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`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`
`These highlights do not include all the information needed to use
`
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`
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`TIBSOVO safely and effectively. See full prescribing information for
`
`TIBSOVO.
`
`TIBSOVO® (ivosidenib tablets), for oral use
`
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`
`Initial U.S. Approval: 2018
`
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` WARNING: DIFFERENTIATION SYNDROME
`
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`See full prescribing information for complete boxed warning.
`
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`Patients treated with TIBSOVO have experienced symptoms of
`
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`differentiation syndrome, which can be fatal if not treated. If
`
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`differentiation syndrome is suspected, initiate corticosteroid therapy
`
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`
`and hemodynamic monitoring until symptom resolution (5.1, 6.1).
`
`
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`
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`
`
`Indications and Usage (1.1)
`05/2019
`
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`Dosage and Administration (2.2)
`05/2019
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`---------------------------INDICATIONS AND USAGE----------------------------
`
`
`TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the
`
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`treatment of acute myeloid leukemia (AML) with a susceptible IDH1
`
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`mutation as detected by an FDA-approved test in:
`
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`• Adult patients with newly-diagnosed AML who are ≥ 75 years old or who
`
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`have comorbidities that preclude use of intensive induction chemotherapy
`
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`(1.1).
`
`
`• Adult patients with relapsed or refractory AML (1.2).
`
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`
`
`-----------------------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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`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`Tablets: 250 mg (3).
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None (4).
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
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`
`QTc Interval Prolongation: Monitor electrocardiograms and electrolytes.
`
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`
`
`
`•
`If QTc interval prolongation occurs, dose reduce or withhold, then
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`resume dose or permanently discontinue TIBSOVO (2.3, 5.2).
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`
`WARNING: DIFFERENTIATION SYNDROME
`
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`
`INDICATIONS AND USAGE
`1
`
`
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`
`
`1.1 Newly-Diagnosed Acute Myeloid Leukemia
`
`
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`
`
`1.2. Relapsed or Refractory Acute Myeloid Leukemia
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
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`2.1 Patient Selection
`
`
`2.2 Recommended Dosage
`
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`2.3 Monitoring and Dose Modifications for Toxicities
`
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`2.4 Dose Modification for Use with Strong CYP3A4 Inhibitors
`
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`DOSAGE FORMS AND STRENGTHS
`3
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`
`CONTRAINDICATIONS
`4
`
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`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Differentiation Syndrome
`
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`5.2 QTc Interval Prolongation
`
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`
`5.3 Guillain-Barré Syndrome
`
`
`ADVERSE REACTIONS
`
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`6.1 Clinical Trials Experience
`
`
`DRUG INTERACTIONS
`
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`7.1 Effect of Other Drugs on Ivosidenib
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`7.2 Effect of Ivosidenib on Other Drugs
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`2
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`
`6
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`
`7
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`
`
`Reference ID: 4427156
`
`
`1
`
`
`•
`
`Guillain-Barré Syndrome: Monitor patients for signs and symptoms of
`
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`new motor and/or sensory findings. Permanently discontinue TIBSOVO
`
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`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%) were fatigue, arthralgia,
`
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`leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis, electrocardiogram
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`QT prolonged, rash, cough, decreased appetite, myalgia, constipation, and
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`pyrexia (6.1).
`
`
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`The most common laboratory abnormalities (≥20%) were hemoglobin
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`decreased, calcium decreased, sodium decreased, magnesium decreased, uric
`
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`acid increased, potassium decreased, alkaline phosphatase increased, aspartate
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`aminotransferase increased, phosphate decreased, and creatinine increased
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`(6.1).
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Agios
`
`
`
`
`
`
`Pharmaceuticals at 1-833-228-8474 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
`
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`interval prolongation (2.4, 5.2, 7.1, 12.3).
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`Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO (7.1,
`
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`
`12.3).
`
`Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO
`
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`(7.2, 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
`
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`
`interval prolongation (5.2, 7.1).
`
`
`
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
`Lactation: Advise women not to breastfeed (8.2).
`
`
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`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
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`
`
`
`Guide.
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`
`Revised: 05/2019
`
`
`
`8
`
`
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`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`11 DESCRIPTION
`
`
`
`12 CLINICAL PHARMACOLOGY
`
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`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
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`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Newly-Diagnosed AML
`
`
`
`14.2 Relapsed or Refractory AML
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`16.2 Storage
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
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`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`
` WARNING: DIFFERENTIATION SYNDROME
`
` 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 peripheral
`
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`
`
` 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
`
`
`
`
`
`
`Newly-Diagnosed Acute Myeloid Leukemia
`1.1
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`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)].
`
`
`
`
`
`
` 2
`
` 2.1
`
`
`
` Patient Selection
`
`
`
`
`
`
`
`
`
`
`
`
`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 without IDH1
`
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`
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`mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge
`
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`
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`
`
`during treatment and at relapse. Information on FDA-approved tests for the detection of IDH1
`
`
`
`
`
`
`mutations in AML is available at http://www.fda.gov/CompanionDiagnostics.
`
`
`
`
`Recommended Dosage
`2.2
`
`
`
`
`
`
`
`
`
`
`
`The recommended dose of TIBSOVO is 500 mg taken orally once daily until disease progression
`
`
`
`
`
`
`
`
`
`
`
`or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat
`
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`
`
`
`for a minimum of 6 months to allow time for clinical response.
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`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
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`
`Reference ID: 4427156
`
`

