Ivosenib Ivosidenib Tablets

[Drug Name]

Generic Name: Ivosidenib Tablets

Brand Names: Tuoshuwo, TIBSOVO, Ivosenib

English Name: Ivosidenib Tablets

Specification: 0.25 g/tablet; 60 tablets/box

Manufacturer: Everest Pharmaceuticals Ltd

[Composition]

Active Ingredient: Ivosidenib

Chemical Name: (2S)-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-2-(5-fluoro-2-pyrimidinyl)-1-pyrrolidinecarboxamide

[Indications]

This product is indicated for the treatment of the following adult patients diagnosed—via a fully validated diagnostic test—as harboring a susceptible Isocitrate Dehydrogenase-1 (IDH1) mutation:

1. Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)

2. Newly Diagnosed Acute Myeloid Leukemia (AML): Patients aged ≥75 years, or those ineligible for intensive induction chemotherapy due to comorbidities; may be used as monotherapy or in combination with azacitidine.

3. Relapsed or Refractory Myelodysplastic Syndromes (MDS)

4. Previously treated, locally advanced or metastatic Cholangiocarcinoma

[Dosage and Administration]

1. Patient Selection

Treatment with this product must be initiated only after the presence of an IDH1 mutation in the patient's tumor specimen or blood has been confirmed using a fully validated diagnostic test.

2. Recommended Dosage

Standard Dose: 500 mg (2 tablets) once daily, administered orally.

Administration Method: May be taken with or without food. Tablets must be swallowed whole; do not break, crush, or chew the tablets.

Timing of Administration: Take the medication at the same time each day to maintain stable blood drug concentrations.

Duration of Treatment: Continue treatment until disease progression or until unacceptable toxicity occurs. For patients without disease progression, it is recommended to continue treatment for at least 6 months to allow for a full assessment of efficacy. 3. Management of Missed Doses and Vomiting

Missed Dose: If a missed dose is discovered, take it as soon as possible; however, if less than 12 hours remain before the next scheduled dose, skip the missed dose and resume the original schedule the following day. Do not take two doses within a 12-hour period.

Vomiting: If vomiting occurs after taking the medication, do not take a replacement dose; resume the scheduled dosing at the next appointed time.

4. Dosage Adjustments (for Adverse Reactions)

(1) Differentiation Syndrome (Life-threatening)

Management: Immediately suspend treatment, initiate intravenous dexamethasone 10 mg every 12 hours (or an equivalent corticosteroid), and monitor hemodynamics.

Resumption: Once symptoms have resolved to Grade ≤1 and remained stable for at least 3 days, treatment may be resumed at 500 mg/day. If symptoms recur, permanently discontinue the drug.

(2) QTc Interval Prolongation

480 ms < QTc ≤ 500 ms: Suspend treatment and correct any electrolyte abnormalities; resume treatment at 500 mg/day once resolved.

QTc > 500 ms: Suspend treatment; once resolved to ≤480 ms, reduce the dosage to 250 mg/day.

Associated with life-threatening arrhythmia: Permanently discontinue the drug.

(3) Grade 3/4 Non-hematologic Toxicity

Suspend treatment until the toxicity resolves to Grade ≤1.

First Resumption: 250 mg/day; if well-tolerated, the dosage may be re-escalated to 500 mg/day.

If Grade 3/4 toxicity recurs at the 250 mg dosage: Permanently discontinue the drug.

(4) Guillain-Barré Syndrome

Permanently discontinue the drug.

5. Dosage Adjustments for Specific Populations

Hepatic Impairment:

Mild/Moderate (Child-Pugh A/B): No dosage adjustment required. 

Severe (Child-Pugh C): Use with caution; a risk-benefit assessment is required.

Renal Impairment:

eGFR ≥ 30 mL/min: No dosage adjustment required. 

eGFR < 30 mL/min or on dialysis: Limited data available; individual assessment is required.

Elderly Patients (≥65 years): No dosage adjustment required based on age. [Adverse Reactions]

1. Most Common Adverse Reactions (≥20%)

AML: Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QTc interval prolongation, rash, pyrexia, cough, constipation.

Cholangiocarcinoma: Fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, anemia, rash.

2. Serious Adverse Reactions (Requiring Urgent Management)

Differentiation Syndrome (Incidence: approx. 11% in AML; approx. 2% in Cholangiocarcinoma): Pyrexia, dyspnea, pulmonary infiltrates, pleural/pericardial effusion, hypotension, renal impairment.

QTc Interval Prolongation: May lead to Torsades de Pointes and sudden death.

Guillain-Barré Syndrome (Rare): Symmetrical weakness in the extremities, paresthesia, diminished tendon reflexes.

