Fruzaqla

Dosage and Administration ( 2.2 ) 2/2025

1. INDICATIONS AND USAGE FRUZAQLA 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. 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. ( 1 )

2. 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. ( 2.1 ) 2.1. Recommended Dosage The recommended dose of FRUZAQLA is 5 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take FRUZAQLA with or without food [see Clinical Pharmacology (12.3) ] at approximately the same time each day. Swallow the FRUZAQLA capsule whole. Take a missed dose if less than 12 hours have passed since the missed scheduled dose. Do not take two doses on the same day to make up for a missed dose. Do not take an additional dose if vomiting occurs after taking FRUZAQLA but continue with the next scheduled dose. 2.2. Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 1. Table 1: Recommended Dose Reductions for FRUZAQLA Dose Level FRUZAQLA Dosage First dose reduction 4 mg orally once daily Second dose reduction 3 mg orally once daily Permanently discontinue FRUZAQLA in patients unable to tolerate 3 mg orally once daily. The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for FRUZAQLA Adverse Reaction Severity Severity as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. FRUZAQLA Dosage Modification Hypertension [see Warnings and Precautions (5.1) ] Grade 3 Withhold FRUZAQLA for Grade 3 hypertension that persists despite optimal anti-hypertensive therapy. If hypertension fully resolves or recovers to Grade 1, resume at the next lower dose level. Grade 4 Permanently discontinue FRUZAQLA. Hemorrhagic Events [see Warnings and Precautions (5.2) ] Grade 2 Withhold FRUZAQLA until bleeding fully resolves or recovers to Grade 1. Resume at the next lower dose level. Grade 3 or Grade 4 Permanently discontinue FRUZAQLA. Hepatotoxicity [see Warnings and Precautions (5.5) ] Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times upper limit of normal (ULN), or greater than 3 times baseline if baseline was abnormal; or bilirubin greater than 1.5 times ULN, or greater than 1.5 times baseline if baseline was abnormal Withhold FRUZAQLA and monitor AST, ALT and total bilirubin until resolution to Grade 1 or baseline. Resume at the next lower dose level. ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 2 times ULN (in the absence of cholestasis or hemolysis) Permanently discontinue FRUZAQLA. AST or ALT greater than 20 times ULN if baseline was normal, or greater than 20 times baseline if baseline was abnormal; or bilirubin greater than 10 times ULN if baseline was normal, or greater than 10 times baseline if baseline was abnormal Permanently discontinue FRUZAQLA. Proteinuria [see Warnings and Precautions (5.6) ] 2 grams or greater proteinuria in 24 hours Withhold FRUZAQLA until proteinuria fully resolves or is <1 gram/24 hours. Upon recovery, resume at the next lower dose level. Permanently discontinue FRUZAQLA for nephrotic syndrome or if proteinuria does not recover to <1 gram/24 hours. Palmar-plantar erythrodysesthesia (PPE) [see Warnings and Precautions (5.7) ] Grade 2 Withhold FRUZAQLA and initiate supportive treatment. If toxicity fully resolves or recovers to Grade 1, resume at the same dose level. Grade 3 Withhold FRUZAQLA and initiate supportive treatment. If toxicity fully resolves or recovers to Grade 1, resume at the next lower dose level. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 Withhold FRUZAQLA. If toxicity fully resolves or recovers to Grade 1, resume at the next lower dose level. Grade 4 Discontinue FRUZAQLA. Consider resuming FRUZAQLA 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.

3. DOSAGE FORMS AND STRENGTHS Capsules: 1 mg: size 3 hard gelatin capsule with standard yellow opaque cap and white opaque body, imprinted with “HM013” over “1 mg” on the body in black ink. 5 mg: size 1 hard gelatin capsule with a red opaque cap and white opaque body, imprinted with “HM013” over “5 mg” on the body in black ink. Capsules: 1 mg and 5 mg. ( 3 )

