Krazati Drug Information

• The following clinically significant adverse reactions are described elsewhere in the labeling:
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ]
• QTc Interval Prolongation [see Warnings and Precautions (5.2) ]
• Hepatotoxicity [see Warnings and Precautions (5.3) ]
• Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.4) ]
• Single agent use in NCSLC: The most common adverse reactions (≥ 25%) were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite. The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils and increased alkaline phosphatase. ( 6.1 )
• In combination with cetuximab in CRC: The most common adverse reactions (≥ 25%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, and cough. The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased potassium, decreased magnesium, decreased hemoglobin, increased aspartate aminotransferase, increased lipase, decreased albumin, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 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 reflect exposure to adagrasib as a single agent at 600 mg orally twice daily in 366 patients with NSCLC and other solid tumors enrolled in KRYSTAL-1 and KRYSTAL-12 (NCT04685135), respectively. Among 366 patients who received adagrasib, 39% of patients were exposed for 6 months or longer and 12% were exposed for greater than one year. In this pooled safety population, the most common (≥ 25%) adverse reactions were nausea (70%), diarrhea (69%), vomiting (57%), fatigue (55%), musculoskeletal pain (38%), hepatotoxicity (37%), renal impairment (33%), edema (30%), dyspnea (26%), and decreased appetite (29%). In this pooled safety population, the most common Grade 3 or 4 (≥ 2%) laboratory abnormalities were decreased lymphocytes (20%), decreased hemoglobin (7%), increased alanine aminotransferase (4.5%), increased aspartate aminotransferase (4.2%), hypokalemia (3.6%), hyponatremia (3.4%), increased lipase (2.5%), decreased leukocytes (2.5%), decreased neutrophils (2.3%), and increased alkaline phosphatase (2.0%). The data described in WARNINGS AND PRECAUTIONS and below also reflects exposure to adagrasib in combination with cetuximab in 94 patients with KRAS G12C-mutated, locally advanced or metastatic CRC in KRYSTAL-1. Non-Small Cell Lung Cancer The safety of adagrasib was evaluated in patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC in KRYSTAL-1 [see Clinical Studies (14.1) ] . Patients received adagrasib 600 mg orally twice daily (n = 116). Among patients who received adagrasib, 45% were exposed for 6 months or longer and 4% were exposed for greater than one year. The median age of patients who received adagrasib was 64 years (range 25 to 89), 56% female, 84% White, 8% Black or African American, and 4.3% Asian. Serious adverse reactions occurred in 57% of patients who received adagrasib. Serious adverse reactions in ≥ 2% of patients were pneumonia (17%), dyspnea (9%), renal impairment (8%), sepsis (5%), hypoxia (4.3%), pleural effusion (4.3%), respiratory failure (4.3%), anemia (3.4%), cardiac failure (3.4%), hyponatremia (3.4%), hypotension (3.4%), muscular weakness (3.4%), pyrexia (3.4%), dehydration (2.6%), diarrhea (2.6%), mental status changes (2.6%), pulmonary embolism (2.6%), and pulmonary hemorrhage (2.6%). Fatal adverse reactions occurred in 11% of patients who received adagrasib due to pneumonia (3.4%), respiratory failure (1.7%), sudden death (1.7%), cardiac failure (0.9%), cerebrovascular accident (0.9%), mental status change (0.9%), pulmonary embolism (0.9%), and pulmonary hemorrhage (0.9%). Permanent discontinuation of adagrasib due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent discontinuation of adagrasib occurring in two patients each (1.7%) were pneumonia and pneumonitis and occurring in one patient each (0.9%) were cerebrovascular accident, dyspnea, decreased ejection fraction, encephalitis, gastrointestinal obstruction, hemorrhage, hepatotoxicity, hypotension, muscular weakness, pulmonary embolism, pyrexia, respiratory failure and sepsis. Dose interruptions of adagrasib due to an adverse reaction occurred in 77% of patients. Adverse reactions requiring dosage interruption in ≥ 2% of patients who received adagrasib included nausea, hepatotoxicity, fatigue, vomiting, pneumonia, renal impairment, diarrhea, QTc interval prolongation, anemia, dyspnea, increased lipase, decreased appetite, dizziness, hyponatremia, muscular weakness, increased amylase, pneumonitis, sepsis and decreased weight. Dose reductions of adagrasib due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients who received adagrasib included hepatotoxicity, fatigue, nausea, diarrhea, vomiting, and renal impairment. The most common adverse reactions (≥ 20%) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium. Table 3 summarizes the adverse reactions in KRYSTAL-1. Table 3: Adverse Reactions (≥ 20%) in Patients with KRAS G12C-mutated NSCLC Who Received Adagrasib in KRYSTAL-1 Adverse Reaction Adagrasib N = 116 All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea Grouped term. 70 0.9 Nausea 69 4.3 Vomiting 56 0.9 Constipation 22 0 Abdominal pain 21 0 General Disorders and Administration Site Conditions Fatigue 59 7 Edema 32 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 41 7 Hepatobiliary Disorders Hepatotoxicity , Hepatotoxicity includes mixed liver injury, blood alkaline phosphatase increased, alanine aminotransferase increased, aspartate aminotransferase increased, liver function test increased, blood bilirubin increased, and bilirubin conjugated increased. 