Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bayer AG, 51368 Leverkusen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations (including fatal outcomes) have been reported in a small proportion of patients (see section 4.8). In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga, compared with Caucasians (see section 4.2).
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.
Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor (see section 4.5). Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s syndrome.
For patients with observed worsening of liver function tests considered related to treatment with Stivarga (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring advice in Table 2 should be followed (see section 4.2).
Regorafenib is eliminated mainly via the hepatic route.
Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 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 and exposure might be increased in these patients.
Stivarga has been associated with an increased incidence of infection events, some of which were fatal (see section 4.8). In cases of worsening infection events, interruption of Stivarga treatment should be considered.
Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were fatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.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.
Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patients treated with Stivarga (see section 4.8). 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.
Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (see section 4.8). 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.
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.
PRES has been reported in association with Stivarga treatment (see section 4.8). 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.
Stivarga has been associated with an increased incidence of arterial hypertension (see section 4.8). 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. In cases of severe or persistent hypertension despite adequate medical management, treatment should be temporarily interrupted and/or the dose reduced at the discretion of the physician (see section 4.2). In case of hypertensive crisis, Stivarga should be discontinued.
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.
As medicinal products with anti-angiogenic properties may suppress or interfere with wound healing, temporary interruption of Stivarga is recommended for precautionary reasons in patients undergoing major surgical procedures. The decision to resume treatment with Stivarga following major surgical intervention should be based on clinical judgment of adequate wound healing.
Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash represent the most frequently observed dermatological adverse reactions with Stivarga (see section 4.8). In clinical trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with Stivarga, compared with Caucasians (see section 4.2). Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use of keratolytic creams (e.g. urea-, salicylic acid-, or alpha hydroxyl acid-based creams applied sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see section 4.2).
Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are generally of mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of Stivarga should be considered in case of persistent or recurrent significant abnormalities (see section 4.2).
This medicinal product contains 55.8 mg sodium per daily dose of 160 mg, equivalent to 3% of the WHO recommended maximum daily intake of 2 g sodium for an adult.Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya).
In the pivotal placebo-controlled phase III study, patients received prior therapy with sorafenib. There is insufficient data on patients who discontinued sorafenib therapy due to sorafenib-related toxicity or only tolerated a low dose (< 400 mg daily) of sorafenib. The tolerability of Stivarga in these patients has not been established.
In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate glucuronosyl transferase UGT1A9.
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of approximately 33%, and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied.
Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic acid) during regorafenib treatment should be avoided, as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied.
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure of active metabolite M-2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John’s wort) may also increase metabolism of regorafenib. Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.
In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state. Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted in an increase of approximately 44% in AUC of SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of approximately 28% was also observed. This indicates that co-administration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates.
Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax.
This indicates that co-administration of regorafenib may increase the plasma concentrations of other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to BCRP substrates.
Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can be given concomitantly with p-glycoprotein substrates, such as digoxin, without a clinically meaningful drug interaction.
In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-glycoprotein and BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere with the exposure of M-2 and M-5. The clinical significance of these findings is unknown (see also section 5.2).
In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced.
A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone) CYP2C9 (S-warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam).
Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see also section 4.4).
The concentration-time profile indicates that regorafenib and its metabolites may undergo enterohepatic circulation (see section 5.2). Co-administration with neomycin, a poorly absorbed antimicrobial agent used for eradicating the gastrointestinal microflora (which may interfere with the enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure, but there was an approximately 80% decrease in the exposure of the active metabolites M-2 and M-5 which showed in vitro and in vivo comparable pharmacological activity as regorafenib. The clinical significance of this neomycin interaction is unknown, but may result in a decreased efficacy of regorafenib. Pharmacokinetic interactions of other antibiotics have not been studied.
Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation (see section 5.2). Bile saltsequestering agents such as cholestyramine and cholestagel may interact with regorafenib by forming insoluble complexes which may impact absorption (or reabsorption), thus resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown, but may result in a decreased efficacy of regorafenib.
