Inlyta Adverse Reactions

Summary of the safety profile: The following risks, including appropriate action to be taken, are discussed in greater detail in Precautions: cardiac failure events, hypertension, thyroid dysfunction, arterial thromboembolic events, venous thromboembolic events, elevation of haemoglobin or haematocrit, haemorrhage, gastrointestinal perforation and fistula formation, wound healing complications, PRES, proteinuria, and elevation of liver enzymes.
The most common (≥20%) adverse reactions observed following treatment with axitinib were diarrhoea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysaesthesia (hand-foot) syndrome, haemorrhage, hypothyroidism, vomiting, proteinuria, cough, and constipation.
Tabulated list of adverse reactions: Table 2 presents adverse reactions reported in a pooled dataset of 672 patients who received axitinib in clinical studies for the treatment of patients with RCC (see Pharmacology: Pharmacodynamics under Actions). Post-marketing adverse reactions identified in clinical studies are also included.
The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency categories are defined as: 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), very rare (<1/10,000), and not known (cannot be estimated from the available data). The current safety database for axitinib is too small to detect rare and very rare adverse reactions.
Categories have been assigned based on absolute frequencies in the pooled clinical studies data. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness. (See Table 2.)

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Description of selected adverse reactions: Cardiac failure events (see Precautions): In a controlled clinical study with axitinib (N = 359) for the treatment of patients with RCC, cardiac failure events were reported in 1.7% patients receiving axitinib, including cardiac failure (0.6%), cardiopulmonary failure (0.6%), left ventricular dysfunction (0.3%), and right ventricular failure (0.3%). Grade 4 cardiac failure adverse reactions were reported in 0.6% of patients receiving axitinib. Fatal cardiac failure was reported in 0.6% of patients receiving axitinib.
In monotherapy studies with axitinib (N = 672) for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 1.8% patients receiving axitinib. Grade 3/4 cardiac failure events were reported in 1.0% patients and fatal cardiac failure events were reported in 0.3% patients receiving axitinib.
Thyroid dysfunction (see Precautions): In a controlled clinical study with axitinib for the treatment of patients with RCC, hypothyroidism was reported in 20.9% of patients and hyperthyroidism was reported in 1.1% of patients. Thyroid stimulating hormone (TSH) increased was reported as an adverse reaction in 5.3% of patients receiving axitinib. During routine laboratory assessments, in patients who had TSH < 5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 32.2% of patients receiving axitinib.
In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, hypothyroidism was reported in 24.6% of patients receiving axitinib. Hyperthyroidism was reported in 1.6% of patients receiving axitinib.
Venous embolic and thrombotic events (see Precautions): In a controlled clinical study with axitinib for the treatment of patients with RCC, venous embolic and thrombotic adverse reactions were reported in 3.9% of patients receiving axitinib, including pulmonary embolism (2.2%), retinal vein occlusion/thrombosis (0.6%) and deep vein thrombosis (0.6%). Grade 3/4 venous embolic and thrombotic adverse reactions were reported in 3.1% of patients receiving axitinib. Fatal pulmonary embolism was reported in one patient (0.3%) receiving axitinib.
In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, venous embolic and thrombotic events were reported in 2.8% of patients receiving axitinib. Grade 3 venous embolic and thrombotic events were reported in 0.9% of patients. Grade 4 venous embolic and thrombotic events were reported in 1.2% of patients. Fatal venous embolic and thrombotic events were reported 0.1% patients receiving axitinib.
Arterial embolic and thrombotic events (see Precautions): In a controlled clinical study with axitinib for the treatment of patients with RCC, arterial embolic and thrombotic adverse reactions were reported in 4.7% of patients receiving axitinib, including myocardial infarction (1.4%), transient ischemic attack (0.8%) and cerebrovascular accident (0.6%). Grade 3/4 arterial embolic and thrombotic adverse reactions were reported in 3.3% of patients receiving axitinib. A fatal acute myocardial infarction and cerebrovascular accident was reported in one patient each (0.3%). In monotherapy studies with axitinib (N = 850), arterial embolic and thrombotic adverse reactions (including transient ischemic attack, myocardial infarction, and cerebrovascular accident) were reported in 5.3% of patients receiving axitinib.
In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, arterial embolic and thrombotic events were reported in 2.8% of patients receiving axitinib. Grade 3 arterial embolic and thrombotic events were reported in 1.2% of patients. Grade 4 arterial embolic and thrombotic events were reported in 1.3% of patients. Fatal arterial embolic and thrombotic events were reported in 0.3% patients receiving axitinib.
Polycythaemia (see Elevation of haemoglobin or haematocrit in Precautions): In a controlled clinical study with axitinib for the treatment of patients with RCC, polycythaemia was reported in 1.4% of patients receiving axitinib. Routine laboratory assessments detected elevated haemoglobin above ULN in 9.7% of patients receiving axitinib. In four clinical studies with axitinib for the treatment of patients with RCC (N = 537), elevated haemoglobin above ULN was observed in 13.6% receiving axitinib.
In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, polycythaemia was reported in 1.5% of patients receiving axitinib.
Haemorrhage (see Precautions): In a controlled clinical study with axitinib for the treatment of patients with RCC that excluded patients with untreated brain metastasis, haemorrhagic adverse reactions were reported in 21.4% of patients receiving axitinib. The haemorrhagic adverse reactions in patients treated with axitinib included epistaxis (7.8%), haematuria (3.6%), haemoptysis (2.5%), rectal haemorrhage (2.2%), gingival bleeding (1.1%), gastric haemorrhage (0.6%), cerebral haemorrhage (0.3%) and lower gastrointestinal haemorrhage (0.3%). Grade ≥ 3 haemorrhagic adverse reactions were reported in 3.1% of patients receiving axitinib (including cerebral haemorrhage, gastric haemorrhage, lower gastrointestinal haemorrhage and haemoptysis). Fatal haemorrhage was reported in one patient (0.3%) receiving axitinib (gastric haemorrhage). In monotherapy studies with axitinib (N = 850), haemoptysis was reported in 3.9% of patients; Grade ≥ 3 haemoptysis was reported in 0.5% of patients.
In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, haemorrhagic events were reported in 25.7% of patients receiving axitinib. Grade 3 haemorrhagic adverse reactions were reported in 3% of patients. Grade 4 haemorrhagic adverse reactions were reported in 1% of patients and fatal haemorrhage were reported in 0.4% of patients receiving axitinib.
Gastrointestinal perforation and fistula formation (see Precautions): In a controlled clinical study with axitinib for the treatment of patients with RCC, gastrointestinal perforation-type events were reported in 1.7% of patients receiving axitinib, including anal fistula (0.6%), fistula (0.3%) and gastrointestinal perforation (0.3%). In monotherapy studies with axitinib (N = 850), gastrointestinal perforation-type events were reported in 1.9% of patients and fatal gastrointestinal perforation was reported in one patient (0.1%).
In pooled clinical studies with axitinib (N = 672) for the treatment of patients with RCC, gastrointestinal perforation and fistula were reported in 1.9% of patients receiving axitinib.
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 national reporting system.