Product Name: LuciAsc

Chinese Name: Asciminib

English Name: Asciminib

Specification: 40 mg/tablet; 60 tablets/box.

[Summary]

Asciminib is indicated for the treatment of adult patients with the following conditions:

1. Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP), who have previously received treatment with two or more tyrosine kinase inhibitors (TKIs).

2. Ph+ CML in the chronic phase (CP) harboring the T315I mutation.

[Indications]

Indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP).

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

1. Recommended Dosage for Ph+ CML-CP Patients Previously Treated with Two or More TKIs

The recommended dosage of Asciminib is 80 mg orally once daily (at approximately the same time each day), or 40 mg orally twice daily (approximately 12 hours apart). The recommended dosage of Asciminib may be taken orally without food. Avoid eating for at least 2 hours before and for at least 1 hour after taking Asciminib.

Continue treatment with Asciminib as long as clinical benefit is observed or until unacceptable toxicity occurs.

2. Recommended Dosage for Ph+ CML-CP Patients with the T315I Mutation

The recommended dosage of Asciminib is 200 mg orally twice daily (approximately 12 hours apart). The recommended dosage of Asciminib may be taken orally without food. Avoid eating for at least 2 hours before and for at least 1 hour after taking Asciminib.

3. Missed Dose

Once-daily dosing regimen: If a dose of Asciminib is missed by more than approximately 12 hours, skip the missed dose and take the next dose at the regularly scheduled time. Twice-daily dosing regimen: If a dose of Asciminib is missed by more than approximately 6 hours, skip the missed dose and take the next dose at the scheduled time.

4. Dose Adjustments

Dose adjustments for Ph+ CML-CP patients previously treated with two or more TKIs: To manage adverse reactions, reduce the Asciminib dose as described in Table 1.

Dose adjustments for Ph+ CML-CP patients with the T315I mutation:

To manage adverse reactions, reduce the Asciminib dose as described in Table 1.

[Adverse Reactions]

a Upper respiratory tract infection includes: nasopharyngitis, upper respiratory tract infection, rhinitis, pharyngitis, respiratory tract infection, and pharyngotonsillitis.

b Musculoskeletal pain includes: pain in extremity, back pain, myalgia, non-cardiac chest pain, neck pain, bone pain, spinal pain, arthritis, musculoskeletal pain, and musculoskeletal chest pain.

c Headache includes: headache and post-traumatic headache.

d Fatigue includes: fatigue and asthenia.

e Rash includes: rash, maculo-papular rash, acneiform dermatitis, pustular rash, eczema, dermatitis, skin exfoliation, exfoliative dermatitis generalized, morbilliform rash, drug eruption, erythema multiforme, and erythematous rash.

f Hypertension includes: hypertension and hypertensive crisis.

g Diarrhea includes: diarrhea and colitis.

Abdominal pain includes: abdominal pain, epigastric pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort.

[Contraindications] None

[Precautions]

1. Myelosuppression

Thrombocytopenia, neutropenia, and anemia have occurred in patients receiving LuciAsc (Asciminib) treatment. Among 356 patients treated with LuciAsc (Asciminib), 98 (28%) experienced thrombocytopenia; specifically, 24 (7%) and 42 (12%) patients reported Grade 3 or Grade 4 thrombocytopenia, respectively. Among patients with Grade 3 or 4 thrombocytopenia, the median time to first onset of the event was 6 weeks (range: 0.1 to 64 weeks). Of the 98 patients with thrombocytopenia, 7 (2%) permanently discontinued LuciAsc (Asciminib), and 45 (13%) temporarily discontinued LuciAsc (Asciminib) due to adverse reactions.

Neutropenia occurred in 69 (19%) patients treated with LuciAsc (Asciminib); Grade 3 and Grade 4 neutropenia were reported in 26 (7%) and 30 (8%) patients, respectively. Among patients with Grade 3 or 4 neutropenia, the median time to first onset of the event was 6 weeks (range: 0.1 to 180 weeks). Of the 69 patients with neutropenia, 4 (1.1%) permanently discontinued LuciAsc (Asciminib), and 34 (10%) temporarily discontinued LuciAsc (Asciminib) due to adverse reactions.

Anemia occurred in 46 (13%) patients treated with LuciAsc (Asciminib), of whom 19 (5%) experienced Grade 3 anemia. Among patients with Grade 3 or 4 anemia, the median time to first onset of the event was 30 weeks (range: 0.4 to 207 weeks). Of the 46 patients with anemia, 2 (0.6%) temporarily discontinued LuciAsc (Asciminib) due to adverse reactions [see "Adverse Reactions"].

During the first 3 months of treatment, perform a complete blood count every 2 weeks; thereafter, perform it monthly or as clinically indicated. Monitor patients for signs and symptoms of myelosuppression.

