TIBSOVO® (ivosidenib tablets)

TIBSOVO® (ivosidenib tablets) is a prescription medicine used to treat adults with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called isocitrate dehydrogenase-1 (IDH1) and are not eligible for standard chemotherapy treatment. TIBSOVO works by targeting the mutated IDH1 enzyme, which is involved in cell growth and differentiation, and inhibiting its activity. This can lead to differentiation of leukemia cells and ultimately their death.

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.

INDICATIONS AND USAGE

Newly Diagnosed Acute Myeloid Leukemia: TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1(IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Relapsed or Refractory Acute Myeloid Leukemia: TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory acutemyeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation asdetected by an FDA-approved test.

Locally Advanced or Metastatic Cholangiocarcinoma: TIBSOVO is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

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 sodium lauryl sulfate. The tablet coating includes FD&C blue #2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin.

Mechanism of Action

Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1(IDH1) enzyme. In patients with AML, 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 in patients with AML 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.

In a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1

R132C, ivosidenib reduced 2-HG levels.

DOSAGE AND ADMINISTRATION

Patient Selection

Acute Myeloid Leukemia: Select patients for the treatment of AML with TIBSOVO based on the presence of IDH1mutations in the blood or bone marrow.

Patients with AML withoutIDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 mayemerge during treatment and at relapse.

Locally Advanced or Metastatic Cholangiocarcinoma: Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with TIBSOVO based on the presence of IDH1 mutations

Information on FDA-approved tests for the detection of IDH1 mutations in AML and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

Newly Diagnosed AML (Combination Regimen): The recommended dosage of TIBSOVO is 500 mg taken orally once daily until diseaseprogression or unacceptable toxicity. Start TIBSOVO administration on Cycle 1 Day 1 incombination with azacitidine 75 mg/m2 subcutaneously or intravenously once daily on Days 1-7(or Days 1-5 and 8-9) of each 28-day cycle.

Refer to the PrescribingInformation for azacitidine for additional dosing information.

For patients without disease progression or unacceptable toxicity, continue TIBSOVO, in combination with azacitidine, for a minimum of 6 months to allow time for clinical response.

Newly Diagnosed AML and Relapsed or Refractory AML (Monotherapy Regimen): The recommended dosage of TIBSOVO is 500 mg taken orally once daily until diseaseprogression or unacceptable toxicity.

For patients without disease progression or unacceptable toxicity, continue TIBSOVO for a minimum of 6 months to allow time for clinical response.

Cholangiocarcinoma: The recommended dosage of TIBSOVO is 500 mg taken orally once daily until diseaseprogression or unacceptable toxicity.

Administer TIBSOVO with or without food. Do not administer TIBSOVO with a high-fat meal because of an increase in ivosidenib concentration. Do not split, crush, or chew TIBSOVO tablets. Administer TIBSOVO tablets orally about the same time each day. If a dose of TIBSOVO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of TIBSOVO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

CONTRAINDICATIONS

None.

Differentiation Syndrome in AML: In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AMLtreated with TIBSOVO plus azacitidine experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias.

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 lifethreatening arrhythmia

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barrésyndrome 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 sensoryneuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficultybreathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Co-administration of TIBSOVO with strong or moderateCYP3A4 inhibitors increased ivosidenib plasma concentrations. Increased ivosidenib plasma concentrations may increase the riskof QTc interval prolongation.

Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with TIBSOVO.

If co-administration of a strong CYP3A4 inhibitor is unavoidable, reduce TIBSOVO to 250 mg once daily.Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Co-administration of TIBSOVO with strong CYP3A4 inducersdecreased ivosidenib plasma concentrations

Avoid co-administration of strong CYP3A4 inducers with TIBSOVO.

QTc Prolonging Drugs: Co-administration of TIBSOVO with QTc prolonging drugs mayincrease the risk of QTc interval prolongation

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

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm whenadministered to a pregnant woman. There are no available data on TIBSOVO use in pregnantwomen to inform a drug-associated risk of major birth defects and miscarriage. In animalembryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbitsduring organogenesis was associated with embryo-fetal mortality and alterations to growthstarting at 2 times the steady state clinical exposure based on the AUC at the recommendedhuman dose. If this drug is used during pregnancy, or if the patient becomes pregnantwhile taking this drug, advise the patient of the potential risk to a fetus.

Lactation: There are no data on the presence of ivosidenib or its metabolites in human milk, the effects onthe breastfed child, or the effects on milk production. Because many drugs are excreted in humanmilk and because of the potential for adverse reactions in breastfed children, advise women notto breastfeed during treatment with TIBSOVO and for 1 month after the last dose.

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

Renal Impairment: No modification of the starting dose is recommended for patients with mild or moderate renalimpairment (eGFR ≥ 30 mL/min/1.73m2, MDRD). The pharmacokinetics and safety ofivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2, MDRD) orrenal impairment requiring dialysis are unknown.

Forpatients with pre-existing severe renal impairment or who are requiring dialysis, consider therisks and potential benefits before initiating treatment with TIBSOVO.

Hepatic Impairment: No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment.

The pharmacokinetics andsafety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. Forpatients with pre-existing severe hepatic impairment, consider the risks and potential benefitsbefore initiating treatment with TIBSOVO.

Gafacom

TIBSOVO® (ivosidenib tablets)

TIBSOVO® (ivosidenib tablets)