DRUG INTERACTIONS-(summary)-                         

1. Effects of Other Drugs on FRUZAQLA Strong CYP3A Inducers-

Avoid concomitant use of drugs that are strong CYP3A inducers with FRUZAQLA. Concomitant use with a strong CYP3A inducer may decrease fruquintinib Cmax and AUC , which may reduce the efficacy of FRUZAQLA. Moderate CYP3A Inducers If possible, avoid concomitant use of drugs that are moderate CYP3A inducers with FRUZAQLA.

If it is not possible to avoid concomitant use of a moderate CYP3A inducer and fruquintinib, continue to administer FRUZAQLA at the recommended dosage. Concomitant use with a moderate CYP3A inducer may decrease fruquintinib Cmax and AUC, which may reduce the efficacy of FRUZAQLA.

BRIEF SUMMARY

FRUQUINTINIB- (Nov 2023)

Indn-     to treat refractory metastatic colorectal cancer  

Comp-    Capsules: 1 mg and 5 mg    The recommended dose of FRUZAQLA is 5 mg orally once daily, with or without food for the first 21 days of each 28-day cycle.

ADR-  Most common adverse reactions (incidence =20%) are hypertension, palmar-plantar erythrodysesthesia,

CI-   None.

 WARNINGS -                                                                                             • Hypertension: Control blood pressure prior to treatment and monitor during treatment. Manage with anti-hypertensive medications and adjustment of the dose of FRUZAQLA, if necessary. Withhold, dose reduce, or permanently discontinue based on severity of hypertension.

• Hemorrhagic Events: Closely monitor patients who are at risk for bleeding. Withhold, reduce dose, or permanently discontinue FRUZAQLA based on severity and persistence of hemorrhage.

Pat Inform-                                                                                                         

 Hypertension-                                                                                                                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

 Hemorrhages-                                                                                                                  Advise patients that FRUZAQLA 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.

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 47

Name-          FRUZAGLA

Active ingedient-     Fruquintinib

Indication              to treat refractory metastatic colorectal cancer                                                                          

Date  of approval       11/15/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                             FRUZAQLA safely and effectively.

See full prescribing information for FRUZAQLA. FRUZAQLA™ (fruquintinib) capsules, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 FRUZAQLA is a kinase inhibitor 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.

 DOSAGE AND ADMINISTRATION-

 The recommended dose of FRUZAQLA is 5 mg orally once daily, with or without food for the first 21 days of each 28-day cycle.

 DOSAGE FORMS AND STRENGTHS -

Capsules: 1 mg and 5 mg. 

 ADVERSE REACTIONS -

 Most common adverse reactions (incidence =20%) are hypertension, palmar-plantar erythrodysesthesia,

CONTRAINDICATIONS-

 None.

 WARNINGS AND PRECAUTIONS-

 • Hypertension: Control blood pressure prior to treatment and monitor during treatment. Manage with anti-hypertensive medications and adjustment of the dose of FRUZAQLA, if necessary. Withhold, dose reduce, or permanently discontinue based on severity of hypertension.

• Hemorrhagic Events: Closely monitor patients who are at risk for bleeding. Withhold, reduce dose, or permanently discontinue FRUZAQLA based on severity and persistence of hemorrhage.

 • Infections: Monitor for infection during treatment and withhold FRUZAQLA during active infections. Do not start FRUZAQLA in patients with active infections.

 • Gastrointestinal (GI) Perforation: Periodically monitor for GI perforation. Permanently discontinue FRUZAQLA in patients who develop GI perforation or fistula.

 • Hepatotoxicity: Monitor liver laboratory tests prior to the start

o Proteinuria: Monitor urine protein. Discontinue FRUZAQLA for nephrotic syndrome

 • Palmar-Plantar Erythrodysesthesia: Withhold FRUZAQLA based on sever

• Posterior Reversible Encephalopathy Syndrome (PRES): Immediately discontinue FRUZAQLA if PRES is suspected and confirmed via Magnetic Resonance Imaging (MRI)

 • Impaired Wound Healing: Withhold FRUZAQLA for 2 weeks before major surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of FRUZAQLA after resolution of wound healing complications has not been established.

 • Arterial Thromboembolic Events: Initiation of FRUZAQLA in patients with a recent history of thromboembolic events should be carefully considered. Discontinue FRUZAQLA in patients who develop arterial thromboembolism.

 • Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF): Contains FD&C Yellow No. 5 (tartrazine) and No. 6 (sunset yellow FCF) as color additives, which may cause allergic reactions (including bronchial asthma) in certain susceptible patients.

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and to use effective contraception.

 ADVERSE RE

DOSAGE AND ADMINISTRATION-

 The recommended dose of FRUZAQLA is 5 mg orally once daily, with or without food for the first 21 days of each 28-day cycle.

 DOSAGE FORMS AND STRENGTHS -

Capsules: 1 mg and 5 mg. 

 PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypertension-                                                                                                                 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

 Hemorrhages-                                                                                                                  Advise patients that FRUZAQLA 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.

