Bacrelba

40 mg film-coated tablets: Violet white, round, biconvex, film-coated tablets with beveled edges, approximately 8.2 mm diameter, unscored, debossed with "Novartis" logo on one side and "40" on the other side.
Active Ingredients: Each 40 mg film-coated tablet contains 43.24 mg asciminib hydrochloride, which is equivalent to 40 mg asciminib.
Excipients/Inactive Ingredients: 40 mg film-coated tablets: Lactose monohydrate, microcrystalline cellulose (E460i), hydroxypropylcellulose (E463), croscarmellose sodium (E468), polyvinyl alcohol (E1203), titanium dioxide (E171), magnesium stearate, talc (E553b), colloidal silicon dioxide, iron oxide (E172, black and red), lecithin (E322), xanthan gum (E415).

Antineoplastic Agent (BCR-ABL Tyrosine Kinase Inhibitor).
Pharmacology: Mechanism of Action: Asciminib is an oral and potent inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein, by specifically targeting the ABL myristoyl pocket.
Pharmacodynamics: In vitro, asciminib inhibits the tyrosine kinase activity of ABL1 at mean IC₅₀ values below 3 nanomolar. In patient-derived cancer cells, asciminib specifically inhibits the proliferation of cells harboring BCR::ABL1 with IC₅₀ values between 1 and 25 nanomolar. In cells expressing the wild-type or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth with mean IC₅₀ values of 0.61 ±0.21 and 7.64 ±3.22 nanomolar, respectively.
In mouse xenograft models of CML, asciminib dose-dependently inhibited the growth of tumor harbouring either the wild-type or the T315I mutant form of BCR::ABL1, with tumor regression being observed at doses above 7.5 mg/kg or 30 mg/kg twice daily, respectively.
Cardiac electrophysiology: Asciminib (Bacrelba) treatment is associated with an exposure-related prolongation of the QT interval. The correlation between asciminib concentration and the estimated maximum mean change from baseline of the QT interval with Fridericia's correction (ΔQTCF) was evaluated in 239 patients with Ph+ CML or Ph+ acute lymphoblastic leukemia (ALL) receiving Asciminib (Bacrelba) at doses ranging from 10 to 280 mg twice daily and 80 to 200 mg once daily. The estimated mean ΔQTCF was 3.35 ms (upper bound of 90% CI: 4.43 ms) for Asciminib (Bacrelba) 40 mg twice-daily dose, 3.64 ms (upper bound of 90% CI: 4.68 ms) for the 80 mg once-daily dose and 5.37 ms (upper bound of 90% CI: 6.77 ms) for the 200 mg twice-daily dose.
Clinical Studies: Newly diagnosed Ph+ CML-CP: The clinical efficacy and safety of Asciminib (Bacrelba) in the treatment of patients with newly diagnosed Philadelphia chromosome-positive myeloid leukemia in chronic phase (Ph+ CML-CP) were demonstrated in the multi-center, randomized, active-controlled and open-label phase III study ASC4FIRST.
In this study, a total of 405 patients were randomized in a 1:1 ratio to receive either Asciminib (Bacrelba) or investigator selected tyrosine kinase inhibitors (IS-TKIs).
Prior to randomization, the investigator selected the TKI (imatinib or second generation [2G] TKI) to be used in the event of randomization to the comparator arm, based on patient characteristics and comorbidities. Patients were stratified according to EUTOS long-term survival (ELTS) risk group (low, intermediate, high), and pre-randomization selection of TKI (imatinib or 2G TKIs stratum). Patients received either Asciminib (Bacrelba) or IS-TKIs, and continued treatment until unacceptable toxicity or treatment failure occurred.
Patients were 36.8% female and 63.2% male, with median age 51 years (range: 18 to 86 years), Of the 405 patients, 23.5% were 65 years or older, while 6.2% were 75 years or older. Patients were Caucasian (53.8%), Asian (44,4%), Black (1%) and 0.7% unknown. The demographic characteristics within the imatinib (N=203) and the 2G TKIs (N=202) strata were: Median age: 55 years and 43 years, respectively; ELTS high risk group: 8.4% and 13.9%, respectively; Framingham cardiovascular disease high risk group: 35.5% and 17.8%, respectively.
The demographic characteristics were balanced across Asciminib (Bacrelba) and IS-TKIs, as well as across the two arms within the imatinib and 2G TKIs strata.
Of the 405 patients, 200 received Asciminib (Bacrelba), while 201 received IS-TKIs. Of the 201 patients receiving IS-TKIs, 99 received imatinib, 49 received nilotinib, 42 received dasatinib, and 11 received bosutinib, Four patients did not receive any treatment.
The median duration of treatment was 69.8 weeks (range: 0.7 to 107.7 weeks) for patients receiving Asciminib (Bacrelba) and 64.3 weeks (range: 1.3 to 103.1 weeks) for patients receiving IS-TKIs, By 48 weeks, 90% of patients on Asciminib (Bacrelba) and 80.6% of patients on IS-TKIs were still receiving treatment.
The study had multiple primary objectives assessing major molecular response rate (MMR) at 48 weeks. One primary objective evaluated Asciminib (Bacrelba) compared to IS-TKls. The other primary objective evaluated Asciminib (Bacrelba) compared to IS-TKIs, within the imatinib stratum. A secondary objective evaluated MMR at 48 weeks evaluating Asciminib (Bacrelba) compared to IS-TKIs, within the 2G TKIs stratum. The main efficacy outcomes from ASC4FIRST are summarized in Table 1. (See Table 1.)