Women of childbearing potential must be informed that regorafenib may cause foetal harm. Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy.
There are no data on the use of regorafenib in pregnant women. Based on its mechanism of action regorafenib is suspected to cause foetal harm when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Stivarga should not be used during pregnancy unless clearly necessary and after careful consideration of the benefits for the mother and the risk to the foetus.
It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib or its metabolites are excreted in milk. A risk to the breast-fed child cannot be excluded. Regorafenib could harm infant growth and development (see section 5.3). Breast-feeding must be discontinued during treatment with Stivarga.
There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility (see section 5.3).
No studies on the effects of Stivarga on the ability to drive or use machines have been performed. If patients experience symptoms affecting their ability to concentrate and react during treatment with Stivarga, it is recommended that they do not drive or use machines until the effect subsides.
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.
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.
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 in patients treated with Stivarga:
Very common: Infection*
Rare: Keratoacanthoma/Squamous cell carcinoma of the skin
Very common: Thrombocytopenia, Anaemia
Common: Leucopenia
Uncommon: Hypersensitivity reaction
Common: Hypothyroidism
Very common: Decreased appetite and food intake
Common: Hypokalaemia, Hypophosphatemia, Hypocalcaemia, Hyponatraemia, Hypomagnesaemia, Hyperuricaemia, Dehydration
Common: Headache, Tremor, Peripheral neuropathy
Rare: Posterior reversible encephalopathy syndrome (PRES)
Uncommon: Myocardial infarction, Myocardial ischaemia
Very common: Haemorrhage*, Hypertension
Uncommon: Hypertensive crisis
Not known: Aneurysms and artery dissections
Very common: Dysphonia
Very common: Diarrhoea, Stomatitis, Vomiting, Nausea
Common: Taste disorders, Dry mouth, Gastrooesophageal reflux, Gastroenteritis
Uncommon: Gastrointestinal perforation*, Gastrointestinal fistula, Pancreatitis
Very common: Hyperbilirubinaemia, Increase in transaminases
Uncommon: Severe liver injury*#
Very common: Hand-foot skin reaction**, Rash
Common: Alopecia, Dry skin, Exfoliative rash
Uncommon: Nail disorder, Erythema multiforme
Rare: Stevens-Johnson syndrome, Toxic epidermal necrolysis
Common: Muscle spasms
Common: Proteinuria
Very common: Asthenia/fatigue, Pain, Fever, Mucosal inflammation
Very common: Weight loss
Common: Increase in amylase, Increase in lipase, Abnormal International normalised ratio
* fatal cases have been reported
** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology
# according to drug-induced liver injury (DILI) criteria of the international DILI expert working group
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 nonJapanese 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 13 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 sections 4.2 and 4.4).
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=4108).
Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 4 and Table 4a (see also section 4.4).
