Overview of basic information in the instructions for Avnibu Tablets

1. Common name: Avonib tablets

Product name:TIBSOVO, TOSOVO

All names: Ivosidenib tablets, Ivosidenib, Ivitinib

2. Indications:

1. Newly diagnosed acute myeloid leukemia (AML): Ivosidenib is indicated in combination with azacitidine or as a single agent for the treatment of newly diagnosed acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation in adults aged 75 years or older, or those with comorbidities that preclude intensive induction chemotherapy;

2. Relapsed or refractory (R/R) acute myeloid leukemia: Ivonib is suitable for the treatment of adult patients with relapsed or refractory acute myeloid leukemia who are susceptible to isocitrate dehydrogenase 1 (IDH1) mutations.

3. Relapsed or refractory (R/R) myelodysplastic syndrome (MDS): Ivonib is suitable for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome who have susceptible isocitrate dehydrogenase 1 (IDH1) mutations.

4. Locally advanced or metastatic cholangiocarcinoma (CCA): Ivonib is suitable for the treatment of adult patients with previously treated locally advanced or metastatic cholangiocarcinoma with isocitrate dehydrogenase 1 (IDH1) mutations.

3. Usage and dosage:

1. Medication management: Based on the presence of IDH1 mutations, doctors will select patients to receive ivonib treatment. Obtain an electrocardiogram before starting treatment; monitor the electrocardiogram at least weekly during the first 3 weeks of treatment, and evaluate blood cell counts and blood chemistry at least weekly during the first month and every other week during the second month. Monitor electrocardiograms and assess blood cell counts and blood chemistry at least monthly during treatment, and monitor blood creatine phosphokinase weekly during the first month of treatment.

2. Recommended dose: The recommended dose of ivonib is 500 mg orally administered once daily until disease progression or unacceptable toxicity occurs. For patients with acute myeloid leukemia or myelodysplastic syndrome who do not have disease progression or unacceptable toxicity, ivosidenib should be continued for at least 6 months to allow time for clinical response. Do not use ivosidenib with a high-fat meal, with or without food.

For newly diagnosed acute myeloid leukemia (combination regimen), start in combination with azacitidine 75 mg/m2 subcutaneously or intravenously on days 1-7 (or days 1-5 and 8-9) of each 28-day cycle. Please see the azacitidine prescribing information for more dosing information.

3. Dose adjustment for strong CYP3A4 inhibitors: If strong CYP3A4 inhibitors must be taken at the same time, the dose of ivonib should be reduced to 250 mg once daily. If a strong CYP3A4 inhibitor is discontinued, increase the ivomonib dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended once-daily dose of 500 mg.

4. Adverse reactions:

In clinical studies of ivonib combination therapy, the most common adverse reactions, including laboratory abnormalities (≥25%), were leukopenia, diarrhea, hemoglobin decrease, thrombocytopenia, glucose increase, fatigue, alkaline phosphatase increase, edema, potassium Decreased, nausea, vomiting, decreased phosphatase, decreased appetite, decreased sodium, leukocytosis, decreased magnesium, increased aspartate aminotransferase, arthralgia, dyspnea, increased uric acid, abdominal pain, increased creatinine, mucositis, rash, QT prolongation on ECG, differentiation syndrome, decreased calcium, neutropenia, and myalgia.

In clinical studies of ivonib for the treatment of MDS and cholangiocarcinoma, the most common (≥ 25%) adverse reactions (including laboratory abnormalities) include increased creatinine, decreased hemoglobin, arthralgia, decreased albumin, increased aspartate aminotransferase, fatigue, diarrhea, cough, decreased sodium, mucositis, decreased appetite, myalgia, decreased phosphate, nausea, abdominal pain, ascites, vomiting, anemia, pruritus, and rash.

5. Storage:

Avosidenib can be stored20°C to 25°C (68°F to 77°F); tolerances are allowed between 15°C to 30°C (59°F to 86°F).

6. Special groups:

1. Women: Because many drugs are excreted through breast milk and breastfed children may experience adverse reactions, it is recommended that women not breastfeed during treatment with ivonib and within 1 month after the last dose.

7. Mechanism of action:

Ivonib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase1 (IDH1) enzyme. For patients with AML, a predisposing IDH1 mutation is defined as a mutation that results in elevated 2-hydroxyglutarate (2-HG) levels in leukemic cells, with efficacy demonstrated by 1) clinically meaningful remission with ivosidenib at recommended doses and/or 2) inhibition of mutant IDH1 enzymatic activity at ivosidenib concentrations that are sustainable at recommended doses based on validated methods. The most common such mutations in AML patients are the R132H and R132C substitutions.

Avosidenib was shown to be more potent than wild type in vitroMuch lower concentrations of IDH1 inhibit selected IDH1 R132 mutants. In a mouse xenograft model of IDH1-mutated AML, inhibition of the mutant IDH1 enzyme by ivonib b resulted in reduced 2-HG levels and induction of myeloid differentiation in vitro and in vivo. In blood samples from IDH1-mutated AML patients, ivosidenib reduced ex vivo 2-HG levels, reduced blast cell counts, and increased the percentage of mature myeloid cells. Avosidenib reduced 2-HG levels in a patient-derived xenograft intrahepatic cholangiocarcinoma mouse model with IDH1 R132C.