Tibsovo Drug Information

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. Acute Myeloid Leukemia In AML, the safety population reflects exposure to TIBSOVO at 500 mg daily in combination with azacitidine or as monotherapy in patients in Studies AG120-C-009 (N=71) and AG120-C-001 (N=213), respectively . In this safety population, the most common adverse reactions including laboratory abnormalities (≥ 25% in either trial) were leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphatase decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia. Newly Diagnosed AML TIBSOVO in Combination with Azacitidine The safety of TIBSOVO was evaluated in AML patients treated in combination with azacitidine, in Study AG120-C-009 . Patients received at least one dose of either TIBSOVO 500 mg daily (N=71) or placebo (N=73). Among patients who received TIBSOVO in combination with azacitidine, the median duration of exposure to TIBSOVO was 6 months (range 0 to 33 months). Thirty-four patients (48%) were exposed to TIBSOVO for at least 6 months and 22 patients (31%) were exposed for at least 1 year.

Common (≥ 5%) serious adverse reactions in patients who received TIBSOVO in combination with azacitidine included differentiation syndrome (8%). Fatal adverse reactions occurred in 4% of patients who received TIBSOVO in combination with azacitidine, due to differentiation syndrome (3%) and one case of cerebral ischemia. Adverse reactions leading to discontinuation of TIBSOVO in ≥2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%). The most common (>5%) adverse reactions leading to dose interruption of TIBSOVO were neutropenia (25%), electrocardiogram QT prolonged (7%), and thrombocytopenia (7%). Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (8%), neutropenia (8%), and thrombocytopenia (1%). The most common adverse reactions and laboratory abnormalities observed in Study AG120-C-009 are shown in Tables 2 and 3. Table 2: Adverse Reactions (≥10%) in Patients with AML Who Received TIBSOVO + azacitidine with a Difference Between Arms of ≥ 2% Compared with Placebo + azacitidine in AG120-C-009 TIBSOVO + Azacitidine N=71 Placebo + Azacitidine N=73 Body System Adverse Reaction All Grades n (%) Grade ≥3 n (%) All Grades n (%) Grade ≥3 n (%) Gastrointestinal disorders Nausea 30 2 28 3 Vomiting Grouped term includes vomiting and retching. 29 0 20 1 Investigations Electrocardiogram QT prolonged 14 7 5 2 Psychiatric Disorders Insomnia 13 1 9 0 Blood system and lymphatic system disorders Differentiation Syndrome Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. 11 7 6 6 Leukocytosis Grouped term includes leukocytosis, white blood cell count increased. 9 0 1 0 Vascular disorders Hematoma Grouped term includes hematoma, eye hematoma, catheter site hematoma, oral mucosa hematoma, spontaneous hematoma, application site hematoma, injection site hematoma, periorbital hematoma. 11 0 3 0 Hypertension Grouped term includes blood pressure increased, essential hypertension, and hypertension. 9 3 6 4 Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes pain in extremity, arthralgia, back pain, musculoskeletal stiffness, cancer pain, and neck pain. 21 3 6 1 Respiratory, thoracic and mediastinal disorders Dyspnea Grouped term includes dyspnea, dyspnea exertional, hypoxia, respiration failure. 14 2 11 4 Nervous system disorders Headache 8 0 2 0 Table 3: Select Laboratory Abnormalities Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown., The denominator used to calculate percentages is the number of treated subjects who can be evaluated for CTCAE criteria for each parameter in each arm. (≥10%) That Worsened from Baseline in Patients with AML Who Received TIBSOVO + azacitidine in AG120-C-009 TIBSOVO + Azacitidine N=71 Placebo + Azacitidine N=73 Parameter All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) Hematology Parameters Leukocytes decreased 46 39 47 42 Platelets decreased 41 30 52 42 Hemoglobin decreased 40 33 48 42 Neutrophils decreased 18 16 25 23 Lymphocytes increased 17 1 7 1 Chemistry Parameters Glucose increased 40 9 34 8 Phosphate decreased 29 7 25 9 Aspartate Aminotransferase increased 26 0 17 0 Magnesium decreased 25 0 19 0 Alkaline Phosphatase increased 23 0 21 0 Potassium increased 17 2 9 1 TIBSOVO Monotherapy The safety profile of single-agent TIBSOVO was studied in 28 adults with newly diagnosed AML treated with 500 mg daily . The median duration of exposure to TIBSOVO was 4.3 months (range 0.3 to 40.9 months). Ten patients (36%) were exposed to TIBSOVO for at least 6 months and 6 patients (21%) were exposed for at least 1 year. Common (≥ 5%) serious adverse reactions included differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES). Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT prolonged (14%) and differentiation syndrome (11%). Two (7%) patients required a dose reduction due to electrocardiogram QT prolonged.