Depending on the severity of thrombocytopenia and/or neutropenia, reduce the dose, temporarily interrupt, or permanently discontinue LuciAsc (Asciminib) [see "Dosage and Administration"]. 2. Pancreatic Toxicity

Among the 356 patients treated with LuciAsc (Asciminib), 9 (2.5%) developed pancreatitis, of whom 4 (1.1%) developed Grade 3 pancreatitis. All cases of pancreatitis occurred in the Phase 1 study (X2101). Of the 9 patients with pancreatitis, 2 (0.6%) permanently discontinued LuciAsc (Asciminib), and 4 (1.1%) temporarily discontinued LuciAsc (Asciminib) due to the adverse reaction. Among the 356 patients treated with LuciAsc (Asciminib), 76 (21%) experienced asymptomatic elevations in serum lipase and amylase; of these, 36 (10%) and 8 (2.2%) patients experienced Grade 3 and Grade 4 elevations in pancreatic enzymes, respectively. Of the 76 patients with elevated pancreatic enzymes, 8 (2.2%) permanently discontinued LuciAsc (Asciminib) due to the adverse reaction [see "Adverse Reactions"].

Assess serum lipase and amylase levels monthly during treatment with LuciAsc (Asciminib) or as clinically indicated. Monitor patients for signs and symptoms of pancreatic toxicity. Monitor patients with a history of pancreatitis more frequently. If elevations in lipase and amylase are accompanied by abdominal symptoms, temporarily discontinue LuciAsc (Asciminib) and consider appropriate diagnostic tests to rule out pancreatitis [see "Dosage and Administration"].

Depending on the severity of the lipase and amylase elevations, reduce the dose, temporarily discontinue, or permanently discontinue LuciAsc (Asciminib) [see "Dosage and Administration"].

3. Hypertension

Among the 356 patients treated with LuciAsc (Asciminib), 68 (19%) developed hypertension; Grade 3 or 4 hypertension was reported in 32 (9%) and 1 (0.3%) patients, respectively. The median time to first onset of Grade 3 or 4 hypertension was 14 weeks (range: 0.1 to 156 weeks). Among 68 patients with hypertension, 3 patients (0.8%) temporarily discontinued LuciAsc (Asciminib) due to adverse reactions [see "Adverse Reactions"].

During treatment with LuciAsc (Asciminib), hypertension should be monitored and managed using standard antihypertensive therapy as clinically indicated; for Grade 3 or higher hypertension, LuciAsc (Asciminib) should be temporarily interrupted, dose-reduced, or permanently discontinued, depending on the persistence of the hypertension [see "Dosage and Administration"].

4. Hypersensitivity Reactions

Among 356 patients treated with LuciAsc (Asciminib), 115 (32%) experienced hypersensitivity reactions, and 6 patients (1.7%) reported Grade 3 or 4 hypersensitivity reactions [see "Adverse Reactions" (6.1)]. Reactions included rash, edema, and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity reactions and initiate appropriate treatment as clinically indicated; for Grade 3 or higher hypersensitivity reactions, LuciAsc (Asciminib) should be temporarily interrupted, dose-reduced, or permanently discontinued, depending on the persistence of the reaction [see "Dosage and Administration"].

5. Cardiovascular Toxicity

Among 356 patients treated with LuciAsc (Asciminib), 46 (13%) and 9 (2.5%) experienced cardiovascular toxicity (including ischemic cardiac and CNS disorders, and arterial thrombotic and embolic disorders) and heart failure, respectively [see "Adverse Reactions" (6.1)]. Twelve patients (3.4%) reported Grade 3 cardiovascular toxicity, and 5 patients (1.4%) reported Grade 3 heart failure. Two patients (0.6%) experienced Grade 4 cardiovascular toxicity, and 3 patients (0.8%) experienced fatal events. Three patients (0.8%) permanently discontinued LuciAsc (Asciminib) due to cardiovascular toxicity, and 1 patient (0.3%) permanently discontinued LuciAsc (Asciminib) due to heart failure. Cardiovascular toxicity occurred in patients with pre-existing cardiovascular disease or risk factors, and/or those with prior exposure to multiple TKIs. Among 356 patients treated with LuciAsc (Asciminib), 24 experienced arrhythmias (including QTc prolongation), of whom 8 (2%) reported Grade 3 arrhythmias. Among the 356 patients treated with LuciAsc (Asciminib), 3 (0.8%) experienced QTc prolongation, and 1 (0.3%) reported Grade 3 QTc prolongation [see "Adverse Reactions"].