Table 4. Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trials in patients with metastatic CRC (CORRECT), GIST (GRID) and HCC (RESORCE):
| mCRC (CORRECT) | GIST (GRID) | HCC (RESORCE) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Laboratory Parameter (in % of samples investigated) | Stivarga plus BSC (n=500) | Placebo plus BSC (n=253) | Stivarga plus BSC (n=500) | Placebo plus BSC (n=253) | Stivarga plus BSC (n=132) | Placebo plus BSC (n=66) | Stivarga plus BSC (n=132) | Placebo plus BSC (n=66) | Stivarga plus BSC (n=374) | Placebo plus BSC (n=193) | Stivarga plus BSC (n=374) | Placebo plus BSC (n=193) |
| Gradea | Gradeb | Gradeb | ||||||||||
| All Grades % | Grade ¾ % | All Grades % | Grade ¾ % | All Grades % | Grade ¾ % | |||||||
| Blood and lymphatic system disorders | ||||||||||||
| Haemoglobin decreased | 78.5 | 66.3 | 5.3 | 2.8 | 75.0 | 72.7 | 3.0 | 1.5 | 72.5 | 71.3 | 6.0 | 4.8 |
| Thrombocytopenia | 40.5 | 16.8 | 2.8 | 0.4 | 12.9 | 1.5 | 0.8 | 1.5 | 63.1 | 50.0 | 5.4 | 0 |
| Neutropenia | 2.8 | 0 | 0.6 | 0 | 15.9 | 12.1 | 3.1 | 3.0 | 13.6 | 14.9 | 3.0 | 1.0 |
| Lymphopenia | 54.1 | 34.8 | 9.3 | 4.0 | 29.9 | 24.2 | 7.6 | 3.0 | 67.8 | 58.5 | 17.4 | 11.7 |
| Metabolism and nutrition disorders | ||||||||||||
| Hypocalcaemia | 59.3 | 18.3 | 1.2 | 1.2 | 16.7 | 4.5 | 1.5 | 0 | 23.4 | 10.1 | 0.3 | 0 |
| Hypokalemia | 25.7 | 8.3 | 4.3 | 0.4 | 20.5 | 3.0 | 3.0 | 0 | 30.7 | 9.0 | 4.3 | 2.1 |
| Hypophosphatemia | 57.4 | 11.1 | 31.1 | 3.6 | 54.5 | 3.1 | 21.2 | 1.5 | 70.4 | 31.4 | 33.9 | 6.9 |
| Hepatobiliary disorders | ||||||||||||
| Hyperbilirubinemia | 44.6 | 17.1 | 12.2 | 8.4 | 33.3 | 12.1 | 3.8 | 1.5 | 78.2 | 54.5 | 15.9 | 15.7 |
| Increased AST | 65.0 | 45.6 | 5.9 | 5.2 | 58.3 | 47.0 | 3.8 | 3.0 | 92.7 | 84.3 | 17.8 | 19.9 |
| Increased ALT | 45.2 | 29.8 | 5.5 | 3.2 | 39.4 | 39.4 | 4.6 | 1.5 | 70.4 | 58.6 | 6.2 | 4.7 |
| Renal and urinary disorders | ||||||||||||
| Proteinuria | 83.6 | 61.0 | 1.8 | 0.8 | 59.2 | 52.5 | 3.1 | 3.4 | 51.0 | 36.5 | 16.7 | 3.1 |
| Investigations | ||||||||||||
| Increased INR* | 23.7 | 16.6 | 4.2 | 1.6 | 9.3 | 12.5 | 1.6 | 4.7 | 44.4 | 35.4 | 0.7 | 2.1 |
| Increased Lipase | 46.0 | 18.7 | 11.4 | 4.4 | 14.4 | 4.6 | 0.8 | 0 | 40.5 | 27.0 | 14.2 | 8.7 |
| Increased Amylase | 25.5 | 16.7 | 2.6 | 2.4 | - | - | - | - | 23.0 | 19.0 | 2.8 | 2.7 |
a Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0
b Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
* International normalized ratio
BSC = Best Supportive Care
Compared 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.
Table 4a. Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR):
| Laboratory parameter, (in % of samples investigated) | Stivarga plus BSC§ (N=136) | Placebo plus BSC§ (N=68) | ||||
|---|---|---|---|---|---|---|
| All Grades* | Grade 3* | Grade 4* | All Grades* | Grade 3* | Grade 4* | |
| Bilirubin increased | 66.7 | 7.4 | 4.4 | 32.8 | 4.5 | 0.0 |
| AST increased | 69.6 | 10.4 | 0.7 | 47.8 | 3.0 | 0.0 |
| ALT increased | 54.1 | 8.9 | 0.0 | 29.9 | 1.5 | 0.0 |
§ Best Supportive Care
* Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
In 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 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 national reporting system listed in Appendix V.
Not applicable.
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