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

Assimini Instructions

Product Name: LuciAsc

Manufacturer: Lucius Pharmaceuticals

Chinese name: Asimini

English name: Asciminib

Drug approval number: 10 L 1034/23

 

 

【Summary】

Aximinib is indicated for the treatment of adult patients with:

1. Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML), chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors (TKIs).

2. Ph+ CML in CP with T315I mutation.

 

【Indications】

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

 

【Specification】  

40mg/tablet, 60 tablets/box.

 

【 Storage】

Store at 20°C to 25°C (68°C to 77°F); short-distance transport is permitted at a temperature range of 15 to 30°C (59–86°F).

 

【Usage and Dosage】

1. Recommended dose for Ph+ CML-CP patients who have received two or more TKI treatments

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

Treatment with asciminib continued as long as clinical benefit was observed or until unacceptable toxicity occurred.

 

2. Recommended dose for patients with Ph+ CML-CP with 2T315I mutation

The recommended dose of Asciminib is 200 mg, taken orally twice daily, approximately 12 hours apart. The recommended dose of Asciminib can be taken orally without food. Avoid eating at least 2 hours before and 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 that dose and take the next dose as scheduled.

Twice-daily dosing regimen: If a dose of Asciminib is missed by more than approximately 6 hours, skip that dose and take the next dose as scheduled.

 

4. Dosage adjustment

Dose Modification in Patients with Ph+ CML-CP Prior to Two or More TKIs To manage adverse reactions, reduce the asciminib dose as described in Table 1.

Dose adjustment for patients with Ph+ CML-CP with T315I mutation

To manage adverse reactions, the asciminib dose was reduced as described in Table 1.

Table 1: Recommended dose reductions for adverse reactions to Asciminib

Dose reduction	Dosage for patients with CP-CML who have received two or more prior TKIs	Dosage for Ph+ CML-CP patients with T315I mutation
First	40 mg once daily or 20 mg twice daily	160 mg twice daily
Subsequent restoration	Permanently discontinue asciminib in patients who are unable to tolerate treatment with 40 mg once daily or 20 mg twice daily .	Permanently discontinue asciminib in patients who cannot tolerate 160 mg twice daily .

Table 2 shows suggested dose modifications for the management of selected adverse reactions.

Table 2: Asciminib dose modifications for management of adverse reactions

Reverse reaction	Dosage Considerations
Thrombocytopenia and/or neutropenia [see WARNINGS AND PRECAUTIONS]
ANC less than 1.0 x 10 9 /L and/or PLT less than 50 x 10 9 /L	Withhold Asciminib until dissolved to an ANC greater than or equal to 1 x 10 9 /L and/or a PLT greater than or equal to 50 x 10 9 /L.   If resolved: a. Within 2 weeks: Resume Asciminib at the starting dose . b. After 2 weeks: Resume Asciminib at a reduced dose . For recurrent severe thrombocytopenia and/or neutropenia, withhold Asciminib treatment until resolved to ANC greater than or equal to 1 x 10 9 /L and PLT greater than or equal to 50 x 10 9 /L, then resume at a reduced dose.
Asymptomatic amylase and/or lipase elevations [see WARNINGS AND PRECAUTIONS]
Altitude greater than 2.0 x ULN	Withhold Asciminib until the concentration drops below 1.5x ULN. If resolved: a. Resume Asciminib at a reduced dose. If the event recurs at a reduced dose, permanently discontinue Asciminib. If not resolved: b. Permanently discontinue Asciminib. Perform diagnostic testing to rule out pancreatitis.
Non-hematologic adverse reactions [see Warnings and Precautions]
Level 31 or above	Suspend Asciminib until it recovers to level 1 or below. If resolved: Resume Asciminib at a reduced dose. If not resolved: Permanently discontinue Asciminib.
Abbreviations: ANC, absolute neutrophil count; PLT, platelet; ULN, upper limit of normal.

【Adverse Reactions】

aUpper respiratory tract infections include: nasopharyngitis, upper respiratory tract infection, rhinitis, pharyngitis, respiratory tract infection, and pharyngeal tonsillitis.

b Musculoskeletal pain includes: limb pain, back pain, muscle pain, 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: tiredness and weakness.

e Rash includes: rash, maculopapular rash, dermatitis acneiformis, pustular rash, eczema, dermatitis, skin peeling, exfoliative dermatitis systemic, rash morbilliform, drug eruption, erythema multiforme, and rash erythematous.

f Hypertension includes: hypertension and hypertensive crisis.

g Diarrhea includes: diarrhea and colitis.

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

 

【Taboo】

none

 

【Notes】

1. Bone marrow suppression

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

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

Anemia occurred in 46 (13%) patients treated with LuciAsc (Asciminib), of which 19 (5%) developed Grade 3 anemia. In patients with Grade 3 or 4 anemia, the median time to first 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"].

 

Perform complete blood counts every 2 weeks during the first 3 months of treatment and monthly thereafter or as clinically indicated. Monitor patients for signs and symptoms of myelosuppression.

Reduce the dose, temporarily interrupt, or permanently discontinue LuciAsc (Asciminib) based on the severity of thrombocytopenia and/or neutropenia [see Dosage and Administration].

