HIGHLIGHTS OF PRESCRIBING INFORMATION 
`These highlights do not include all the information needed to use
`TIBSOVO safely and effectively. See full prescribing information for
`TIBSOVO.
`
`TIBSOVO® (ivosidenib tablets), for oral use
`Initial U.S. Approval: 2018
`
`
`WARNING: DIFFERENTIATION SYNDROME IN AML
`
`See full prescribing information for complete boxed warning.
`
`Patients treated with TIBSOVO have experienced symptoms of
`differentiation syndrome, which can be fatal. If differentiation
`syndrome is suspected, initiate corticosteroid therapy and
`hemodynamic monitoring until symptom resolution (5.1, 6.1).
`
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`Indications and Usage (1.1)
`
`
` 5/2022
`Indications and Usage (1.3)
`
`
` 8/2021
`Dosage and Administration (2.2)
`
`
` 5/2022
`
`---------------------------INDICATIONS AND USAGE----------------------------
`TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for
`patients with a susceptible IDH1 mutation as detected by an FDA-approved
`test with:
`Newly Diagnosed Acute Myeloid Leukemia (AML)
` In combination with azacitidine or as monotherapy for the treatment of
`newly diagnosed AML in adults 75 years or older, or who have
`comorbidities that preclude use of intensive induction chemotherapy (1.1).
`Relapsed or refractory AML
` For the treatment of adult patients with relapsed or refractory AML (1.2).
`Locally Advanced or Metastatic Cholangiocarcinoma
` For the treatment of adult patients with locally advanced or metastatic
`cholangiocarcinoma who have been previously treated (1.3).
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`500 mg orally once daily with or without food until disease progression or
`unacceptable toxicity (2.2). Avoid a high-fat meal.
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 250 mg (3).
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None (4).
`
`-----------------------WARNINGS AND PRECAUTIONS-------------------------
`
`2
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: DIFFERENTIATION SYNDROME
`1
`INDICATIONS AND USAGE
`1.1 Newly Diagnosed Acute Myeloid Leukemia
`1.2. Relapsed or Refractory Acute Myeloid Leukemia
`1.3. Locally Advanced or Metastatic Cholangiocarcinoma
`DOSAGE AND ADMINISTRATION
`2.1 Patient Selection
`2.2 Recommended Dosage
`2.3 Monitoring and Dosage Modifications for Toxicities
`2.4 Dosage Modification for Use with Strong CYP3A4 Inhibitors
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Differentiation Syndrome
`5.2 QTc Interval Prolongation
`5.3 Guillain-Barré Syndrome
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 Effect of Other Drugs on Ivosidenib
`7.2 Effect of Ivosidenib on Other Drugs
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`
`6
`
`7
`
`8
`
`Reference ID: 4989264
`
` QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If
`QTc interval prolongation occurs, dose reduce or withhold, then resume
`dose or permanently discontinue TIBSOVO (2.3, 5.2).
` Guillain-Barré Syndrome: Monitor patients for signs and symptoms of new
`motor and/or sensory findings. Permanently discontinue TIBSOVO in
`patients who are diagnosed with Guillain-Barré syndrome (2.3, 5.3).
`
`
`-------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions including laboratory abnormalities
`(≥25%) in patients with AML are leukocytes decreased, diarrhea, hemoglobin
`decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase
`increased, edema, potassium decreased, nausea, vomiting, phosphate
`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 (6.1).
`
`The most common adverse reactions (≥15%) in patients with
`cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough,
`decreased appetite, ascites, vomiting, anemia, and rash (6.1).
`
`The most common laboratory abnormalities (≥10%) in patients with
`cholangiocarcinoma are hemoglobin decreased, aspartate aminotransferase
`increased, and bilirubin increased (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Servier
`Pharmaceuticals at 1-800-807-6124 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------------
` Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with
`strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc
`interval prolongation (2.4, 5.2, 7.1, 12.3).
` Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO (7.1,
`12.3).
` Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO (7.2,
`12.3).
` QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-
`administration is unavoidable, monitor patients for increased risk of QTc
`interval prolongation (5.2, 7.1).
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`Lactation: Advise women not to breastfeed (8.2).
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`Revised: 5/2022
`
`
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Newly Diagnosed AML
`14.2 Relapsed or Refractory AML
`14.3. Locally Advanced or Metastatic Cholangiocarcinoma
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`