One patient each required permanent discontinuation due to diarrhea and PRES. The most common adverse reactions reported in the trial are shown in Table 4. Table 4: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Newly Diagnosed AML in AG120-C-001 TIBSOVO (500 mg daily) N=28 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) Gastrointestinal disorders Diarrhea 17 2 Nausea 10 2 Abdominal pain Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 8 1 Constipation 6 1 Vomiting 6 1 Mucositis Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 6 0 Dyspepsia 3 0 General disorders and administration site conditions Fatigue Grouped term includes asthenia and fatigue. 14 4 Edema Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face. 12 0 Metabolism and nutrition disorders Decreased appetite 11 1 Blood system and lymphatic system disorders Leukocytosis Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 10 2 Differentiation Syndrome Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. 7 3 Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 9 1 Myalgia Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 7 1 Respiratory, thoracic, and mediastinal disorders Dyspnea Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure. 8 1 Cough Grouped term includes cough, productive cough, and upper airway cough syndrome. 4 0 Investigations Electrocardiogram QT prolonged 6 3 Weight decreased 3 0 Nervous system disorders Dizziness 6 0 Neuropathy Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy. 4 0 Headache 3 0 Skin and subcutaneous tissue disorders Pruritus 4 1 Rash Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer. 4 1 Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in Table 5. Table 5: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly Diagnosed AML Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. in AG120-C-001 TIBSOVO (500 mg daily) N=28 Parameter All Grades n (%) Grade ≥ 3 n (%) Hemoglobin decreased 15 12 Alkaline phosphatase increased 13 0 Potassium decreased 12 3 Sodium decreased 11 1 Uric acid increased 8 1 Aspartate aminotransferase increased 8 1 Creatinine increased 8 0 Magnesium decreased 7 0 Calcium decreased 7 1 Phosphate decreased 6 2 Alanine aminotransferase increased 4 1 Relapsed or Refractory AML The safety profile of single-agent TIBSOVO was studied in 179 adults with relapsed or refractory AML treated with 500 mg daily . The median duration of exposure to TIBSOVO was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to TIBSOVO for at least 6 months and 16 patients (9%) were exposed for at least 1 year. Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML). The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%). The most common adverse reactions reported in the trial are shown in Table 6. Table 6: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of Patients with Relapsed or Refractory AML TIBSOVO (500 mg daily) N=179 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) General disorders and administration site conditions Fatigue Grouped term includes asthenia and fatigue. 69 6 Edema Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema. 57 2 Pyrexia 41 2 Chest pain Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain 29 5 Blood system and lymphatic system disorders Leukocytosis Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count. 68 15 Differentiation Syndrome Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. 34 23 Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity. 64 8 Myalgia Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and myalgia intercostal. 33 1 Gastrointestinal disorders Diarrhea 60 4 Nausea 56 1 Mucositis Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis. 51 6 Constipation 35 1 Vomiting Grouped term includes vomiting and retching. 32 2 Abdominal pain Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness. 29 2 Respiratory, thoracic, and mediastinal disorders Dyspnea Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional. 59 16 Cough Grouped term includes cough, productive cough, and upper airway cough syndrome. 40 1 (<1) Pleural effusion 23 5 Investigations Electrocardiogram QT prolonged 46 18 Skin and subcutaneous tissue disorders Rash Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer. 46 4 Metabolism and nutrition disorders Decreased appetite 33 3 Tumor lysis syndrome 14 11 Nervous system disorders Headache 28 0 Neuropathy Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barré syndrome, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance. 21 2 Vascular disorders Hypotension Grouped term includes hypotension and orthostatic hypotension. 22 7 Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 7. Table 7: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.

