Approval Date.
Furoquantinib Capsules Instructions
Please read the instructions carefully and use under the guidance of a doctor
Drug Name]
Generic name: Furoquintinib Capsules
Trade name: Aiyutel® / Elunate®
English Name: Fruquintinib Capsules
Hanyu Pinyin：Fukuitini Jiaonang
Ingredients
The main ingredient of this product is Fruquintinib.
Chemical name: 6-(6,7-dimethoxyquinazolin-4-oxo)-N,2-dimethylbenzofuran-3-carboxamide
Chemical structure formula.
Molecular formula: C21H19N3O5
Molecular weight: 393.39
Properties
The content of this product is white to off-white powder.
Indications
It is indicated as a single agent for patients with metastatic colorectal cancer (mCRC) who have received prior fluorouracil-based, oxaliplatin and irinotecan-based chemotherapy, and who have received or are not suitable for prior anti-vascular endothelial growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy (RAS wild type).
【Specifications】.
(1) 1mg; (2) 5mg.
Dosage]
This product should be used under the supervision of an experienced antineoplastic doctor.
Recommended dosage and administration method
5mg per dose (1 capsule containing 5mg of furoquinitinib per capsule) once daily; 3 weeks of continuous dosing, followed by 1 week of discontinuation (every 4 weeks as a treatment cycle). This product may be taken orally with food or on an empty stomach and should be swallowed whole. It is recommended to take the drug at the same time of day. If the patient vomits after taking the drug, no refill is required; missed doses should not be added the next day and the next prescribed dose should be taken as usual.
Duration of treatment
Continue to take the drug according to the treatment cycle until disease progression or intolerable toxicity occurs.
Dose adjustment
The physician should closely monitor the patient during dosing and adjust the dose according to the individual patient’s safety and tolerability, including suspension, dose reduction, or permanent discontinuation of the product. Dose adjustment should follow the principle of suspending the drug before adjusting the dose downward.
If adverse reactions return to ≤ grade 1 within 1 week after suspension, continue to take the drug at the original dose; if they return to ≤ grade 1 within 2 weeks, dose adjustment is recommended under physician’s supervision: first dose adjustment to 4 mg daily (4 capsules containing 1 mg of furoquintinib each); second dose adjustment to 3 mg daily (3 capsules containing 1 mg of furoquintinib each); if 3 mg daily is still not tolerated, discontinue the drug permanently . The general principles of dose adjustment are shown in Table 1; the principles of dose adjustment for the most common hand-foot skin reaction (or palmoplantar erythema and pain syndrome) are detailed in Table 2.
Table 1 Dose adjustment principles for furoquinitinib for metastatic colorectal cancer
Dose adjustment scheme applicable to the occurrence of adverse reactions suspension of dosing grade 2 bleeding at any site
Grade 2 skin reactions in hands and feet and recurrent oral mucositis
Grade 2 thrombocytopenia (50~75×109/L)
24-hour urine protein quantification ≥ 2.0g
All grade 3 or 4 adverse reactions (except those requiring permanent discontinuation) lower dose suspension within 2 weeks adverse reactions return to ≤ grade 1 permanent discontinuation grade 3 or higher bleeding
Gastrointestinal perforation, wound dehiscence requiring clinical management, fistula, nephrotic syndrome, or hypertensive crisis
Grade 4 abnormal or impaired liver function (transaminases > 20 times the upper limit of normal)
Dose of 3 mg daily remains intolerable
The severity of adverse reactions that did not return to ≤ grade 1 adverse reactions after suspension of the drug for more than 2 weeks was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Table 2 Dose adjustment principles for the occurrence of skin reactions in the hands and feet
CTCAE Grading Criteria Dose Adjustment Protocol Grade 1 paresthesia, dullness of sensation, abnormal sensation, numbness, painless swelling, erythema of the hands and feet or discomfort of the hands and feet but not affecting normal activities maintaining the original dose level.
and initiate supportive measures1 to relieve symptoms. grade 2 erythema and swelling of the hands and feet with pain, and/or discomfort in the hands and feet that interferes with daily activities withhold medication.
return to ≤ grade 1 within 2 weeks, maintaining the original dose level.
or the clinician may reduce the dose level by one depending on the patient’s condition. grade 3 wet peeling, ulceration, herpes, pain, or severe hand and foot discomfort that prevents the patient from working and living a normal life is suspended at first presentation.
Recovery to ≤ grade 1 within 2 weeks requires a reduction of one dose level to 4 mg. suspension on second occurrence.
Recovery to ≤ Grade 1 within 2 weeks requires a reduction of one dose level to 3 mg. third occurrence of suspension.
Permanent discontinuation required if still intolerable.1 Avoid friction, pressure and contact with hot objects on hands and feet. Keep the skin of the hands and feet moist or use urea creams or creams containing lanolin as appropriate to help reduce symptoms and heal the lesion.
