Regorafenib

Brand Names: Stivarga

Drug Class: General Prescription

Overview

11 DESCRIPTION STIVARGA (regorafenib) is a multikinase inhibitor with 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 C 21 H 15 ClF 4 N 4 O 3 • H 2 O and a molecular weight of 500.83.

Mechanism of Action

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, metastasis and tumor immunity. 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, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically.

Indications

  • 1 INDICATIONS AND USAGE STIVARGA is a kinase inhibitor indicated for the treatment of adult 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. ( 1.1 ) • Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. ( 1.2 ) • Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib ( 1.3 ) 1.

Common Doses

  • 160 mg
  • 40 mg
  • 80 mg
  • 120 mg

Dosage

2 DOSAGE AND ADMINISTRATION • Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. ( 2.1 ) • Take STIVARGA after a low-fat meal. ( 2.1 , 12.3 ) 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 )] .

Black Box Warning

WARNING: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials [see Warnings and Precautions ( 5.1 )] . • Monitor hepatic function prior to and during treatment [see Warnings and Precautions ( 5.1 )]. • 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 )] . WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning.

Contraindications

  • 4 CONTRAINDICATIONS None. None.

Side Effects

  • 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions ( 5.1 )] • Infections [see Warnings and Precautions ( 5.2 )] • Hemorrhage [see Warnings and Precautions ( 5.3 )] • Gastrointestinal Perforation or Fistula [see Warnings and Precautions ( 5.4 )] • Dermatological Toxicity [see Warnings and Precautions ( 5.5 )] • Hypertension [see Warnings and Precautions ( 5.6 )] • Cardiac Ischemia and Infarction [see Warnings and Precautions ( 5.

Interactions

  • 7 DRUG INTERACTIONS • Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. ( 7.1 ) • Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. ( 7.2 ) • BCRP substrates: Monitor patients closely for symptoms of increased exposure to BCRP substrates. ( 7.3 ) 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-administration of a strong CYP3A4 inducer with STIVARGA decreased the plasma concentrations of regorafenib, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2 [see Clinical Pharmacology...