Elunate

The content of the capsule is white to off-white powder.
The active ingredient of Elunate is fruquintinib.
Chemical Name: 6-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3 carboxamide.
Molecular formula: C₂₁H₁₉N₃O₅.
Molecular weight: 393.39.
Excipients/Inactive Ingredients: Corn starch, microcrystalline cellulose, talc.
Capsule shell: 1mg capsule: FD&C Yellow No. 5 (tartrazine), FD&C Yellow No. 6 (sunset yellow FCF), gelatin, and titanium dioxide.
5mg capsule: FD&C Blue No. 1 (brilliant blue FCF), FD&C Red No. 40 (allura red AC), gelatin, and titanium dioxide.
Printing ink: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, ferrosoferric oxide.

Pharmacology: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2 and 3, and has an inhibitory effect on VEGFR kinase activity, VEGFR 2/3 phosphorylation in cells and tissues, endothelial cell proliferation, and lumen formation, micro-angiogenesis in chick embryo chorioallantoic membrane model, and tumor angiogenesis, thereby inhibiting tumor growth.
Pharmacodynamics: Based on a concentration-QTc analysis in patients with colorectal cancer, fruquintinib had a relative low risk of causing heart rate-corrected QT interval prolongation (>10 ms) at the recommended dose (5mg once daily, 3 weeks on/1 week off), and no significant correlation was observed between fruquintinib plasma concentration and changes in QTc interval from baseline.
Clinical Trials: A randomised, controlled phase 3 FRESCO clinical study of fruquintinib monotherapy for metastatic colorectal cancer has been completed, and the main results are as follows.
Phase 3 clinical study (FRESCO): FRESCO is a randomised, double-blind, placebo-controlled, multicenter phase 3 clinical study comparing fruquintinib combined with BSC and placebo combined with BSC in patients with metastatic colorectal cancer who have failed the second-line or above standard chemotherapy. A total of 416 patients were randomised into the study based on a 2:1 ratio (278 patients in the fruquintinib arm, 138 patients in the placebo arm). Apart from one patient in the placebo arm who did not receive treatment, the other patients received either fruquintinib or placebo monotherapy, 5mg once daily via oral administration, with 3 weeks of continuous drug administration and 1 week of drug free period. The enrolled patients had histologically and/or cytologically confirmed metastatic colorectal cancer (stage IV), and had previously received at least second-line standard chemotherapy and failed (treatment failure was defined as occurrence of disease progression or intolerable toxicity during the treatment process or within 3 months after the last treatment; standard treatment regimens must include fluoropyrimidine, oxaliplatin and irinotecan). All patients had an Eastern Cooperative Oncology Group (ECOG) score of ≤1.
The median duration of treatment of the fruquintinib and placebo was 3.7 months and 1.8 months respectively. Refer to Table 1 for the main baseline status of patients. Except for the relatively high percentage of male patients (70.3%), the demographic and baseline characteristics in the placebo arm were basically consistent with those of the fruquintinib arm. (See Table 1.)