Monitor patients with a history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate appropriate treatment as clinically indicated; for Grade 3 or higher cardiovascular toxicity, depending on the persistence of the cardiovascular toxicity, temporarily interrupt, reduce the dose, or permanently discontinue LuciAsc (Asciminib) [see "Dosage and Administration"].

6. Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, LuciAsc (Asciminib) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of asciminib to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes—including embryo-fetal mortality and malformations—at maternal exposures (AUC) equal to or lower than that in patients at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus if LuciAsc (Asciminib) is used during pregnancy or if the patient becomes pregnant while taking LuciAsc (Asciminib). Verify the pregnancy status of females of reproductive potential prior to initiating treatment with LuciAsc (Asciminib). Females of reproductive potential should use effective contraception during treatment with LuciAsc (Asciminib) and for 1 week after the last dose [see "Use in Specific Populations"].

[Use in Specific Populations]

1. Pregnancy

Based on findings from animal studies and its mechanism of action, LuciAsc (Asciminib) may cause embryo-fetal harm when administered to pregnant women. There are no available data regarding the use of LuciAsc (Asciminib) in pregnant women to assess drug-associated risks.

Animal reproduction studies conducted in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced structural abnormalities, embryo-fetal mortality, and growth alterations.

Advise pregnant women and women of reproductive potential of the potential risk to the fetus.

2. Lactation

There are currently no data regarding the presence of LuciAsc (Asciminib) or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with LuciAsc (Asciminib) and for 1 week after the last dose.

3. Females and Males of Reproductive Potential

Based on findings from animal studies, LuciAsc (Asciminib) may cause embryo-fetal harm when administered to pregnant women [see "Use in Specific Populations"].

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with LuciAsc (Asciminib).

Females of reproductive potential should use effective contraception during treatment with LuciAsc (Asciminib) and for 1 week after the last dose.

Based on findings from animal studies, LuciAsc (Asciminib) may impair fertility in females of reproductive potential. The reversibility of this effect on fertility is unknown.

4. Pediatric Use

The safety and efficacy of LuciAsc (Asciminib) in pediatric patients have not been established.

5. Geriatric Use

Overall, no differences in safety or efficacy were observed in patients aged 65 years and older receiving LuciAsc (Asciminib) compared to younger patients. The number of patients aged 75 years and older was insufficient to assess whether differences in safety or efficacy exist. 6. Renal Impairment

For patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min/1.73 m²) who do not require dialysis, no dose adjustment of LuciAsc (Asciminib) is necessary.

7. Hepatic Impairment

For patients receiving LuciAsc (Asciminib) treatment who have mild [total bilirubin ≤ Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) > ULN; or total bilirubin > 1 to 1.5 times ULN and any AST] to severe [total bilirubin > 3 times ULN and any AST] hepatic impairment, no dose adjustment is necessary.

[Drug Interactions]

Certain CYP3A4 Substrates

Asciminib is a CYP3A4 inhibitor. Concomitant use of LuciAsc (Asciminib) increases the Cmax and AUC of CYP3A4 substrates, which may increase the risk of adverse reactions associated with these substrates.

Closely monitor patients receiving a total daily dose of 80 mg of LuciAsc (Asciminib) in combination with certain CYP3A4 substrates—specifically those for which minimal changes in concentration may lead to serious adverse reactions—for signs of adverse reactions. Avoid the concomitant administration of 200 mg of LuciAsc (Asciminib) twice daily with certain CYP3A4 substrates for which minimal changes in concentration may lead to serious adverse reactions.

CYP2C9 Substrates

Asciminib is a CYP2C9 inhibitor. Concomitant use of LuciAsc (Asciminib) increases the Cmax and AUC of CYP2C9 substrates, which may increase the risk of adverse reactions associated with these substrates.

Avoid the concomitant administration of a total daily dose of 80 mg of LuciAsc (Asciminib) with certain CYP2C9 substrates for which minimal changes in concentration may lead to serious adverse reactions. If concomitant use is unavoidable, reduce the dose of the CYP2C9 substrate as recommended in its prescribing information. Avoid the concomitant administration of LuciAsc (Asciminib) 200 mg twice daily with sensitive CYP2C9 substrates and certain other CYP2C9 substrates in cases where minimal changes in concentration could lead to serious adverse reactions. If concomitant use is unavoidable, consider alternative therapies that are not CYP2C9 substrates.

Certain P-gp Substrates

Asciminib is a P-gp inhibitor. Concomitant use of LuciAsc (Asciminib) increases the plasma concentrations of P-gp substrates, which may increase the risk of adverse reactions associated with these substrates.

Closely monitor patients receiving any recommended dose of LuciAsc (Asciminib) in combination with P-gp substrates—particularly those for which minimal changes in concentration could lead to serious toxicity—for adverse reactions.