`

` 
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: DIFFERENTIATION SYNDROME IN AML
`Patients treated with TIBSOVO have experienced symptoms of differentiation
`syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia,
`pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral
`edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation
`syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring
`until symptom resolution [see Warnings and Precautions (5.1) and Adverse Reactions
`(6.1)].
`
`1. INDICATIONS AND USAGE
`1.1
` Newly Diagnosed Acute Myeloid Leukemia
`
`TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of
`newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1
`(IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have
`comorbidities that preclude use of intensive induction chemotherapy [see Dosage and
`Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14.1)].
`
`
`1.2
` Relapsed or Refractory Acute Myeloid Leukemia
`
`TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory acute
`myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical Pharmacology
`(12.1) and Clinical Studies (14.2)].
`
`1.3
` Locally Advanced or Metastatic Cholangiocarcinoma
`
`TIBSOVO is indicated for the treatment of adult patients with previously treated, locally
`advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation
`as detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical
`Pharmacology (12.1), and Clinical Studies (14.3)].
`2
`DOSAGE AND ADMINISTRATION
`2.1
` Patient Selection
`Acute Myeloid Leukemia
`Select patients for the treatment of AML with TIBSOVO based on the presence of IDH1
`mutations in the blood or bone marrow [see Clinical Studies (14.1)]. Patients with AML without
`IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may
`emerge during treatment and at relapse.
`Locally Advanced or Metastatic Cholangiocarcinoma
`Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with
` 
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`Reference ID: 4989264
`
`

`

` 
`
`TIBSOVO based on the presence of IDH1 mutations [see Clinical Studies (14.3)].
`
`Information on FDA-approved tests for the detection of IDH1 mutations in AML and
`cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.
`
`2.2
` Recommended Dosage
`
`Newly Diagnosed AML (Combination Regimen)
`The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease
`progression or unacceptable toxicity. Start TIBSOVO administration on Cycle 1 Day 1 in
`combination with azacitidine 75 mg/m2 subcutaneously or intravenously once daily on Days 1-7
`(or Days 1-5 and 8-9) of each 28-day cycle [see Clinical Studies (14.1)]. Refer to the Prescribing
`Information for azacitidine for additional dosing information.
`For patients without disease progression or unacceptable toxicity, continue TIBSOVO, in
`combination with azacitidine, for a minimum of 6 months to allow time for clinical response.
`Newly Diagnosed AML and Relapsed or Refractory AML (Monotherapy Regimen)
`The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease
`progression or unacceptable toxicity [see Clinical Studies (14.1 and 14.2)].
`For patients without disease progression or unacceptable toxicity, continue TIBSOVO for a
`minimum of 6 months to allow time for clinical response.
`Cholangiocarcinoma
`The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease
`progression or unacceptable toxicity [see Clinical Studies (14.3)].
`
`Administer TIBSOVO with or without food. Do not administer TIBSOVO with a high-fat meal
`because of an increase in ivosidenib concentration [see Warnings and Precautions (5.2) and
`Clinical Pharmacology (12.3)]. Do not split, crush, or chew TIBSOVO tablets. Administer
`TIBSOVO tablets orally about the same time each day. If a dose of TIBSOVO is vomited, do not
`administer a replacement dose; wait until the next scheduled dose is due. If a dose of TIBSOVO
`is missed or not taken at the usual time, administer the dose as soon as possible and at least 12
`hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not
`administer 2 doses within 12 hours.
`
`2.3
` Monitoring and Dosage Modifications for Toxicities
`
`Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once
`weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy.
`Manage any abnormalities promptly [see Adverse Reactions (6.1)].
`
`Interrupt dosing or reduce dose for toxicities. See Table 1 for dose modification guidelines.
`Table 1:
`Recommended Dosage Modifications for TIBSOVO
`Adverse Reactions
`Recommended Action
` Differentiation syndrome
`If differentiation syndrome is suspected, administer
`systemic corticosteroids and initiate hemodynamic
`monitoring until symptom resolution and for a
`
`
`
` 
`
`Reference ID: 4989264
`
`

