`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
` TIBSOVO safely and effectively. See full prescribing information for
`
`
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`
`
`
`
` TIBSOVO.
`
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`
`
` TIBSOVO® (ivosidenib tablets), for oral use
`
` Initial U.S. Approval: 2018
`
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` WARNING: DIFFERENTIATION SYNDROME IN AML
`
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` See full prescribing information for complete boxed warning.
`
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`
`
` Patients treated with TIBSOVO have experienced symptoms of
`
` differentiation syndrome, which can be fatal if not treated. If
`
`
`
`
`
`
`
`
` differentiation syndrome is suspected, initiate corticosteroid therapy
`
`
`
`
`
` and hemodynamic monitoring until symptom resolution (5.1, 6.1).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ---------------------------RECENT MAJOR CHANGES--------------------------
`
` 08/2021
`
`
`
`
`
` Indications and Usage (1.3)
`
`
` Dosage and Administration (2)
`
`
` 08/2021
`
`
`
`
`
`
`
` ---------------------------INDICATIONS AND USAGE---------------------------
`
` TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the
`
`
`
`
`
`
` treatment of adult patients with a susceptible IDH1 mutation as detected by an
`
`
`
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`
`
`
`
` FDA-approved test with:
`
`
`
`
` Acute Myeloid Leukemia (AML)
`
`
`
`
`• Newly-diagnosed AML who are ≥ 75 years old or who have comorbidities
`
`
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`
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` that preclude use of intensive induction chemotherapy (1.1).
`
`
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`• Relapsed or refractory AML (1.2).
`
`
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`
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`
` Locally Advanced or Metastatic Cholangiocarcinoma
`• 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
`
`
`
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`
`
`
`
`
`
` unacceptable toxicity (2.2). Avoid a high-fat meal.
`
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`
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`
`
`• 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).
`
`
`
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`
`
`
`
`
`
` -------------------------------ADVERSE REACTIONS-----------------------------
` The most common adverse reactions (≥20%) in patients with AML were
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` fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis,
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` electrocardiogram QT prolonged, rash, cough, decreased appetite, myalgia,
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` constipation, and pyrexia (6.1).
`
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`
`
` The most common laboratory abnormalities (≥20%) in patients with AML
` were hemoglobin decreased, calcium decreased, sodium decreased,
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`
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` magnesium decreased, uric acid increased, potassium decreased, alkaline
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` phosphatase increased, aspartate aminotransferase increased, phosphate
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` decreased, and creatinine increased (6.1).
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` The most common adverse reactions (≥15%) in patients with
`
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` cholangiocarcinoma were fatigue, nausea, abdominal pain, diarrhea, cough,
` decreased appetite, ascites, vomiting, anemia, and rash (6.1).
`
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` The most common laboratory abnormalities (≥10%) in patients with
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`
`
` cholangiocarcinoma were hemoglobin decreased, aspartate aminotransferase
` increased, and bilirubin increased.
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`
`
` 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,
`
`
`
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`
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`
`
` 12.3).
`• Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO (7.2,
`
`
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` 12.3).
`
`• QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-
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`
`
` administration is unavoidable, monitor patients for increased risk of QTc
`
`
`
`
`
`
` interval prolongation (5.2, 7.1).
`
`
`
`
`
`
` ----------------------DOSAGE FORMS AND STRENGTHS--------------------
`
`
`
`
` Tablets: 250 mg (3).
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`
`
` None (4).
`
`
`
` -----------------------WARNINGS AND PRECAUTIONS----------------------
`
`
`
`• QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If
`
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`
`
` QTc interval prolongation occurs, dose reduce or withhold, then resume
`
`
`
`
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`
`
` dose or permanently discontinue TIBSOVO (2.3, 5.2).
`
`
`
`
`
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`
`
` --------------------------USE IN SPECIFIC POPULATIONS--------------------
`
` Lactation: Advise women not to breastfeed (8.2).
`
`
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and Medication
`
` Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Revised: 8/2021
`
`
`
`
`
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`
`
` 8.2 Lactation
`
`
`
` 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
`
`
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`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
` WARNING: DIFFERENTIATION SYNDROME
`
` INDICATIONS AND USAGE
`
`
`
` 1
`
`
`
` 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 Dose Modifications for Toxicities
`
`
`
`
` 2.4 Dose 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
`
`
`
`
` 2
`
`
`
` 6
`
`
`
` 7
`
`
`
` 8
`
`Reference ID: 4847005
`
`
`
`
`
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed
`
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`
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`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` WARNING: DIFFERENTIATION SYNDROME IN AML
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients treated with TIBSOVO have experienced symptoms of differentiation
`
`
` syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea,
`
`
`
`
`
`
`
`
`
`
` hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or
`
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`
`
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` 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
`
`
`
`
`
`
`
`
`
` Newly-Diagnosed Acute Myeloid Leukemia
`
`
`
`
`
`
`
`
`
`
`
` TIBSOVO is indicated 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 adult patients who are ≥ 75 years old 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` Relapsed or Refractory Acute Myeloid Leukemia
`
`
`1.1
`
`
`
`
`
`
`
`
`
`
`
`
`1.2
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
` Locally Advanced or Metastatic Cholangiocarcinoma
`
`
`
`
`
`
`
`
`2
`
`
`2.1
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
` The recommended dose of TIBSOVO is 500 mg taken orally once daily until disease progression
` or unacceptable toxicity.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommended Dosage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 or crush 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.