Click on icon to see table/diagram/image

The primary efficacy endpoint of the study was overall survival (OS), and the secondary efficacy endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response/duration of stable disease (DoR/ DoS). The OS of the fruquintinib arm was significantly prolonged, and the median OS was extended by 2.7 months and the risk of death was reduced by 35% as compared to the placebo arm. The secondary efficacy endpoints of fruquintinib were all significantly better than the placebo. Refer to Table 2 for the efficacy results. Refer to the figure as follows for the Kaplan-Meier curve of overall survival (OS). (See Table 2 and figure.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Pharmacokinetics: Absorption: In healthy subjects, the mean plasma maximum drug concentration (C_max) was 155 ng/mL, the median time to maximum drug concentration (T_max) was 3 hours (1.5 to 24 hours), and the mean area under the plasma drug concentration-time curve (AUC_0-∞) was 5,700 h·ng/mL following a single oral administration of 5mg fruquintinib capsules. In patients with advanced cancer, the mean C_max was 195 ng/mL, the median T_max was 2 hours (0.5 to 2 hours) and the mean AUC_0-72 was 5,495 h·ng/mL following a single oral administration of 5mg fruquintinib capsules.
The exposure (AUC) to fruquintinib within the dose range of 1mg to 6mg basically increased in proportion with the dose. The exposure to fruquintinib in patients with advanced cancer reached the steady state after 14 days of continuous once daily drug administration. The mean steady state exposure at 5mg (AUC_SS) was approximately thrice that of the first drug exposure (AUC_0-24).
Healthy subjects were given a single dose of 4mg of fruquintinib capsules via oral administration after a high-fat meal, and the C_max reduced by about 17% (the geometric mean ratio was 82.9%, and the 90% confidence interval was 76.7%-89.5%) and AUC_0-∞ was similar (the geometric mean ratio was 97.2%, and the 90% confidence interval was 94.0%-100.4%) as compared to the fasting state.
Distribution: The results of the in vitro study showed that the human plasma protein binding to fruquintinib was approximately 95.3%. After a single oral administration of 5mg of fruquintinib, the mean apparent volume of distribution at the elimination phase after oral administration was 32.5 L and 42.2 L in healthy subjects and patients with advanced cancer, respectively.
Metabolism: The in vivo metabolism and mass balance study of [¹⁴C] labeled fruquintinib showed that fruquintinib mainly exists in human plasma in its unchanged form, accounting for approximately 72% of total exposure in the plasma. The CYP3A4-mediated demethylated metabolites account for approximately 17% of total exposure in plasma. Other metabolic pathways include multiple site mono-oxidation, O-demethylation, N-demethylation, O-dequinazoline ring, and amide hydrolysis. The phase II metabolites are mainly glucuronide and sulphate conjugates of phase I products.
Excretion: In patients with advanced cancer who were orally administered with 2mg to 6mg of fruquintinib, the mean elimination half-life was 35.2 to 48.5 hours and the mean oral clearance was 9.98 to 17.8 mL/min. In healthy subjects who were orally administered with 5mg of ¹⁴C-labeled fruquintinib, the mean cumulative recovery of radioactive substances within 336 hours was 90.1%, including 60.3% in urine (0.5% was the unchanged drug) and 29.8% in stool (5.3% was the unchanged drug). Fruquintinib is mainly excreted as metabolites through the kidneys into urine.
Special Populations: Age, gender and body weight had no clinically significant effect on the pharmacokinetics of fruquintinib.
Patients with renal impairment: Based on the population pharmacokinetic analysis result, there were no significant clinical differences in the pharmacokinetics of fruquintinib between patients with mild renal impairment (creatinine clearance of 60 to 89 mL/min) and normal renal function. The pharmacokinetics of fruquintinib has not been evaluated in patients with moderate or severe renal impairment.
Drug Interactions: Effect of CYP3A inhibitors on fruquintinib: No significant changes in fruquintinib exposure (C_max and AUC) were observed when fruquintinib was in combination with multiple doses of itraconazole, a strong CYP3A inhibitor (200mg BID on the first day, followed by 200mg QD).
Effect of CYP3A inducers on fruquintinib: Coadministration of multiple doses of rifampicin (600mg QD), a strong CYP3A inducer, the C_max of fruquintinib was reduced by 12% and the AUC_0-∞ was reduced by 65%. Based on the physiological-based pharmacokinetic modeling (PBPK) and simulation results, there was no significant change in the C_max of fruquintinib and AUC_0-∞ was reduced by 28% when fruquintinib was in combination with multiple doses of efavirenz, a moderate CYP3A inducer (600mg QD); there was no significant change in C_max or AUC_0-∞ when fruquintinib was in combination with multiple doses of dexamethasone (8mg BID), a weak CYP3A inducer.
Effect of Gastric Acid Reducing Agents on fruquintinib: In the clinical pharmacokinetic study, no significant differences in fruquintinib exposure (C_max and AUC) were observed when coadministration of multiple doses of proton pump inhibitor (PPI) rabeprazole.
Effect of fruquintinib on transporter substrates: Fruquintinib has an inhibitory effect on efflux transporter P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) as shown by in vitro data.
Pharmacogenetics: Pharmacogenetic data is not available for this product.
Toxicology: Toxicological studies: General toxicity: In a 26-week oral gavage repeated-dose toxicity study in rats, the lowest-observed-adverse-effect level was 0.5/0.25mg/kg/day (the dose was decreased from Day 50 of dosing phase), and the target organs were bile duct, liver, kidneys, adrenal glands, thymus, spleen and femur. In a 39-week oral repeated-dose toxicity study in dogs, the no observed adverse effect level was 0.03mg/kg/day, and the main target organs were liver, kidneys, thymus, spleen, lymph nodes and gastrointestinal tract.
Genotoxicity: The Ames test and the mice bone marrow micronucleus test of fruquintinib were negative. The chromosome aberration test results of fruquintinib in Chinese hamster lung fibroblasts were positive under non-metabolic activation conditions for 24 hours (36μg/mL), and the results were negative under metabolic activation conditions (up to 36μg/mL).
Reproductive Toxicity: Oral administration of fruquintinib to male rats up to 3mg/kg/day and oral administration of fruquintinib to female rats up to 0.5mg/kg/day had no adverse effect on the fertility of male or female rats. At 0.5mg/kg/day, fruquintinib caused an increase in the number of absorbed embryos and number of post-implantation losses and a decrease in the number of live fetuses. The no-observed adverse effect level (NOAEL) on early embryonic development in rats was 0.15mg/kg/day, which was about 0.29 times the recommended clinical dose for humans (5mg/day) based on body surface area conversion.
Fruquintinib was orally administered to rats from gestation days (GDs) 6 to 15, the NOAEL was 0.025mg/kg/day for embryo-fetal development, which was about 0.048 times the recommended clinical dose for humans (5mg/day) based on the conversion of body surface area, and about 2.8% of the recommended clinical dose for humans (5mg/d) based on AUC. Fruquintinib caused decreased fetal weight, malformation and delayed ossification at doses of 0.1mg/kg/day and above. No significant accumulation of fruquintinib was observed in pregnant rats.
Carcinogenicity: No carcinogenicity study was conducted for fruquintinib.

