Fruzaqla Drug Information
Generic name: FRUQUINTINIB
Uses of 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.
Dosage & Administration of Fruzaqla
| First dose reduction | 4 mg orally once daily |
|---|---|
| Second dose reduction | 3 mg orally once daily |
Side Effects of Fruzaqla
Vascular Hypertension 38 14 9 0.9 Gastrointestinal Stomatitis 31 2.2 7.8 0.4
Abdominal Pain 25 3.5 20 3 Diarrhea 24 3.7 11 0 Endocrine Disorders Hypothyroidism 21 0.4 0.4 0 Skin and Subcutaneous Palmar-plantar erythrodysesthesia (hand-foot skin reactions) 19 6 2.6 0 Renal Proteinuria 18 1.8 5
Respiratory Dysphonia 18 0 5 0 Musculoskeletal Musculoskeletal Pain 16 1.1 7
0 Arthralgia 11 0.9 4.3 0 Other important adverse reactions (all grades) that occurred in <10% of patients treated with FRUZAQLA included urinary tract infection (4.6%), epistaxis (3.9%), proctalgia (3.5%), pneumonia (2.4%), gastrointestinal hemorrhage (1.5%), gastrointestinal perforation (1.3%), pancreatitis (0.7%), thrombotic microangiopathy (0.2%), and posterior reversible encephalopathy syndrome (0.2%). Table 4 provides laboratory abnormalities observed in FRESCO-2. Table 4: Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in FRESCO-2 Laboratory Graded according to NCI CTCAE version 5.0. Abnormality FRUZAQLA (N=456) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: FRUZAQLA (range: 409-444) and placebo (range: 195-216). Placebo (N=230) All Grade (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Triglycerides Increased 53 2.8 22
Albumin Decreased 35 1.6 32 1.4 Sodium Decreased 35 1.1 27 0.9
Alanine Aminotransferase Increased 34 5 22
Platelets Decreased 30 0.2 4.7 0 Activated Partial Thromboplastin Time Increased 21
2.7 18
Other clinically relevant laboratory abnormalities (all grades) that occurred in <20% of
patients treated with FRUZAQLA included pancreatic enzymes increased (3.9%). FRESCO Study The safety of FRUZAQLA was evaluated in FRESCO, a randomized, double-blind, placebo-controlled study . Patients received either FRUZAQLA 5 mg daily for the first 21 days of each 28-day cycle plus BSC (n=278) or matching placebo plus BSC (n=137). The median duration of therapy with FRUZAQLA was 3.68 months (range: 0.3 to 22.1 months). Serious adverse reactions occurred in 15% of patients treated with FRUZAQLA. Serious adverse reactions in ≥2% of patients included intestinal obstruction (2.9%) and hemorrhage (2.2%). Fatal adverse reaction(s) occurred in 7 (2.5%) patients who received FRUZAQLA including cerebral infarction (n=1), gastrointestinal hemorrhage (n=1), hemoptysis (n=1), bacterial infection (n=1), lung/lower respiratory infection (n=2), and multiple organ dysfunction (n=1). Adverse reactions leading to treatment discontinuation occurred in 15% of patients who received FRUZAQLA. Adverse reactions leading to treatment discontinuations of FRUZAQLA in ≥1% were intestinal obstruction, proteinuria and hepatic function abnormalities. Dose interruptions of FRUZAQLA due to an adverse reaction occurred in 35% of patients. Adverse reactions leading to dose interruptions of FRUZAQLA in ≥2% of patients were PPE, proteinuria, platelet count decreased, ALT increased, hypertension, and diarrhea.
