Fruquintinib (Monograph)
Brand name: Fruzaqla
Drug class: Antineoplastic Agents
Introduction
Antineoplastic agent; inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3.
Uses for Fruquintinib
Colorectal Cancer
Used for treatment of metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens; an anti-VEGF therapy; and in those bearing the wild-type (nonmutated) RAS genes, and when medically appropriate, an epidermal growth factor receptor inhibitor (anti-EGFR therapy).
American Society of Clinical Oncology (ASCO) guidelines on metastatic colorectal cancer and late-stage colorectal cancer do not discuss the specific place in therapy for fruquintinib.
Fruquintinib Dosage and Administration
General
Pretreatment Screening
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Control BP prior to initiation of fruquintinib; do not initiate fruquintinib if BP is not adequately controlled.
-
Assess liver function tests (ALT, AST, and bilirubin).
-
Monitor for proteinuria.
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Because of the potential increased risk for arterial thrombotic events with fruquintinib, carefully consider initiation of fruquintinib in patients with a recent history of thromboembolic events.
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Verify pregnancy status in females of reproductive potential.
Patient Monitoring
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Monitor BP weekly during the first month of therapy, then at least once monthly and as clinically indicated.
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Monitor liver function (ALT, AST, and bilirubin) periodically during therapy.
-
Monitor for proteinuria periodically during therapy.
-
Closely monitor for hemorrhagic events in patients who are at risk for bleeding.
-
Monitor the INR in patients receiving anticoagulants.
-
Monitor for infection.
-
Periodically monitor for GI perforation during therapy.
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Assess for posterior reversible encephalopathy syndrome in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.
Other General Considerations
-
Withhold fruquintinib for ≥2 weeks prior to major surgery.
-
Withhold fruquintinib for ≥2 weeks after major surgery and until there is adequate wound healing.
Administration
Oral Administration
Available as capsules containing 1 or 5 mg of fruquintinib.
Administer with or without food, at approximately same time each day. Swallow capsules whole.
If a dose is missed, take missed dose if <12 hours have elapsed; do not take 2 doses on same day to make up for missed dose.
If vomiting occurs after taking a dose, do not administer an additional dose but continue with next scheduled dose.
Dosage
Adults
Metastatic Colorectal Cancer
Oral
5 mg once daily for first 21 days of each 28-day cycle. Continue until disease progression or unacceptable toxicity.
Dosage Modification for Toxicity
Temporary interruption, dosage reduction, and/or permanent discontinuance of fruquintinib may be necessary if adverse effects occur.
If dosage modification required, reduce dosage of fruquintinib as described in Table 1.
Permanently discontinue fruquintinib in patients unable to tolerate dosage of 3 mg orally once daily.
Dosage Reduction Level |
Recommended Dosage |
---|---|
First dose reduction |
4 mg orally once daily |
Second dose reduction |
3 mg orally once daily |
Refer to Table 2 for recommended fruquintinib dosage modifications based on adverse reaction.
