Fruzaqla

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.

5. 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. ( 2.2 , 5.1 ) 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. ( 2.2 , 5.2 ) Infections: Monitor for infection during treatment and withhold FRUZAQLA during active infections. Do not start FRUZAQLA in patients with active infections. ( 5.3 ) Gastrointestinal (GI) Perforation: Periodically monitor for GI perforation. Permanently discontinue FRUZAQLA in patients who develop GI perforation or fistula. ( 5.4 ) Hepatotoxicity: Monitor liver laboratory tests prior to the start of FRUZAQLA and periodically during treatment. Withhold, reduce the dose, or permanently discontinue based on severity. ( 2.2 , 5.5 ) Proteinuria: Monitor urine protein. Discontinue FRUZAQLA for nephrotic syndrome ( 2.2 , 5.6 ) Palmar-Plantar Erythrodysesthesia: Withhold FRUZAQLA based on severity. ( 2.2 , 5.7 ) Posterior Reversible Encephalopathy Syndrome (PRES): Immediately discontinue FRUZAQLA if PRES is suspected and confirmed via Magnetic Resonance Imaging (MRI). ( 5.8 ) 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. ( 5.9 ) 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. ( 5.10 ) 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. ( 5.11 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.12 , 8.1 , 8.3 ) 5.1. Hypertension FRUZAQLA can cause hypertension. Hypertension occurred in 450 of 911 (49%) patients with mCRC treated with FRUZAQLA, 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 FRUZAQLA. Do not initiate FRUZAQLA 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 FRUZAQLA based on the severity of hypertension [see Dosage and Administration (2.2) ] . 5.2. Hemorrhagic Events FRUZAQLA can cause serious hemorrhagic events, which may be fatal. In 911 patients with mCRC treated with FRUZAQLA, 6% of patients experienced a gastrointestinal hemorrhage, including 13 patients (1%) with a Grade ≥3 event and 2 patients with fatal hemorrhages. Permanently discontinue FRUZAQLA in patients with severe or life-threatening hemorrhage. Monitor the International Normalized Ratio (INR) levels in patients receiving anticoagulants [see Dosage and Administration (2.2) ] . 5.3. Infections FRUZAQLA can cause an increased risk of infections, including fatal infections. In 781 patients treated with FRUZAQLA 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 FRUZAQLA, the most common infections were urinary tract infections (6.8%…

4. CONTRAINDICATIONS None. None. ( 4 )

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.

8.1. 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.

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…