艾伏尼布(ivosidenib)的详细说明书：作用与功效,用法用量,副作用,注意事项

ivosidenib is an anti-tumor drug and a potent and highly selective inhibitor of isocitrate dehydrogenase-1 (IDH1).

Efficacy and effects of ivosidenib

1. Acute myeloid leukemia (AML)

As a monotherapy, it is used for newly diagnosed AML patients with susceptible IDH1 mutations who are ≥75 years old or are not suitable for intensive induction chemotherapy due to other reasons.

In combination with azacitidine, it is indicated for the treatment of newly diagnosed AML patients with susceptible IDH1 mutations who are ≥75 years of age or who are otherwise ineligible for intensive induction chemotherapy.

Azacitidine, with or without azacitidine, is generally recommended as one of several regimens that may be considered for the treatment of newly diagnosed AML patients who are elderly or have significant comorbidities.

For the treatment of adult patients with relapsed or refractory AML who have susceptible IDH1 mutations.

The National Cancer Institute (NCI) points out that there is no standard treatment option for relapsed or refractory AML; patients who are unable or unwilling to undergo intensive therapy may be candidates for reduced-intensity therapy, including the use of ivonib.

Before starting treatment, the presence of an IDH1 mutation needs to be confirmed using an FDA-approved diagnostic test (e.g., AbbottRealTimeIDH1 test).

Orphan drug designation: Designated by the FDA as an orphan drug for the treatment of AML.

2. Relapsed or refractory myelodysplastic syndrome (MDS)

For the treatment of adult patients with relapsed or refractory MDS who have susceptible IDH1 mutations.

Before starting treatment, the presence of an IDH1 mutation needs to be confirmed using an FDA-approved diagnostic test (e.g., AbbottRealTimeIDH1 test).

Orphan drug designation: Designated by the FDA as an orphan drug for the treatment of MDS.

3. Locally advanced or metastatic cholangiocarcinoma

It is used to treat adult patients with previously treated locally advanced or metastatic cholangiocarcinoma who carry IDH1 mutations.

Before starting treatment, the presence of an IDH1 mutation needs to be confirmed using an FDA-approved diagnostic test (e.g., AbbottRealTimeIDH1 test).

Orphan drug designation: Designated by the FDA as an orphan drug for the treatment of cholangiocarcinoma.

ivosidenib Medication Guide

1. Pre-treatment screening

Confirm the presence of IDH1 mutation (peripheral blood or bone marrow) before starting treatment.

Carry out an electrocardiogram (ECG).

For patients with AML or MDS, perform a complete blood count (CBC) and blood chemistry tests.

2. Patient monitoring

For patients with AML or MDS, monitor CBC and blood chemistry at least weekly during the first month of treatment, every two weeks for the next month, and monthly thereafter.

For patients with AML or MDS, monitor serum creatine kinase (CK) concentrations at least weekly during the first week of treatment.

Perform ECG examinations at least weekly during the first three weeks of treatment and at least monthly thereafter.

More frequent monitoring may be necessary in patients with other risk factors for QT prolongation (e.g., congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, concomitant use of CYP3A4 inhibitors, or drugs known to prolong the QTc interval).

Monitor electrolyte levels as clinically indicated.

Monitor for signs or symptoms of motor and/or sensory neuropathy (e.g., unilateral or bilateral weakness, sensory changes, paresthesia, dyspnea).

Monitor for signs or symptoms of differentiation syndrome (e.g., noninfectious leukocytosis, peripheral edema, fever, dyspnea, hypotension); if suspected, initiate corticosteroid therapy and hemodynamic monitoring as needed.

The pictures are from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

3. Administration method

Oral administration, once a day at about the same time, without taking into account the eating situation; but high-fat diet should be avoided. Swallow tablets whole; do not chew, crush or break.

4. Dosage

(1), Newly diagnosed AML (monotherapy)

Once a day, 500 mg each time. Continue treatment until disease progression or unacceptable toxicity.

Most patients achieve optimal response within 6 months of starting ivosidenib; therefore, treatment should be continued for at least 6 months to allow time for response.

(2) Newly diagnosed AML (combination therapy)

500 mg once a day, combined with azacitidine. Continue treatment until disease progression or unacceptable toxicity.

Most patients achieve optimal response within 6 months of starting ivonib; therefore, combination therapy with azacitidine should be continued for at least 6 months to allow time for response.

Start taking ivonib on day 1 of each 28-day cycle, and simultaneously inject azacitidine 75 mg/m² subcutaneously or intravenously on days 1-7 (or days 1-5 and 8-9), once daily. For additional dosing information for azacitidine, see its Prescribing Information.