Special Patient Groups
Patients with hepatic insufficiency
Clinical studies have shown that transaminases may be elevated in patients with mild to moderate hepatic insufficiency and that patients with severe hepatic insufficiency should use this product with caution under medical supervision and monitor liver function closely.
Patients with renal insufficiency
Patients with moderate to severe renal insufficiency (creatinine clearance <50mL/min) were excluded from clinical studies and therefore no clinical data are available for such patients with moderate to severe renal insufficiency. Clinical studies have shown that proteinuria may occur with this product, so patients with renal insufficiency should use this product with caution under medical supervision and monitor renal function closely. In the phase III clinical study FRESCO, there were 91 patients (21.9%) with mild renal insufficiency (creatinine clearance <80mL/min); 61 of them were in the furoquinotinib group. The results showed that the overall safety profile of patients with mild renal insufficiency was not significantly different from all patients compared with all patients. Therefore, no adjustment of the starting dose is required in patients with mild renal insufficiency. Patients with moderate renal insufficiency should use this product with caution under medical supervision and monitor renal function closely, and this product is contraindicated in patients with severe renal insufficiency.
Pediatric Patients
There are no clinical data on the use of this product in children or adolescents under the age of 18 years and it is not recommended.
Geriatric Patients
It is recommended that elderly patients should use this product with caution and without adjustment of the starting dose under medical supervision, as described in [Geriatric Use].
[Adverse Reactions].
This instruction describes the adverse reactions observed in clinical studies judged to be possibly caused by furoquinitinib and their approximate incidence. Because clinical studies are conducted under a variety of conditions, the incidence of adverse reactions observed in one clinical study cannot be directly compared to the incidence of adverse reactions observed in another clinical study and may not reflect the actual incidence in clinical practice.
Safety Summary
The safety summary for furoquantinib is based on data from 577 patients who received study drug in randomized, double-blind, placebo-controlled clinical studies, including a randomized, double-blind, placebo-controlled FRESCO study in stage III metastatic colorectal cancer (278 in the furoquantinib arm and 137 in the placebo arm), a randomized, double-blind, placebo-controlled study in stage II metastatic colorectal cancer (47 in the furoquantinib arm and 24 in the placebo arm) 47 in the furoquintinib group and 24 in the placebo group), and a randomized, double-blind, placebo-controlled study of stage II non-small cell lung cancer (61 in the furoquintinib group and 30 in the placebo group). A total of 386 patients were treated with furoquinitinib and 191 patients were treated with placebo in these three studies.
In the three placebo-controlled clinical studies, the incidence of all levels of adverse drug reactions in patients in the furoquinitinib group was 97.4%, and the most common (incidence ≥20%) adverse drug reactions were hypertension, proteinuria, skin reactions in the hands and feet, dysphonia, bleeding, elevated transaminases, abnormal thyroid function tests, abdominal pain/abdominal discomfort, oral mucositis, fatigue/weakness, diarrhea, infection, elevated blood bilirubin elevation, and decreased appetite.
The incidence of grade 3 or higher adverse drug reactions in patients treated with furoquinitinib was 51.3%, and common (≥2% incidence) grade ≥3 adverse drug reactions were hypertension, hand-foot skin reaction, proteinuria, decreased platelet count, abnormal liver function, elevated bilirubin, abdominal pain/abdominal discomfort, diarrhea, fatigue/weakness, decreased appetite, and bleeding.
Adverse reactions in clinical studies
Metastatic colorectal cancer
Information on adverse reactions to furoquinitinib for metastatic colorectal cancer was primarily derived from a randomized, double-blind, placebo-controlled, multicenter Phase III clinical study (FRESCO) and a randomized, double-blind, placebo-controlled, multicenter Phase II clinical study.
FRESCO is a randomized, double-blind, placebo-controlled, multicenter phase III clinical study comparing furoquinitinib in combination with best supportive care (BSC) to placebo in combination with BSC in patients with metastatic colorectal cancer who have failed second-line and higher standard chemotherapy. The study excluded patients with severe active bleeding, uncontrolled active infection, active peptic ulcer, unhealed gastrointestinal perforation or gastrointestinal fistula, pregnant and lactating women, and moderate to severe renal insufficiency. A total of 416 patients were randomized in a 2:1 ratio to receive either furoquinitinib (5 mg) or placebo (1 patient in the placebo group was randomized but did not receive treatment); every 4 weeks for 3 weeks (once daily by mouth) with 1 week off. A total of 278 patients were treated with furoquinitinib 5 mg for a median treatment duration of 3.7 months (range: 0.1 to 21.9 months). Overall the product was well tolerated at the recommended dose.
In this study, the incidence of all levels of adverse drug reactions in patients in the furoquinitinib group was 97.1%. The most common (incidence ≥20%) adverse reactions were hypertension, proteinuria, skin reactions in the hands and feet, bleeding, dysphonia, elevated transaminases, abdominal pain/abdominal discomfort, elevated blood bilirubin, abnormal thyroid function tests, infection, diarrhea, fatigue/weakness, decreased appetite, oral mucositis, decreased body weight, fecal occult blood, and decreased platelet count.