`
`
`
`
`
` Patients with Acute Myeloid Leukemia
`
`
`
`
`
`
`
`
` For patients without disease progression or unacceptable toxicity, treat for a minimum of
` 6 months to allow time for clinical response.
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients with the Comorbidities of Severe Renal or Severe Hepatic Impairment
`
`
`
`
`
`
`
`
`
` Treatment with TIBSOVO has not been studied in patients with pre-existing severe renal or
` hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider
`
`
`
`
`
`
`
`
` the risks and potential benefits before initiating treatment with TIBSOVO [see Use in Specific
`
`
`
`
`
`
` Populations (8.6, 8.7)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.3 Monitoring and Dose 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.
`
`
`
`
`
`
`
`
`
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`
`
`
`
`
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`
`
`
`
`
`
`
`
` Table 1:
`
`
`
` Recommended Dose 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
`
`
`
` 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
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
`
`
`
`
`• 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
`
`
`• QTc interval greater than 500 msec
`
`
`
`
`
`
`• QTc interval prolongation with
`
`
`
` signs/symptoms of life-threatening
`
`
`
` arrhythmia
`• Guillain-Barré syndrome
`
`
`
`
`• Other Grade 3* adverse reactions
`
`
`
`
`
`
`
`Reference ID: 4847005
`
` and Precautions (5.1)].
`
`
`• Resume TIBSOVO when signs and symptoms
`
`
`
`
`
`
`
`
` improve to Grade 2* or lower.
`
`•
`
`
`
`
`
`
`
` 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.
`
`
`
`
`• 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.
`
`
`• Discontinue TIBSOVO permanently [see Warnings
`
`
`
`
` and Precautions (5.2)].
`
`
`
`
`
`• Discontinue TIBSOVO permanently [see Warnings
`
`
`
`
` and Precautions (5.3)].
`
`
`
` AML:
`
`
`
`
`
`•
`
`
`•
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`
`
`
`
`
`
` 5.1 Differentiation Syndrome in AML
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` In the clinical trial, 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. Differentiation syndrome is associated with rapid proliferation and differentiation of
`
`
`
`
` myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
` Dose Modification for Use with Strong CYP3A4 Inhibitors
`
`
`
`
`
`
`
`
`3
`
`
`
`
`
` 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 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 QTc Interval Prolongation
`
`
`
`
`
`
`
`
`
`
`
`
` Patients treated with TIBSOVO can develop QT (QTc) prolongation [see Clinical Pharmacology
` (12.2)] and ventricular arrhythmias.
`
`
`
`
`
` Of the 258 patients with hematological malignancies treated with TIBSOVO in the clinical trial
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of
` patients had an increase from baseline QTc greater than 60 msec. 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. 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
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` (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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
` Clinical Trials Experience
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
` The safety of TIBSOVO as a single agent at 500 mg daily was evaluated in 213 patients with
` AML in Study AG120-C-001 [see Clinical Studies (14.1 and 14.2)]. The median age of
`
`
`
`
`
`
`
`
`
` TIBSOVO treated patients was 68 (range 18-87) with 68% ≥ 65 years, 51% male, 66% White,
`
`
`
`
`
`
`
`
`
`
`
` 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5%
`
`
`
`
`
`
`
`
`
`
`
` American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who
`
`
`
`
`
`
`
`
` received TIBSOVO, 37% were exposed for 6 months or longer and 14% were exposed for 12
`
`
`
`
`
`
`
`
`
`
`
` months or longer. The most common adverse reactions including laboratory abnormalities in ≥
`
`
`
`
`
`
`
`
`
`
` 20% of 213 patients who received TIBSOVO were hemoglobin decreased, fatigue, arthralgia,
`
`
`
`
`
`
`
` calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema,
`
`
`
`
`
`
`
`
` nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
`
`
`
`
`
`
`
`
` mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT
`
`
` prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and
`
`
`
`
`
`
` pyrexia.
`
`
`
`
`
`
` Newly-Diagnosed AML
`
`
`
`
`
`
`
` 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 2.