This product as monotherapy is indicated for patients with metastatic colorectal cancer (mCRC) who have previously received fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy, and those who have previously received or are not suitable for receiving anti-vascular endothelial growth factor (VEGF) therapy or anti-epidermal growth factor receptor (EGFR) therapy (RAS wild-type).

This product must be used under the guidance of an experienced physician in cancer treatment.
Recommended Dose and Method of Administration: The recommended dose is 5mg once daily (1 capsule; each capsule contains 5mg of fruquintinib), for three consecutive weeks followed by one week of drug free period (Every 4 weeks as one treatment cycle). This product may be taken with food or on empty stomach, and it must be swallowed whole. It is recommended to take the drug at the same time each day. If the patient vomits after administering the drug, there is no need to make up for the dose; if a dose is missed, instruct the patient not to make up for the dose in the next day, but to take the next dose at its next scheduled time.
Duration of Treatment: Continue the treatment cycle until disease progression or unacceptable toxicity.
Dose Adjustment: The physician should closely monitor the patient during the course of the treatment, and adjust the dose based on safety and tolerability of individual patient, which includes drug interruption, dose reduction or permanent discontinuation. Dose adjustment should adhere to the principle of drug interruption first followed by dose reduction.
If the adverse reaction is resolved to ≤ Grade 1 within 1 week after drug interruption, the patient should continue to take the drug based on the original dose; if the adverse reaction is resolved to ≤ Grade 1 within 2 weeks, it is recommended to adjust the dose to 4mg a day (4 capsules, each capsule contains 1mg of fruquintinib) under the guidance of a physician in the first dose adjustment; adjust the dose to 3mg a day in the second dose adjustment (3 capsules, each capsule contains 1mg of fruquintinib); discontinue the drug permanently if the patient still experiences intolerance after taking 3mg a day. Refer to Table 3 for the overall dose adjustment principles; refer to Table 4 for the details on the dose adjustment principles for the most commonly seen hand-foot skin reaction (or palmar-plantar erythrodysesthesia syndrome). (See Tables 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Special Patient Population: Patients with hepatic impairment: At present, there are no studies of fruquintinib in patients with hepatic impairment. Clinical studies have shown that transaminase level may be elevated in patients treated with fruquintinib. Patients with mild to moderate hepatic impairment should use this product with caution under the guidance of the physician and hepatic function must be closely monitored, and patients with severe hepatic impairment are prohibited from using this product.
Patients with renal impairment: No dose adjustment is recommended for patients with mild renal impairment (creatinine clearance 60 to 89 mL/min). Patients with moderate renal impairment should use this product with caution under the guidance of the physician and kidney function must be closely monitored, and patients with severe renal impairment are prohibited from using this product.
Paediatric patients: At present, there is no clinical data on the use of this product on children or adolescent patients under the age of 18, hence it is not recommended for such patients to take this product.
Elderly patients: It is recommended that elderly patients use this product with caution under the guidance of the physician, and no adjustment is required for the initial dose. Refer to Use in the Elderly under Precautions for details.

