Fruzaqla
Generic: FRUQUINTINIB
Basic Information
Manufacturer
Takeda Pharmaceuticals America, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
186d786e-dc8a-45f2-b5e1-01ac0201879f
Indications & Usage
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 )
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 )
Adverse Reactions
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) Placebo (N=230) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General Fatigue Represents a composite of multiple related terms.
53 12 39 4.8 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 0.9 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 1.0 Cholesterol Increased 37 1.9 22 1.9 Aspartate Aminotransferase Increased 36 4.3 24 1.9 Albumin Decreased 35 1.6 32 1.4 Sodium Decreased 35 1.1 27 0.9 Alanine Aminotransferase Increased 34 5 22 1.4 Bilirubin Increased 30 7 21 8 Alkaline Phosphatase Increased 20 1.6 27 0.5 Magnesium Decreased 20 0.5 10 0.5 Hematology Lymphocytes Decreased 30 6 32 4.7 Platelets Decreased 30 0.2 4.7 0 Activated Partial Thromboplastin Time Increased 21 2.7 18 1.5 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 [see Clinical Studies (14.1) ] .
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 2.2 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 1.5 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 1.5 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 1.5 Glucose Increased 43 1.1 31 3.0 Aspartate Aminotransferase Increased 42 3.6 31 1.5 Alkaline Phosphatase Increased 40 4.3 34 6 Bilirubin Increased 39 4.7 34 8 Alanine Aminotransferase Increased 33 2.2 18 1.5 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 2.3 Hematology Platelets Decreased 29 3.6 6 0.7 Hemoglobin Decreased 23 0.7 33 4.5 Other clinically relevant laboratory abnormalities (all grades) that occurred in <20% of patients treated with FRUZAQLA included pancreatic enzymes increased (4.3%).
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) Placebo (N=230) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General Fatigue Represents a composite of multiple related terms.
53 12 39 4.8 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 0.9 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 1.0 Cholesterol Increased 37 1.9 22 1.9 Aspartate Aminotransferase Increased 36 4.3 24 1.9 Albumin Decreased 35 1.6 32 1.4 Sodium Decreased 35 1.1 27 0.9 Alanine Aminotransferase Increased 34 5 22 1.4 Bilirubin Increased 30 7 21 8 Alkaline Phosphatase Increased 20 1.6 27 0.5 Magnesium Decreased 20 0.5 10 0.5 Hematology Lymphocytes Decreased 30 6 32 4.7 Platelets Decreased 30 0.2 4.7 0 Activated Partial Thromboplastin Time Increased 21 2.7 18 1.5 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 [see Clinical Studies (14.1) ] .
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 2.2 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 1.5 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 1.5 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 1.5 Glucose Increased 43 1.1 31 3.0 Aspartate Aminotransferase Increased 42 3.6 31 1.5 Alkaline Phosphatase Increased 40 4.3 34 6 Bilirubin Increased 39 4.7 34 8 Alanine Aminotransferase Increased 33 2.2 18 1.5 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 2.3 Hematology Platelets Decreased 29 3.6 6 0.7 Hemoglobin Decreased 23 0.7 33 4.5 Other clinically relevant laboratory abnormalities (all grades) that occurred in <20% of patients treated with FRUZAQLA included pancreatic enzymes increased (4.3%).