(3), Relapsed or refractory AML

Once a day, 500 mg each time. Continue treatment until disease progression or unacceptable toxicity.

Most patients achieve optimal response within 6 months of starting ivosidenib; therefore, treatment should be continued for at least 6 months to allow time for response.

(4), Relapsed or refractory MDS

Once a day, 500 mg each time. Continue treatment until disease progression or unacceptable toxicity.

For patients without disease progression or unacceptable toxicity, ivosidenib should be continued for at least 6 months to allow time for clinical response.

(5), locally advanced or metastatic cholangiocarcinoma

Take 500 mg once a day. Continue treatment until disease progression or unacceptable toxicity.

5. Post-vomiting treatment

If you vomit after taking the medicine, do not take additional doses; you should wait for the next scheduled dose.

6. Treatment of missed doses

If you miss a dose or do not take it at the usual time, you should take it as soon as possible and at least 12 hours before the next scheduled dose. Resume your normal dose the next day and do not take two doses within 12 hours.

ivosidenib dose adjustment for toxicity

1. Differentiation syndrome

If severe signs or symptoms of differentiation syndrome (e.g., fever, acute respiratory distress, pulmonary infiltration edema, pleural or pericardial effusion, hypotension, peripheral edema, rapid weight gain, hepatic or renal impairment, multiple organ dysfunction) that persists after more than 48 hours of systemic corticosteroid therapy, ivosidenib should be withheld until toxicity improves to Grade 2 or less.

2. Non-infectious leukocytosis

If non-infectious leukocytosis (WBC>25,000/mm³ or absolute increase in total WBC>15,000/mm³) persists after starting hydroxyurea treatment, use of ivonib should be suspended. After resolution of the leukocytosis, treatment was resumed at a dose of 500 mg daily.

3. QT interval prolongation

If the QTc interval is 480–500 milliseconds, suspend ivonib treatment; when the QTc interval improves to ≤480 milliseconds, resume treatment at the same dose (500 mg daily). Monitor ECG at least weekly for at least 2 weeks after resolution of QTc prolongation.

If the QTc interval is >500 msec, suspend ivonib therapy; when the QTc interval improves to ≤480 msec or increases by ≤30 msec from baseline, resume treatment at the reduced daily dose of 250 mg.

If another cause of QT prolongation is confirmed, the dose may be readjusted to 500 mg daily.

If symptomatic QTc prolongation occurs (e.g., life-threatening arrhythmias), permanently discontinue ivosidenib.

4. Guillain-Barré syndrome

If Guillain-Barré syndrome occurs, permanently discontinue ivonib.

5. Other toxicities in patients with AML or MDS receiving monotherapy

If an adverse reaction of grade 3 or above occurs during the monotherapy of AML or MDS with ivosidenib, suspend ivosidenib.

When toxicity improves to Grade 2 or less, resume ivonib at a reduced dose of 250 mg daily; when toxicity improves to Grade 1 or less, the dose can be re-escalated to 500 mg daily.

If grade 3 or above adverse reactions recur, discontinue ivosidenib

6. Other toxicities in AML patients receiving combination therapy with azacitidine and patients with cholangiocarcinoma

If grade 3 or above adverse reactions occur during the combined treatment of AML with azacitidine or during the treatment of cholangiocarcinoma, suspend ivosidenib.

When toxicity improves to Grade 1 or less, or returns to baseline, resume ivosidenib at a reduced dose: to 500 mg daily for Grade 3 toxicity and to 250 mg daily for Grade 4 toxicity.

If a second recurrence of grade 3 or above adverse reactions occurs, reduce the dose to 250 mg daily until toxicity subsides, then return to 500 mg daily.

If grade 3 toxicity recurs for a third time or grade 4 toxicity recurs, discontinue ivosidenib.

Dose adjustment of ivosidenib for special groups

1. Hepatic insufficiency

(1), mild or moderate hepatic insufficiency (Child-Pugh class A or B): No adjustment of the initial dose is required.

(2) Severe hepatic insufficiency (Child-Pugh C grade): No research has been conducted, and the potential risks and benefits of the drug should be considered before starting treatment.

2. Renal insufficiency

(1), mild or moderate renal insufficiency (eGFR30 to <90mL/min/1.73m²): No need to adjust the initial dose.

(2), severe renal insufficiency (eGFR<30mL/min/1.73m²) or dialysis: Not studied, the potential risks and benefits of the drug should be considered before starting treatment.

3. Elderly patients

No special dosage recommendations are provided.

Contraindications of ivosidenib

None.