`
`Table 2: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patients with Newly-Diagnosed AML
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` TIBSOVO (500 mg daily)
`
`
`
` N=28
`
`
`
` Body System
`
`
`
` All Grades
`
`
`
` Grade ≥ 3
`
`
`
` Adverse Reaction
`
`
`
`
`
` n (%)
`
`
`
`
`
`
`
` n (%)
`
`
`
` Gastrointestinal disorders
`
`
`
` Diarrhea
`
`
`
` Nausea
`
`
`
` Abdominal pain1
`
`
`
` Constipation
`
`
`
` Vomiting
`
`
`
` Mucositis2
`
`
`
` Dyspepsia
`
`
`
`
`
` 17 (61)
`
`
`
` 10 (36)
`
`
`
` 8 (29)
`
`
`
` 6 (21)
`
`
`
` 6 (21)
`
`
`
` 6 (21)
`
`
`
` 3 (11)
`
`
`
`
`
` 2 (7)
`
`
`
` 2 (7)
`
`
`
` 1 (4)
`
`
`
` 1 (4)
`
`
`
` 1 (4)
`
`
`
` 0
`
`
`
` 0
`
` General disorders and administration site conditions
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
`
`
`
`
`
`
` Fatigue3
`
`
`
` Edema4
`
`
`
` TIBSOVO (500 mg daily)
`
`
`
` N=28
`
`
`
` 14 (50)
`
`
`
` 12 (43)
`
`
`
` 4 (14)
`
`
`
` 0
`
` Metabolism and nutrition disorders
`
`
`
`
`
`
`
`
`
`
`
` Decreased appetite
`
`
`
` 11 (39)
`
`
`
` 1 (4)
`
` Blood system and lymphatic system disorders
`
`
`
`
`
`
`
`
`
`
`
`
`
` Leukocytosis5
`
`
`
` Differentiation Syndrome6
`
` Musculoskeletal and connective tissue disorders
`
`
`
`
`
`
`
`
`
`
`
` Arthralgia7
`
`
`
` Myalgia8
`
` Respiratory, thoracic, and mediastinal disorders
`
`
`
`
`
`
`
`
`
`
`
`
`
` Dyspnea9
`
` Cough10
`
`
`
` 10 (36)
`
`
`
` 7 (25)
`
`
`
` 9 (32)
`
`
`
` 7 (25)
`
`
`
` 8 (29)
`
` 4 (14)
`
`
`
` 2 (7)
`
`
`
` 3 (11)
`
`
`
` 1 (4)
`
`
`
` 1 (4)
`
`
`
` 1 (4)
`
` 0
`
`
`
`
`
` Investigations
`
`
`
`
`
`
`
` Electrocardiogram QT prolonged
`
`
`
`
`
`
`
` Weight decreased
`
`
`
` Nervous system disorders
`
`
`
`
`
`
`
`
`
` Dizziness
`
`
`
` Neuropathy11
`
`
`Headache
`
`
`
` 6 (21)
`
`
`
` 3 (11)
`
`
`
` 6 (21)
`
`
`
` 4 (14)
`
`
`
` 3 (11)
`
`
`
` 4 (14)
`
`
`
` 4 (14)
`
`
`
` 3 (11)
`
`
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`
`
` 1 (4)
`
`
`
` 1 (4)
`
`
`
`
`
` Pruritis
`
`
`
` Rash12
`
`
`
`
`
`
`
`Reference ID: 4847005
`
`
`
` 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, tumo r lysis
`
`
`
`
`
`
`
`
`
`
`
`
` syndrome, and creatinine increased.
`
`
`
`
` 7 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Skin and subcutaneous tissue disorders
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
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` 11 Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor
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` neuropathy.
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` 12 Grouped term includes dermatitis acneiform, dermatitis, rash, rash maculo-papular, urticaria, rash erythematous, rash macular, rash
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` pruritic, rash generalized, rash papular, skin exfoliation, and skin ulcer.
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` Changes in selected post-baseline laboratory values that were observed in patients with newly
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` diagnosed AML are shown in Table 3.
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`Table 3: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory
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` Abnormalities Reported in Patients with Newly-Diagnosed AML1
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` TIBSOVO (500 mg daily)
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` N=28
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` Parameter
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` Grade ≥ 3
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` All Grades
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` n (%)
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` n (%)
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` Hemoglobin decreased
` 12 (43)
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` 15 (54)
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` Alkaline phosphatase increased
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` 13 (46)
` 0
` Potassium decreased
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` 3 (11)
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` 12 (43)
` Sodium decreased
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` 1 (4)
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` 11 (39)
` Uric acid increased
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` 1 (4)
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` 8 (29)
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` Aspartate aminotransferase increased
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` 1 (4)
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` 8 (29)
` Creatinine increased
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` 0
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` 8 (29)
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` Magnesium decreased
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` 0
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` 7 (25)
` Calcium decreased
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` 1 (4)
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` 7 (25)
` Phosphate decreased
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` 2 (7)
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` 6 (21)
` Alanine aminotransferase increased
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` 1 (4)
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` 4 (14)
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` 1 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is
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` unknown.
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` Relapsed or Refractory AML
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` The safety profile of single-agent TIBSOVO was studied in 179 adults with relapsed or
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` refractory AML treated with 500 mg daily [see Clinical Studies (14.2)].
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` The median duration of exposure to TIBSOVO was 3.9 months (range 0.1 to 39.5 months).
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` Sixty-five patients (36%) were exposed to TIBSOVO for at least 6 months and 16 patients (9%)
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` Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and
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` electrocardiogram QT prolonged (7%). There was one case of progressive multifocal
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` leukoencephalopathy (PML).
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` The most common adverse reactions leading to dose interruption were electrocardiogram QT
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` 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
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` leading to a dose reduction included electrocardiogram