Elunate Adverse Reactions

This monograph describes the adverse reactions that may possibly be caused by fruquintinib and their approximate incidences determined in the observation of clinical studies. As clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study cannot be directly compared to the rates in another clinical study and may not reflect the actual incidence in clinical practice.
Safety Summary: The safety summary of fruquintinib is based on the data of 577 patients who received the study drug in the randomised, double-blind, placebo controlled clinical studies, which includes a phase 3 randomised, double-blind, placebo-controlled study (FRESCO) in patients with metastatic colorectal cancer (278 patients in the fruquintinib arm, 137 patients in the placebo arm), a phase 2 randomised, double-blind, placebo-controlled study in patients with metastatic colorectal cancer (47 patients in the fruquintinib arm, 24 patients in the placebo arm), and a phase 2 randomised, double-blind, placebo-controlled study in patients with non-small cell lung cancer (61 patients in the fruquintinib arm, 30 patients in the placebo arm). In the three studies mentioned previously, a total of 386 patients received the fruquintinib treatment and 191 patients received the placebo treatment.
In the three placebo-controlled clinical studies, the incidence of all grades of adverse drug reactions of patients in the fruquintinib arm was 97.4%, and the most common (incidence ≥20%) adverse drug reactions were hypertension, proteinuria, hand-foot skin reaction, dysphonia, haemorrhage, transaminases increased, thyroid function test abnormal, abdominal pain/abdominal discomfort, stomatitis, fatigue/asthenia, diarrhoea, infection, blood bilirubin increased and decreased appetite.
Among patients who received fruquintinib treatment, the incidence rate of Grade 3 or above adverse drug reactions was 51.3%, and the common (incidence ≥ 2%) Grade ≥3 adverse drug reactions were hypertension, hand-foot skin reaction, proteinuria, platelet count decreased, hepatic function abnormal, blood bilirubin increased, abdominal pain/abdominal discomfort, diarrhoea, fatigue/asthenia, decreased appetite and haemorrhage.
Adverse Reactions in Clinical Studies: Metastatic Colorectal Cancer: The adverse reaction information of fruquintinib in the treatment of metastatic colorectal cancer is mainly from a randomised, double-blind, placebo-controlled, multicenter phase 3 clinical study (FRESCO) and a randomised, double-blind, placebo-controlled, multicenter phase 2 clinical study.
FRESCO is a randomised, double-blind, placebo-controlled, multicenter phase 3 clinical study comparing fruquintinib combined with best supportive care (BSC) and placebo combined with BSC in patients with metastatic colorectal cancer who have failed the second-line or above standard chemotherapy. This study excluded patients with severe active haemorrhage, clinically uncontrolled active infection, active gastrointestinal ulcers, unhealed gastrointestinal perforation or gastrointestinal fistula, pregnant or breastfeeding women, and patients with moderate to severe renal impairment, etc.. A total of 416 patients were randomised based on a 2:1 ratio to receive either fruquintinib (5mg) or placebo treatment (1 patient in the placebo arm was randomised but did not receive the treatment); Every 4 weeks as one treatment cycle, with 3 weeks of continuous drug administration (once daily oral administration) followed by 1 week of drug free period. A total of 278 patients were treated with 5mg of fruquintinib, and the median duration of treatment was 3.7 months (range: 0.1~21.9 months). Overall, this product was well tolerated under the recommended dose.
In this study, the incidence rate of all grades of adverse drug reactions of patients in the fruquintinib arm was 97.1%, and the most common (incidence ≥ 20%) adverse reactions were hypertension, proteinuria, hand-foot skin reaction, haemorrhage, dysphonia, transaminases increased, abdominal pain/abdominal discomfort, blood bilirubin increased, thyroid function test abnormal, infection, diarrhoea, fatigue/asthenia, decreased appetite, stomatitis, weight decreased, fecal occult blood and platelet count decreased.
Among patients who received fruquintinib treatment, the incidence of Grade 3 or above adverse drug reactions was 55.0%. The common (incidence ≥ 2%) Grade ≥3 adverse reactions were hypertension, hand-foot skin reaction, proteinuria, platelet count decreased, abdominal pain/abdominal discomfort, hepatic function abnormal, blood bilirubin increased, diarrhoea, fatigue/asthenia and decreased appetite.