`

`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2
`
`
`
`
`
`
`
`
`
`
`
`
`doses within 12 hours.
`
`
`
` 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
`
`
`
`
`
`
`
`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. Monitor electrocardiograms (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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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • 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)
`
`
`
`
`
`
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`
`
`
`
`
`
` • QTc interval greater than 480 msec
`
`to 500 msec
`
`
`
`
`
`
`
`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
`
`
`
`
` 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
`
`
`
`
`
`
`Reference ID: 4427156
`
`

`

`
` • QTc interval greater than 500 msec
`
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • QTc interval prolongation with
`
`
`
`
`
` signs/symptoms of life-threatening
`
` arrhythmia
`
` • Guillain-Barré syndrome
`
`
`
`
`
`
` • Other Grade 3* or higher toxicity
`
`
`
`
`
`
` considered related to treatment
`
`
` • Discontinue TIBSOVO permanently [see Warnings
`
`
` and Precautions (5.3)].
`
`
` 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.
`
`
`
` *Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
`
` Dose Modification for Use with Strong CYP3A4 Inhibitors
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
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` half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.
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` 3
` DOSAGE FORMS AND STRENGTHS
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`Tablets: 250 mg as a blue oval-shaped film-coated tablet debossed “IVO” on one side and “250”
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`Reference ID: 4427156
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`

`

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`CONTRAINDICATIONS
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`4
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`None.
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`5 WARNINGS AND PRECAUTIONS
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` 5.1
` Differentiation Syndrome
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`In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of
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`patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation
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`syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of
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`myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation
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`syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral
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`edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema,
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`pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine
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`increased. Of the 7 patients with newly diagnosed AML who experienced differentiation
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`syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who
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`experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose
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`interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3
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`months after TIBSOVO initiation and has been observed with or without concomitant
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`leukocytosis.
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`If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an
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`equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until
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`improvement [see Dosage and Administration (2.3)]. If concomitant noninfectious leukocytosis
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`is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper
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`corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for
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`a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature
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`discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms
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`persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs
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`and symptoms are no longer severe [see Dosage and Administration (2.3)].
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`5.2 QTc Interval Prolongation
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`Patients treated with TIBSOVO can develop QT (QTc) prolongation [see Clinical Pharmacology
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`(12.2)] and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated
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`with TIBSOVO in the clinical trial, 9% were found to have a QTc interval greater than 500 msec
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`and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient
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`developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients
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`with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle
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`branch block) or with a history of long QT syndrome or uncontrolled or significant
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`cardiovascular disease.
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`Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-
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`arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and
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`CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions
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`(7.1), Clinical Pharmacology (12.2)]. Conduct monitoring of electrocardiograms (ECGs) and
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`electrolytes [see Dosage and Administration (2.3)].
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`Reference ID: 4427156
`
`

`

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` In patients with congenital long QTc syndrome, congestive heart failure, electrolyte
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` frequent monitoring may be necessary.
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`Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt
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`and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue
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`TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-
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`threatening arrhythmia [see Dosage and Administration (2.3)].
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`5.3 Guillain-Barré Syndrome
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`Guillain-Barré syndrome occurred in < 1% (2/258) of patients treated with TIBSOVO in the
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`clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor
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`and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations,
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`paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are
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`diagnosed with Guillain-Barré syndrome [see Dosage and Administration (2.3)].
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`6
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`The following clinically significant adverse reactions are described elsewhere in the labeling:
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`• Differentiation Syndrome [see Warnings and Precautions (5.1)]
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`• QTc Interval Prolongation [see Warnings and Precautions (5.2)]
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`• Guillain-Barré Syndrome [see Warnings and Precautions (5.3)]
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`Clinical Trials Experience
`6.1
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
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`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
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`of another drug and may not reflect the rates observed in practice.
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`The safety of TIBSOVO as a single agent at 500 mg daily was evaluated in 213 patients with
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`AML in Study AG120-C-001 [see Clinical Studies (14.1 and 14.2)]. The median age of
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`TIBSOVO treated patients was 68 (range 18-87) with 68% ≥ 65 years, 51% male, 66% White,
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`6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5%
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`American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who
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`received TIBSOVO, 37% were exposed for 6 months or longer and 14% were exposed for 12
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`months or longer. The most common adverse reactions including laboratory abnormalities in ≥
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`20% of 213 patients who received TIBSOVO were hemoglobin decreased, fatigue, arthralgia,
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`calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema,
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`nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased,
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`mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT
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`prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and
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`pyrexia.
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`Newly-Diagnosed AML
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`The safety profile of single-agent TIBSOVO was studied in 28 adults with newly-diagnosed
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`AML treated with 500 mg daily [see Clinical Studies (14.1)]. The median duration of exposure
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`ADVERSE REACTIONS
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`Reference ID: 4427156
`
`

`

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` to TIBSOVO was 4.3 months (range 0.3 to 40.9 months). Ten patients (36%) were exposed to
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` TIBSOVO for at least 6 months and 6 patients (21%) were exposed for at least 1 year.
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`Common (≥ 5%) serious adverse reactions included differentiation syndrome (18%),
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`electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior
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`reversible encephalopathy syndrome (PRES).
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`Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT
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`prolonged (14%) and differentiation syndrome (11%). Two (7%) patients required a dose
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`reduction due to electrocardiogram QT prolonged. One patient each required permanent
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`discontinuation due to diarrhea and PRES.
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`The most common adverse reactions reported in the trial are shown in Table 2.
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` Table 2: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of
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` Patients with Newly-Diagnosed AML
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` TIBSOVO (500 mg daily)
`N=28
`
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` All Grades
` n (%)
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` Body System
`
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`
` Adverse Reaction
` Blood System and Lymphatic System Disorders
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` 10 (36)
` Leukocytosis1
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` 7 (25)
` Differentiation Syndrome2
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` Gastrointestinal Disorders
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` 17 (61)
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` Diarrhea
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` 10 (36)
`
` Nausea
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` 8 (29)
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`
` Abdominal pain3
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` 6 (21)
` Constipation
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`
` 6 (21)
`
` Vomiting
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` 6 (21)
`
` Mucositis4
`
` 3 (11)
`
` Dyspepsia
` General Disorders and Administration Site Conditions
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`
` 14 (50)
`
` Fatigue5
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` 12 (43)
`
` Edema6
` Investigations
`
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` Electrocardiogram QT prolonged
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` Weight decreased
` Metabolism and Nutrition Disorders
`
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` Decreased appetite
`
` Musculoskeletal and Connective Tissue Disorders
`
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` Arthralgia7
`
` Myalgia8
`
` Nervous System Disorders
` Dizziness
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` Neuropathy9
`Headache
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` Respiratory, Thoracic and Mediastinal Disorders
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`
`Reference ID: 4427156
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`
` 6 (21)
`
` 3 (11)
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` 11 (39)
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`
` 9 (32)
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` 7 (25)
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` 6 (21)
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` 4 (14)
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` 3 (11)
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` Grade ≥ 3
`
` n (%)
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` 2 (7)
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` 3 (11)
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`
` 2 (7)
`
` 2 (7)
`
` 1 (4)
`
` 1 (4)
`
` 1 (4)
`
` 0
`
` 0
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`
` 4 (14)
`
` 0
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`
` 3 (11)
`
` 0
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`
`
` 1 (4)
`
`
` 1 (4)
`
` 1 (4)
`
`
` 0
`
` 0
`
` 0
`
`

