Fruquintinib (Monograph)

Brand name: Fruzaqla
Drug class: Antineoplastic Agents

Introduction

Fruquintinib, a small molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR), is an antineoplastic agent.

Uses for Fruquintinib

Fruquintinib has the following uses:

Fruquintinib is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

Fruquintinib Dosage and Administration

General

Fruquintinib is available in the following dosage form(s) and strength(s):

Capsules: 1 mg and 5 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

The recommended dose of fruquintinib is 5 mg orally once daily, with or without food, for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

See Full Prescribing Information for recommended dose modifications for adverse reactions.

Cautions for Fruquintinib

Contraindications

None.

Warnings/Precautions

Hypertension

Fruquintinib can cause hypertension. Hypertension occurred in 450 of 911 (49%) patients with mCRC treated with fruquintinib, including Grade 3-4 events in 19%, and hypertensive crisis in three patients (0.3%). The median time to first onset of hypertension was 14 days from first dose of fruquintinib.

Do not initiate fruquintinib unless blood pressure is adequately controlled. Monitor blood pressure weekly the first month, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue fruquintinib based on the severity of hypertension.

Hemorrhagic Events

Fruquintinib can cause serious hemorrhagic events, which may be fatal. In 911 patients with mCRC treated with fruquintinib, 6% of patients experienced a gastrointestinal hemorrhage, including 13 patients (1%) with a Grade ≥3 event and 2 patients with fatal hemorrhages.

Permanently discontinue fruquintinib in patients with severe or life-threatening hemorrhage. Monitor the International Normalized Ratio (INR) levels in patients receiving anticoagulants.

Infections

Fruquintinib can cause an increased risk of infections, including fatal infections. In 781 patients treated with fruquintinib across three randomized, placebo-controlled trials, the overall incidence of infections was higher (18% vs. 12%) including for fatal infections (1% vs. 0.3%) as compared to the placebo arms (n=391).

In 911 patients with mCRC treated with fruquintinib, the most common infections were urinary tract infections (6.8%), upper respiratory tract infections (3.2%), and pneumonia (2.5%); fatal infections included pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract infection (0.1%), and septic shock (0.1%).

Withhold fruquintinib for Grade 3 or 4 infections, or worsening infection of any grade. Resume fruquintinib at the same dose when the infection has resolved.

Gastrointestinal Perforation

Fruquintinib can cause gastrointestinal perforation. In 911 patients with mCRC treated with fruquintinib, 12 patients (1.3%) experienced a Grade ≥3 gastrointestinal perforation, including one fatal event.

Permanently discontinue fruquintinib in patients who develop gastrointestinal perforation or fistula.

Hepatotoxicity

Fruquintinib can cause liver injury. In 911 patients with mCRC treated with fruquintinib, 48% experienced increased ALT or AST, including Grade ≥3 events in 5%, and fatal events in 0.2%. Median time to first onset of elevated liver enzymes was 29 days from first dose of fruquintinib.

Monitor liver function tests (ALT, AST, and bilirubin) before initiation and periodically throughout treatment with fruquintinib. Temporarily hold and then reduce or permanently discontinue fruquintinib depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests.

Proteinuria

Fruquintinib can cause proteinuria. In 911 patients with mCRC treated with fruquintinib, 36% experienced proteinuria and 2.5% of patients experienced Grade ≥3 events. Median time to first onset of proteinuria was 22 days from first dose of fruquintinib.

Monitor for proteinuria before initiation and periodically throughout treatment with fruquintinib. For proteinuria ≥2 g/24 hours, withhold fruquintinib until improvement to ≤Grade 1 proteinuria; then resume fruquintinib at a reduced dose. Discontinue fruquintinib in patients who develop nephrotic syndrome.

Palmar-plantar Erythrodysesthesia (PPE)

Fruquintinib can cause PPE. In 911 patients with mCRC treated with fruquintinib, PPE occurred in 35%, including 8% with Grade 3 events. Median time to first onset of PPE was 19 days from first dose of fruquintinib.

Based on severity, withhold fruquintinib and then resume at the same or reduced dose

Posterior Reversible Encephalopathy Syndrome (PRES)

Fruquintinib can cause PRES, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI. PRES occurred in one of 911 patients with mCRC treated with fruquintinib.

Perform an evaluation 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

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. In 911 patients with mCRC treated with fruquintinib, 1 patient experienced a Grade 2 event of wound dehiscence.

