Stivarga should be prescribed by physicians experienced in the administration of anticancer therapy. Posology The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy.
This 4-week period is considered a treatment cycle. If a dose is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose. In case of vomiting after regorafenib administration, the patient should not take additional tablets.
4). Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limited data in patients with PS ≥2. 3 Posology adjustments Dose interruptions and/or dose reductions may be required based on individual safety and tolerability.
Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg. The maximum daily dose is 160 mg. For recommended dose modifications and measures in case of hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome see Table 1.
Table 1:
Recommended dose modifications and measures for HFSR Skin toxicity grade Occurrence Recommended dose modification and measures Grade 1 Any Maintain dose level and immediately institute supportive measures for symptomatic relief. Grade 2 1st occurrence Decrease dose by 40 mg (one tablet) and immediately institute supportive measures.
If no improvement occurs despite dose reduction, interrupt therapy for a minimum of 7 days, until toxicity resolves to Grade 0-1. A dose re-escalation is permitted at the discretion of the physician. No improvement within 7 days or 2nd occurrence Interrupt therapy until toxicity resolves to Grade 0-1.
When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician. 3rd occurrence Interrupt therapy until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet).
A dose re-escalation is permitted at the discretion of the physician. 4th occurrence Discontinue treatment with Stivarga permanently. Grade 3 1st occurrence Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0-1.
When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician. 2nd occurrence Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0-1.
When re-starting treatment, decrease dose by 40 mg (one tablet). 3rd occurrence Discontinue treatment with Stivarga permanently. 4). 4 Table 2: Recommended measures and dose modifications in case of drug-related liver function test abnormalities Observed elevations of ALT and/or AST Occurrence Recommended measures and dose modification ≤5 times upper limit of normal (ULN) (maximum Grade 2) Any occurrence Continue Stivarga treatment.
Monitor liver function weekly until transaminases return to <3 times ULN (Grade 1) or baseline. >5 times ULN ≤20 times ULN (Grade 3) 1st occurrence Interrupt Stivarga treatment. Monitor transaminases weekly until return to <3 times ULN or baseline.
Restart:
If the potential benefit outweighs the risk of hepatotoxicity, re-start Stivarga treatment, reduce dose by 40 mg (one tablet), and monitor liver function weekly for at least 4 weeks. Re-occurrence Discontinue treatment with Stivarga permanently.
>20 times ULN (Grade 4) Any occurrence Discontinue treatment with Stivarga permanently. >3 times ULN (Grade 2 or higher) with concurrent bilirubin >2 times ULN Any occurrence Discontinue treatment with Stivarga permanently. Monitor liver function weekly until resolution or return to baseline.
Exception: patients with Gilbert’s syndrome who develop elevated transaminases should be managed as per the above outlined recommendations for the respective observed elevation of ALT and/or AST. Hepatic impairment Regorafenib is eliminated mainly via the hepatic route.
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose adjustment is required in patients with mild hepatic impairment.
Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can be provided. 2). Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population.
Renal impairment Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. 2). 2). Gender In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male and female patients.
2). Ethnic differences In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. A higher incidence of hand foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome, […]