Level of severity as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Adverse Reaction |
Fruquintinib Dosage Modification Based on Severity |
---|---|
Hypertension |
Grade 3:Temporarily withhold fruquintinib for grade 3 hypertension that persists despite antihypertensive therapy. Upon full resolution of hypertension or recovery to grade 1, resume fruquintinib at the next lower dosage level. Grade 4: Permanently discontinue fruquintinib. |
Hemorrhagic events |
Grade 2:Temporarily withhold fruquintinib until full bleeding resolution or recovery to grade 1, then resume fruquintinib at the next lower dosage level. Grade 3 or 4: Permanently discontinue fruquintinib. |
Hepatotoxicity |
ALT or AST >3 times ULN with total bilirubin ≤2 times ULN:Temporarily withhold fruquintinib and monitor AST/ALT and total bilirubin until total resolution to grade 1 or baseline, then resume fruquintinib at the next lower dosage level. ALT or AST >3 times ULN with concurrent total bilirubin >2 times ULN (without cholestasis or hemolysis):Permanently discontinue fruquintinib. AST or ALT >20 times ULN or bilirubin >10 times ULN:Permanently discontinue fruquintinib. |
Proteinuria |
Proteinuria ≥2 grams/24 hours:Temporarily withhold fruquintinib until proteinuria fully resolves or is <1 gram/24 hours. Upon recovery of proteinuria, resume fruquintinib at the next lower dosage level. Presence of nephrotic syndrome or if proteinuria does not recover to <1 gram/24 hours:Permanently discontinue fruquintinib. |
Palmar-plantar erythrodysesthesia (PPE) |
Grade 2:Temporarily withhold fruquintinib and initiate supportive care. Upon full resolution of PPE or recovery to grade 1, resume fruquintinib at the same dosage level. Grade 3:Temporarily withhold fruquintinib and initiate supportive care. Upon full resolution of PPE or recovery to grade 1, resume fruquintinib at the next lower dosage level. |
Other adverse reactions |
Grade 3:Temporarily withhold fruquintinib; upon full resolution of toxicity or recovery to grade 1, resume fruquintinib at the next lower dosage level. Grade 4: Discontinue fruquintinib. Consider resumption of fruquintinib at the next lower dosage level only if the toxicity is non-life threatening and fully resolves or recovers to grade 1 and the potential benefits of therapy outweigh the risks. |
Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN, or total bilirubin >1–1.5 times ULN and any AST): No dosage adjustment necessary.
Moderate hepatic impairment (total bilirubin >1.5 times and <3 times ULN and any AST): Not adequately studied.
Severe hepatic impairment (total bilirubin >3 times ULN and any AST): Not recommended.
Renal Impairment
No specific dosage recommendations at this time.
Geriatric Patients
No specific dosage recommendations at this time.
Cautions for Fruquintinib
Contraindications
-
None.
Warnings/Precautions
Hypertension
Hypertension, including hypertensive crisis, reported.
Do not initiate fruquintinib unless BP adequately controlled. Monitor BP weekly during first month of therapy, then at least once monthly and as clinically indicated. Initiate or adjust antihypertensive therapy as needed. Withhold, reduce dosage, or permanently discontinue fruquintinib based on severity of hypertension.
Hemorrhagic Events
Serious hemorrhagic events, some fatal, reported.
Permanently discontinue fruquintinib if severe or life-threatening hemorrhage occurs. Monitor INR in patients receiving anticoagulants.
Infections
Increased risk for infections, including fatal infections. Infections reported include urinary tract infections, upper respiratory tract infections, and pneumonia; fatal infections reported include pneumonia, sepsis, bacterial infection, lower respiratory tract infection, and septic shock.
Withhold fruquintinib if grade 3 or 4 infections occur, or if there is worsening infection of any grade. Upon resolution of infection, resume fruquintinib at same dosage.
Gastrointestinal Perforation
Gastrointestinal perforation reported.
Permanently discontinue fruquintinib in patients who develop GI perforation or fistula.
Hepatotoxicity
Liver injury can occur; ALT or AST increases reported.
Monitor liver function tests (ALT, AST, and bilirubin) before initiating fruquintinib and periodically during therapy. Temporarily withhold and then reduce or permanently discontinue fruquintinib based on severity and persistence of hepatotoxicity.
Proteinuria
Proteinuria reported.
Monitor for proteinuria before initiating fruquintinib and periodically during therapy. Withhold fruquintinib in patients with proteinuria ≥2 g/24 hours until improvement to grade 1 proteinuria or lower, then resume at reduced dosage. Discontinue fruquintinib if nephrotic syndrome occurs.
Palmar-plantar Erythrodysesthesia
Palmar-plantar erythrodyesthesia (PPE) reported.
Based on PPE severity, withhold fruquintinib and resume at same or reduced dosage.
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome (PRES) reported.
Evaluate for PRES in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue fruquintinib in patients who develop PRES.
Impaired Wound Healing
Potential for impaired wound healing.
Withhold fruquintinib for ≥2 weeks prior to major surgery. Withhold fruquintinib for ≥2 weeks after major surgery and until adequate wound healing. Safety of resuming fruquintinib after resolution of wound healing complications not established.
Arterial Thrombotic Events
Potential increased risk of arterial thrombotic events. Clinical trials of fruquintinib excluded patients with clinically important cardiovascular disease, uncontrolled hypertension, or prior thromboembolic events within last 6 months.