Dose reductions of FRUZAQLA due to an adverse reaction occurred in 24% of patients. Adverse reactions leading to dose reduction of FRUZAQLA in ≥2% of patients were PPE, proteinuria, and hypertension. Table 5 summarizes the adverse reactions in FRESCO. Table 5: Adverse Reactions (≥10%) in Patients who Received FRUZAQLA and with a Difference Between Arms of ≥5% Compared to Placebo in FRESCO (All Grades) Adverse Reaction Fruquintinib (N=278) Placebo (N=137) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Vascular Hypertension Represents a composite of multiple related terms. 61 23 17
Hemorrhage 28 1.1 14 0 Renal Proteinuria 55 4.7 30 0 Skin
and Subcutaneous Palmar-plantar erythrodysesthesia (hand-foot skin reactions) 49 11 2.9 0 Respiratory Dysphonia 38 0 1.5 0 Throat Pain 10 0 1.5 0 Gastrointestinal Stomatitis 33 0.7 2.9 0 Abdominal Pain 29 4 17
Diarrhea 25 3.6 5 0 General Fatigue 25 2.5 13 1.5 Metabolism
Anorexia 21 1.4 9 0 Musculoskeletal Musculoskeletal Pain 22 2.2 6
Back Pain 15 1.8 7 0 Arthralgia 13 0.4 2.2 0 Endocrine
Disorders Hypothyroidism 17 0 2.2 0 Other clinically important adverse reactions (all grades) that occurred in <10% of patients treated with FRUZAQLA included urinary tract infection (9%), rash (9%), upper respiratory tract infection (4.7%), proctalgia (3.6%), pneumonia (2.9%), and gastrointestinal perforation or fistula (2.2%). Table 6 provides laboratory abnormalities observed in FRESCO. Table 6: Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in FRESCO Laboratory Graded according to NCI CTCAE version 4.03. Abnormality FRUZAQLA (N=278) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: FRUZAQLA (range: 257-277) and placebo (range: 126-134). Placebo (N=137) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Creatinine Increased 87 0.7 75
Alkaline Phosphatase Increased 40 4.3 34 6 Bilirubin Increased 39 4.7 34
8 Alanine Aminotransferase Increased 33 2.2 18
Sodium Decreased 33 6 31 5 Urate Increased 26 26 22 22
Calcium Decreased 25 0.4 13 0 Potassium Decreased 22 1.8 15
Other clinically relevant laboratory abnormalities (all grades) that occurred in <20% of
patients treated with FRUZAQLA included pancreatic enzymes increased (4.3%).
Warnings & Cautions for Fruzaqla
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.
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 of FRUZAQLA and periodically during treatment. Withhold, reduce the dose, or permanently discontinue based on severity. Proteinuria: Monitor urine protein.
Discontinue FRUZAQLA for nephrotic syndrome Palmar-Plantar Erythrodysesthesia: Withhold FRUZAQLA based on severity. 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. 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 . 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 . 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%), upper respiratory tract infections (3.2%) and pneumonia (2.5%); fatal infections included pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract infection (0.1%), and septic shock (0.1%). Withhold FRUZAQLA for Grade 3 or 4 infections, or worsening infection of any grade. Resume FRUZAQLA at the same dose when the infection has resolved. 5.4. Gastrointestinal Perforation FRUZAQLA can cause gastrointestinal perforation.
In 911 patients with mCRC treated with FRUZAQLA, 12 patients (1.3%) experienced a Grade ≥3 gastrointestinal perforation, including one fatal event. Permanently discontinue FRUZAQLA in patients who develop gastrointestinal perforation or fistula. 5.5. Hepatotoxicity FRUZAQLA can cause liver injury. In 911 patients with mCRC treated with FRUZAQLA, 48% experienced increased ALT or AST, including Grade ≥3 events in 5%, and fatal events in 0.2%. Median time to first onset of elevated liver enzymes was 29 days from first dose of FRUZAQLA. Monitor liver function tests (ALT, AST, and bilirubin) before initiation and periodically throughout treatment with FRUZAQLA. Temporarily hold and then reduce or permanently discontinue FRUZAQLA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests . 5.6. Proteinuria FRUZAQLA can cause proteinuria.
