p;• For the first occurrence of Grade 2 HFSR of any duration • After recovery of any Grade 3 or 4 adverse reaction • For Grade 3 aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity
Reduce the dose of Stivarga to 80 mg:
• For re-occurrence of Grade 2 HFSR at the 120 mg dose • After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)
Discontinue Stivarga permanently for the following:
• Failure to tolerate 80 mg dose • Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN) • Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN • Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg • For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
3 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.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Hepatoxicity
Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1100 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver.
Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2)].
5.2 Hemorrhage
Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% in Stivarga-treated patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) of Stivarga-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts.
Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].
5.3 Dermatological Toxicity
Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE) and rash frequently requiring dose modification. The overall incidence of HFSR (45% versus 7%) and the incidence of Grade 3 HFSR (17% versus 0) were increased in Stivarga-treated patients in Study 1. The overall incidence of rash (26% versus 4%) and the incidence of Grade 3 rash (6% versus <1%) were higher in Stivarga-treated patients in Study 1 [see Adverse Reactions (6.1)]. The on |