 

2. Pancreatic toxicity

Of the 356 patients treated with LuciAsc (Asciminib), 9 (2.5%) developed pancreatitis, of which 4 (1.1%) developed Grade 3 pancreatitis. All cases of pancreatitis occurred in the Phase I 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 adverse reactions. Of the 356 patients treated with LuciAsc (Asciminib), 76 (21%) developed asymptomatic elevations in serum lipase and amylase, of which 36 (10%) and 8 (2.2%) patients had Grade 3 and 4 pancreatic enzyme elevations, respectively. Of the 76 patients with elevated pancreatic enzymes, 8 (2.2%) permanently discontinued LuciAsc (Asciminib) due to adverse reactions [see "Adverse Reactions"].

Assess serum lipase and amylase levels monthly during LuciAsc (Asciminib) treatment 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 associated with abdominal symptoms, temporarily withhold LuciAsc (Asciminib) and consider appropriate diagnostic testing to rule out pancreatitis [see "Dosage and Administration"].

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

 

3. Hypertension

Hypertension occurred in 68 (19%) of 356 patients treated with LuciAsc (Asciminib), with Grade 3 or 4 hypertension 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). Of the 68 patients with hypertension, 3 (0.8%) temporarily discontinued LuciAsc (Asciminib) due to adverse reactions [see "Adverse Reactions"].

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

 

4. Hypersensitivity reaction

Hypersensitivity reactions occurred in 115 (32%) of 356 patients treated with LuciAsc (Asciminib), with Grade 3 or 4 hypersensitivity reactions reported in 6 (1.7%) patients [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 withhold, reduce the dose, or permanently discontinue LuciAsc (Asciminib) based on the persistence of the hypersensitivity reaction [see Dosage and Administration].

 

5. Cardiovascular toxicity

Of the 356 patients treated with LuciAsc (Asciminib), 46 (13%) and 9 (2.5%) experienced cardiovascular toxicity (including ischemic heart and CNS disease, arterial thrombosis, and embolic disease) and heart failure, respectively [see Adverse Reactions (6.1)]. Grade 3 cardiovascular toxicity was reported in 12 (3.4%) patients, and Grade 3 heart failure was reported in 5 (1.4%) patients. Grade 4 cardiovascular toxicity occurred in 2 (0.6%) patients, and 3 (0.8%) patients died. LuciAsc (Asciminib) was permanently discontinued in 3 (0.8%) patients due to cardiovascular toxicity, and 1 (0.3%) patient was permanently discontinued due to heart failure. Cardiovascular toxicity occurred in patients with pre-existing cardiovascular disease or risk factors and/or prior exposure to multiple TKIs.

Cardiac arrhythmias (including QTc prolongation) occurred in 24 of 356 patients treated with LuciAsc (Asciminib), with Grade 3 arrhythmias reported in 8 (2%) patients. QTc prolongation occurred in 3 (0.8%) of 356 patients treated with LuciAsc (Asciminib), with Grade 3 QTc prolongation reported in 1 (0.3%) patient [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 withhold, reduce dose, or permanently discontinue LuciAsc (Asciminib) based on persistence of cardiovascular toxicity [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 the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and malformations in patients at maternal exposures (AUC) equal to or less than the recommended dose. Inform 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 LuciAsc (Asciminib) treatment. Females of reproductive potential should use effective contraception during LuciAsc (Asciminib) treatment and for 1 week after the last dose [see "Use in Specific Populations"].

 

【Use in special populations】

1. Pregnancy

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

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

Inform pregnant women and females of reproductive potential of the potential risk to a fetus.

 

2. Lactation

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

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

 

3. Males and females of reproductive potential

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

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

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. Medication for children

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

 

5. Medication for the elderly

Overall, no differences in safety or efficacy were observed in patients aged 65 years and older taking LuciAsc (Asciminib) compared with younger patients. There were insufficient numbers of patients aged 75 years and older to assess whether there were differences in safety or efficacy.

 

6. Renal impairment

No dose adjustment is required for patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min/1.73 m2) who are not receiving dialysis for LuciAsc (Asciminib).

 

7. Liver damage

No dose adjustment is required 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 hepatic impairment (total bilirubin > 3 times ULN and any AST) receiving LuciAsc (Asciminib).

 

【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 of these substrates.

Closely monitor patients receiving 80 mg total daily dose of LuciAsc (Asciminib) in combination with certain CYP3A4 substrates for adverse reactions, where minimal concentration changes may result in serious adverse reactions. Avoid coadministration of 200 mg SCEmblix twice daily with certain CYP3A4 substrates, where minimal concentration changes may result in 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 of these substrates.

Avoid coadministration of LuciAsc (Asciminib) at a total daily dose of 80 mg with certain CYP2C9 substrates, in which case minimal changes in concentration may result in serious adverse reactions. If coadministration is unavoidable, reduce the CYP2C9 substrate dose as recommended in its prescribing information.

Avoid coadministration of LuciAsc (Asciminib) 200 mg twice daily with sensitive CYP2C9 substrates and certain CYP2C9 substrates, where minimal concentration changes may result in serious adverse reactions. If coadministration 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 plasma concentrations of P-gp substrates, which may increase the risk of adverse reactions of these substrates.

Closely monitor patients for adverse reactions at all recommended doses of LuciAsc (Asciminib) in combination with P-gp substrates, where minimal changes in concentrations may result in serious toxicity.