Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bayer AG, 51368 Leverkusen, Germany
Stivarga is indicated as monotherapy for the treatment of adult patients with
Stivarga should be prescribed by physicians experienced in the administration of anticancer therapy.
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.
Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs (see section 4.4).
Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limited data in patients with PS ≥2.
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. |
For recommended measures and dose modifications in case of worsening of liver function tests considered related to treatment with Stivarga see Table 2 (see also section 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. |
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. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2).
Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population.
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. No dose adjustment is required in patients with mild, moderate or severe renal impairment (see also section 5.2).
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between elderly (aged 65 years and above) and younger patients (see also section 5.2).
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male and female patients. No dose adjustment is necessary based on gender (see also section 5.2).
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, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga compared with Caucasians. The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%). There is limited data on regorafenib in the black patient population. No dose adjustment is necessary based on ethnicity (see section 5.2).
There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer.
The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumours (GIST) have not been established. No data are available. There is no relevant use of Stivarga in the paediatric population in the indication of hepatocellular carcinoma.
Stivarga is for oral use.
Stivarga should be taken at the same time each day. The tablets should be swallowed whole with water after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat).
The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue.
There is no specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga should be discontinued immediately, with best supportive care initiated by a medical professional, and the patient should be observed until clinical stabilisation.
Shelf life: 3 years.
Once the bottle is opened the medicinal product has shown to be stable for 7 weeks. Thereafter, the medicinal product is to be discarded.
Store in the original package in order to protect from moisture.
Keep the bottle tightly closed.
White opaque HDPE bottle closed with a PP/PP (polypropylene) screw cap with sealing insert and a molecular sieve desiccant.
Each bottle contains 28 film-coated tablets.
Pack sizes:
Pack of 28 film-coated tablets.
Pack of 84 (3 bottles of 28) film-coated tablets.
Not all pack sizes may be marketed.
Keep the desiccant in the bottle.
This medicinal product may pose a risk to the environment (see section 5.3).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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