[Product Name] Asciminib Tablets

[English Name] Asciminib Tablets

[Other Names] Asciminib Tablets

[Specification] 40 mg × 60 tablets/box

[Manufacturer] Lao United Pharmaceutical Group Co., Ltd.

[Approval Number (Lao National Drug Administration)] 10 L 1221/24

[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 (taken at approximately the same time each day), or 40 mg orally twice daily (taken approximately 12 hours apart). The recommended dosage of Asciminib may be taken without food. Patients should avoid eating for at least 2 hours before and 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 (taken approximately 12 hours apart). The recommended dosage of Asciminib may be taken without food. Patients should avoid eating for at least 2 hours before and 1 hour after taking Asciminib. 3. Missed Doses

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

Dose adjustments for patients with Ph+ CML-CP 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 treatment with Asciminib tablets. Among 356 patients treated with 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 Asciminib, and 45 (13%) temporarily discontinued Asciminib due to the adverse reaction.

Neutropenia occurred in 69 (19%) patients treated with Asciminib; specifically, 26 (7%) and 30 (8%) patients reported Grade 3 and Grade 4 neutropenia, 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 Asciminib, and 34 (10%) temporarily discontinued Asciminib due to the adverse reaction.

Anemia occurred in 46 (13%) patients treated with 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 Asciminib due to the adverse reaction [see "Adverse Reactions"].

During the first 3 months of treatment, complete blood counts should be performed every 2 weeks, and thereafter 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 Asciminib [see "Dosage and Administration"].

2. Pancreatic Toxicity

Among 356 patients treated with Asciminib, 9 (2.5%) developed pancreatitis, including 4 (1.1%) with 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 Asciminib, and 4 (1.1%) temporarily interrupted Asciminib due to the adverse reaction. Among the 356 patients treated with 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 Asciminib due to the adverse reaction [see "Adverse Reactions"].

Assess serum lipase and amylase levels monthly during treatment with Asciminib or as clinically indicated. Monitor patients for signs and symptoms of pancreatic toxicity. Monitor patients with a history of pancreatitis more frequently. If lipase and amylase elevations are accompanied by abdominal symptoms, temporarily interrupt 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 interrupt, or permanently discontinue Asciminib [see "Dosage and Administration"]. 3. Hypertension

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

During treatment with Asciminib, monitor and manage hypertension using standard antihypertensive therapy as clinically indicated; for Grade 3 or higher hypertension, temporarily interrupt, reduce the dose, or permanently discontinue Asciminib depending on the persistence of the hypertension [see "Dosage and Administration"].

4. Hypersensitivity

Among the 356 patients treated with Asciminib, 115 (32%) experienced hypersensitivity reactions, and 6 (1.7%) reported Grade 3 or Grade 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, temporarily interrupt, reduce the dose, or permanently discontinue Asciminib depending on the persistence of the reaction [see "Dosage and Administration"].

5. Cardiovascular Toxicity

Among the 356 patients treated with Asciminib, 46 (13%) and 9 (2.5%) experienced cardiovascular toxicity (including ischemic cardiac and CNS disorders, and arterial thromboembolic 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. Grade 4 cardiovascular toxicity occurred in 2 patients (0.6%), and death occurred in 3 patients (0.8%). Three patients (0.8%) permanently discontinued Asciminib due to cardiovascular toxicity, and 1 patient (0.3%) permanently discontinued Asciminib due to heart failure. Cardiovascular toxicity occurred in patients with pre-existing cardiovascular disease or risk factors and/or prior exposure to multiple TKIs.

Among the 356 patients treated with Asciminib, 24 experienced arrhythmias (including QTc prolongation), of whom 8 patients (2%) reported Grade 3 arrhythmias. Among the 356 patients treated with Asciminib, 3 patients (0.8%) experienced QTc prolongation, and 1 patient (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, temporarily interrupt, reduce the dose, or permanently discontinue Asciminib, depending on the persistence of the cardiovascular toxicity [see "Dosage and Administration"].

6. Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, 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 less than that in patients at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus if Asciminib is used during pregnancy or if the patient becomes pregnant while taking Asciminib. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with Asciminib. Females of reproductive potential should use effective contraception during treatment with 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, Asciminib may cause embryo-fetal harm when administered to pregnant women. There are no available data regarding the use of 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 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 Asciminib and for 1 week after the last dose.

3. Females and Males of Reproductive Potential

Based on findings from animal studies, 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 Asciminib.

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

Based on findings from animal studies, 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 Asciminib in pediatric patients have not been established.

5. Geriatric Use

Overall, no differences in safety or efficacy were observed between patients aged 65 years and older and younger patients receiving Asciminib. The number of patients aged 75 years and older was insufficient to assess whether there were differences in safety or efficacy. 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 is necessary.

7. Hepatic Impairment

For patients with 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 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 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 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 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 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 Asciminib tablets (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 co-administration is unavoidable, consider using alternative therapies that are not CYP2C9 substrates.

Certain P-gp Substrates

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

Closely monitor patients receiving Asciminib tablets (at any recommended dose) in combination with P-gp substrates for adverse reactions, particularly in cases where minimal changes in concentration could lead to serious toxicity.