The incidence of grade 3 or higher adverse drug reactions was 55.0% in patients treated with furoquinitinib. Common (≥2% incidence) Grade ≥3 adverse reactions were hypertension, skin reactions in the hands and feet, proteinuria, decreased platelet count, abdominal pain/abdominal discomfort, abnormal liver function, elevated bilirubin, diarrhea, fatigue/weakness, and decreased appetite.
Among patients treated with furoquinitinib, 9.0% discontinued the drug permanently due to adverse reactions, 32.4% suspended the drug due to adverse reactions, and 22.3% reduced the dose due to adverse reactions.
A summary of all graded adverse reactions with an incidence of ≥5% and ≥2% of ≥Grade 3 adverse reactions in patients treated with furoquinitinib is shown in Table 3.
The adverse reactions with an incidence <5% in patients treated with furoquinitinib were elevated blood amylase (4.3%) and anal pain (3.6%).
Another randomized, double-blind, placebo-controlled, multicenter phase II clinical study was completed in 71 patients (47 in the furoquinitinib group and 24 in the placebo group) with metastatic colorectal cancer who had failed second-line or higher standard chemotherapy and showed a safety profile generally consistent with that of the FRESCO study.
Table 3 Summary of adverse reactions of all grades with an incidence of ≥ 5% and ≥ 2% of ≥ grade 3 in the FRESCO study
Incidence of adverse reactions (%) Furoquinitinib group (N=278) Placebo group (N=137) All grades ≥3 All grades ≥3 Vascular and lymphovascular diseases Hypertension 61.2 23.4 16.8 2.2 Bleeding 133.81.816.10 Gastrointestinal bleeding 212.6 1.4 5.1 0 Hematuria 11.5 07.3 0 Epistaxis 9.0 0 1.50 Renal and urinary disorders Proteinuria 55.0 4.7 29.2 0 Skin and subcutaneous tissue disorders Skin reactions of hands and feet 49.3 10.8 2.9 0 Rash 9.7 0 1.5 0 Dermatitis 6.1 0.7 0.7 0.7 0 Respiratory, thoracic and mediastinal disorders Dysphonia 37.8 0 1.5 0 Sore throat/throat discomfort 10.4 0 1.5 0 Gastrointestinal disorders Abdominal pain/abdominal discomfort 29.5 4.0 16.8 1.5 Diarrhea 25.2 3.2 5.8 0 Oral mucositis 324.1 0.7 0.7 0 Oral and gingival pain 9.4 0 2.2 0 Infectious and invasive diseases Infection 425.5 5.4 13.9 0 Respiratory tract infection 512.6 2.9 6.6 0 Urinary tract infection 8.60.75.80 Systemic diseases and various reactions at the site of administration Fatigue/weakness 25.2 2.5 13.1 1.5 Metabolic and nutritional disorders Decreased appetite 24.8 2.2 13.9 0.7 Endocrine system disorders Hypothyroidism 16.5 0 2.2 0 Various musculoskeletal and connective tissue disorders Back pain 15.1 1.8 6.6 0 Skeletal muscle pain 612.2 0.7 4.4 0 Arthralgia 9.0 00.7 0 Hepatobiliary system disorders Abnormal liver function 77.9 4.0 2.9 0 Laboratory tests Elevated transaminases 830.2 1.4 18.2 2.2 Abnormal thyroid function tests 927.7 0 0 5.1 0 Elevated blood bilirubin 27.7 3.6 15.3 5.8 Decreased platelet count 20.9 4.0 2.9 0 Decreased body weight 21.2 1.4 8.8 0 Positive fecal occult blood 21.2 0 11.7 0 Decreased white blood cell count 15.5 0.4 3.6 0.7 Decreased neutrophil count 10.1 0.4 2.9 0 Positive urine occult blood 9.0 0 3.6 0 1 Bleeding refers to bleeding from various sites.
2 Gastrointestinal bleeding includes: upper gastrointestinal bleeding, gastrointestinal bleeding, intestinal bleeding, anastomotic bleeding, lower gastrointestinal bleeding, hemorrhoid bleeding, blood in stool, anal bleeding, etc.
3 Oral mucositis includes: aphthous ulcer, aphthous oral mucositis, oral ulcer, oral mucositis, gingival ulcer, etc.
4 Infections refer to infections in various parts of the body.
5 Respiratory tract infections include: upper respiratory tract infection, lower respiratory tract infection, lower respiratory tract fungal infection, respiratory tract infection, tonsillitis, pharyngitis, nasopharyngitis, fungal sinusitis, bronchitis, lung infection, influenza, catarrhitis, etc.