Do not administer fruquintinib for at least 2 weeks prior to major surgery.

Do not administer fruquintinib for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of fruquintinib after resolution of wound healing complications has not been established.

Arterial Thromboembolic Events

Fruquintinib may increase the risk of arterial thromboembolic events. In 911 patients with mCRC treated with fruquintinib, 7 patients (0.8%) experienced an arterial thromboembolic event; additionally, fruquintinib studies excluded patients with clinically significant cardiovascular disease, uncontrolled hypertension, or with thromboembolic events within the prior 6 months. Initiation of fruquintinib in patients with a recent history of thromboembolic events should be carefully considered. In patients who develop arterial thromboembolism, discontinue fruquintinib.

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 may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Fruquintinib 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic reactions.

Embryo-fetal Toxicity

Based on findings in animal studies and its mechanism of action, fruquintinib can cause fetal harm when administered to pregnant women. In an embryo-fetal developmental study in rats, embryotoxic and teratogenic effects were observed at exposures below the clinical exposure.

Advise pregnant women of the potential risk to a fetus. Advise females of childbearing potential and males with female partners of childbearing potential to use effective contraception during treatment with fruquintinib and for 2 weeks after the last dose.

Specific Populations

Pregnancy

Based on findings in animal studies and its mechanism of action, fruquintinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryolethality at exposures below the clinical exposure. There are no data on the use of fruquintinib in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

There are no data regarding the presence of fruquintinib or its metabolites in human milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with fruquintinib and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to initiating fruquintinib.

Females of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment and for 2 weeks after the last dose of fruquintinib.

Pediatric Use

The safety and efficacy of fruquintinib in patients younger than 18 years of age have not been established.

Geriatric Use

In the FRESCO-2 study, 212 (46%) patients who received fruquintinib were ≥65 years of age and older, of whom 43 (20%) of patients were ≥75 years of age. There were no observed overall differences in safety and effectiveness of fruquintinib in geriatric compared to younger patients.

Of the total number of fruquintinib-treated patients in the FRESCO study, 50 (18%) were 65 years of age and older, and one patient was ≥75 years of age. There were no observed overall differences in safety and effectiveness of fruquintinib in geriatric compared to younger patients.

Hepatic Impairment

No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to the ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST).

Fruquintinib has not been sufficiently studied in patients with moderate hepatic impairment (total bilirubin greater than 1.5 times and less than 3 times ULN and any AST). Fruquintinib is not recommended for use in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST).

Common Adverse Effects

Most common adverse reactions (incidence ≥20%) are hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Strong or Moderate CYP3A Inducers: Avoid concomitant use.

Actions

Mechanism of Action

Fruquintinib is a small molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 with IC₅₀ values of 33, 35, and 0.5 nM, respectively. In vitro studies showed fruquintinib inhibited VEGF-mediated endothelial cell proliferation and tubular formation. In vitro and in vivo studies showed fruquintinib inhibited VEGF-induced VEGFR-2 phosphorylation. In vivo studies showed fruquintinib inhibited tumor growth in a tumor xenograft mouse model of colon cancer.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling.
Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or new neurologic symptoms.
Advise patients that fruquintinib may increase the risk of bleeding and to contact their healthcare provider for unusual, severe, or persistent bleeding, bruising, or symptoms of bleeding, such as lightheadedness.
Advise patients to contact their healthcare provider if they experience signs and symptoms of infection.
Advise patients to contact a healthcare provider immediately if they experience severe abdominal pains, or other symptoms of gastrointestinal 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.
Advise patients that they will need to undergo laboratory tests to monitor for proteinuria and to contact their healthcare provider for signs or symptoms of proteinuria.
Risk of palmar-plantar erythrodysesthesia (PPE); advise patients to contact their healthcare provider for progressive or intolerable rash.
Risk of posterior reversible encephalopathy syndrome (PRES); advise patients to immediately contact their healthcare provider for new onset or worsening neurological function.
Advise patients that fruquintinib may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure.
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 females to inform their healthcare provider if they are pregnant or become pregnant. Inform females of the risk to a fetus and potential loss of pregnancy.
Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of fruquintinib.
Advise males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks following the last dose of fruquintinib.
Advise patients not to breastfeed during treatment with fruquintinib and for 2 weeks after the last dose of fruquintinib.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.