At present, the possible harm due to an overdose of this product is still unclear. In the early dose-finding clinical studies of this product, some patients with solid tumors took 6mg of fruquintinib daily, and it was observed that the dose-limiting toxicity under the dose was hand-foot skin reaction and asthenia. In the Phase II, III clinical studies of metastatic colorectal cancer, it was found that only individual patients had single drug overdose event (the maximum dose was 10mg/day), but no significant abnormal clinical manifestations occurred.
There are no specific antidotes for overdose of this product. In the event of suspected drug overdose, this product must be discontinued immediately and the patient should be closely monitored. Adopt the best supportive care when necessary.

Hypersensitivity to the active substance or to any of the excipients of fruquintinib capsule. Patients with severe active haemorrhage, active gastrointestinal ulcer, unhealed gastrointestinal perforation or gastrointestinal fistula are prohibited from using this product. Patients with severe hepatic impairment and renal impairment are prohibited from using this product. Pregnant, breastfeeding women are prohibited from using this product.

Haemorrhage: It was observed in clinical studies that this product may increase the risk of haemorrhage. The haemorrhage mainly includes gastrointestinal haemorrhage, haematuria, epistaxis, haemoptysis, and gingival haemorrhage, etc.; there were case reports of fatal outcomes which involved haemorrhage of the digestive tract and respiratory tract (refer to Adverse Reactions).
Clinicians should pay close attention to the risk of haemorrhage when using the drug and monitor the complete blood count and coagulation indicators of patients; especially for patients who take anticoagulants (such as warfarin) during the treatment period, increase the monitoring frequency of coagulation indicators such as the international normalized ratio (INR). Once signs of haemorrhage requiring urgent medical intervention occur, permanent discontinuation of this product should be considered (refer to Dosage & Administration).
Patients with potential risk of haemorrhage before the administration of this product, such as activated partial thromboplastin time (aPTT) or prothrombin time (PT) more than 1.5 times the upper limit of normal, within one month after major surgery, etc., should use this product with caution. Patients with severe active haemorrhage and active gastrointestinal ulcers are not advised to use this product.
Infection: It was observed in clinical studies that this product may increase the risk of infection, and the most common infections were upper respiratory tract infection and urinary tract infection. Among them, there were case reports on pulmonary infection with fatal outcomes (refer to Adverse Reactions).
For patients with severe infections prior the administration of this product, fruquintinib should be used only after the infection is effectively controlled. This product must be interrupted for patients who experience Grade 3 or above infection during the treatment period until the infection is well under controlled.
Transaminases increased and hepatic function abnormal: It was observed in clinical studies that this product may cause transaminases increased, blood bilirubin increased and hepatic function abnormal, and the majority were Grade 1-2. There were no reports on drug-induced liver injury (refer to Adverse Reactions).
Liver function tests (transaminase and bilirubin) must be conducted before administering this product, and routine monitoring of liver function must be conducted during the treatment period. If a patient experiences Grade ≥3 transaminases increased or clinically indicated during the treatment period, this product should be promptly interrupted, reduced dose or permanently discontinued based on the situation, hepatoprotective treatment should be actively applied and the liver function should be closely monitored. The monitoring frequency can be increased to once a week or every two weeks until the transaminase level resolves to Grade 1 or the level before drug administration (refer to Dosage & Administration).
As there is no clinical data on patients with hepatic impairment for this product, patients with hepatic impairment should use this product with caution.
Hypertension: It was observed in clinical studies that this product may increase the risk of hypertension, and majority were Grade 1-2; there were no occurrences of Grade 4 hypertension or hypertensive crisis (refer to Adverse Reactions).
In the clinical studies, hypertension usually occurred approximately 10 days after drug administration, and good control could usually be achieved through conventional antihypertensive treatment. Grade 3 hypertension can basically resolve to Grade 1 or the level before drug administration through active antihypertensive treatment or dose adjustment.
It is necessary to control the patient's blood pressure at the optimum level (<140/90 mmHg) before administration of this product; the blood pressure should be routinely monitored during the treatment period, once a week in the first three cycles and once per cycle thereafter. The monitoring frequency of blood pressure can be increased if clinically indicated.
Hand-foot skin reaction: It was observed in clinical studies that this product may increase the risk of hand-foot skin reaction, and majority were Grade 1-2 (refer to Adverse Reactions).
