Tibsovo Drug Information

Patient Selection

Select patients for treatment with TIBSOVO based on the presence of IDH1 mutations. Information on FDA-approved tests for the detection of IDH1 mutations in AML, MDS, and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients with AML or MDS without disease progression or unacceptable toxicity, continue TIBSOVO 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. 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. Refer to the Prescribing Information for azacitidine for additional dosing information.

Monitoring and Dosage Modifications for Toxicities Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly.

Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. Table 1: Recommended Dosage Modifications for TIBSOVO Adverse Reactions Recommended Action Differentiation syndrome If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days.

QTc interval greater than 480 msec to 500 msec Monitor and supplement electrolyte levels as clinically indicated. Interrupt TIBSOVO. Interrupt TIBSOVO.

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Discontinue TIBSOVO permanently. Guillain-Barré syndrome Discontinue TIBSOVO permanently. Patients with AML or MDS 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.

Dosage Modification for Use with Strong CYP3A4 Inhibitors If a strong CYP3A4 inhibitor must be coadministered, reduce the TIBSOVO dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the TIBSOVO dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acute Myeloid Leukemia In AML, the safety population reflects exposure to TIBSOVO at 500 mg daily in combination with azacitidine or as monotherapy in patients in Studies AG120-C-009 (N=71) and AG120-C-001 (N=213), respectively. In this safety population, the most common adverse reactions including laboratory abnormalities (≥ 25% in either trial) were leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphatase decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia.

Newly Diagnosed AML TIBSOVO in Combination with Azacitidine The safety of TIBSOVO was evaluated in AML patients treated in combination with azacitidine, in Study AG120-C-009. Patients received at least one dose of either TIBSOVO 500 mg daily (N=71) or placebo (N=73). Among patients who received TIBSOVO in combination with azacitidine, the median duration of exposure to TIBSOVO was 6 months (range 0 to 33 months).

Common (≥ 5%) serious adverse reactions in patients who received TIBSOVO in combination with azacitidine included differentiation syndrome (8%). Fatal adverse reactions occurred in 4% of patients who received TIBSOVO in combination with azacitidine, due to differentiation syndrome (3%) and one case of cerebral ischemia. Adverse reactions leading to discontinuation of TIBSOVO in ≥2% of patients were differentiation syndrome (3%) and pulmonary embolism (3%).

Adverse reactions leading to dose reduction of TIBSOVO included electrocardiogram QT prolonged (8%), neutropenia (8%), and thrombocytopenia (1%). The most common adverse reactions and laboratory abnormalities observed in Study AG120-C-009 are shown in Tables 2 and 3. Table 2: Adverse Reactions (≥10%) in Patients with AML Who Received TIBSOVO + azacitidine with a Difference Between Arms of ≥ 2% Compared with Placebo + azacitidine in AG120-C-009 Table 3: Select Laboratory Abnormalities Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown., The denominator used to calculate percentages is the number of treated subjects who can be evaluated for CTCAE criteria for each parameter in each arm. (≥10%) That Worsened from Baseline in Patients with AML Who Received TIBSOVO + azacitidine in AG120-C-009 TIBSOVO Monotherapy The safety profile of single-agent TIBSOVO was studied in 28 adults with newly diagnosed AML treated with 500 mg daily.

The median duration of exposure to TIBSOVO was 4.3 months (range 0.3 to 40.9 months). There was one case of posterior reversible encephalopathy syndrome (PRES). Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT prolonged (14%) and differentiation syndrome (11%).

Two (7%) patients required a dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES. The most common adverse reactions reported in the trial are shown in Table 4.

Table 5: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Newly Diagnosed AML Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. in AG120-C-001 4 1 Relapsed or Refractory AML The safety profile of single-agent TIBSOVO was studied in 179 adults with relapsed or refractory AML treated with 500 mg daily. The median duration of exposure to TIBSOVO was 3.9 months (range 0.1 to 39.5 months). There was one case of progressive multifocal leukoencephalopathy (PML).

Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Table 7: Most Common (≥ 10%) or ≥ 5% (Grade ≥ 3) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or if baseline is unknown. 28 1 Relapsed or Refractory Myelodysplastic Syndromes The safety of TIBSOVO was evaluated in 19 adults with relapsed or refractory MDS treated with 500 mg daily in AG120-C-001. The median duration of exposure to TIBSOVO was 9.3 months (range 3.3 to 78.8 months).

Permanent discontinuation of TIBSOVO due to an adverse reaction occurred in 5% of patients. The adverse reaction which resulted in permanent discontinuation of TIBSOVO was fatigue. Adverse reactions leading to dosage interruption of TIBSOVO occurred in 16% of patients.

Adverse reactions which required dosage interruption in ≥ 5% were differentiation syndrome, leukocytosis, and rash. Dose reductions of TIBSOVO due to an adverse reaction occurred in 16% of patients. Adverse reactions which required a dose reduction in ≥ 5% included differentiation syndrome, fatigue, and rash.

The most common (≥ 25%) adverse reactions, including laboratory abnormalities, were creatinine increased, hemoglobin decrease, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash. Table 8 summarizes the adverse reactions in AG120-C-001. Table 9: Select Laboratory Abnormalities (≥ 15%) That Worsened from Baseline in Patients with Relapsed or Refractory MDS in AG120-C-001 0 Locally Advanced or Metastatic Cholangiocarcinoma The safety of TIBSOVO was studied in patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005.

Patients received at least one dose of either TIBSOVO 500 mg daily (N=123) or placebo (N=59). The median duration of treatment was 2.8 months (range 0.1 to 34.4 months) with TIBSOVO. Serious adverse reactions occurred in 34% of patients receiving TIBSOVO.

Serious adverse reactions in ≥2% of patients in the TIBSOVO arm were pneumonia, ascites, hyperbilirubinemia, and jaundice cholestatic. Fatal adverse reactions occurred in 4.9% of patients receiving TIBSOVO, including sepsis (1.6%) and pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (each 0.8%). TIBSOVO was permanently discontinued in 7% of patients.

The most common adverse reactions leading to permanent discontinuation was acute kidney injury (1.6%). Dose interruptions due to adverse reactions occurred in 29% of patients treated with TIBSOVO. The most common (>2%) adverse reactions leading to dose interruption were hyperbilirubinemia, alanine aminotransferase increased, aspartate aminotransferase increased, ascites, and fatigue.

Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (3.3%) and neuropathy peripheral (0.8%). The most common adverse reactions (≥15%) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. Adverse reactions and laboratory abnormalities observed in Study AG120-C-005 are shown in Tables 10 and 11.

Table 10: Adverse Reactions Occurring in ≥ 10% of Patients Receiving TIBSOVO in Study AG120-C-005: Selected Laboratory Abnormalities Occurring in ≥ 10% of Patients Receiving TIBSOVO in Study AG120-C-005 Laboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown.

Effect of Other Drugs on Ivosidenib Strong or Moderate CYP3A4 Inhibitors Clinical Impact Co-administration of TIBSOVO with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations. Increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation. Prevention or Management 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 Clinical Impact Co-administration of TIBSOVO with strong CYP3A4 inducers decreased ivosidenib plasma concentrations.

Prevention or Management Avoid co-administration of strong CYP3A4 inducers with TIBSOVO. QTc Prolonging Drugs Clinical Impact Co-administration of TIBSOVO with QTc prolonging drugs may increase the risk of QTc interval prolongation. Prevention or Management Avoid co-administration of QTc prolonging drugs with TIBSOVO or replace with alternative therapies.

Effect of Ivosidenib on Other Drugs

Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates. Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during TIBSOVO treatment.

If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 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.

Pregnancy 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 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.

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