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Stivarga is a brand name for Regorafenib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Stivarga is indicated as monotherapy for the treatment of adult patients with - metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy (see…
Verbatim from this product's EMA label. Tap a section to expand.
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.
Summary of the safety profile The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC), 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular carcinoma (HCC).
The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies.
10 The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage, gastrointestinal perforation and infection. The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are pain, hand foot skin reaction, asthenia/fatigue, diarrhoea, decreased appetite and food intake, hypertension and infection.
Tabulated list of adverse reactions The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and not known (cannot be estimated from the available data).
Within each frequency group, undesirable effects are presented in order of decreasing seriousness.
Table 3:
Adverse drug reactions (ADRs) reported in clinical trials and postmarketing in patients treated with Stivarga System Organ Class (MedDRA) Very common Common Uncommon Rare Not known Infections and infestations Infection * Neoplasms benign, malignant and unspecified (including cysts and polyps) Keratoacan- thoma/ Squamous cell carcinoma of the skin Blood and lymphatic system disorders Thrombo- cytopenia Anaemia Leucopenia Thrombotic microangiop athy Immune system disorders Hypersensiti- vity reaction Endocrine disorders Hypo- thyroidism 11 System Organ Class (MedDRA) Very common Common Uncommon Rare Not known Metabolism and nutrition disorders Decreased appetite and food intake Hypo- kalaemia Hypophos- phatemia Hypo- calcaemia Hypo- natraemia Hypomag- nesaemia Hyperuri- caemia Dehy- dration Nervous system disorders Headache Tremor Peripheral neuropathy Posterior reversible encephalo- pathy syndrome (PRES) Hyperammon aemic encephalopat hy Cardiac disorders Myocardial infarction Myocardial ischaemia Vascular disorders Haemorrhage* Hypertension Hypertensive crisis Aneurysms and artery dissections Respiratory, thoracic and mediastinal disorders Dysphonia Gastro- intestinal disorders Diarrhoea Stomatitis Vomiting Nausea Constipation Taste disorders Dry mouth Gastro- oesopha- geal reflux Gastro- enteritis Gastro- intestinal perforation* Gastro- intestinal fistula Pancreatitis Hepatobiliary disorders Hyper- bilirubinaemia Increase in transaminases Severe liver injury (including hepatic failure)*# Skin and subcutaneous tissue disorders Hand-foot skin reaction** Rash Alopecia Dry skin Exfoliative rash Nail disorder Erythema multiforme Stevens- Johnson syndrome Toxic epidermal necrolysis 12 System Organ Class (MedDRA) Very common Common Uncommon Rare Not known Musculo- skeletal and connective tissue disorders Muscle spasms Renal and urinary disorders Proteinuria General disorders and administration site conditions Asthenia/ fatigue Pain*** Fever Mucosal inflammation Investigations Weight loss Increase in amylase Increase in lipase Abnormal Inter- national normalised ratio * fatal cases have been reported ** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology ***Most frequently reported types of pain (≥10%) are abdominal pain and back pain # according to drug-induced liver injury (DILI) criteria of the international DILI expert working group Description of selected adverse reactions In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase.
Hepatic effects Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with Stivarga. 8). 2). It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months of treatment.
Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated. 5). Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s syndrome. e. 2). Regorafenib is eliminated mainly via the hepatic route.
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 and exposure might be increased in these patients. 8). 6 In cases of worsening infection events, interruption of Stivarga treatment should be considered.
8). g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. Screening for and subsequent treatment of oesophageal varices in patients with liver cirrhosis should be performed as per standard of care before starting treatment with Stivarga.
In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be considered. 8). These events are also known to be common disease-related complications in patients with intra-abdominal malignancies.
Discontinuation of Stivarga is recommended in patients developing gastrointestinal perforation or fistula. 8). Patients with unstable angina or new onset angina (within 3 months of starting Stivarga therapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded from the clinical studies.
1.
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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, […]
1%). 5% in patients receiving placebo. 1%). 7%), and included cerebral, respiratory, gastrointestinal and genitourinary events. 6% vs. 2%). 6%). 3%), and were mainly respiratory events. 4% vs. 7% vs. 3% HCC). Most cases of hand-foot skin reaction in patients treated with Stivarga appeared during the […]
Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction, interruption of Stivarga is recommended until resolution.
The decision to re-start Stivarga therapy should be based on careful consideration of the potential benefits and risks of the individual patient. Stivarga should be permanently discontinued if there is no resolution. 8). In patients who develop unexplained lethargy or changes in mental status, ammonia levels should be measured and appropriate clinical management should be initiated.
If hyperammonaemic encephalopathy is confirmed, permanent discontinuation of regorafenib should be considered. 8). Signs and symptoms of PRES include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension.
A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES, discontinuation of Stivarga, along with control of hypertension and supportive medical management of other symptoms is recommended. 8). Blood pressure should be controlled prior to initiation of treatment with Stivarga.
It is recommended to monitor blood pressure and to treat hypertension in accordance with standard medical practice. 2). In case of hypertensive crisis, Stivarga should be discontinued. Aneurysms and artery dissections The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections.
Before initiating Stivarga, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. 7 Thrombotic […]