`

`Adverse Reactions
`
`
`
`Recommended Action
`minimum of 3 days [see Warnings and Precautions
`(5.1)].
`Interrupt TIBSOVO if severe signs and/or
`symptoms persist for more than 48 hours after
`initiation of systemic corticosteroids [see Warnings
`and Precautions (5.1)].
` Resume TIBSOVO when signs and symptoms
`improve to Grade 2* or lower.
`
` Noninfectious leukocytosis (white
`blood cell [WBC] count greater
`than 25 x 109/L or an absolute
`increase in total WBC of greater
`than 15 x 109/L from baseline)
`
` QTc interval greater than 480 msec
`to 500 msec
`
`
`
`
`
`Initiate treatment with hydroxyurea, as per standard
`institutional practices, and leukapheresis if
`clinically indicated.
` Taper hydroxyurea only after leukocytosis
`improves or resolves.
`Interrupt TIBSOVO if leukocytosis is not improved
`with hydroxyurea, and then resume TIBSOVO at
`500 mg daily when leukocytosis has resolved.
` Monitor and supplement electrolyte levels as
`clinically indicated [see Warnings and Precautions
`(5.2)].
` Review and adjust concomitant medications with
`known QTc interval-prolonging effects [see Drug
`Interactions (7.1)].
`
`Interrupt TIBSOVO.
` Restart TIBSOVO at 500 mg once daily after the
`QTc interval returns to less than or equal to 480
`msec.
` Monitor ECGs at least weekly for 2 weeks
`following resolution of QTc prolongation.
` QTc interval greater than 500 msec  Monitor and supplement electrolyte levels as
`clinically indicated [see Warnings and Precautions
`(5.2)].
` Review and adjust concomitant medications with
`known QTc interval-prolonging effects [see Drug
`Interactions (7.1)].
`
`Interrupt TIBSOVO.
` Resume TIBSOVO at a reduced dose of 250 mg
`once daily when QTc interval returns to within 30
`msec of baseline or less than or equal to 480 msec.
` Monitor ECGs at least weekly for 2 weeks
`following resolution of QTc prolongation.
` Consider re-escalating the dose of TIBSOVO to
`500 mg daily if an alternative etiology for QTc
`prolongation can be identified.
`
` 
`
` 
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`Reference ID: 4989264
`
`

`

` 
`
`Adverse Reactions
` QTc interval prolongation with
`signs/symptoms of life-threatening
`arrhythmia
` Guillain-Barré syndrome
`
` Other Grade 3* adverse reactions
`
`Recommended Action
` Discontinue TIBSOVO permanently [see Warnings
`and Precautions (5.2)].
`
`
`
`
`
`
`
` Discontinue TIBSOVO permanently [see Warnings
`and Precautions (5.3)].
`AML monotherapy:
`
`Interrupt TIBSOVO until toxicity resolves to
`Grade 2* or lower.
` Resume TIBSOVO at 250 mg once daily; may
`increase to 500 mg once daily if toxicities
`resolve to Grade 1* or lower.
`If Grade 3* or higher toxicity recurs,
`discontinue TIBSOVO.
`AML in combination with azacitidine,
`Cholangiocarcinoma:
`
`Interrupt TIBSOVO until toxicity resolves to
`Grade 1* or lower, or baseline, then resume at
`500 mg daily (Grade 3 toxicity) or 250 mg daily
`(Grade 4 toxicity).
`If Grade 3 toxicity recurs (a second time),
`reduce TIBSOVO dose to 250 mg daily until
`the toxicity resolves, then resume 500 mg daily.
`If Grade 3 toxicity recurs (a third time), or
`Grade 4 toxicity recurs, discontinue TIBSOVO.
`*Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
`Patients with Acute Myeloid Leukemia
`Assess blood counts and blood chemistries prior to the initiation of TIBSOVO, at least once
`weekly for the first month, once every other week for the second month, and once monthly for
`the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of
`therapy.
`
`2.4
` Dosage Modification for Use with Strong CYP3A4 Inhibitors
`
`If a strong CYP3A4 inhibitor must be coadministered, reduce the TIBSOVO dose to 250 mg
`once daily. If the strong inhibitor is discontinued, increase the TIBSOVO dose (after at least 5
`half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.
`3
`DOSAGE FORMS AND STRENGTHS
`
`Tablets: 250 mg as a blue oval-shaped film-coated tablet debossed “IVO” on one side and “250”
`on the other side.
`4
`CONTRAINDICATIONS
`
`None.
`
` 
`
`Reference ID: 4989264
`
`