In clinical studies, hand-foot skin reactions usually occurred in the first cycle after drug administration. Grade 3 hand-foot skin reactions can basically be relieved or alleviated through symptomatic treatment and dose adjustment. Refer to Dosage & Administration for details on dose adjustment related to hand and foot skin reactions.
Proteinuria: It was observed in clinical studies that this product may increase the risk of proteinuria, which was mainly Grade 1-2. No nephrotic syndrome occurred (refer to Adverse Reactions).
In clinical studies, proteinuria occurred approximately 20 days after drug administration, and Grade 3 proteinuria can basically resolve to Grade 1 or the level before drug administration through dose adjustment and active symptomatic treatment.
During the treatment of this product, patients must undergo routine urine test regularly and should seek medical treatment promptly if proteinuria is observed. Urinary protein should be closely monitored in patients with renal impairment while receiving this product.
Gastrointestinal perforation or fistula formation: Gastrointestinal perforation or fistula formation are common disease-related complications in patients with peritoneal cancer. It was observed in clinical studies that the incidence of gastrointestinal perforation and fistula formation after administration of this product was both 0.8%, of which the incidence of Grade ≥3 gastrointestinal perforation and gastrointestinal fistula was 0.8% and 0.5%, respectively. The incidence of gastrointestinal perforation in the placebo arm was 0.5%; there were no case reports of gastrointestinal fistula. There were no case reports of fatal outcome in both arms.
During the treatment of this product, patients with gastrointestinal infiltration or previous history of gastrointestinal perforation must be closely monitored. If a patient has gastrointestinal perforation, this product must be permanently discontinued immediately, and the patient must be promptly treated. Gastrointestinal perforation is often accompanied by characteristic symptoms, such as sudden severe pain in the upper abdomen, persistent discomfort or burning pain that rapidly spreads to the entire abdomen.
Patients with unhealed gastrointestinal perforation or gastrointestinal fistula are not recommended to use this product.
Arterial thrombosis: It was observed in clinical studies that the incidence of arterial thrombosis caused by the administration of this product was 0.5%, which included 1 case report of cerebral infarction with fatal outcome.
During the treatment of this product, patients with high-risk factors of arterial thrombosis (including elderly, hypertension, diabetes, myocardial ischemia and infarction, cerebral ischemia and infarction) must be closely monitored. Discontinue this product immediately in patients who develop arterial thrombosis or stroke.
Patients with pre-existing arterial thrombosis or stroke must use this product with caution.
Reversible posterior leukoencephalopathy syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS) was not observed in clinical studies, but there are relevant reports for similar products. The signs and symptoms of RPLS include seizure, headache, altered mental status, visual impairment or cortical blindness, with or without associated hypertension. The diagnosis of RPLS must be verified using brain magnetic resonance imaging (MRI). Patients with suspected RPLS are recommended to permanently discontinue this product, along with control of hypertension and supportive medical measures for other medical symptoms.
Delayed wound healing: Antiangiogenic drugs may suppress or interfere wound healing. In order to prevent such situation, it is recommended for patients who require major surgery during the treatment period to interrupt the use of this product. The decision to resume treatment following major surgical intervention with this product should be based on clinical judgment of confirmed complete wound healing.
Effects on driving and machine operation: At present, there is still no study about the effects of this product on driving or machine operation. If the patient experiences symptoms that affect his/her attention and response during the treatment with this product, it is recommended to drive or operate machines after the symptoms have subsided.
Use in Children: At present, there is no clinical data on the use of this product on children or adolescent patients under the age of 18, hence paediatric patients are not recommended to take this product.
Use in the Elderly: In the Phase 1 clinical study of fruquintinib, there was no significant difference in the plasma drug concentration between elderly patients aged 65 years and above and patients aged below 65 years. In the Phase 3 FRESCO clinical study, there were a total of 78 elderly patients, accounting for 18.8%; among whom 50 patients came from the fruquintinib arm. In comparison to patients aged below 65 years, the efficacy was basically consistent. However, the incidence of Grade 3 or 4 adverse events and dose adjustment in elderly patients was slightly higher than patients aged below 65 years. Therefore, it is recommended for elderly patients to use this product with caution under the guidance of the physician. It is not required to adjust the initial dose for elderly patients.