TIBSOVO (500 mg daily) N=179 Parameter All Grades n (%) Grade ≥ 3 n (%) Hemoglobin decreased 108 83 Sodium decreased 69 8 Magnesium decreased 68 0 Uric acid increased 57 11 Potassium decreased 55 11 Alkaline phosphatase increased 49 1 Aspartate aminotransferase increased 49 1 Phosphate decreased 45 15 Creatinine increased 42 2 Alanine aminotransferase increased 26 2 Bilirubin increased 28 1 Relapsed or Refractory Myelodysplastic Syndromes The safety of TIBSOVO was evaluated in 19 adults with relapsed or refractory MDS treated with 500 mg daily in AG120-C-001 . The median duration of exposure to TIBSOVO was 9.3 months (range 3.3 to 78.8 months). Fourteen patients (74%) were exposed to TIBSOVO for at least 6 months and 8 patients (42%) were exposed for at least 1 year. Serious adverse reactions in ≥ 5% included differentiation syndrome (11%), fatigue (5%), and rash (5%). Permanent discontinuation of TIBSOVO due to an adverse reaction occurred in 5% of patients. The adverse reaction which resulted in permanent discontinuation of TIBSOVO was fatigue.

Adverse reactions leading to dosage interruption of TIBSOVO occurred in 16% of patients. Adverse reactions which required dosage interruption in ≥ 5% were differentiation syndrome, leukocytosis, and rash. Dose reductions of TIBSOVO due to an adverse reaction occurred in 16% of patients.

Adverse reactions which required a dose reduction in ≥ 5% included differentiation syndrome, fatigue, and rash. The most common (≥ 25%) adverse reactions, including laboratory abnormalities, were creatinine increased, hemoglobin decrease, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash. Table 8 summarizes the adverse reactions in AG120-C-001. Table 8: Adverse Reactions ≥ 10% in Patients with Relapsed or Refractory MDS in AG120-C-001 TIBSOVO (500 mg daily) N=19 Body System Adverse Reaction All Grades % Grade 3 or 4 % Musculoskeletal and connective tissue disorders Arthralgia Grouped term includes arthralgia, back pain, pain in extremity, flank pain, joint swelling, and neck pain. 42 16 Myalgia Grouped term includes myalgia, muscle spasms, muscle discomfort, and musculoskeletal chest pain. 26 0 General disorders and administration site conditions Fatigue Grouped term includes fatigue and asthenia. 37 11 Respiratory, thoracic, and mediastinal disorders Cough 32 0 Dyspnea Grouped term includes dyspnea and dyspnea exertional. 21 0 Gastrointestinal disorders Diarrhea 32 0 Mucositis Grouped term includes oropharyngeal pain, gingivitis, mouth ulceration, stomatitis. 26 5 Constipation 16 0 Nausea 16 0 Skin and subcutaneous tissue disorders Pruritus 26 0 Rash Grouped term includes rash, catheter site erythema, and urticaria. 26 0 Metabolism and nutrition disorders Decreased appetite 26 0 Blood system and lymphatic system disorders Leukocytosis Grouped term includes leukocytosis, hyperleukocytosis, and white blood cell count increased. 16 5 Differentiation Syndrome 11 0 Nervous system disorders Headache 16 0 Vascular disorders Hypertension 16 16 Investigations Electrocardiogram QT prolonged 11 0 Table 9 summarizes laboratory abnormalities in AG120-C-001. Table 9: Select Laboratory Abnormalities (≥ 15%) That Worsened from Baseline in Patients with Relapsed or Refractory MDS in AG120-C-001 TIBSOVO Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.