Others: Hepatotoxicity, pancreatitis, infection.

[Contraindications]

Contraindicated in patients with hypersensitivity to ivosidenib or to any of the excipients in this product.

[Precautions]

1. Monitoring for Differentiation Syndrome

Closely monitor for signs and symptoms—such as pyrexia, respiratory distress, changes in blood pressure, and edema—from one month prior to initiation of therapy until after discontinuation.

If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and temporarily suspend administration of the drug.

2. Monitoring for QTc Interval Prolongation

Perform electrocardiogram (ECG) assessments prior to initiating therapy, during the first week, during the third week, and monthly thereafter.

Monitor serum potassium and magnesium levels, and maintain them within the normal range.

Avoid concomitant use with strong QTc-prolonging medications (e.g., antiarrhythmics, certain fluoroquinolones, tricyclic antidepressants).

3. Neurological Toxicity

Be alert for Guillain-Barré syndrome: If symptoms such as limb weakness, numbness, or difficulty walking occur, immediately discontinue the drug and seek medical attention.

4. Monitoring of Hepatic and Renal Function

Assess hepatic and renal function prior to initiating therapy, monthly during the first 3 months of treatment, and every 3 months thereafter.

5. Embryo-Fetal Toxicity

Contraindicated in pregnant women.

Women and Men of Reproductive Potential: Strict contraception is required during treatment and for at least one month after discontinuing the drug. 6. Lactation

Discontinue breastfeeding during treatment and for at least 1 month after the last dose.

[Drug Interactions]

Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Significantly increase plasma concentrations of ivosidenib; avoid concomitant use.

Strong CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine): Significantly decrease plasma concentrations of ivosidenib; avoid concomitant use.

Sensitive CYP3A4 Substrates (e.g., midazolam, simvastatin): Ivosidenib may decrease their concentrations; avoid concomitant use or monitor for efficacy.

QTc-prolonging Drugs: Increase the risk of arrhythmias; avoid concomitant use.

[Pharmacology and Toxicology]

Mechanism of Action: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) enzyme. Mutant IDH1 leads to the accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which results in a block in cellular differentiation and promotes oncogenesis. This product inhibits mutant IDH1, reduces 2-HG levels, and restores normal cellular differentiation function.

Carcinogenicity and Reproductive Toxicity: Long-term carcinogenicity studies have not been conducted. Animal studies have demonstrated embryo-fetal toxicity (including miscarriage and reduced fetal body weight).

[Pharmacokinetics]

Absorption: Peak plasma concentrations are reached at a median of 3 hours after oral administration. A high-fat meal increases AUC by 98% and Cmax by 45%.

Distribution: Plasma protein binding is 97%.

Metabolism: Primarily metabolized via CYP3A4.

Elimination: The elimination half-life is approximately 93 hours. Excretion occurs primarily via feces (73%) and urine (17%).

[Storage]

Keep tightly closed; store at 15°C to 30°C.

[Packaging]

60 tablets per bottle.

[Shelf Life]

24 months. Product Specifications

Product Name: Ivosenib Tablets 0.25g × 60 Tablets/Box (Ivosenib / Ivosidenib Tablets)

Common Name: Ivosenib Tablets

Active Ingredient: Ivosenib

Dosage Form: Round, film-coated tablets

Specification: 0.25g/tablet; 60 tablets/box

Manufacturer: Everest Pharmaceuticals Ltd.

Indications: This product is indicated for the following adult patients diagnosed—via a fully validated diagnostic test—as harboring a susceptible Isocitrate Dehydrogenase-1 (IDH1) mutation:

1. Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)

2. Newly Diagnosed Acute Myeloid Leukemia (AML): Patients aged ≥75 years, or those with comorbidities precluding the use of intensive induction chemotherapy; may be used as monotherapy or in combination with azacitidine.

3. Relapsed or Refractory Myelodysplastic Syndromes (MDS)

4. Previously treated, locally advanced or metastatic Cholangiocarcinoma

Dosage and Administration: 1. Patient Selection

Treatment with this product must be initiated only after the presence of an IDH1 mutation in the patient's tumor specimen or blood has been confirmed using a fully validated diagnostic test.

2. Recommended Dosage

Standard Dose: 5g (2 tablets), once daily, administered orally.

Administration Method: May be taken with or without food. Tablets must be swallowed whole; do not break, crush, or chew.

Timing of Administration: Take the medication at a fixed time each day to maintain stable blood drug concentrations.

Duration of Treatment: Continue treatment until disease progression or the occurrence of intolerable toxicity. For patients without disease progression, it is recommended to continue treatment for at least 6 months to allow for a full assessment of efficacy.