Contraception: Women of childbearing age must be informed that this product may cause harm to fetus. Women of childbearing age are required to undergo a pregnancy test to rule out the possibility of pregnancy before taking this product.
Women of childbearing age should take effective contraceptive measures during the treatment period and up to 1 month after treatment.
Male patients should take effective contraceptive measures during the treatment period and up to 1 month after treatment.
Pregnancy: At present, there is still no clinical study about the effects of this product on pregnant women. Based on its mechanism of action, this product may cause harm to the fetus if a pregnant woman takes this product. In a developmental toxicity study in rats, it was observed that fruquintinib has teratogenicity, embryotoxicity and fetotoxicity when the maternal exposure is lower than the human exposure based on recommended clinical dose. Hence, the use of this product is prohibited during pregnancy.
Breastfeeding: At present, it is still unclear whether this product is excreted through human breast milk. As most of the drugs are excreted through breast milk, the risk of this product to nursing infants cannot be ruled out. Breastfeeding must be discontinued during the treatment with this product.
Fertility: At present, there is no data on the effects of this product on human fertility. Results from animal studies showed that fruquintinib may damage the fertility of male and female animals (refer to Pharmacology: Toxicology under Actions).

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.)

Click on icon to see table/diagram/image

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.

Pharmacokinetic Interactions: No dose adjustment is required when fruquintinib is used in combination with CYP3A inhibitors (refer to Pharmacology under Actions).
The combination of fruquintinib with moderate or strong CYP3A inducers reduces the exposure to fruquintinib, avoid concomitant use of moderate or strong CYP3A inducers. Alternative treatment with weak CYP3A inducing properties should be considered (refer to Pharmacology under Actions).
Based on in vitro studies, no inhibitory effect was observed with fruquintinib on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5 and no induction was observed with fruquintinib on CYP1A2, CYP2B6, or CYP3A4.
Fruquintinib inhibits efflux transporter P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), when concomitant use fruquintinib with P-gp and BCRP substrates, monitor patients more closely for any adverse reactions and make appropriate dose adjustments of the concomitant medications when necessary.
Fruquintinib can be used concomitantly with gastric acid reducing agents without any restrictions (refer to Pharmacology under Actions).

Seal and store below 30°C.
Shelf Life: 36 months.

Targeted Cancer Therapy

L01EK04 - fruquintinib ; Belongs to the class of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.

P₁S₁S₃