4. CONTRAINDICATIONS None. None. ( 4 )

6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypertension [see Warnings and Precautions (5.1) ] . Hemorrhagic Events [see Warnings and Precautions (5.2) ] . Infections [see Warnings and Precautions (5.3) ] . Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] . Hepatotoxicity [see Warnings and Precautions (5.5) ]. Proteinuria [see Warnings and Precautions (5.6) ] . Palmar-Plantar Erythrodysesthesia (PPE) [see Warnings and Precautions (5.7) ] . Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.8) ] . Most common adverse reactions (incidence ≥20%) are hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-844-662-8532 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS and below reflects exposure to FRUZAQLA as a single agent in 911 patients with mCRC who were enrolled in three randomized, placebo-controlled studies (FRESCO-2, FRESCO and 2012-013-00CH1) (N=781); three open-label studies (2009-013-00CH1, 2012-013-00CH3 and 2015-013-00US1) (N=124); and an open-label lead-in cohort of FRESCO-2 (N=6). Among the 911 patients who received FRUZAQLA, 23% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. These patients received at least one dose of FRUZAQLA at the recommended dosage of 5 mg daily for the first 21 days of each 28-day cycle. The median age was 60 years (range: 23 to 82) and 34% were 65 years of age or older. The most common adverse reactions (incidence ≥20%) that occurred in pooled monotherapy studies were hypertension, PPE, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia. Metastatic Colorectal Cancer FRESCO-2 Study The safety of FRUZAQLA was evaluated in FRESCO-2, a randomized, double-blind, placebo-controlled study [see Clinical Studies (14.1) ] . Patients received either FRUZAQLA 5 mg daily for the first 21 days of each 28-day cycle plus best supportive care (BSC) (n=456) or matching placebo plus BSC (n=230). The median duration of therapy with FRUZAQLA was 3 months (range: 0.3 to 19.1 months). Serious adverse reactions occurred in 38% of patients treated with FRUZAQLA. Serious adverse reactions in ≥2% of patients treated with FRUZAQLA included hemorrhage (2.2%) and gastrointestinal perforation (2.0%). Fatal adverse reaction(s) occurred in 14 (3.1%) patients who received FRUZAQLA. Fatal adverse reactions occurring in ≥2 patients include pneumonia (n=3), sepsis/septic shock (n=2), and hepatic failure/encephalopathy (n=2). Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with FRUZAQLA. Adverse reactions leading to treatment discontinuations of FRUZAQLA in ≥1% of patients were asthenia and gastrointestinal perforation. Dose interruptions of FRUZAQLA due to an adverse reaction occurred in 47% of patients. Adverse reactions leading to dose interruptions of FRUZAQLA in ≥2% of patients were PPE, proteinuria, asthenia, abdominal pain, hypertension, vomiting, and diarrhea. Dose reductions of FRUZAQLA due to an adverse reaction occurred in 24% of patients. Adverse reactions leading to dose reductions of FRUZAQLA in ≥2% of patients were PPE, hypertension and asthenia. Table 3 summarizes the adverse reactions in FRESCO-2. Table 3: Adverse Reactions (≥10%) in Patients who Received FRUZAQLA and with a Difference Between Arms of ≥5% Compared to Placebo in FRESCO-2 (All Grades) Adverse Reaction FRUZAQLA (N=456) Pla …

7. DRUG INTERACTIONS Strong or Moderate CYP3A Inducers: Avoid concomitant use. ( 7.1 ) 7.1. 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 C max and AUC [see Clinical Pharmacology (12.3) ] , 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 C max and AUC [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of FRUZAQLA.

8. USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1. 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 (see Data ) . 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. Data Animal Data In an embryo-fetal developmental study in pregnant rats, daily oral administration of fruquintinib at doses ≥0.1 mg/kg [approximately 0.2 times the recommended clinical dose of 5 mg based on body surface area (BSA)] during the period of organogenesis resulted in fetal external (edema and head and tail abnormalities), visceral, and skeletal malformations. At doses of 0.25 mg/kg (approximately 0.5 times the recommended clinical dose of 5 mg based on BSA), an increase in post-implantation loss and reduction in live fetuses was observed. 8.2. 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. 8.3. 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 [see Warnings and Precautions (5.11) and Nonclinical Toxicology (13.1) ] . Infertility Females and Males There are no data on the effects of fruquintinib on human fertility. Based on findings in animal studies, FRUZAQLA may impair female fertility [see Nonclinical Toxicology (13.1) ] . 8.4. Pediatric Use The safety and efficacy of FRUZAQLA in patients younger than 18 years of age have not been established. 8.5. Geriatric Use In 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. 8.6. 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 [see Clinical Pharmacology (12.3) ] . 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).

12.1. Mechanism of Action Fruquintinib is a small molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 with IC 50 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.

11. DESCRIPTION Fruquintinib is a kinase inhibitor with the chemical name 6-[(6,7-dimethoxyquinazolin-4-yl)oxy]- N ,2-dimethyl-1-benzofuran-3-carboxamide. Its molecular formula is C 21 H 19 N 3 O 5 , which corresponds to a molecular weight of 393.39 g/mol. Fruquintinib has the following chemical structure: Fruquintinib is a white to off-white powder with a dissociation constant (pK a ) of 2.78. The aqueous solubility of fruquintinib is pH-dependent with a solubility of 0.9 μg/mL at pH 6.8 that increases under acidic conditions to 129.9 μg/mL at pH 1. FRUZAQLA (fruquintinib) capsules for oral administration contain 1 mg or 5 mg of fruquintinib. The inactive ingredients are corn starch, microcrystalline cellulose, and talc. The 1 mg capsule shell contains FD&C Yellow No. 5 (tartrazine), FD&C Yellow No. 6 (sunset yellow FCF), gelatin, and titanium dioxide. The 5 mg capsule shell contains FD&C Blue No. 1 (brilliant blue FCF), FD&C Red No. 40 (allura red AC), gelatin, and titanium dioxide. The printing ink for 1 mg and 5 mg capsules contains butanol, dehydrated alcohol, ferrosoferric oxide, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution. Chemical Structure

16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied Capsule Strength Description Package Configuration NDC Number 1 mg Size 3 hard gelatin capsule with yellow opaque cap and white opaque body, imprinted with “HM013” over “1 mg” on the body in black ink White high-density polyethylene (HDPE) bottle with child-resistant closure packaged in a carton. Each bottle contains 21 capsules. 63020-210-21 5 mg Size 1 hard gelatin capsule with a red opaque cap and white opaque body, imprinted with “HM013” over “5 mg” on the body in black ink 63020-225-21 Storage and handling 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). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.