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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.
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 6. 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. (See Table 6.)
Click on icon to see table/diagram/imageDescription 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. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga, compared with non-Japanese patients (<0.1%).
In the placebo-controlled phase III trials, the overall incidence of haemorrhage was 18.2% in patients treated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably epistaxis (6.1%). Fatal outcome in patients treated with Stivarga was uncommon (0.7%), and included cerebral, respiratory, gastrointestinal and genitourinary events.
In the placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga, compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 23.0%), and included urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) as well as pneumonia (2.6%). Fatal outcomes associated with infection were observed more often in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), and were mainly respiratory events.
In the placebo-controlled phase III trials, the overall incidence of hand-foot skin reaction was higher in patients treated with Stivarga, compared to patients receiving placebo (all grades: 51.4% vs. 6.5% CRC, 66.7% vs. 15.2% GIST and 51.6% vs.7.3% HCC). Most cases of hand-foot skin reaction in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 34.3%, CRC, 44.7%, GIST and 39.3%, HCC). The incidence of Grade 3 hand-foot skin reaction was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). The overall incidence of hand-foot skin reaction (74.8%, CRC, 88.2%, GIST and 67.1%, HCC) was higher in Stivarga-treated Asian patients, compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 20.5% (CRC), 23.5% (GIST) and 13.5% (HCC) (see Dosage & Administration and Precautions).
In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Stivarga, compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 20.9%, CRC, 31.8%, GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 8.7% (CRC), 28.0% (GIST) and 15.2% (HCC). One case of Grade 4 hypertension was reported in the GIST trial.
In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was 9.1% in patients treated with Stivarga, compared to 1.9% in patients receiving placebo. Of these events, 35.6% in the Stivarga arm and 54.5% in the placebo arm have been reported as not recovered/not resolved.
Across all clinical trials, cardiac disorder events (all grades) have been more often (13.7% vs. 6.5%) reported in Stivarga-treated patients aged 75 years or older (N= 410), compared to Stivarga-treated patients below 75 years (N= 4,108).
Laboratory test abnormalities: Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 7 and Table 8 (see also Precautions). (See Table 7.)
Click on icon to see table/diagram/imageCompared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (>90%) East Asian patients enrolled. (See Table 8.)
Click on icon to see table/diagram/imageIn the placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 34.6% of patients treated with Stivarga and in 17.2% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.5% of patients treated with Stivarga and in 1.3% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 29.2% of patients treated with Stivarga and in 20.4% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.1% of patients treated with Stivarga and 5.6% of patients receiving placebo. Overall approximately 4.6% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacement treatment.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the local reporting system.
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