6 Skeletal muscle pain including: neck pain, bone pain, chest pain, chest musculoskeletal pain, skeletal muscle pain, etc.
7 Abnormal liver function including: elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) with elevated blood bilirubin
8 Elevated transaminases include: elevated or abnormal AST, elevated or abnormal ALT, elevated or abnormal transaminases, etc.
9 Abnormal thyroid function tests include: elevated or decreased thyroid stimulating hormone (TSH), elevated or decreased triiodothyronine (T3) or thyroxine (T4), elevated thyroid hormone, and abnormal thyroid function tests.
Description of specific adverse reactions
Information on specific adverse reactions to furoquinitinib was obtained from the three randomized, double-blind, placebo-controlled studies described above, in which a total of 386 patients were treated with furoquinitinib and 191 patients were treated with placebo. The common (incidence >1%) serious adverse drug reactions in patients treated with furoquinitinib were primarily bleeding, abnormal liver function, pulmonary infection, and hypertension.
Hemorrhage
In three randomized, double-blind, placebo-controlled studies, the incidence of bleeding events in patients in the furoquinitinib group was 30.3%. The majority (28.2%) of bleeding events in patients in the furoquinitinib group were grade 1-2 in severity, with the most common (incidence ≥5%) including: gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade ≥3 bleeding events was 2.1%, including: gastrointestinal bleeding (1.6%) and hemoptysis (0.5%). Fatal outcome bleeding events involving the respiratory and gastrointestinal tracts were reported in patients in the furoquinitinib group, of which the incidence in the FRESCO study was 0.7%. The incidence of bleeding events in the placebo group was 15.7%; of these, the incidence of grade ≥3 bleeding events was 0.5% (hemoptysis) and no cases with fatal outcomes were reported.
Elevated transaminases and abnormal liver function
In three randomized, double-blind, placebo-controlled studies, the incidence of transaminase elevation and liver function abnormalities in the furoquinitinib group was 29.8% and 6.5%, respectively; of these, the incidence of grade ≥3 transaminase elevation and liver function abnormalities was 1.3% and 3.4%, respectively. The incidence of transaminase elevation and liver function abnormalities in the placebo group was 15.2% and 2.6%, respectively; among them, the incidence of grade ≥3 transaminase elevation was 2.1%. No cases of drug-induced liver injury were reported in either group.
Infection
In three randomized double-blind placebo-controlled studies, the incidence of infection in patients in the furoquinitinib group was 25.1%. The majority (20.2%) of these infections were grade 1-2, with the most common (incidence ≥5%) being upper respiratory tract infections (10.9%) and urinary tract infections (8.0%); the incidence of grade ≥3 infections was 4.9%, primarily lower respiratory tract/pulmonary infections (1.8%). The incidence of fatal outcome pulmonary infections was 0.7% in the FRESCO study. The incidence of infection in the placebo group was 14.1%; of these, the incidence of grade ≥3 infection was 0.5% and no cases of fatal outcome were reported.
Hypertension
In three randomized double-blind placebo-controlled studies, the incidence of hypertension in patients in the furoquinitinib group was 55.4%. Of these, the majority (33.4%) had grade 1-2 hypertension, the incidence of grade 3 hypertension was 22.0%, and no cases of grade 4 hypertension or hypertensive crisis were reported. The incidence of hypertension in the placebo group was 14.1%; among them, the incidence of grade 3 hypertension was 2.1%.
[Contraindications].
Contraindicated in patients with hypersensitivity to any component of this product.
Contraindicated in patients with severe active bleeding, active peptic ulcer, unhealed gastrointestinal perforation, and gastrointestinal fistula. Forbidden in patients with severe hepatic or renal insufficiency. Forbidden for pregnant and lactating women.
Precautions]
Bleeding
An increased risk of bleeding has been observed in clinical studies. The main causes of bleeding include gastrointestinal bleeding, hematuria, epistaxis, hemoptysis, and gingival bleeding; cases involving bleeding from the gastrointestinal and respiratory tracts have been reported with fatal outcomes (see [Adverse Reactions]).
Clinicians should pay close attention to the risk of bleeding when administering the drug and need to routinely monitor patients’ routine blood and coagulation parameters, especially for patients taking anticoagulants (e.g., warfarin) during treatment, and to increase the frequency of monitoring coagulation parameters such as the international normalized ratio (INR). Permanent discontinuation of this product should be considered once a patient shows signs of bleeding that require urgent medical intervention (see [DOSAGE AND ADMINISTRATION]).
This product should be used with caution in patients at potential risk of bleeding prior to administration of this product, such as activated partial thromboplastin time (aPTT) or prothrombin time (PT) exceeding 1.5 times the upper limit of normal, or within one month after major surgery. This product is not recommended for patients with severe active bleeding or active peptic ulcers.
Infection
An increased risk of infection has been observed with this product in clinical studies, most commonly upper respiratory tract infections and urinary tract infections, with fatal outcomes reported in cases of pulmonary infections (see [Adverse Reactions]).