Infections-                                                                                                                   Advise patients to contact their healthcare provider if they experience signs and symptoms of infection 

Gastrointestinal Perforation-                                                                                        Advise patients to contact a healthcare provider immediately if they experience severe abdominal pains, or other symptoms of gastrointestinal perforation or fistula

 Hepatotoxicity-                                                                                                         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

Proteinuria-                                                                                                                   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

 Palmar-plantar erythrodysesthesia (PPE)-                                                              Advise patients to contact their healthcare provider for progressive or intolerable rash [

Posterior Reversible Encephalopathy Syndrome (PRES)-                                           Advise patients to immediately contact their healthcare provider for new onset or worsening neurological function

 Impaired Wound Healing-                                                                                       Advise patients that FRUZAQLA may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure

 Arterial Thrombosis-                                                                                                        Advise patients to 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)

Advise patients that FRUZAQLA 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 FRUZAQLA 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF) which may cause allergic-type reactions

 Embryo-Fetal Toxicity 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 FRUZAQLA

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks following the last dose of FRUZAQLA ].

Lactation-                                                                                                                      Advise patients not to breastfeed during treatment with FRUZAQLA and for 2 weeks after the last dose of FRUZAQLA 

. Distributed by: Takeda Pharmaceuticals America, Inc. Lexington, MA 02421 FRUZAQLA™ is a trademark of HUTCHMED Group Enterprises Limited, used under license. TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited. ©2023 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. FRU380 R1

CLINICAL PHARMACOLOGY

1. 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.

2. Pharmacodynamics-                                                                                              Fruquintinib exposure-response relationships and the time course of pharmacodynamic response are unknown.

Cardiac Electrophysiology-                                                                                              A mean increase in QTc interval >20 milliseconds (ms) was not observed at the approved recommended dosage.

3. Pharmacokinetics-                                                                                                    The fruquintinib steady-state geometric mean (% coefficient of variation [CV]) maximum concentration (Cmax) is 300 ng/mL (28%) and area under the concentration-time curve for the dosing interval (AUC0-24h) is 5880 ng·h/mL (29%) at the recommended dosage.

Absorption-                                                                                                                    The fruquintinib median (min, max) time to Cmax is approximately 2 hours (0, 26 hours).

Effect of Food-                                                                                                                 No clinically significant differences in fruquintinib pharmacokinetics were observed following administration of a high-fat meal (800 to 1000 calories, 50% fat).

Distribution-                                                                                                                   The mean (SD) apparent volume of distribution of fruquintinib is approximately 46 (13) L. Plasma protein binding of fruquintinib is approximately 95%.

Elimination-                                                                                                                    The fruquintinib mean (SD) elimination half-life is approximately 42 (11) hours and the apparent clearance is 14.8 (4.4) mL/min.

Metabolism-                                                                                                                Fruquintinib is primarily eliminated by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) metabolism. CYP3A and to a lesser extent CYP2C8, CYP2C9, and CYP2C19 are the CYP450 enzymes involved in fruquintinib metabolism.

Excretion-                                                                                                               Following oral administration of a 5 mg radiolabeled fruquintinib dose, approximately 60% of the dose was recovered in urine (0.5% unchanged) and 30% of the dose was recovered in feces (5% unchanged).

Specific Populations-                                                                                                       No clinically significant differences in the pharmacokinetics of fruquintinib were observed based on age (18 to 82 years), sex, race (Asian, Black, and White), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), body weight (48 to 108 kg), mild to moderate renal impairment (CrCL 30 to Reference ID: 5275059 89 mL/min), mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST).

The effect of moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) on fruquintinib pharmacokinetics is unknown.

Drug Interaction Studies-                                                                                        Clinical Studies and Model-Informed Approaches Strong CYP3A inducers: Fruquintinib Cmax decreased by 12% and AUCinf by 65% following concomitant use with rifampin (strong CYP3A inducer).

Moderate CYP3A inducers: Fruquintinib Cmax is predicted to decrease by 4% and AUCinf by 32% following concomitant use with efavirenz (moderate CYP3A inducer).

In Vitro Studies Cytochrome P450 Enzymes: Fruquintinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, or an inducer of CYP1A2, CYP2B6, CYP3A.

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

Fruquintinib is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K.

8. USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

 Based on findings in animal studies and its mechanism of action, FRUZAQLA 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 embryo lethality at exposures below the clinical exposure 

There are no data on the use of FRUZAQLA 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.

2. Lactation Risk Summary-                                                                                               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 FRUZAQLA and for 2 weeks after the last dose.

3. Females and Males of Reproductive Potential-                                                       Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating FRUZAQLA. 

Contraception Females and Males 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 FRUZAQLA

4. Pediatric Use-                                                                                                            The safety and efficacy of FRUZAQLA in patients younger than 18 years of age have not been established.

5.Geriatric use                                                                                                                        FRESCO-2, 212 (46%) patients who received FRUZAQLA were =65 years of age and older, of whom 43 (20%) of patients were =75 years. There were no observed overall differences in safety and effectiveness of FRUZAQLA in geriatric compared to younger patients.

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

6. 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 

FRUZAQLA 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). FRUZAQLA is not recommended for use in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST).