`
`
`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 (≥20%) were fatigue, leukocytosis,
`
`arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT
`
`prolonged, rash, pyrexia, cough, and constipation (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
`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: 07/2018
`
`8
`
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
` NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` CLINICAL STUDIES
`
`14.1 Acute Myeloid Leukemia
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`16.2 Storage
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed
`
`13
`
`14
`
` 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
`See full prescribing information for complete boxed warning.
`
`
`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).
`
`---------------------------INDICATIONS AND USAGE---------------------------­
`
`TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the
`treatment of adult patients with relapsed or refractory acute myeloid leukemia
`
`(AML) with a susceptible IDH1 mutation as detected by an FDA-approved
`test (1.1).
`
`
`-----------------------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----------------------­
`
`
`QTc Interval Prolongation: Monitor electrocardiograms and electrolytes.
`
`
`
`If QTc interval prolongation occurs, dose reduce or
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: DIFFERENTIATION SYNDROME
`INDICATIONS AND USAGE
`1
`
`1.1 Acute Myeloid Leukemia
`
` 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
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
`CONTRAINDICATIONS
`
`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
`
`
`
`
`
`2
`
`6
`
`7
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4294285
`
`1
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`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
`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
`
`
`Acute Myeloid Leukemia
`1.1
`
`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 (14.1)].
`
`
`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
`mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge
`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
`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
`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 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
`
`Reference ID: 4294285
`
`2
`
`

`

`
`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.
`
`
`
` 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
`
`Reference ID: 4294285
`
`3
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
` 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.
`
` 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.
`
`
`
`
`
`
`
`
` QTc interval prolongation with
`signs/symptoms of life-threatening
`arrhythmia
`
` Guillain-Barré syndrome
`
`
` Other Grade 3* or higher toxicity
`considered related to treatment
`
`
`CONTRAINDICATIONS
`
`
` 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
`half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`Tablets: 250 mg as a blue oval-shaped film-coated tablet debossed “IVO” on one side and “250”
`on the other side.
`
`
`4
`
`None.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`Differentiation Syndrome
`5.1
`
`In the clinical trial, 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 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 34 patients who experienced differentiation
`syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO.
`
`Reference ID: 4294285
`
`4
`
`

`

`
`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 treated with TIBSOVO in the clinical
`
`trial, 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.
`
`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 occurred in < 1% (2/258) of patients treated with TIBSOVO in the
`clinical study. 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)].
`
`
`
`
`
`Reference ID: 4294285
`
`5
`
`

`

`
`
`
`
` ADVERSE REACTIONS
`
`
`6
`
`The following serious adverse reactions are described elsewhere in the labeling:
`
`
` Differentiation Syndrome [see Warnings and Precautions (5.1)]
`
`
` QTc Interval Prolongation [see Warnings and Precautions (5.2)]
`
` Guillain-Barré Syndrome [see Warnings and Precautions (5.3)]
`
`
`Clinical Trials Experience
`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.
`
`The safety profile of single-agent TIBSOVO is based on experience in 179 adults with relapsed
`or refractory AML treated with 500 mg daily [see Clinical Studies (14.1)]. The median duration
`of exposure to TIBSOVO was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%)
`were exposed to TIBSOVO for at least 6 months and 16 patients (9%) were exposed for at least 1
`year.
`
`Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and
`electrocardiogram QT prolonged (7%). There was one case of progressive multifocal
`
`leukoencephalopathy (PML).
`
`The most common adverse reactions leading to dose interruption were electrocardiogram QT
`prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out
`of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions
`leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%),
`nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions
`leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%),
`
`stomatitis (1%), and creatinine increased (1%).
`
`The most common adverse reactions (≥ 20%) of any grade were fatigue, leukocytosis, arthralgia,
`diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia,
`cough, and constipation. 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 Relapsed or Refractory AML
`TIBSOVO (500 mg daily)
`N=179
`
`
`All Grades
`n (%)
`
`≥ Grade 3
`n (%)
`
`68 (38)
`34 (19)
`
`60 (34)
`56 (31)
`51 (28)
`
`15 (8)
`23 (13)
`
`4 (2)
`1 (1)
`6 (3)
`
`
`
`Body System
`
`Adverse Reaction
`Blood System and Lymphatic System Disorders
`Leukocytosis1
` Differentiation Syndrome2
`
`Gastrointestinal Disorders
`
`Diarrhea
`Nausea
`Mucositis3
`
`Reference ID: 4294285
`
`6
`
`

`

`35 (20)
`32 (18)
`29 (16)
`
`1 (1)
`2 (1)
`2 (1)
`
`Constipation
`Vomiting4
`
` Abdominal pain5
`
`General Disorders and Administration Site Conditions
`
` Fatigue6
`
` Edema7
`Pyrexia
` Chest pain8
`
` Investigations
`
`Electrocardiogram QT prolonged
`Metabolism and Nutrition Disorders
`Decreased appetite
`Tumor lysis syndrome
`
`Musculoskeletal and Connective Tissue Disorders
`
` Arthralgia9
`Myalgia10
`
` Nervous System Disorders
`
`Headache
`
`Neuropathy11
`Respiratory, Thoracic and Mediastinal Disorders
`Cough12
` Dyspnea13
`
`Pleural effusion
`Skin and Subcutaneous Tissue Disorders
`Rash14
`
` Vascular Disorders
`
`
`Hypotension15
`22 (12)
` 1 Grouped term includes leukocytosis, hyperleukocytosis, and increased white blood cell count.
`
`
`
`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 aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, mouth ulceration,
`
`
`
`mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis.
`
`
`4 Grouped term includes vomiting and retching.
`
`5 Grouped term includes abdominal pain, upper abdominal pain, abdominal discomfort, and abdominal tenderness.
`
`
`6 Grouped term includes asthenia and fatigue.
`
`
`7 Grouped term includes peripheral edema, edema, fluid overload, fluid retention, and face edema.
`
`8 Grouped term includes angina pectoris, chest pain, chest discomfort, and non-cardiac chest pain.
`
`
`
`
`9 Grouped term includes arthralgia, back pain, musculoskeletal stiffness, neck pain, and pain in extremity.
`
`
`10 Grouped term includes myalgia, muscular weakness, musculoskeletal pain, musculoskeletal chest pain,
`
`musculoskeletal discomfort, and myalgia intercostal.
`
`
`11 Grouped term includes ataxia, burning sensation, gait disturbance, Guillain-Barré syndrome, neuropathy
`
`
`
`peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, and sensory disturbance.
`
`
`
`12 Grouped term includes cough, productive cough, and upper airway cough syndrome.
`
`
`13 Grouped term includes dyspnea, respiratory failure, hypoxia, and dyspnea exertional.
`
`
`
`14 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.
`
`
`
`15 Grouped term includes hypotension and orthostatic hypotension.
`
`
`
`TIBSOVO (500 mg daily)
`
` N=179
`
`69 (39)
`57 (32)
`41 (23)
`29 (16)
`
`46 (26)
`
`33 (18)
`14 (8)
`
`64 (36)
`33 (18)
`
`28 (16)
`21 (12)
`
`40 (22)
`59 (33)
`23 (13)
`
`46 (26)
`
`6 (3)
`2 (1)
`2 (1)
`5 (3)
`
`18 (10)
`
`3 (2)
`11 (6)
`
`8 (4)
`1 (1)
`
`0
`2 (1)
`
`1 (<1)
`16 (9)
`5 (3)
`
`4 (2)
`
`7 (4)
`
`
`
`
`
`
`
`
`
`Reference ID: 4294285
`
`7
`
`

`

`
`Changes in selected post-baseline laboratory values that were observed in patients with relapsed
`or refractory AML are shown in Table 3.
`
`
`Table 3: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening
`Laboratory Abnormalities Reported in Patients with Relapsed or
`Refractory AML1
`
`
`
`
`Parameter
`
`
`
`
`TIBSOVO (500 mg daily)
`N=179
`≥ Grade 3
`All Grades
`
`n (%)
`n (%)
`
`83 (46)
`108 (60)
`Hemoglobin decreased
`8 (4)
`69 (39)
`Sodium decreased
`0
`68 (38)
`Magnesium decreased
`11 (6)
`57 (32)
`Uric acid increased
`11 (6)
`55 (31)
`Potassium decreased
`1 (1)
`49 (27)
`Alkaline phosphatase increased
`1 (1)
`49 (27)
`Aspartate aminotransferase increased
`15 (8)
`45 (25)
`Phosphate decreased
`2 (1)
`42 (23)
`Creatinine increased
`
`2 (1)
`26 (15)
`Alanine aminotransferase increased
`1 (1)
`28 (16)
`Bilirubin increased
`
`
`
` 1Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or
`
`if baseline is unknown.
`
`
`
`7
`
`7.1
`
`Strong or Moderate CYP3A4 Inhibitors
`
` Co-administration of TIBSOVO with strong or moderate
`CYP3A4 inhibitors increased ivosidenib plasma concentrations
`[see Clinical Pharmacology (12.3)].
`Increased ivosidenib plasma concentrations may increase the risk
`of QTc interval prolongation [see Warnings and Precautions
`(5.2)].
`
` Consider alternative therapies that are not strong or moderate
`CYP3A4 inhibitors during treatment with TIBSOVO.
`If co-administration of a strong CYP3A4 inhibitor is unavoidable,
`reduce TIBSOVO to 250 mg once daily [see Dosage and
`Administration (2.3)].
`
`
` Monitor patients for increased risk of QTc interval prolongation
`[see Warnings and Precautions (5.2)].
`
`
`DRUG INTERACTIONS
`
`
`
`
`Effect of Other Drugs on Ivosidenib
`
`Clinical Impact
`
`Prevention or Management
`
`
`
`
`
`
`
`Strong CYP3A4 Inducers
`
`
`Clinical Impact
`
`
` Co-administration of TIBSOVO with strong CYP3A4 inducers
`
`decreased ivosidenib plasma concentrations [see Clinical
`Pharmacology (12.3)].
`
`Prevention or Management  Avoid co-administration of strong CYP3A4 inducers with
`
`
`Reference ID: 4294285
`
`8
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`

`
`
`QTc Prolonging Drugs
`
`Clinical Impact
`
`Prevention or Management
`
`
`
` TIBSOVO.
`
`
` Co-administration of TIBSOVO with QTc prolonging drugs may
`increase the risk of QTc interval prolongation [see Warnings and
`
` Precautions (5.2)].
`
` Avoid co-administration of QTc prolonging drugs with TIBSOVO
`or replace with alternative therapies.
`If co-administration of a QTc prolonging drug is unavoidable,
`monitor patients for increased risk of QTc interval prolongation
`
` [see Warnings and Precautions (5.2)].
`
`
`
`
`Effect of Ivosidenib on Other Drugs
`
`USE IN SPECIFIC POPULATIONS
`
`
`7.2
`
`Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease
`concentrations of drugs that are sensitive CYP3A4 substrates and may decrease the
`concentrations of drugs that are sensitive CYP2C9 substrates [see Clinical Pharmacology
`(12.3)]. Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9
`during TIBSOVO treatment. Do not administer TIBSOVO with itraconazole or ketoconazole
`(CYP3A4 substrates) due to expected loss of antifungal efficacy. Co-administration of
`TIBSOVO may decrease the concentrations of hormonal contraceptives, consider alternative
`methods of contraception in patients receiving TIBSOVO. If co-administration of TIBSOVO
`
`sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of
`
`therapeutic effect of these drugs.
`
`
`8
`
`Pregnancy
`8.1
`
`Risk Summary
`Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when
`administered to a pregnant woman. There are no available data on TIBSOVO use in pregnant
`women to inform a drug-associated risk of major birth defects and miscarriage. In animal
`embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits
`during organogenesis was associated with embryo-fetal mortality and alterations to growth
`starting at 2 times the steady state clinical exposure based on the AUC at the recommended
`human dose (see Data). If this drug is used during pregnancy, or if the patient becomes pregnant
`while taking this drug, advise the patient of the potential risk to a fetus.
`
`The background risk of major birth defects and miscarriage for the indicated population is
`unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use
`of medications. In the U.S. general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%,
`
`respectively.
`
`Data
`Animal Data
`Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis
`(gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal
`
`Reference ID: 4294285
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`9
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`

`
`
`
`weights, and skeletal variations. These effects occurred in rats at approximately 2 times the
`human exposure at the recommended dose of 500 mg daily.
`
`In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was
`maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human
`exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as
`decreased fetal weights, skeletal variations, and visceral variations.
`
` Lactation
`8.2
`
`Risk Summary
`There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on
`the breastfed child, or the effects on milk production. Because many drugs are excreted in human
`milk and because of the potential for adverse reactions in breastfed children, advise women not
`to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.
`
`Pediatric Use
`8.4
`
`The safety and effectiveness of TIBSOVO in pediatric patients have not been established.
`
`8.5 Geriatric Use
`
`One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the
`clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No
`overall differences in effectiveness or safety were observed between patients 65 years and older
`and younger patients.
`
`
`11
`
`TIBSOVO (ivosidenib) is an inhibitor of isocitrate dehydrogenase 1 (IDH1) enzyme. The
`chemical name is (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2­
`oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide.
`The chemical structure is:
`
`
`DESCRIPTION
`
`
`
`
`The molecular formula is C28H22ClF3N6O3 and the molecular weight is 583.0 g/mol. Ivosidenib
`is practically insoluble in aqueous solutions between pH 1.2 and 7.4.
`
`TIBSOVO (ivosidenib) is available as a film-coated 250 mg tablet for oral administration. Each
`tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose
`sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and
`
`Reference ID: 4294285
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`10
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`

`

` CLINICAL PHARMACOLOGY
`
`
`
`
`sodium lauryl sulfate. The tablet coating includes FD&C blue #2, hypromellose, lactose
`monohydrate, titanium dioxide, and triacetin.
`
`
`12
`
`
`12.1 Mechanism of Action
`
`Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1
`(IDH1) enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of
`2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically
`meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant
`IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage
`according to validated methods. The most common of such mutations are R132H and R132C
`substitutions.
`
`Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than
`
`wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2­
`HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of
`IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib
`decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature
`
`myeloid cells.
`
`12.2 Pharmacodynamics
`
`Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG
`concentrations in patients with hematological malignancies to levels similar to those observed at
`baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.
`
`Cardiac Electrophysiology
`A concentration-dependent QTc interval prolongation of approximately 16.1 msec (90% CI:
`13.3, 18.9) was observed at the steady-state Cmax following a 500 mg daily dose based on an
`analysis of 171 patients with an IDH1 mutation, including 136 patients with relapsed or
`refractory AML, who received TIBSOVO 500 mg daily [see Warnings and Precautions (5.1)].
`Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc
`interval prolongation from baseline.
`
`12.3 Pharmacokinetics
`
`The following ivosidenib pharmacokinetic parameters were observed following administration of
`
`ivosidenib 500 mg as a single dose or daily dose (for steady-state), unless otherwise specified.
`
`The mean peak plasma concentration (Cmax) is 4,503 ng/mL [% coefficient of variation (%CV:
`38)] after a single dose, and 6,551 ng/mL (%CV: 44) at steady-state. The steady-state area under
`the concentration time curve (AUC) is 117,348 ng·hr/mL (%CV: 50).
`
`The AUC and Cmax of ivosidenib increase in a less than dose-proportional manner from 200 mg
`
`to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios
`were approximately 1.9 for AUC and 1.5 for Cmax over one month. Steady-state plasma levels are
`reached within 14 days.
`
`Reference ID: 4294285
`
`11
`
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`

`

`
` Absorption
`
`
`The median time to Cmax is approximately 3 hours.
`
`
`Effect of Food
`
`Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900
`
`to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories)
`
`increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%.
`
`
`
`Distribution
`
`The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (%CV: 47).
`
`Protein binding of ivosidenib ranges from 92 to 96% in vitro.
`
`
` Elimination
`
`Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance (CL/F) of
`4.3 L/hour (%CV: 50).
`
`Metabolism
`
`Ivosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is
`primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic
`pathways.
`
`Excretion
`
`After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of
`ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as
`unchanged).
`
`Specific Populations
`
`No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on
`age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38
`to 150 kg), ECOG performance status, mild or moderate renal impairment (eGFR ≥30
`mL/min/1.73m2, MDRD), or mild hepatic impairment (total bilirubin ≤ upper limit of normal
`[ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin 1.0 to 1.5 times ULN and
`any AST).
`
`The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30
`mL/min/1.73m2, MDRD), renal impairment requiring dialysis, moderate hepatic impairment
`(total bilirubin 1.5 to 3.0 times the ULN and any value for AST),