Fruzaqla (fruquintinib)

If adverse reactions occur during fruquintinib therapy, temporary interruption, dosage reduction, and/or permanent discontinuance of the drug may be necessary.

If dosage modification is required, reduce the dosage of fruquintinib as described in Table 1. Permanently discontinue fruquintinib in patients who cannot tolerate a dosage of 3 mg orally once daily.

Table 1. Recommended Dosage Reduction for Fruquintinib Toxicity.

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 dosage modifications for fruquintinib based on adverse reaction.

Table 2. Recommended Dosage Modification for Fruquintinib Adverse Reactions.

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 disco ntinue 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 upper limit of normal (ULN), or >3 times baseline if baseline was abnormal; or bilirubin >1.5 times ULN, or >1.5 times baseline if baseline was abnormal: 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 if baseline was normal, or >20 times baseline if baseline was abnormal; or bilirubin >10 times ULN if baseline was normal, or >10 times baseline if baseline was abnormal: 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 doe s not recover to <1 gram/24 hours: Permanently discontinue fruquintinib. Palmar-plantar erythrodysesthesia Grade 2: Temporarily withhold (PPE) 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 r esolution 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.

Level of severity as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Fruquintinib is available as capsules containing 1 or 5 mg of the drug.

Administer fruquintinib orally with or without food, at approximately the same time each day. Swallow fruquintinib capsules whole.

If a dose of fruquintinib is missed, take the missed dose if <12 hours have elapsed; do not take 2 doses on the same day to make up for a missed dose.

If vomiting occurs after taking a dose, do not administer an additional dose but continue with the next scheduled dose.

Store fruquintinib capsules at 20-25degreesC (brief excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

Fruquintinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A, and to a lesser extent by CYP2C8, CYP2C9, and CYP2C19. Fruquintinib also undergoes metabolism via non-CYP mediated routes (i.e., sulfation and glucuronidation).

In vitro studies indicate that fruquintinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, or CYP3A.

Fruquintinib is not a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1, or OATP1B3. Fruquintinib 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.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Fruquintinib/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of fruquintinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of fruquintinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: If possible, avoid concurrent use of moderate inducers of CYP3A4 with fruquintinib. If concurrent use cannot be avoided, continue to administer fruquintinib at the recommended dosage.(1)

DISCUSSION: Concomitant use with efavirenz (moderate CYP3A4 inducer) is predicted to decrease the fruquintinib maximum concentration (Cmax) by 4% and the area-under-curve (AUC) by 32%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Fruquintinib/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of fruquintinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of fruquintinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with fruquintinib.(1)

DISCUSSION: Concomitant use with rifampin (strong CYP3A4 inducer) decreased the fruquintinib maximum concentration (Cmax) by 12% and the area-under-curve (AUC) by 65%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Fruquintinib; Surufatinib/Anticoagulants; Antiplatelets

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of fruquintinib and surufatinib.(1,2)

CLINICAL EFFECTS: Concurrent use of fruquintinib or surufatinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with fruquintinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of fruquintinib.(1) Patients receiving concurrent therapy with surufatinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in INR.If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of surufatinib.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with fruquintinib in three randomized, double-blinded, placebo-controlled clinical trials. The incidence of grade 1 and grade 2 bleeding events was 28.2%, including gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade 3 or higher bleeding events was 2.1% and included gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1) Bleeding has been reported with surufatinib in clinical trials. Grade 1 and 2 bleeding events included gastrointestinal bleeding, blood in the urine, and gum bleeding. The incidence of grade 3 or greater bleeding events was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of patients. The incidence of permanent discontinuation due to bleeding was 2.6% and the incidence of suspension of surufatinib due to bleeding was 3.8%.(2)

*None.

• Lactation

• Hemorrhage
• Hypertension
• Infection
• Invasive surgical procedure
• Pregnancy
• Thromboembolic disorder

• Proteinuria

Adverse effects reported in >=20% of patients receiving fruquintinib include hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

Less Frequent

• Gastrointestinal hemorrhage
• Gastrointestinal obstruction
• Hemorrhage

Rare or Very Rare

• Acute arterial thromboembolism
• Bacterial infection
• Gastrointestinal perforation
• Pancreatitis
• Posterior reversible encephalopathy syndrome
• Sepsis

More Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Arthralgia
• Diarrhea
• Fatigue
• General weakness
• Hyperbilirubinemia
• Hypercholesterolemia
• Hyperglycemia
• Hypertension
• Hypertriglyceridemia
• Hypoalbuminemia
• Hypomagnesemia
• Hyponatremia
• Hypothyroidism
• Lymphopenia
• Musculoskeletal pain
• Palmar-plantar erythrodysesthesia
• Prolonged activated partial thromboplastin time
• Proteinuria
• Stomatitis
• Thrombocytopenic disorder
• Voice change

Less Frequent

• Anorexia
• Elevated serum amylase
• Elevated serum lipase
• Epistaxis
• Hypocalcemia
• Hypokalemia
• Pneumonia
• Rectal pain
• Skin rash
• Upper respiratory infection
• Urinary tract infection
• Vomiting

Rare or Very Rare

• Impaired wound healing
• Lower respiratory infection
• Thrombotic microangiography

No enhanced messaging available.

Safety and effectiveness of fruquintinib in pediatric patients <18 years of age have not been established.

Based on animal data and the mechanism of action of fruquintinib, the drug may cause fetal harm when administered during pregnancy.

In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure. No data are available on the use of fruquintinib in pregnant women.

Verify pregnancy status in females of reproductive potential prior to initiating fruquintinib. Advise pregnant women of the potential fetal risk.

No data are available on the presence of fruquintinib or its metabolites in human milk. The effects of fruquintinib on the breast-fed child or on milk production are unknown.

Due to the potential for serious adverse reactions in the breast-fed child, advise women to avoid breast-feeding while receiving fruquintinib and for 2 weeks following the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the FRESCO-2 study, 46% of patients receiving fruquintinib were >=65 years of age, which included 20% of patients >=75 years of age. No overall differences in safety or effectiveness of fruquintinib were observed between geriatric and younger patients.

In the FRESCO study, 18% of patients receiving fruquintinib were >=65 years of age, and 1 patient was >=75 years of age. No overall differences in safety or effectiveness of fruquintinib were observed between geriatric and younger patients.