;
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 INR ***
24
4
N/A
17
2
N/A
Increased Lipase
46
9
2
19
3
2
Increased Amylase
26
2
<1
17
2
<1
7 DRUG INTERACTIONS
7.1 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 (12.3)].
7.2 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 (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.9)]
Risk Summary
Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Animal Data
In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically r