37 10 Renal and Urinary Disorders Renal impairment , Renal impairment includes acute kidney injury and increased blood creatinine. 36 6 Respiratory Dyspnea 35 10 Cough 24 0.9 Metabolism and Nutrition Disorders Decreased appetite 30 4.3 Infections and Infestations Pneumonia 24 17 Nervous System Disorders Dizziness 23 0.9 Cardiac Disorders Electrocardiogram QT prolonged 20 6 Table 4 summarizes the laboratory abnormalities in KRYSTAL-1. Table 4: Select Laboratory Abnormalities Occurring (≥ 25%) That Worsened from Baseline in Patients with KRAS G12C-mutated NSCLC Who Received Adagrasib in KRYSTAL-1 Laboratory Abnormality Adagrasib Denominator used to calculate the rate varied from 106 to 113 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 64 25 Hemoglobin decreased 51 8 Platelets decreased 27 0 Chemistry Aspartate aminotransferase increased 52 6 Sodium decreased 52 8 Creatinine increased 50 0 Albumin decreased 50 0.9 Alanine aminotransferase increased 46 5 Lipase increased 35 1.8 Magnesium decreased 26 0 Potassium decreased 26 3.5 Colorectal Cancer The safety of adagrasib combined with cetuximab was evaluated in 94 patients with KRAS G12C-mutated, locally advanced or metastatic CRC in KRYSTAL-1 [see Clinical Studies (14.2) ] . Patients started treatment with adagrasib 600 mg twice daily in combination with cetuximab weekly (n = 17) or every two weeks (n = 77) . Among patients who received adagrasib in combination with cetuximab, 60% were exposed for greater than 6 months and 12% were exposed for greater than 12 months. Serious adverse reactions occurred in 30% of patients who received adagrasib in combination with cetuximab. The most common serious adverse reactions (≥ 2%) were pneumonia (4.3%), pleural effusion, pyrexia, acute kidney injury, dehydration, and small intestinal obstruction (2.1% each). A fatal adverse reaction of pneumonia occurred in 1 patient who received adagrasib in combination with cetuximab. Adverse reactions leading to discontinuation of adagrasib occurred in 2 patients. Adverse reactions which resulted in permanent discontinuation of adagrasib (1 patient each) included abdominal pain and prolonged QT interval. Adverse reactions leading to dose interruptions of adagrasib occurred in 62% of patients. The most common adverse reactions or laboratory abnormalities leading to dose interruption in ≥ 2% of patients who received adagrasib included diarrhea, nausea, vomiting, abdominal pain, dizziness, headache, pneumonia, alanine aminotransferase increased, aspartate aminotransferase increased, dyspnea, fatigue, pleural effusion, rash, anemia, electrocardiogram QT prolongation, blood bilirubin increased, blood creatinine increased, decreased appetite, dehydration, hemorrhage, hypomagnesemia, lipase increased, muscular weakness, musculoskeletal pain, and pyrexia. Adverse reactions leading to dose reductions of adagrasib occurred in 35% of patients. The most common adverse reactions or laboratory abnormalities leading to dose reductions in ≥ 2% of patients who received adagrasib included fatigue, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, decreased appetite, electrocardiogram QT prolongation, dizziness, acute kidney injury, diarrhea, dysarthria, and vomiting. The most common adverse reactions (≥ 20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, increased alanine aminotransferase, decreased magnesium, decreased albumin, increased lipase, decreased potassium, increased aspartate aminotransferase, increased creatinine, decreased sodium, decreased calcium, increased amylase, and increased alkaline phosphatase. Table 5 summarizes the adverse reactions in patients with metastatic CRC in KRYSTAL-1. Table 5: Adverse Reactions (≥ 20 %) in Patients with KRAS G12C-mutated CRC Received Adagrasib in Combination with Cetuximab in KRYSTAL-1 Adverse Reaction Graded per CTCAE version 5.0. Adagrasib in Combination with Cetuximab N = 94 All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term; includes multiple related terms. 84 4.3 Dry skin 36 0 Gastrointestinal Disorders Nausea 68 2.1 Diarrhea 65 5 Vomiting 57 0 Abdominal pain 30 4.3 Constipation 23 0 General Disorders and Administration Site Conditions Fatigue 57 3.2 Musculoskeletal pain 47 4.3 Edema 28 0 Hepatobiliary Disorders Hepatotoxicity 38 10 Nervous System Disorders Headache 37 4.3 Dizziness 24 2.1 Peripheral neuropathy 20 1.1 Metabolism and Nutrition Disorders Decreased appetite 30 0 Blood and lymphatic system disorders Anemia 27 7 Respiratory Cough 25 0 Other clinically relevant adverse reactions observed in less than 20% of patients were infusion related reactions (15%). Table 6 summarizes the laboratory abnormalities in patients with metastatic CRC in KRYSTAL-1. Table 6: Selected Laboratory Abnormalities (≥ 25%) in Patients Who Received Adagrasib in Combination with Cetuximab in KRYSTAL-1 Laboratory Abnormality Adagrasib in Combination with Cetuximab The denominator used to calculate the rate varied from 82 to 92 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 63 17 Hemoglobin decreased 48 5 Leukocytes decreased 27 1.1 Chemistry Alanine aminotransferase increased 51 2.2 Magnesium decreased 49 7 Albumin decreased 46 2.2 Lipase increased 41 3.3 Potassium decreased 40 9 Aspartate aminotransferase increased 39 4.3 Creatinine increased 30 1.1 Sodium decreased 30 0 Calcium decreased 29 1.1 Amylase increased 29 0 Alkaline phosphatase increased 29 1.1

