STIVARGA- regorafenib monohydrate tablet, film coated
Bayer HealthCare Pharmaceuticals Inc.
WARNING: HEPATOTOXICITY
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Severe and sometimes fatal hepatotoxicity has occurred in clinical trials [see Warnings and Precautions (5.1)].
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Monitor hepatic function prior to and during treatment [see Warnings and Precautions (5.1)].
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Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (2.2)].
1 INDICATIONS AND USAGE
1.1 Colorectal Cancer
STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy.
1.2 Gastrointestinal Stromal Tumors
STIVARGA is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dose is 160 mg STIVARGA (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.
Take STIVARGA at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology (12.3)]. Do not take two doses of STIVARGA on the same day to make up for a missed dose from the previous day .
DOSAGE FORMS AND STRENGTHS
STIVARGA is a 40 mg, light pink, oval-shaped, film-coated tablet, debossed with 'BAYER" on one side and '40" on the other side.
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
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Hepatotoxicity [see Warnings and Precautions (5.1)]
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Hemorrhage [see Warnings and Precautions ( 5.2)]
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Dermatological Toxicity [see Warnings and Precautions ( 5.3)]
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Hypertension [see Warnings and Precautions (5.4)]
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Cardiac Ischemia and Infarction [see Warnings and Precautions ( 5.5)]
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Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions ( 5.6)]
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Gastrointestinal Perforation or Fistula [see Warnings and Precautions ( 5.7)]
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, decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.
The most serious adverse reactions in patients receiving STIVARGA are hepatotoxicity, hemorrhage, and gastrointestinal perforation.
DESCRIPTION
STIVARGA (regorafenib) has the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula:
Stivarga Chemical Structure
(click image for full-size original)
Regorafenib is a monohydrate and it has a molecular formula C21 H15 ClF4 N4 O3 � H2 O and a molecular weight of 500.83. Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone.
STIVARGA tablets for oral administration are formulated as light pink, oval-shaped tablets debossed with "BAYER" on one side and "40″ on the other. Each tablet contains 40 mg of regorafenib in the anhydrous state, which corresponds to 41.49 mg of regorafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.