For patients with serious infections prior to administration of this product, the product should be started only after the infection has been effectively controlled. If grade 3 or higher infections occur during treatment, the product should be withheld until the infection is effectively controlled.
Elevated transaminases and abnormal liver function
In clinical studies, elevated transaminases, elevated bilirubin, and abnormal liver function have been observed, most of which are grade 1-2.
Liver function (transaminases and bilirubin) needs to be tested prior to administration of this product, and liver function needs to be routinely monitored during treatment. When patients develop grade ≥3 aminotransferase elevations or clinical indications during treatment, the product should be suspended, reduced or permanently discontinued as appropriate, and liver function should be closely monitored, either weekly or biweekly, until aminotransferases return to grade 1 or pre-dose levels (see [DOSAGE AND ADMINISTRATION]).
This product should be used with caution in patients with hepatic insufficiency as there are no clinical data available on this product.
Hypertension
An increased risk of hypertension, mostly grade 1-2, has been observed in clinical studies, with no grade 4 hypertension or hypertensive crisis occurring (see [Adverse Reactions]).
In clinical studies, hypertension was most often observed about 10 days after dosing and was usually well controlled with conventional antihypertensive therapy. grade 3 hypertension was largely restored to grade 1 or pre-dose levels after aggressive antihypertensive management or dose adjustment.
The patient’s blood pressure should be controlled to the desired level (<140/90 mmHg) before the drug is administered; blood pressure should be monitored routinely during treatment, once a week for the first three cycles and once a cycle thereafter, with more frequent blood pressure measurements when clinically indicated.
Skin reactions on hands and feet
An increased risk of hand-foot skin reactions, primarily grade 1-2, has been observed in clinical studies (see [Adverse Reactions]).
In clinical studies, hand-foot skin reactions mostly occurred within the first cycle after dosing. Grade 3 hand-foot skin reactions were largely resolved or reduced with symptomatic treatment and dose adjustment. See [Dosage] for details of dose adjustments related to hand-foot skin reactions.
Proteinuria
An increased risk of proteinuria, primarily grade 1-2, without the development of nephrotic syndrome was observed in clinical studies (see [Adverse Reactions]).
In clinical studies, proteinuria mostly appeared about 20 days after dosing. Grade 3 proteinuria can basically return to grade 1 or pre-dose levels with dose adjustment and aggressive symptomatic management.
Patients should check urinary routine regularly during the use of this product, and seek medical attention if proteinuria occurs. When this product is used in patients with renal insufficiency, urine protein should be closely monitored.
Gastrointestinal perforation or fistula formation
Gastrointestinal perforation or fistula formation is a common disease-related complication in patients with intra-abdominal malignancies. In clinical studies, the incidence of gastrointestinal perforation or fistula formation after taking this product was observed to be 0.8% in both cases, with the incidence of grade ≥3 gastrointestinal perforation and gastrointestinal fistula being 0.8% and 0.5%, respectively. The incidence of gastrointestinal perforation in the placebo group was 0.5%; no cases of gastrointestinal fistula were reported. No cases of fatal outcome were reported in either group.
Patients with GI infiltration or a previous history of gastrointestinal perforation need to be closely monitored during treatment with this product, and any gastrointestinal perforation needs to be immediately and permanently discontinued and promptly treated. Gastrointestinal perforation is often associated with characteristic symptoms, such as sudden onset of severe pain in the upper abdomen, with persistent cutting or burning pain that quickly spreads to the entire abdomen.
This product is not recommended for patients with unhealed gastrointestinal perforation or gastrointestinal fistula.
Arterial thrombosis
A 0.5% incidence of arterial thrombosis due to administration of this product has been observed in clinical studies, including one case report of cerebral infarction with a fatal outcome.
Patients with high risk factors for arterial thrombosis (including old age, hypertension, diabetes mellitus, myocardial ischemia and infarction, and cerebral ischemia and infarction) should be closely monitored during treatment with this product and discontinued immediately in the event of arterial thrombosis or stroke.
Use with caution in patients with prior arterial thrombosis or stroke.
Reversible posterior leukoencephalopathy syndrome (RPLS)
Reversible posterior leukoencephalopathy syndrome (RPLS) has not been observed in clinical studies, but has been reported in similar products. signs and symptoms of RPLS include seizures, headache, altered mental status, visual disturbances or cortical blindness, with or without hypertension. the diagnosis of RPLS requires confirmation by magnetic resonance imaging (MRI) of the brain. For patients with suspected RPLS, permanent discontinuation of the product and control of hypertension are recommended, with supportive medical measures for other medical symptoms.
Delayed wound healing
Anti-angiogenic drugs may inhibit or impede wound healing, and as a precautionary measure, it is recommended that this product be withheld in patients who require major surgery during treatment. Treatment should not be resumed until the wound has healed completely after major surgery as determined by the clinician.