Among patients who received fruquintinib treatment, 9.0% of patients experienced permanent drug discontinuation due to adverse reactions, 32.4% of patients experienced drug interruption due to adverse reactions, and 22.3% of patients experienced dose reduction due to adverse reactions.
Refer to Table 5 for the summary of Grade ≥3 adverse reactions with incidence ≥ 2% and all grades adverse reactions occurring at incidence ≥ 5% among patients who received fruquintinib treatment.
The adverse reactions with incidence < 5% in patients who received fruquintinib treatment were blood amylase increased (4.3%) and proctalgia (3.6%).
Another randomised, double-blind, placebo-controlled, multicenter phase 2 clinical study was completed in 71 patients (47 patients in the fruquintinib arm, and 24 patients in the placebo arm) with metastatic colorectal cancer who have failed the second-line or above standard chemotherapy. The results showed that the safety profile was basically consistent with that in the FRESCO study. (See Table 5.)

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Description of Specific Adverse Reactions: The specific adverse reaction information of fruquintinib was from three randomised, double-blind, placebo-controlled studies mentioned previously, in which a total of 386 patients received fruquintinib treatment and 191 patients received placebo treatment. Among the patients who received fruquintinib treatment, the common (incidence >1%) serious adverse drug reactions were mainly haemorrhage, hepatic function abnormal, pulmonary infection and hypertension.
Haemorrhage: In the three randomised, double-blind placebo-controlled studies, the incidence of haemorrhagic events of patients in the fruquintinib arm was 30.3%. Most haemorrhage events (28.2%) of patients in the fruquintinib arm were Grade 1-2 in severity, and the most common (incidence ≥ 5%) haemorrhage events included: gastrointestinal haemorrhage (10.9%), haematuria (10.6%) and epistaxis (7.5%). Of which, the incidence of Grade ≥3 haemorrhage events was 2.1%, including: gastrointestinal haemorrhage (1.6%) and haemoptysis (0.5%). There were haemorrhage events with fatal outcomes reported in patients in the fruquintinib arm, which involved the respiratory tract and digestive tract, of which the incidence in the FRESCO study was 0.7%. The incidence of haemorrhage events in the placebo arm was 15.7%; among which, the incidence of Grade ≥3 haemorrhage events was 0.5% (haemoptysis), and there were no case reports of fatal outcome.
Transaminases increased and hepatic function abnormal: In the three randomised, double-blind, placebo-controlled studies, the incidence of transaminases increased and hepatic function abnormal of patients in the fruquintinib arm was 29.8% and 6.5% respectively; of which, the incidence of Grade ≥3 transaminases increased and hepatic function abnormal was 1.3% and 3.4% respectively. The incidence of transaminases increased and hepatic function abnormal in the placebo arm was 15.2% and 2.6% respectively; of which, the incidence of Grade ≥3 transaminases increased was 2.1%. There were no case reports of drug-induced liver injury in both arms.
Infection: In the three randomised, double-blind, placebo-controlled studies, the incidence of infection in the fruquintinib arm was 25.1%. Of which, most infections (20.2%) were Grade 1-2, and the most common (incidence ≥ 5%) infections were upper respiratory tract infection (10.9%) and urinary tract infection (8.0%); the incidence of Grade ≥3 infection was 4.9%, and the main infections were lower respiratory tract infection/ pulmonary infection (1.8%). The incidence of pulmonary infection with fatal outcome in the FRESCO study was 0.7%. The incidence of infection in the placebo arm was 14.1%; of which, the incidence of Grade ≥3 infection was 0.5%, and there were no case reports of fatal outcome.
Hypertension: In the three randomised, double-blind, placebo-controlled studies, the incidence of hypertension in the fruquintinib arm was 55.4%. Of which, most hypertension (33.4%) was Grade 1-2, and the incidence of Grade 3 hypertension was 22.0%; there were no case reports of Grade 4 hypertension or hypertensive crisis. The incidence of hypertension in the placebo arm was 14.1%; of which, the incidence of Grade 3 hypertension was 2.1%.
Post-marketing experience: After fruquintinib was approved for marketing, gastrointestinal perforation, hypertensive crisis, reversible posterior leukoencephalopathy syndrome (RPLS), cerebral haemorrhage and nephrotic syndrome were reported in addition to the adverse reactions reported previously. Since these adverse reactions were reported voluntarily from a population of unknown size, it is not possible to accurately estimate their incidence or establish a causal relationship with drug exposure.