Precautions for ivosidenib

1. Differentiation syndrome in acute myeloid leukemia and myelodysplastic syndrome

There have been reports of differentiation syndrome related to ivosidenib treatment; symptoms These include acute respiratory distress (dyspnea and/or hypoxemia), pulmonary infiltrates, renal impairment, multiorgan dysfunction, fever, pulmonary or peripheral edema, rapid weight gain, rash, hypotension, tumor lysis syndrome, leukocytosis without infectious etiology, and pleural or pericardial effusion.

It is first observed 1 day to 3 months after starting Ivonib. If no alternative etiology is clear, differentiation syndrome should be suspected.

If signs or symptoms suggestive of differentiation syndrome occur, initiate intravenous or oral corticosteroid therapy and continue for at least 3 days until symptoms resolve, then gradually reduce the corticosteroid dose; monitor hemodynamic parameters until symptoms improve.

If leukocytosis without infectious etiology occurs simultaneously, initiate hydroxyurea therapy according to standard practice and perform leukapheresis as needed.

If signs or symptoms of differentiation syndrome persist for more than 48 hours after corticosteroid therapy, interrupt ivosidenib therapy.

2. QT interval prolongation

QTc interval prolongation and ventricular arrhythmia (ie, ventricular fibrillation) have been reported. Monitor the ECG at least weekly during the first three weeks of treatment and at least monthly thereafter.

Congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, CYP3A4 inhibitors, and drugs known to prolong the QTc interval increase the risk of QT prolongation. More frequent monitoring (i.e., ECG, serum electrolytes) may be required.

Monitor blood chemistry at baseline, at least weekly for the first month of treatment, every two weeks for the next month, and monthly thereafter.

Correct electrolyte abnormalities as clinically indicated before initiating treatment with ivosidenib and during treatment.

If QTc interval prolongation occurs, it may be necessary to temporarily interrupt, reduce the dose, or discontinue ivonib. After resolution of QTc interval prolongation, monitor ECG at least weekly for two weeks.

3. Guillain-Barré syndrome

Occasionally, Guillain-Barré syndrome has been reported.

Monitor for signs or symptoms of motor and/or sensory neuropathy, such as unilateral or bilateral weakness, sensory changes, paresthesia, dyspnea. If Guillain-Barré syndrome occurs, discontinue ivosidenib.

Usage of ivosidenib in special populations

1. During pregnancy

It may cause fetal harm; it has been proven to have embryo-fetal toxicity and teratogenicity in animals.

Pregnancy should be avoided during treatment. Patients should use adequate contraceptive measures during treatment. If used during pregnancy, patients should be informed of the potential risk to the fetus.

2. Lactation

It is not known whether ivonib or its metabolites are excreted into human milk, or whether the drug has any effects on breast milk secretion or nursing infants. Breastfeeding should be discontinued during treatment and for at least 1 month after the last dose.

3. Pediatric use

Safety and effectiveness have not been established.

4. Medication for the elderly

Compared with young adults, there is generally no difference in safety and effectiveness.

5. Hepatic insufficiency

Mild or moderate hepatic insufficiency (Child-Pugh class A or B) will reduce the systemic exposure of ivonib.

Not studied in patients with severe hepatic impairment (Child-Pugh class C).

6. Renal insufficiency

In a population pharmacokinetic analysis, mild or moderate renal insufficiency (eGFR30 to <90mL/min/1.73m²) did not change systemic exposure.

Not studied in patients with severe renal insufficiency (eGFR<30mL/min/1.73m²) and those requiring dialysis.

Common adverse reactions of ivosidenib

1. AML patients

Common adverse reactions include laboratory abnormalities (≥25%): leukopenia, diarrhea, decreased hemoglobin, thrombocytopenia, increased blood sugar, fatigue, increased alkaline phosphatase, edema, decreased serum potassium, nausea, vomiting, decreased serum phosphorus, decreased appetite, decreased serum sodium, and increased leukocytosis.

Decreased serum magnesium, elevated aspartate aminotransferase (AST), joint pain, dyspnea, elevated uric acid, abdominal pain, elevated creatinine, mucositis, rash, QT prolongation, differentiation syndrome, reduced serum calcium, neutropenia, and myalgia.

2. Patients with relapsed or refractory MDS

Common adverse reactions include laboratory abnormalities (≥25%): increased creatinine, decreased hemoglobin, joint pain, decreased albumin, increased AST, fatigue, diarrhea, cough, decreased serum sodium, mucositis, decreased appetite, myalgia, decreased serum phosphorus, itching and rash.

3. Patients with cholangiocarcinoma

Common adverse reactions (≥15%) include: fatigue, nausea, abdominal pain, diarrhea, cough, loss of appetite, ascites, vomiting, anemia and rash.