Effects on driving and machine handling
There are no studies on the effects of this product on the ability to drive or operate machinery. If a patient experiences symptoms that impair concentration and response during treatment with this product, he or she is advised to wait until the symptoms have resolved before driving or operating machinery.
For Pregnant and Lactating Women
Contraception
Women of childbearing age must be informed that this product may harm the fetus. Pregnancy tests should be performed to rule out pregnancy before women of childbearing age take this product.
Women of childbearing potential need to ensure effective contraception during and for 1 month after treatment.
Male patients need to ensure effective contraception during treatment and for 3 months after treatment.
Pregnancy
There are no clinical studies on the effects of this product in pregnant women. Depending on its mechanism of action, this product may lead to fetal harm when administered to pregnant women. In rat developmental toxicity studies, teratogenicity, embryotoxicity and fetal toxicity were observed with furoquinitinib when maternal exposure was below the clinically recommended dose for human exposure. Therefore, the use of this product is contraindicated during pregnancy.
Lactation
It is not known whether this product is excreted in human milk. Since most drugs are excreted in breast milk, the risk of this product to nursing infants cannot be excluded. Breastfeeding must be discontinued during treatment with this product.
Fertility
There are no data on the effect of this product on human fertility. The results of animal studies suggest that furoquinitinib may impair male or female fertility (see [Pharmacology and Toxicology]).
Pediatric Use]
There are no clinical data on the use of this product in pediatric or adolescent patients under the age of 18 years; it is not recommended for pediatric patients.
Geriatric Use]
In the phase I clinical study of furoquinitinib, there was no significant difference in blood levels between elderly patients 65 years of age and older and patients under 65 years of age taking this product. In the phase III clinical study FRESCO, there were 78 elderly patients, accounting for 18.8%; 50 of them were in the furoquinitinib group. Compared with patients under 65 years of age, the efficacy was basically the same, but the incidence of grade 3 or 4 adverse events and dose adjustment was slightly higher in elderly patients than in patients under 65 years of age; therefore, it is recommended that elderly patients should use this product with caution under medical supervision. No adjustment of starting dose is required in elderly patients.
Drug Interactions]
There is no clinical information on drug interactions with this product.
Furoquinitinib exists mainly in its native form in vivo, with a small portion metabolized by CYP3A4. It is expected that CYP3A4 inhibitors or inducers will have limited effect on the in vivo exposure of furoquinitinib.
No inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 by furoquinitinib and no induction of CYP1A2 and CYP3A4 by furoquinitinib were seen in in vitro assays.
Furoquinotinib has inhibitory effects on the efflux transporter P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Patients should carefully combine P-gp and BCRP substrates, closely monitor adverse effects, and adjust the combined dose appropriately if necessary.
Overdose]
The possible hazards of overdose are not known at this time. In clinical studies of early dose exploration of this product, some patients with solid tumors were given up to 6 mg of furoquinitinib daily, and the dose-limiting toxicities observed at this dose were hand-foot skin reactions and malaise. In phase II and III clinical studies in metastatic colorectal cancer, only a single overdose (up to a dose of 10 mg/day) was observed in a single patient, but no clinically significant abnormalities were observed.
There is no specific antidote for overdose of this product. If an overdose is suspected, the product should be discontinued immediately, the patient should be closely observed, and best supportive treatment should be taken if necessary.
[Clinical Studies].
A randomized controlled phase III FRESCO clinical study has been completed with furoquinitinib monotherapy for metastatic colorectal cancer, and the main results are as follows.
Phase III clinical study (FRESCO)
FRESCO is a randomized, double-blind, placebo-controlled, multicenter phase III clinical study comparing furoquinitinib in combination with BSC to placebo in combination with BSC in patients with metastatic colorectal cancer who have failed second-line and higher standard chemotherapy. A total of 416 patients were randomized to the study in a 2:1 ratio (278 in the furoquintinib group and 138 in the placebo group), and all patients received monotherapy with furoquintinib or placebo 5 mg orally once daily for 3 weeks with 1 week off, except for 1 patient in the placebo group who did not receive treatment after randomization. Patients were enrolled with a histologically and/or cytologically confirmed diagnosis of metastatic colorectal cancer (stage IV) who had received and failed at least second-line standard chemotherapy in the past (treatment failure was defined as disease progression or intolerable toxicities during or within 3 months of the last treatment; these standard treatment regimens had to include fluorouracil analogs, oxaliplatin, and irinotecan). Eastern U.S. Collaborative Oncology Group (ECOG) score ≤1 in all patients.
Median treatment duration was 3.7 months and 1.8 months for furoquintinib and placebo, respectively. The primary baseline status of patients is shown in Table 4, and the demographic data and baseline characteristics of the placebo group were generally consistent with those of the furoquinitinib group, except for a slightly higher proportion of men (70.3%).