• See full prescribing information for clinically significant drug interactions with KRAZATI. ( 7 )
• Strong CYP3A4 Inducers : Avoid concomitant use. ( 7.1 )
• Strong CYP3A4 Inhibitors : Avoid concomitant use until adagrasib concentrations have reached steady state. ( 7.1 )
• Sensitive CYP3A4 Substrates : Avoid concomitant use with sensitive CYP3A4 substrates. ( 7.2 )
• Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates : Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions. ( 7.2 )
• Drugs That Prolong QT Interval : Avoid concomitant use with KRAZATI. ( 7.3 ) 7.1 Effects of Other Drugs on KRAZATI Strong CYP3A4 Inducers Avoid concomitant use of KRAZATI with strong CYP3A inducers. Adagrasib is a CYP3A4 substrate. Concomitant use of KRAZATI with a strong CYP3A inducer reduces adagrasib exposure [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of KRAZATI. Strong CYP3A4 Inhibitors Avoid concomitant use of KRAZATI with strong CYP3A inhibitors until adagrasib concentrations have reached steady state (after approximately 8 days). Adagrasib is a CYP3A4 substrate. If adagrasib concentrations have not reached steady state, concomitant use of a strong CYP3A inhibitor will increase adagrasib concentrations, [see Clinical Pharmacology (12.3) ], which may increase the risk of KRAZATI adverse reactions. 7.2 Effects of KRAZATI on Other Drugs Sensitive CYP3A Substrates Avoid concomitant use of KRAZATI with sensitive CYP3A substrates unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP3A inhibitor. Concomitant use with KRAZATI increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Sensitive CYP2C9 Substrates Avoid concomitant use of KRAZATI with sensitive CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP2C9 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2C9 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Sensitive CYP2D6 Substrates Avoid concomitant use of KRAZATI with sensitive CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP2D6 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. P-gp Substrates Avoid concomitant use of KRAZATI with P-gp substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a P-gp inhibitor. Concomitant use with KRAZATI increases exposure of P-gp substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. 7.3 Drugs That Prolong QTc Interval Avoid concomitant use of KRAZATI with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, monitor electrocardiogram and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.2) ]. Withhold KRAZATI if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Dosage and Administration (2.3) ]. Adagrasib causes QTc interval prolongation [see Clinical Pharmacology (12.2) ]. Concomitant use of KRAZATI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death [see Warnings and Precautions (5.2) ].

Pregnancy Risk Summary There are no available data on the use of KRAZATI in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during the period of organogenesis did not cause adverse development effects or embryo-fetal lethality at exposures below the human exposure at the recommended dose of 600 mg twice daily (see Data). 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 a rat embryo-fetal development study, once daily oral administration of adagrasib to pregnant rats during the period of organogenesis resulted in maternal toxicity (reduced body weight and food intake, and adverse clinical signs leading to moribund condition and early termination) and lower fetal body weight at 270 mg/kg dose level (approximately 2 times the recommended dose of 600 mg twice daily based on body surface area ). Adagrasib induced skeletal malformations, such as bent limbs, and skeletal variations, such as bent scapula, wavy ribs, and supernumerary short cervical ribs at 270 mg/kg, which were secondary to maternal toxicity and reduced fetal body weight.

In a rabbit embryo-fetal development study, once daily oral administration of adagrasib during the period of organogenesis resulted in lower fetal body weight and increased litter frequency of unossified sternebra at 30 mg/kg (approximately 0.11 times the human exposure based on area under the curve at the clinical dose of 600 mg twice daily). This skeletal variation was associated with maternal toxicities, including reduced mean body weight and decreased food consumption. Adagrasib exposure did not cause adverse developmental effects and did not affect embryo-fetal survival in rabbits at doses up to 30 mg/kg once daily.

Pediatric Use The safety and effectiveness of KRAZATI has not been established in pediatric patients.