Fruzaqla

— THERAPEUTIC CATEGORIES —
  • Colorectal and other GI cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Fruzaqla Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Fruquintinib 1mg*, 5mg; caps; *contains tartrazine, sunset yellow FCF.

    Pharmacological Class

    Kinase inhibitor.

    How Supplied

    Caps—21

    Storage

    Store at 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C and 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature). 

    Manufacturer

    Takeda Pharmaceutical Company

    Generic Availability

    NO

    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.

    Fruzaqla Indications

    Indications

    In adults with metastatic colorectal cancer (mCRC) 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. 

    Fruzaqla Dosage and Administration

    Adult

    Swallow whole. ≥18yrs: 5mg once daily for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Dose modifications for adverse reactions: see full labeling. 

    Children

    <18yrs: not established. 

    Hepatic Impairment

    Hepatotoxicity

    • ALT or AST >3xULN with total bilirubin ≤2xULN: Withhold and monitor AST/ALT and total bilirubin until resolution to Grade 1 or baseline. Resume at the next lower dose level.
    • ALT or AST >3xULN with concurrent total bilirubin >2xULN (in the absence of cholestasis or hemolysis):  Permanently discontinue.
    • AST or ALT >20xULN or bilirubin >10xULN: Permanently discontinue.

    Other Modifications

    Proteinuria

    • ≥2g proteinuria in 24 hours: Withhold until proteinuria fully resolves or is <1g/24hrs. Upon recovery, resume at the next lower dose level. 
    • Permanently discontinue for nephrotic syndrome or if proteinuria does not recover to <1g/24hrs.

    Palmar-Plantar Erythrodysesthesia

    • Grade 2: Withhold and initiate supportive treatment. If toxicity fully resolves or recovers to Grade 1, resume at the same dose level.
    • Grade 3: Withhold and initiate supportive treatment. If toxicity fully resolves or recovers to Grade 1, resume at the next lower dose level.

    Other Adverse Reactions

    • Grade 3: Withhold. If toxicity fully resolves or recovers to Grade 1, resume at the next lower dose level.
    • Grade 4: Discontinue. Consider resuming at the next lower dose level only if the toxicity is non-life-threatening and fully resolves or recovers to Grade 1 and the potential benefit outweighs the risks.

    Fruzaqla Contraindications

    Not Applicable

    Fruzaqla Boxed Warnings

    Not Applicable

    Fruzaqla Warnings/Precautions

    Warnings/Precautions

    Withhold, reduce dose, or permanently discontinue based on severity of reactions (see full labeling). Control BP prior to treatment; monitor weekly for the 1st month, then at least monthly thereafter and as clinically indicated. Permanently discontinue if severe or life-threatening hemorrhage, GI perforation or fistula develops. Increased risk for infections. Monitor LFTs (ALT, AST, bilirubin; see full labeling), proteinuria prior to and periodically during therapy. Withhold dose if proteinuria ≥2g/24hrs until improvement to ≤Grade 1; resume at reduced dose. Permanently discontinue if nephrotic syndrome or proteinuria not recovered to <1g/24hrs. Evaluate for posterior reversible encephalopathy syndrome (PRES) if symptoms develop; discontinue if occurs. Impaired wound healing: do not give for ≥2 weeks prior to and after major surgery, and until adequate healing. Recent history of thromboembolic events. Discontinue if arterial thromboembolism develops. Hepatic impairment (severe): not recommended; (moderate): not studied. Embryo-fetal toxicity. Advise females of reproductive potential and males (w. female partners) to use effective contraception during and for 2 weeks after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 2 weeks after the last dose). 

    Pregnancy Considerations

    Risk Summary

    • May cause fetal harm when administered to a pregnant woman. No date on the use in pregnant women.

    Nursing Mother Considerations

    Risk Summary

    • No data regarding the presence of fruquintinib or its metabolites in human milk or its effects on a breastfed child or on milk production.
    • Do not breastfeed during and for 2 weeks after the last dose.

    Pediatric Considerations

    Safety and efficacy in patients <18yrs of age: not established.

    Geriatric Considerations

    No observed overall differences in safety and effectiveness of Fruzaqla in geriatric compared to younger patients.

    Hepatic Impairment Considerations

    Mild hepatic impairment (total bilirubin ≤ULN with AST >ULN or total bilirubin >1 to 1.5 times ULN with any AST): no dosage adjustment is recommended.

    Moderate hepatic impairment (total bilirubin >1.5x and <3xULN and any AST): not studied.