Table 4 Patient Baseline Status – Phase III Clinical Study (FRESCO)
Baseline status Furoquinitinib group (N=278) Placebo group (N=138) Age Median age (years) 55.057.0<65 years (%) 82.079.7 Gender Male (%) 56.870.3 Female (%) 43.229.7 ECOG score 0 (%) 27.726.81 (%) 72.373.2 Primary at first diagnosis site (%) Colon 52.950.7 Rectum 45.043.5 Colon-rectum 2.25.1 Cecum 00.7 K-Ras gene status (%) Wild type 56.553.6 Mutant 43.546.4 Liver metastases (%) Yes 66.573.9 No 33.526.1 Metastatic site (%) Single 4.72.9 Multiple 95.397.1 Previous systemic Chemotherapy (%) 2 or 3 lines 68.371.03 More than one line 31.729.0 Previous targeted therapy (except VEGFR) (%) No anti-VEGF and no anti-EGFR 60.160.1 Anti-VEGF and/or anti-EGFR 39.939.9
The primary efficacy evaluation endpoint of the study was overall survival (OS), and the secondary efficacy endpoints were progression-free survival (PFS), objective remission rate (ORR), disease control rate (DCR), and duration of remission/duration of stabilization (DoR/DoS). OS was significantly prolonged in the furoquinitinib group, with a median OS extension of 2.7 months and a 35% reduction in the risk of death compared with the placebo group. Secondary efficacy indicators were significantly better than in the placebo group. The validity results are shown in Table 5; the Kaplan-Meier curves for overall survival (OS) are shown in Figure 1.
Table 5 Validity results (ITT set) – Phase III clinical study (FRESCO)
Efficacy endpoint Furoquinitinib group Placebo group Overall survival (OS) N=278N=138 Median (months) (95% CI) 9.3 (8.18, 10.45) 6.6 (5.88, 8.11) HR (95% CI) 0.65 (0.51, 0.83) p-value 1<0.001 Progression-free survival (PFS) N=278N= 138 Median (months) (95% CI) 3.7 (3.65, 4.63) 1.8 (1.81, 1.84) HR (95% CI) 0.26 (0.21, 0.34) p-value 1<0.001 Objective remission rate (ORR) N=278N=138 ORR (%) (95% CI) 4.7 (2.51, 7.86) 0 ( 0.00, 2.64) OR (95% CI) NE (2.00, NE) p-value 20.012 Disease control rate (DCR) N=278N=138 DCR (%) (95% CI) 62.2 (56.25, 67.95) 12.3 (7.34, 18.99) OR (95% CI) 12.16 (6.87, 21.53) p-value 3<0.001 Duration of remission (DoR) N=13N=0 Median (months) (95% CI) NE (5.6, NE)NE Duration of stabilization (DoS) N=160N=17 Median (months) (95% CI) 5.5 (5.5, 5.6)3.7 (3.7, 4.8)Abbreviations: CI=confidence interval, HR=risk ratio ( furoquantinib/placebo), ITT=intentional analysis set, NE=not estimable, OR=ratio.
Stratified Log-Rank test.
Exact test.
Stratified Cochran-Mantel-Haenszel test.
Figure 1 Kaplan-Meier curves for overall survival (OS) (ITT set) – Phase III clinical study (FRESCO)
Abbreviations: ITT = intentional analysis set, OS = overall survival.
[Pharmacological and toxicological].
Pharmacological effects
Furoquinitinib is a highly selective inhibitor of tumor angiogenesis, its main targets are VEGFR kinase family VEGFR1, 2 and 3. Furoquinitinib inhibits the activity of VEGFR kinase at the molecular level; at the cellular level, it inhibits the phosphorylation of VEGFR2/3 and inhibits endothelial cell proliferation and lumen formation; at the tissue level, furoquinitinib significantly inhibits the proliferation of chick embryo At the tissue level, furoquinitinib significantly inhibited the formation of new microvessels in the chick embryo chorioallantoic membrane model; at the whole animal level, furoquinitinib inhibited VEGFR2/3 phosphorylation after oral administration, inhibiting tumor angiogenesis and thus tumor growth. In whole animals, furoquinitinib showed potent and dose-dependent inhibition of growth in colorectal cancer as well as a variety of other tumor types using once-a-day dosing, with tumor shrinkage and regression found in sensitive models.
Toxicological studies
Long-term toxicity: In a 26-week oral long-term toxicity study in rats, the lowest dose with adverse effects was 0.5/0.25 mg/kg/day (dose reduction from day 50), with toxic effects seen in the bile ducts, liver, kidneys, adrenal glands, thymus, spleen and femur. In a long-term toxicity study in dogs administered orally for 39 weeks, no adverse reactions were observed at a dose of 0.03 mg/kg/day, with major toxic reactions seen in the liver, kidneys, thymus, spleen, lymph nodes, and gastrointestinal tract. Toxic reactions seen in dogs and rats were fully or partially recovered after 4 weeks of drug withdrawal.