In 911 patients with mCRC treated with FRUZAQLA, 36% experienced proteinuria and 2.5% of patients experienced Grade ≥3 events. Median time to first onset of proteinuria was 22 days from first dose of FRUZAQLA. Monitor for proteinuria before initiation and periodically throughout treatment with FRUZAQLA. For proteinuria ≥2 g/24 hours, withhold FRUZAQLA until improvement to ≤Grade 1 proteinuria, resume FRUZAQLA at a reduced dose. Discontinue FRUZAQLA in patients who develop nephrotic syndrome. 5.7. Palmar-Plantar Erythrodysesthesia (PPE) FRUZAQLA can cause PPE. In 911 patients with mCRC treated with FRUZAQLA, PPE occurred in 35%, including 8% with Grade 3 events.
Median time to first onset of PPE was 19 days from first dose of FRUZAQLA. Based on severity, withhold FRUZAQLA and then resume at the same or reduced dose. 5.8. Posterior Reversible Encephalopathy Syndrome (PRES) FRUZAQLA can cause PRES, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI. PRES occurred in one of 911 patients with mCRC treated with FRUZAQLA. Perform an evaluation for PRES in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue FRUZAQLA in patients who develop PRES. 5.9. Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. In 911 patients with mCRC treated with FRUZAQLA, 1 patient experienced a Grade 2 event of wound dehiscence.
Do not administer FRUZAQLA for at least 2 weeks prior to major surgery. Do not administer FRUZAQLA for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of FRUZAQLA after resolution of wound healing complications has not been established. 5.10. Arterial Thromboembolic Events FRUZAQLA may increase the risk of arterial thromboembolic events.
In 911 patients with mCRC treated with FRUZAQLA, 7 patients (0.8%) experienced an arterial thromboembolic event; additionally, FRUZAQLA studies excluded patients with clinically significant cardiovascular disease, uncontrolled hypertension, or with thromboembolic events within the prior 6 months. Initiation of FRUZAQLA in patients with a recent history of thromboembolic events should be carefully considered. In patients who develop arterial thromboembolism discontinue FRUZAQLA. 5.11. Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF) FRUZAQLA 1 mg capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.
Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. FRUZAQLA 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic reactions. 5.12. Embryo-Fetal Toxicity Based on findings in animal studies and its mechanism of action, FRUZAQLA can cause fetal harm when administered to pregnant women. In an embryo-fetal developmental study in rats, embryotoxic and teratogenic effects were observed at exposures below the clinical exposure . Advise pregnant women of the potential risk to a fetus.
Advise females of childbearing potential and males with female partners of childbearing potential to use effective contraception during treatment with FRUZAQLA and for 2 weeks after the last dose .
Drug Interactions with Fruzaqla
7. DRUG INTERACTIONS Strong or Moderate CYP3A Inducers: Avoid concomitant use. 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 , 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 , which may reduce the efficacy of FRUZAQLA.
Pregnancy Safety for 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 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.
Pediatric Use of Fruzaqla
8.4. Pediatric Use The safety and efficacy of FRUZAQLA in patients younger than 18 years of age have not been established.
Contraindications for Fruzaqla
4. CONTRAINDICATIONS None. None.
Clinical Studies of Fruzaqla
Hazard Ratio
The Hazard Ratio and its 95% CI were estimated using a stratified Cox proportional hazards model. (95% CI) 0.66 0.65 P -Value P -Value (2-sided) was calculated using a stratified log-rank test. <0.001 <0.001 PFS Number of patients with event (%) 392 (85%) 213 (93%) 235 (85%) 125 (91%) Median in months (95% CI) 3.7 1.8 3.7
Hazard Ratio (95% CI) 0.32 0.26 P -Value P -Value for the
PFS analysis in FRESCO was not included due to lack of multiplicity adjustment for this analysis. <0.001 - Figure 1: Kaplan-Meier Curve for Overall Survival in FRESCO-2 Figure 2: Kaplan-Meier Curve for Overall Survival in FRESCO figure1 figure2
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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