`

` 
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Differentiation Syndrome in AML
`
`In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML
`treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse
`Reactions (6.1)]. Differentiation syndrome is associated with rapid proliferation and
`differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation
`syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral
`edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema,
`pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine
`increased. Of the 11 patients with newly diagnosed AML who experienced differentiation
`syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome
`occurred as early as 3 days after start of therapy and during the first month on treatment.
`
`In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed
`AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO
`experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 7 patients with newly
`diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the
`34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27
`(79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation
`syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been
`observed with or without concomitant leukocytosis.
`
`If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an
`equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until
`improvement [see Dosage and Administration (2.3)]. If concomitant noninfectious leukocytosis
`is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper
`corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for
`a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature
`discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms
`persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs
`and symptoms are no longer severe [see Dosage and Administration (2.3)].
`
`5.2
`
`Patients treated with TIBSOVO can develop QT (QTc) prolongation [see Clinical Pharmacology
`(12.2)] and ventricular arrhythmias.
`
`Of the 71 patients with newly diagnosed AML treated with TIBSOVO in combination with
`azacitidine in the clinical trial (Study AG120-C-009), 10 (14%) were found to have a heart-rate
`corrected QT interval (using Fridericia’s method) (QTcF) greater than 500 msec and 15 out of 69
`(22%) had an increase from baseline QTcF greater than 60 msec [see Adverse Reactions (6.1)].
`The clinical trial excluded patients with a QTcF ≥ 470 msec or other factors that increased the
`risk of QT prolongation or arrhythmic events (e.g. NYHA Class III or IV congestive heart
`failure, hypokalemia, family history of long QT interval syndrome).
`
`Of the 258 patients with hematological malignancies treated with TIBSOVO monotherapy in the
`clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and
`
` QTc Interval Prolongation
`
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`Reference ID: 4989264
`
`

`

` 
`
`14% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions
`(6.1)]. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial
`excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a
`pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or
`significant cardiovascular disease.
`
`Of the 123 patients with cholangiocarcinoma treated with TIBSOVO in the clinical trial (Study
`AG120-C-005), 2% were found to have a QTc interval greater than 500 msec. and 5% of patients
`had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1)]. The
`clinical trial excluded patients with a heart-rate corrected QT interval (using Fridericia’s
`formula) (QTcF) ≥ 450 msec or other factors that increased the risk of QT prolongation or
`arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval
`syndrome).
`
`Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-
`arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and
`CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions
`(7.1), Clinical Pharmacology (12.2)]. Conduct monitoring of electrocardiograms (ECGs) and
`electrolytes [see Dosage and Administration (2.3)].
`
`In patients with congenital long QTc syndrome, congestive heart failure, electrolyte
`abnormalities, or those who are taking medications known to prolong the QTc interval, more
`frequent monitoring may be necessary.
`
`Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt
`and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue
`TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-
`threatening arrhythmia [See Dosage and Administration (2.3)].
`5.3
` Guillain-Barré Syndrome
`
`Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barré
`syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in study AG120-C-001
`[see Adverse Reactions (6.1)].
`
`Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory
`neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty
`breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-
`Barré syndrome [see Dosage and Administration (2.3)].
`6
`
`ADVERSE REACTIONS
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
` Differentiation Syndrome in AML [see Warnings and Precautions (5.1)]
` QTc Interval Prolongation [see Warnings and Precautions (5.2)]
` Guillain-Barré Syndrome [see Warnings and Precautions (5.3)]
`
`6.1
`
`
` Clinical Trials Experience
`
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`
`