Common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma include: decreased hemoglobin, increased AST, and increased bilirubin.

ivosidenib drug interactions

1. Moderate or strong CYP3A4 inhibitors

may increase the systemic exposure of ivosidenib and the risk of toxicity (e.g., QT interval prolongation). Consider alternative medications with less CYP3A inhibitory potential.

If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the ivosidenib dose from 500 mg once daily to 250 mg once daily.

When a strong CYP3A4 inhibitor is discontinued (after at least 5 half-lives of the strong CYP3A4 inhibitor), resume the ivosidenib dose to 500 mg once daily.

Monitor patients concurrently receiving moderate or strong CYP3A4 inhibitors for signs of ivosidenib toxicity (i.e., QT interval prolongation).

2. Strong CYP3A4 inducers

may reduce ivosidenib exposure, so avoid simultaneous use.

3. Sensitive CYP3A4 substrates

may reduce the exposure of CYP3A4 substrates and reduce their efficacy. Avoid concurrent use; consider alternative drugs that are non-sensitive CYP3A4 substrates. If concurrent use cannot be avoided, monitor for failure of the substrate drug.

4. Drugs that prolong the QT interval

may have additive effects on QT interval prolongation. Avoid concurrent use; consider an alternative drug that does not prolong the QT interval. If concurrent use cannot be avoided, monitor ECG and electrolytes more frequently.

ivosidenib pharmacokinetics

1, absorption

(1), bioavailability

The peak plasma concentration and AUC of ivosidenib showed a less than dose-proportional increase in the daily dose range of 200–1200 mg.

The median time to peak avonib is approximately 2 to 3 hours.

After once-daily dosing, steady-state concentrations are reached within 14 days; systemic accumulation is observed (approximately 1.2- to 1.9-fold increase in peak plasma concentration and AUC).

Pharmacokinetics at steady state were similar in patients with newly diagnosed AML, relapsed or refractory disease, and relapsed or refractory MDS, and were lower in patients with cholangiocarcinoma.

(2), Food

Taking a single dose of 500 mg with a high-fat meal (900–1000 calories, of which 500–600 calories are from fat) increased the peak plasma concentration and AUC of ivonib by 98% and approximately 25%, respectively.

2. Distribution

It is unclear whether ivosidenib or its metabolites will be distributed into human milk.

Plasma protein binding: 92%–96%.

3. Metabolism

Mainly metabolized by CYP3A4, followed by N-dealkylation and hydrolysis.

After taking the radiolabeled dose, unchanged ivosidenib accounted for more than 92% of the total radioactivity in the plasma.

4. Elimination

It is mainly eliminated through feces (77%; 67% is original drug), and a small amount is eliminated through urine (17%; 10% is original drug).

Half-life: In patients with cholangiocarcinoma, relapsed or refractory AML, newly diagnosed AML in combination with azacitidine, and relapsed or refractory MDS, the half-life is 129, 58, 98, and 96 hours, respectively.

Special population pharmacokinetics of ivosidenib

1. Mild or moderate hepatic insufficiency (Child-Pugh class A or B): Systemic exposure does not change significantly.

2. Severe hepatic insufficiency (Child-Pugh C grade): not studied.

3. Mild or moderate renal insufficiency (eGFR30 to <90mL/min/1.73m²): In a population pharmacokinetic analysis, systemic exposure did not change.

4. Severe renal insufficiency (eGFR<30mL/min/1.73m²) or dialysis: not studied.

ivosidenib Storage

Tablets should be stored at 20–25ºC (excursions between 15–30ºC allowed).

Mechanism of action of ivosidenib

Ivosidenib is a potent and selective IDH1 inhibitor. About 6%–16% of AML cases carry IDH1 mutations.

IDH1 mutations lead to the reduction of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate, causing epigenetic dysregulation, subsequent histone and DNA hypermethylation, and arrest of hematopoietic stem cell differentiation.

Susceptible IDH1 mutations are defined as those that result in elevated 2-hydroxyglutarate levels in leukemia cells and for which ivosidenib is expected to produce clinically meaningful responses at recommended doses and/or where sustained ivosidenib concentrations are expected to inhibit IDH1 mutational activity at recommended doses. The most common ivosidenib-susceptible IDH1 mutations are R132C or R132H substitution mutations.

In vitro, the concentration required to inhibit R132C, R132H, R132G, R132L or R132S mutant IDH1 is much lower than the concentration required to inhibit the IDH1 wild-type enzyme.

Reduced 2-hydroxyglutarate levels and induced myeloid cell differentiation in vitro and in a tumor xenograft mouse model expressing IDH1 mutations and an intrahepatic cholangiocarcinoma mouse model.

In AML patients expressing IDH1 mutations, 2-hydroxyglutarate levels were reduced, blast counts were reduced, and the percentage of mature myeloid cells was increased.