N=19 Laboratory Abnormality All Grades % Grade 3 or 4 % Creatinine increased 95 5 Hemoglobin decreased 42 32 Albumin decreased 37 0 Aspartate Aminotransferase increased 37 5 Sodium decreased 32 5 Phosphate decreased 26 5 Alanine Aminotransferase increased 21 5 Bilirubin increased 21 0 Magnesium decreased 21 0 Alkaline Phosphatase increased 16 0 Potassium increased 16 0 Locally Advanced or Metastatic Cholangiocarcinoma The safety of TIBSOVO was studied in patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005 . Patients received at least one dose of either TIBSOVO 500 mg daily (N=123) or placebo (N=59). The median duration of treatment was 2.8 months (range 0.1 to 34.4 months) with TIBSOVO. Serious adverse reactions occurred in 34% of patients receiving TIBSOVO. Serious adverse reactions in ≥2% of patients in the TIBSOVO arm were pneumonia, ascites, hyperbilirubinemia, and jaundice cholestatic. Fatal adverse reactions occurred in 4.9% of patients receiving TIBSOVO, including sepsis (1.6%) and pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (each 0.8%). TIBSOVO was permanently discontinued in 7% of patients. The most common adverse reactions leading to permanent discontinuation was acute kidney injury (1.6%). Dose interruptions due to adverse reactions occurred in 29% of patients treated with TIBSOVO. The most common (>2%) adverse reactions leading to dose interruption were hyperbilirubinemia, alanine aminotransferase increased, aspartate aminotransferase increased, ascites, and fatigue.

Dose reductions of TIBSOVO due to an adverse reaction occurred in 4.1% of patients. Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (3.3%) and neuropathy peripheral (0.8%). The most common adverse reactions (≥15%) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. Adverse reactions and laboratory abnormalities observed in Study AG120-C-005 are shown in Tables 10 and 11. Table 10: Adverse Reactions Occurring in ≥ 10% of Patients Receiving TIBSOVO in Study AG120-C-005 TIBSOVO (500 mg daily) N=123 Placebo N=59 Body System Adverse Reaction All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) General disorders and administration site conditions Fatigue Grouped term includes asthenia and fatigue. 53 4 18 3 Gastrointestinal disorders Nausea 51 3 17 1 Diarrhea 43 0 10 0 Abdominal pain Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, epigastric discomfort, abdominal tenderness, and gastrointestinal pain. 43 3 13 2 Ascites 28 11 9 4 Vomiting Grouped term includes vomiting and retching. 28 3 12 0 Respiratory, thoracic, and mediastinal disorders Cough Grouped term includes cough and productive cough. 33 0 5 0 Metabolism and nutrition disorders Decreased appetite 30 2 11 0 Blood and lymphatic system disorders Anemia 22 8 3 0 Skin and subcutaneous tissue disorders Rash Grouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity. 19 1 4 0 Nervous system disorders Headache 16 0 4 0 Neuropathy peripheral Grouped term includes neuropathy peripheral, peripheral sensory neuropathy, and paresthesia. 13 0 0 0 Investigations Electrocardiogram QT prolonged 12 2 2 0 Table 11: Selected Laboratory Abnormalities Occurring in ≥ 10% of Patients Receiving TIBSOVO in Study AG120-C-005 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown.

TIBSOVO (500 mg daily) N=123 Placebo N=59 Parameter All Grades n (%) Grade ≥ 3 n (%) All Grades n (%) Grade ≥ 3 n (%) AST increased 41 5 14 1 Bilirubin increased 36 15 11 2 Hemoglobin decreased 48 8 14 0

Effect of Other Drugs on Ivosidenib Strong or Moderate

CYP3A4 Inhibitors Clinical Impact Co-administration of TIBSOVO with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations. Increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation. Prevention or Management Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with TIBSOVO. If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce TIBSOVO to 250 mg once daily.

Monitor patients for increased risk of QTc interval prolongation . Strong CYP3A4 Inducers Clinical Impact Co-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations. Prevention or Management Avoid co-administration of strong CYP3A4 inducers with TIBSOVO. QTc Prolonging Drugs Clinical Impact Co-administration of TIBSOVO with QTc prolonging drugs may increase the risk of QTc interval prolongation. Prevention or Management Avoid co-administration of QTc prolonging drugs with TIBSOVO or replace with alternative therapies.

If co-administration of a QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation.

Effect of Ivosidenib on Other Drugs Ivosidenib induces

CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates . Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during TIBSOVO treatment. If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 due to expected loss of antifungal efficacy.

Co-administration of TIBSOVO may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving TIBSOVO.

Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data ). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data Animal Data Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily. In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations.

Pediatric Use The safety and effectiveness of TIBSOVO in pediatric patients have not been established.