Genotoxicity: Salmonella typhimurium revertant mutation studies and mouse bone marrow micronucleus studies have shown no genotoxicity. The Chinese hamster lung fibroblast chromosomal aberration study showed a significant increase in chromosomal structural aberrations only after 24 hours of action under 36.0 μg/mL non-metabolic activation conditions, and no increase in chromosomal structural aberrations was seen under the remaining treatment conditions (doses up to 36.0 μg/mL).
Reproductive toxicity: In the toxicity study of fertility and early embryonic development in rats (oral doses up to 3 and 0.5 mg/kg/day in males and females, respectively), no adverse effects on fertility were observed in males and females; only in females at 0.5 mg/kg/day an increase in the number of absorbed fetuses and post-implantation loss and a decrease in the number of live fetuses were observed, and no adverse effects on early embryonic development were observed at a dose of 0.15 mg/kg/day. In an oral embryo-fetus developmental toxicity study in pregnant rats, no adverse effects were observed in the embryo-fetus at a dose of 0.025 mg/kg/day, while malformation, reduced body weight and delayed ossification were observed in the fetus at doses ≥0.1 mg/kg/day.
Pharmacokinetics
Absorption
The mean peak plasma drug concentration (Cmax) was 155 ng/mL, the median time to peak (Tmax) was 3 hours (1.5 to 24 hours), and the mean area under the plasma drug concentration time curve (AUC0-∞) was 5700 h∙ng/mL for a single oral dose of 5 mg of furoquinitinib capsules in healthy subjects. Cmax was 195 ng/mL, median Tmax was 2 hours (0.5 to 2 hours), and mean AUC0-72 was 5495 h∙ng/mL.
Furoquinitinib exposure (AUC) increased essentially proportionally with dose in the 1 mg to 6 mg dose range, and after 14 days of continuous once-daily dosing in patients with advanced cancer, furoquinitinib exposure reached steady-state, with mean steady-state exposure (AUCSS) at 5 mg being approximately three times the first dose exposure (AUC 0-24).
Compared to the fasted state, a single oral dose of 4 mg furoquinitinib capsules after a high-fat meal in healthy subjects was associated with an approximately 17% decrease in Cmax (geometric mean ratio 82.9%, 90% confidence interval 76.7%-89.5%) and a similar AUC 0-∞ (geometric mean ratio 97.2%, 90% confidence interval 94.0%-100.4%).
Distribution
In vitro test results showed that furoquinitinib binds to approximately 80% of human plasma proteins. A single oral dose of 5 mg of furoquinitinib resulted in a mean oral elimination phase apparent volume of distribution of 32.5 L and 42.2 L in healthy subjects and patients with advanced cancer, respectively.
Metabolism
In vivo metabolism and material balance studies of [14C]-labeled furoquinitinib showed that furoquinitinib is predominantly present in human plasma in its native form, accounting for approximately 72% of the total plasma exposure, with CYP3A4-mediated demethylated metabolites accounting for approximately 17% of the total plasma exposure. Other metabolic pathways include multi-site mono-oxidation, O-demethylation, N-demethylation, O-dequinolizole ring, and amide bond hydrolysis. phase II metabolites are primarily glucuronide and sulfate conjugates of phase I products.
Excretion
Single oral doses of 2 mg to 6 mg furoquinitinib in patients with advanced cancer had a mean elimination half-life of 35.2 to 48.5 hours and a mean oral clearance of 9.98 to 17.8 mL/min. The cumulative recovery of radioactivity in healthy subjects from oral doses of 5 mg 14C-labeled furoquinitinib averaged 90.1% over 336 hours, with 60.3% in urine (prodrug was 0.5%) and 29.8% in feces (5.3% for prodrugs). Furoquinitinib is mainly excreted as metabolites in urine via the kidneys.
Storage
Sealed, 30°C
Store below.
Package】
Polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets and double aluminum blister plates sealed by heat sealing with aluminum foil for pharmaceutical packaging.
1mg: 7 capsules/plate, 3 plates/box.
5mg: 7 capsules/plate, 1 plate/box.
[Expiration date
24 months
【Execution standard
【Approval number】
【Drug marketing license holder】
Company Name: Hutchison Whampoa Pharmaceutical (Shanghai) Co.
Address: No. 4, Lane 720, Cailun Road, China (Shanghai) Pilot Free Trade Zone
Postal Code: 201203
Telephone number: 021-20673000
Fax Number: 021-20673186
Product Consultation Phone Number：400-658-6360
Trusted manufacturer]
Company name: Hutchison Whampoa Pharmaceutical (Suzhou) Co.
Address: Building C32, No. 188 Dongping Street, Suzhou Industrial Park, Suzhou, Jiangsu Province
Postal Code: 215123
Telephone number: 0512-62605899
Fax Number: 0512-62605850