    Severe hepatic impairment (total bilirubin >3xULN and any AST): not recommended.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

     

    Fruzaqla Pharmacokinetics

    Absorption

    Median time to Cmax: ~2 hours. 

    Distribution

    Apparent volume of distribution: ~46 L.

    Plasma protein bound: ~95%.

    Metabolism

    CYP3A, CYP2C8, CYP2C9, CYP2C19.

    Elimination

    Renal (60%), fecal (30%). Half-life: 42 hours. Apparent clearance: 14.8 mL/min.

    Fruzaqla Interactions

    Interactions

    May be antagonized by strong CYP3A inducers; avoid concomitant use. If possible, avoid concomitant moderate CYP3A inducers; if unavoidable, continue fruquintinib at recommended dose. Monitor INR with concomitant anticoagulants.

    Fruzaqla Adverse Reactions

    Adverse Reactions

    Hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, asthenia, lab abnormalities; intestinal obstruction, hemorrhagic events, GI perforation, hepatotoxicity.

    Fruzaqla Clinical Trials

    Clinical Trials

    The approval was based on data from two phase 3 trials: FRESCO-2 (ClinicalTrials.gov Identifier: NCT04322539) and FRESCO (ClinicalTrials.gov Identifier: NCT02314819). 

    The FRESCO-2 study was an international, double-blind, placebo-controlled trial that enrolled 691 patients with refractory metastatic colorectal cancer. Study participants (mean age, 64 years; 56% male; 81% White, 9% Asian, 2.9% Black, and 0.7% Native Hawaiian/Pacific Islander) were randomly assigned to receive fruquintinib 5mg orally once daily (n=461) for the first 21 days of each 28-day cycle plus best supportive care (BSC) or placebo (n=230) plus BSC until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); progression free survival (PFS) was an additional outcome measure.

    Findings showed a statistically significant improvement in OS (7.4 months vs 4.8 months; hazard ratio [HR], 0.66 [95% CI, 0.55-.80]; P <.001) and PFS  (3.7 months vs 1.8 months; HR, 0.32 [95% CI, 0.27-0.39]; P <.001) with fruquintinib plus BSC compared with placebo plus BSC.

    The FRESCO trial was a double-blind, placebo-controlled study conducted in China that included 416 patients with refractory metastatic colorectal cancer. Study participants (median age, 56 years; 61% male; 100% Asian) were randomly assigned to receive fruquintinib 5mg orally once daily (n=278) for the first 21 days of each 28-day cycle plus BSC or placebo (n=138) plus BSC until disease progression or unacceptable toxicity. The primary endpoint was OS, with PFS as an additional outcome measure.

    The addition of fruquintinib to BSC resulted in a statistically significant improvement in OS compared with placebo plus BSC (9.3 months vs 6.6 months; HR, 0.65 [95% CI, 0.51-0.83]; P <.001). Median PFS was 3.7 months for the fruquintinib group and 1.8 months for the placebo group (HR, 0.26 [95% CI, 0.21-0.34]. 

    Fruzaqla Note

    Not Applicable

    Fruzaqla Patient Counseling

    Patient Counseling

    Hypertension

    • Monitor blood pressure regularly and contact health care provider if blood pressure is elevated or if symptoms from hypertension develop.

    Hemorrhages

    • May increase the risk of bleeding. Contact health care provider if unusual, severe, or persistent bleeding, bruising, or symptoms of bleeding, such as lightheadedness, develop.

    Infections

    • Contact health care provider if infection occurs.

    Gastrointestinal Perforation

    • Contact health care provider if severe abdominal pains, or other symptoms of gastrointestinal perforation or fistula occur.

    Hepatotoxicity, Proteinuria

    • Patients will need to undergo laboratory tests to monitor liver function and for proteinuria. Contact health care provider if any new symptoms indicating hepatic toxicity or failure, or proteinuria occur.

    Palmar-plantar erythrodysesthesia (PPE), Posterior Reversible Encephalopathy Syndrome (PRES) 

    • Contact health care provider if progressive or intolerable rash, or new onset or worsening neurological function, occur.

    Arterial Thrombosis

    • Seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke.

    Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF) 

    • Fruzaqla 1mg contains FD&C Yellow No. 5 (tartrazine) and FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic-type reactions

    Embryo-Fetal Toxicity

    • 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.

    Lactation

    • Do not breastfeed during and for 2 weeks after the last dose.

    Cost Savings Program

    Takeda Oncology Here2Assist

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