`

` 
`
`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 [see Clinical Studies (14.1 and 14.2)]. 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,
`neutrophils decreased, differentiation syndrome, calcium 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 [see Clinical Studies (14.1)]. 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). 34 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.
`
`
` 
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`Reference ID: 4989264
`
`

`

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`
`
`
`Body System
`Adverse Reaction
`
`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
`All Grades
`Grade ≥3
`n (%)
`n (%)
`
`Placebo + Azacitidine
`N=73
`Grade ≥3
`n (%)
`
`All
`Grades
`n (%)
`
`28 (38)
`20 (27)
`
`5 (7)
`
`Gastrointestinal disorders
`Nausea
`Vomiting1
`Investigations
`Electrocardiogram QT prolonged
`Psychiatric Disorders
`13 (18)
`Insomnia
`Blood system and lymphatic system disorders
`Differentiation Syndrome2
`11 (15)
`Leukocytosis3
`9 (13)
`Vascular disorders
`11 (15)
`Hematoma4
`9 (13)
`Hypertension5
`Musculoskeletal and connective tissue disorders
`Arthralgia6
` 21 (30)
`Respiratory, thoracic and mediastinal disorders
`Dyspnea7
`14 (20)
`Nervous system disorders
`0
`2 (3)
`0
`8 (11)
`Headache
`1 Grouped term includes vomiting and retching.
`2 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.
`3 Grouped term includes leukocytosis, white blood cell count increased.
`4 Grouped term includes hematoma, eye hematoma, catheter sire hematoma, oral mucosa hematoma, spontaneous hematoma, application site
`hematoma, injection site hematoma, periorbital hematoma.
`5 Grouped term includes blood pressure increased, essential hypertension, and hypertension.
`6 Grouped term includes pain in extremity, arthralgia, back pain, musculoskeletal stiffness, cancer pain, and neck pain.
`7 Grouped term includes dyspnea, dyspnea exertional, hypoxia, respiration failure.
`
`
`30 (42)
`29 (41)
`
`14 (20)
`
`
`2 (3)
`0
`
`7 (10)
`
`1 (1)
`
`7 (10)
`0
`
`0
`3 (4)
`
`3 (4)
`
`2 (3)
`
`
`
`
`
`
`
`9 (12)
`
`6 (8)
`1 (1)
`
`3 (4)
`6 (8)
`
`6 (8)
`
`11 (15)
`
`
`3 (4)
`1 (1)
`
`2 (3)
`
`0
`
`6 (8)
`0
`
`0
`4 (5)
`
`1 (1)
`
`4 (5)
`
`
`Table 3: Select Laboratory Abnormalities1, 2 (≥10%) That Worsened from Baseline in
`Patients with AML Who Received TIBSOVO + azacitidine in AG120-C-009
`TIBSOVO + Azacitidine
`Placebo + Azacitidine
`N=71
`N=73
`All Grades
`Grade ≥ 3
`All Grades
`Grade ≥ 3
`n (%)
`n (%)
`n (%)
`n (%)
`
`
`
`Parameter
`Hematology Parameters
`Leukocytes decreased
`Platelets decreased
`Hemoglobin decreased
`Neutrophils decreased
`Lymphocytes increased
`
` 
`
`Reference ID: 4989264
`
`46 (65)
`41 (58)
`40 (56)
`18 (25)
`17 (24)
`
`39 (55)
`30 (42)
`33 (46)
`16 (23)
`1 (1)
`
`47 (64)
`52 (71)
`48 (66)
`25 (35)
`7 (10)
`
`42 (58)
`42 (58)
`42 (58)
`23 (32)
`1 (1)
`
`