Carefully consider initiation of fruquintinib in patients with recent history of thromboembolic events. Discontinue fruquintinib if arterial thromboembolism occurs.
Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF)
Fruquintinib 1 mg capsules contain FD&C Yellow No. 5 (tartrazine), which can lead to allergic-type reactions (including bronchial asthma) in susceptible patients. Tartrazine sensitivity more frequently observed in patients who also have aspirin hypersensitivity.
Fruquintinib 1 mg capsules also contain FD&C Yellow No. 6 (sunset yellow FCF), which can cause allergic reactions.
Fetal/Neonatal Morbidity and Mortality
Can cause fetal harm based on animal data and drug mechanism of action. Embryotoxic and teratogenic effects demonstrated in animals.
Verify pregnancy status in females of reproductive potential before initiating fruquintinib. Advise pregnant women of potential fetal risk.
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose.
Specific Populations
Pregnancy
May cause fetal harm based on animal data and drug mechanism of action.
No data available on use in pregnant women. Embryotoxic and teratogenic effects demonstrated in animals.
Verify pregnancy status in females of reproductive potential prior to initiating fruquintinib. Advise pregnant women of potential fetal risk.
Lactation
Not known whether fruquintinib or its metabolites present in milk. Effects on breast-fed child or on milk production also unknown.
Advise women to avoid breast-feeding during treatment and for 2 weeks following the last dose.
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiation.
No genotoxicity demonstrated in animals.
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose.
Pediatric Use
Safety and effectiveness not established.
Geriatric Use
Clinical studies included patients ≥65 years of age, including those ≥75 years of age.
No overall differences in safety or effectiveness observed between geriatric and younger patients.
Hepatic Impairment
No clinically important differences in fruquintinib pharmacokinetics observed in mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN, or total bilirubin >1–1.5 times ULN with any AST).
Not adequately studied in moderate hepatic impairment (total bilirubin >1.5 times and <3 times ULN and any AST).
Not recommended for use in severe hepatic impairment (total bilirubin >3 times ULN and any AST).
Effect of moderate to severe hepatic impairment on fruquintinib pharmacokinetics unknown.
Renal Impairment
No clinically important differences in fruquintinib pharmacokinetics observed in mild to moderate renal impairment (Clcr30–89 mL/minute).
Common Adverse Effects
Common adverse effects (incidence ≥20%): hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, asthenia.
Drug Interactions
Metabolized principally by CYP3A, and to a lesser extent by CYP2C8, CYP2C9, and CYP2C19. Also metabolized via non-CYP mediated routes (i.e., sulfation, glucuronidation).
Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Does not induce CYP1A2, CYP2B6, or CYP3A.
Not a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1, or OATP1B3. Does not inhibit OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, or MATE2-K.
Drugs Affecting Hepatic Microsomal Enzymes
Strong CYP3A Inducers
Concomitant use may decrease fruquintinib peak plasma concentration and AUC, which may reduce efficacy of fruquintinib.
Avoid concomitant use.
Moderate CYP3A Inducers
Concomitant use may decrease fruquintinib peak plasma concentration and AUC, which may reduce efficacy of fruquintinib.
If possible, avoid concomitant use. If concomitant use unavoidable, continue to administer fruquintinib at recommended dosage.
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Dabigatran etexilate |
No clinically important effect on pharmacokinetics of dabigatran etexilate (P-gp substrate) observed |
|
Efavirenz |
Efavirenz (moderate CYP3A inducer) expected to decrease peak plasma concentration and AUC of fruquintinib by 4 and 32%, respectively |
Avoid concomitant use if possible; if concomitant use unavoidable, continue to administer fruquintinib at recommended dosage |
Itraconazole |
No clinically important effect on fruquintinib pharmacokinetics observed when used concomitantly with itraconazole (strong CYP3A inhibitor) |
|
Rabeprazole |
No clinically important effect on fruquintinib pharmacokinetics observed when used concomitantly with rabeprazole (proton pump inhibitor) |
|
Rifampin |
Rifampin (strong CYP3A inducer) decreased peak plasma concentration and AUC of fruquintinib by 12 and 65%, respectively |
Avoid concomitant use |
Rosuvastatin |
No clinically important effect on pharmacokinetics of rosuvastatin (breast cancer resistance protein [BCRP] substrate) observed |
Fruquintinib Pharmacokinetics
Absorption
Bioavailability
Peak plasma concentration and AUC dose-proportional over dosage range of 1–6 mg.
