||
| HFSR/PPE | 67 | 22 | 15 | 2 |
| Rasha | 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 | ||||
| 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 | 32 | 5 | 5 | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite and food intake | 31 | < 1 | 21 | 3 |
| Hypothyroidismb | 18 | 0 | 6 | 0 |
| Nervous system disorders | ||||
| Headache | 16 | 0 | 9 | 0 |
| Investigations | ||||
| Weight loss | 14 | 0 | 8 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal stiffness | 14 | 0 | 3 | 0 |
| aThe term rash represents reports of events of rash,
erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic
rash. bHypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline. |
||||
Laboratory Abnormalities
Laboratory abnormalities observed in Study 2 are shown in Table 4.
Table 4 : Laboratory test abnormalities
reported in Study 2
| Laboratory Parameter | Stivarga (N=132a) |
Placebo (N=66a) |
||||
| Gradeb | Gradeb | |||||
| All % | 3% | 4% | All % | 3% | 4% | |
| Blood and lymphatic system disorders | ||||||
| Thrombocytopenia | 13 | 1 | 0 | 2 | 0 | 2 |
| Neutropenia | 16 | 2 | 0 | 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 | 33 | 3 | -c | 30 | 3 | -c |
| Investigations Increased Lipase | 14 | 0 | 1 | 5 | 0 | 0 |
| a % based on number of patients with
post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). b CTCAE, v4.0. c No Grade 4 denoted in CTCAE, v4.0. |
||||||
Read the entire FDA prescribing information for Stivarga (Regorafenib Tablets) »
Additional Stivarga Information
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