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Stivarga

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Stivarga

Side Effects
Interactions

SIDE EFFECTS

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

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 Stivarga (regorafenib tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effect of Strong CYP3A4 Inducers on Regorafenib

Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) [see CLINICAL PHARMACOLOGY].

Effect of Strong CYP3A4 Inhibitors on Regorafenib

Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) [see CLINICAL PHARMACOLOGY].

Read the Stivarga Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 3/7/2013
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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