ment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)].
Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been studied in this population.
8.7 Renal Impairment
No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.
8.8 Females and Males of Reproductive Potential
Contraception
Use effective contraception during treatment and up to 2 months after completion of therapy.
Infertility
There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)].
10 OVERDOSAGE
The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue.
There is no specific antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization.
11 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:
Regorafenib is a monohydrate and it has a molecular formula C21H15ClF4N4O3 • H2O 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 met