`

` 
`
`
`
`TIBSOVO + Azacitidine
`N=71
`All Grades
`Grade ≥ 3
`n (%)
`n (%)
`
`Placebo + Azacitidine
`N=73
`All Grades
`Grade ≥ 3
`n (%)
`n (%)
`
`Parameter
`Chemistry Parameters
`8 (11)
`34 (47)
`9 (13)
`40 (56)
`Glucose increased
`9 (12)
`25 (34)
`7 (10)
`29 (41)
`Phosphate decreased
`0
`17 (23)
`0
`26 (37)
`Aspartate Aminotransferase increased
`0
`19 (26)
`0
`25 (35)
`Magnesium decreased
`0
`21 (29)
`0
`23 (32)
`Alkaline Phosphatase increased
`1 (1)
`9 (12)
`2 (3)
`17 (24)
`Potassium increased
`1 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown.
`2 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.
`
`TIBSOVO Monotherapy
`
`The safety profile of single-agent TIBSOVO was studied in 28 adults with newly diagnosed
`AML treated with 500 mg daily [see Clinical Studies (14.1)]. 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
`All Grades
`n (%)
`
`17 (61)
`10 (36)
`8 (29)
`6 (21)
`6 (21)
`6 (21)
`3 (11)
`
`
`
`Body System
`Adverse Reaction
`Gastrointestinal disorders
`Diarrhea
`Nausea
`Abdominal pain1
`Constipation
`Vomiting
`Mucositis2
`Dyspepsia
`General disorders and administration site conditions
`Fatigue3
`14 (50)
`
`Grade ≥ 3
`n (%)
`
`2 (7)
`2 (7)
`1 (4)
`1 (4)
`1 (4)
`0
`0
`
`4 (14)
`
` 
`
`Reference ID: 4989264
`
`

`

` 
`
`
`
`TIBSOVO (500 mg daily)
`N=28
`All Grades
`n (%)
`12 (43)
`
`Grade ≥ 3
`n (%)
`0
`
`11 (39)
`
`10 (36)
`7 (25)
`
`9 (32)
`7 (25)
`
`8 (29)
`4 (14)
`
`6 (21)
`3 (11)
`
`6 (21)
`4 (14)
`3 (11)
`
`1 (4)
`
`2 (7)
`3 (11)
`
`1 (4)
`1 (4)
`
`1 (4)
`0
`
`3 (11)
`0
`
`0
`0
`0
`
`Body System
`Adverse Reaction
`Edema4
`Metabolism and nutrition disorders
`Decreased appetite
`Blood system and lymphatic system disorders
`Leukocytosis5
`Differentiation Syndrome6
`Musculoskeletal and connective tissue disorders
`Arthralgia7
`Myalgia8
`Respiratory, thoracic, and mediastinal disorders
`Dyspnea9
`Cough10
`Investigations
`Electrocardiogram QT prolonged
`Weight decreased
`Nervous system disorders
`Dizziness
`Neuropathy11
`Headache
`Skin and subcutaneous tissue disorders
`1 (4)
`4 (14)
`Pruritis
`1 (4)
`4 (14)
`Rash12
`1 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness.
`2 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal
`inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis.
`3 Grouped term includes asthenia and fatigue.
`4 Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face.
`5 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.
`6 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 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.
`8 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort,
`and myalgia intercostal.
`9 Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure.
`10 Grouped term includes cough, productive cough, and upper airway cough syndrome.
`11 Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor
`neuropathy.
`12 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.
`
`
`Changes in selected post-baseline laboratory values that were observed in patients with newly
`diagnosed AML are shown in Table 5.
`
` 
`
`Reference ID: 4989264
`
`

`

` 
`
`Table 5: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory
`Abnormalities Reported in Patients with Newly Diagnosed AML1 in
`AG120-C-001
`
`
`TIBSOVO (500 mg daily)
`N=28
`
`Parameter
`
`Grade ≥ 3
`All Grades
`n (%)
`n (%)
`12 (43)
`15 (54)
`Hemoglobin decreased
`0
`13 (46)
`Alkaline phosphatase increased
`3 (11)
`12 (4