`

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` TIBSOVO (500 mg daily)
`N=28
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` Dyspnea10
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`Cough11
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` Skin and Subcutaneous Tissue Disorders
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` 4 (14)
` Pruritis
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` 4 (14)
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` Rash12
`1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.
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`2 Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia,
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`dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis
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`syndrome, and creatinine increased.
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`3 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness.
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` 4 Grouped term includes aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration, mucosal inflammation,
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` oral pain, oropharyngeal pain, proctalgia, and stomatitis.
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`5 Grouped term includes asthenia and fatigue.
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`6 Grouped term includes edema, face edema, fluid overload, fluid retention, hypervolemia, peripheral edema, and swelling face.
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` 7 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.
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` 8 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, and
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` myalgia intercostal.
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` 9 Grouped term includes burning sensation, lumbosacral plexopathy, neuropathy peripheral, paresthesia, and peripheral motor neuropathy.
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` 10 Grouped term includes dyspnea, dyspnea exertional, hypoxia, and respiratory failure.
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` 11 Grouped term includes cough, productive cough, and upper airway cough syndrome.
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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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` 8 (29)
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` 4 (14)
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` 1 (4)
`
` 0
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`
` 1 (4)
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` 1 (4)
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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)
`
` N=28
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`
` Parameter
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`
` Grade ≥ 3
`
` All Grades
` n (%)
`
` n (%)
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` 12 (43)
`
`
` 15 (54)
`
`
` Hemoglobin decreased
` 0
`
` 13 (46)
`
` Alkaline phosphatase increased
`
`
`
` 3 (11)
`
` 12 (43)
` Potassium decreased
`
`
`
` 1 (4)
`
`
` 11 (39)
`
` Sodium decreased
`
`
`
` 1 (4)
`
` 8 (29)
`
`
` Uric acid increased
`
` 1 (4)
`
`
` 8 (29)
` Aspartate aminotransferase increased
`
`
` 0
`
` 8 (29)
` Creatinine increased
`
`
`
` 0
`
` 7 (25)
`
` Magnesium decreased
`
`
` 1 (4)
` 7 (25)
`
` Calcium decreased
`
`
`
` 2 (7)
`
`
` 6 (21)
`
`
` Phosphate decreased
`
` 1 (4)
`
` 4 (14)
`
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` Alanine aminotransferase increased
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` 1Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is 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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`
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` refractory AML treated with 500 mg daily [see Clinical Studies (14.2)].
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`
`
`
`
`
`
`
`Reference ID: 4427156
`
`

`

`
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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%)
` were exposed for at least 1 year.
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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
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`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 QT prolonged (1%), diarrhea (1%),
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`
`nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions
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`leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%),
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`stomatitis (1%), and creatinine increased (1%).
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`The most common adverse reactions reported in the trial are shown in Table 4.
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`Table 4: Adverse Reactions Reported in ≥ 10% (Any Grade) or ≥ 5% (Grade ≥ 3) of
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`Patients with Relapsed or Refractory AML
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` Body System
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` Adverse Reaction
` Blood System and Lymphatic System Disorders
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`Leukocytosis1
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` Differentiation Syndrome2
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` Gastrointestinal Disorders
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` Diarrhea
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` Nausea
`Mucositis3
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` Constipation
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` Vomiting4
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` Abdominal pain5
` General Disorders and Administration Site Conditions
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` Fatigue6
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` Edema7
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` Pyrexia
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` Chest pain8
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` Investigations
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` Electrocardiogram QT prolonged
` Metabolism and Nutrition Disorders
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` Decreased appetite
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` Tumor lysis syndrome
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` Musculoskeletal and Connective Tissue Disorders
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` Arthralgia9
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` Myalgia10
` Nervous System Disorders
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`Reference ID: 4427156
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` TIBSOVO (500 mg daily)
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`N=179
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` All Grades
` n (%)
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` Grade ≥ 3
` n (%)
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` 68 (38)
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` 34 (19)
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` 60 (34)
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` 56 (31)
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` 51 (28)
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` 35 (20)
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` 32 (18)
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` 29 (16)
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` 69 (39)
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` 57 (32)
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` 41 (23)
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` 29 (16)
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` 46 (26)
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` 33 (18)
` 14 (8)
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` 64 (36)
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` 33 (18)
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`
` 15 (8)
` 23 (13)
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` 4 (2)
`
` 1 (1)
`
` 6 (3)
`
` 1 (1)
`
` 2 (1)
`
` 2 (1)
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`
` 6 (3)
`
` 2 (1)
`
` 2 (1)
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` 5 (3)
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`
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` 18 (10)
`
`
` 3 (2)
` 11 (6)
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`
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` 8 (4)
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` 1 (1)
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`

`

`
` 28 (16)
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` 21 (12)
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` 0
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` 2 (1)
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` 40 (22)
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` 59 (33)
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` 23 (13)
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` 46 (26)
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` 1 (<1)
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` 16 (9)
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` 5 (3)
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` 4 (2)
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` 7 (4)
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`Headache
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`Neuropathy11
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` Respiratory, Thoracic and Mediastinal Disorders
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`Cough12
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` Dyspnea13
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` Pleural effusion
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` Skin and Subcutaneous Tissue Disorders
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` Rash14
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` Vascular Disorders
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` 22 (12)
`Hypotension15
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` 1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.
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`2 Differentiation syndrome can be associated with other commonly reported events such as peripheral edema, leukocytosis, pyrexia, dyspnea,
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`pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonia, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and
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`creatinine increased.
`3 Grouped term inc