Median time to peak plasma concentration: approximately 2 hours.
Steady-state concentrations achieved after 14 days; accumulation based on AUC is 4-fold.
Food
Administration of high-fat meal (800–1000 calories, 50% fat) did not substantially affect pharmacokinetics.
Distribution
Extent
Not known whether fruquintinib or its metabolites distribute into human milk.
Plasma Protein Binding
Approximately 95%.
Elimination
Metabolism
Metabolized principally via CYP pathway (by CYP3A, and to a lesser extent by CYP2C8, CYP2C9, and CYP2C19) and non-CYP pathway (sulfation and glucuronidation).
Elimination Route
Eliminated in urine (60% [0.5% as unchanged drug]) and in feces (30% [5% as unchanged drug]).
Half-life
Approximately 42 hours.
Special Populations
Age (18–82 years), sex, race (Asian, Black, and white), ethnicity (Hispanic/Latino versus non-Hispanic/Latino), and body weight (48–108 kg) do not substantially affect pharmacokinetics.
Stability
Storage
Oral
Capsules
20–25°C; brief excursions permitted to 15–30°C.
Actions
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Small molecule kinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3.
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In vitro, inhibits VEGF-mediated endothelial cell proliferation and tubular formation.
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In vitro and in vivo, inhibits VEGF-induced VEGFR-2 phosphorylation.
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In vivo, inhibits tumor growth in a colon cancer tumor xenograft mouse model.
Advice to Patients
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Advise patients to read the FDA-approved patient labeling.
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Advise patients to undergo regular BP monitoring and to contact their clinician if BP is elevated or if symptoms from hypertension occur, including severe headache, lightheadedness, or new neurologic symptoms.
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Advise patients that fruquintinib may increase the risk of bleeding and to contact their clinician if they experience unusual, severe, or persistent bleeding, bruising, or symptoms of bleeding, such as lightheadedness.
-
Advise patients to contact their clinician if they experience signs and symptoms of infection.
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Advise patients to immediately contact a clinician if they experience severe abdominal pain, or other symptoms of GI perforation or fistula.
-
Advise patients that they will need to undergo laboratory tests to monitor liver function and to report any new symptoms indicating hepatic toxicity or failure.
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Advise patients that they will need to undergo laboratory tests to monitor for proteinuria and to contact their clinician for signs or symptoms of proteinuria.
-
Inform patients of the risk of palmar-plantar erythrodysesthesia; advise patients to contact their clinician for progressive or intolerable rash.
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Inform patients of the risk of posterior reversible encephalopathy syndrome; advise patients to immediately contact their clinician for new onset or worsening neurological function.
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Advise patients that fruquintinib may impair wound healing. Advise patients to inform their clinician of any planned surgical procedure.
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Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke.
-
Advise patients that fruquintinib 1 mg contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons or in patients who also have aspirin hypersensitivity.
-
Advise patients that fruquintinib 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic-type reactions.
-
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
-
Advise patients to inform their clinician if they are or plan to become pregnant. Inform patients of the potential hazard to a fetus and potential loss of pregnancy.
-
Advise females of reproductive potential to use effective contraception during treatment with fruquintinib and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with fruquintinib and for 2 weeks after the last dose.
-
Advise patients to inform their clinician if they plan to breast-feed. Advise patients not to breast-feed during treatment with fruquintinib and for 2 weeks after the last dose.
-
Inform patients of other important precautionary information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Fruquintinib is obtained through designated specialty pharmacies. Visit the Fruzaqla website ([Web]) for specific availability information.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
1 mg |
Fruzaqla |
Takeda Pharmaceuticals America |
5 mg |
Fruzaqla |
Takeda Pharmaceuticals America |
AHFS DI Essentials™. © Copyright 2025, Selected Revisions December 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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