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The predicted MMR rate at 48 weeks for the Asciminib (Bacrelba) 40 mg twice-daily dose is comparable to the MMR rate at 48 weeks observed in ASC4FIRST with the Asciminib (Bacrelba) 80 mg once-daily dose, based on exposure-response analysis.
Median time to MMR in patients receiving Asciminib (Bacrelba), IS-TKIs, IS-TKIs within the imatinib stratum, and IS-TKIs within the 2G TKIs stratum were: 24.3 weeks (95% CI: 24.1 to 24.6 weeks), 36.4 weeks (95% CI: 36.1 to 48.6 weeks), 48.6 weeks (95% CI: 36.1 to 59.6 weeks), and 36.1 weeks (95% CI: 24.4 to 48.1 weeks), respectively.
MMR rates at 48 weeks by ELTS risk group in patients receiving Asciminib (Bacrelba), IS-TKIs, IS-TKIs within the imatinib stratum, and IS-TKIs within the 2G TKIs stratum were: 72.1%, 57.6%, 50% and 65.6% for low risk, respectively; 64.3%, 36.8%, 26.7% and 48.2% for intermediate risk, respectively; 52.2%, 31.8%, 12.5% and 42.9% for high risk, respectively.
By 48 weeks, MR4.0 achieved by patients receiving Asciminib (Bacrelba), IS-TKIs, IS-TKIs within the imatinib stratum, and IS-TKIs within the 2G TKIs stratum was: 40.8%, 22.1%, 15.7%, and 28.4%, respectively. By 48 weeks, MR4.5 achieved by patients receiving Asciminib (Bacrelba), IS-TKIs, IS-TKIs within the imatinib stratum and IS-TKIs within 2G TKIs stratum was: 19.9%, 11.8%, 5.9%, and 17.7%, respectively.
Ph+ CML-CP, previously treated with two or more TKIs: The clinical efficacy and safety of Asciminib (Bacrelba) in the treatment of patients with Ph+ CML-CP previously treated with two or more tyrosine kinase inhibitors were demonstrated in the multi-center, randomized, active-controlled and open-label phase III study ASCEMBL.
In this study, a total of 233 patients were randomized in a 2:1 ratio and stratified according to major cytogenetic response (MCyR) status at baseline to receive either Asciminib (Bacrelba) 40 mg twice daily (N=157) or bosutinib 500 mg once daily (N=76). Patients continued treatment until unacceptable toxicity or treatment failure occurred.
Patients with Ph+ CML-CP previously treated with two or more TKIs were 51.5% female and 48.5% male with median age 52 years (range: 19 to 83 years). Of the 233 patients, 18.9% were 65 years or older, while 2.6% were 75 years or older. Patients were Caucasian (74.7%), Asian (14.2%) and Black (4.3%). Of the 233 patients, 80.7% and 18% had Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, respectively. Patients who had previously received 2, 3, 4, 5 or more prior lines of TKIs were 48.1%, 31.3%, 14.6% and 6%, respectively. The median duration of treatment was 156 weeks (range: 0.1 to 256.3 weeks) for patients receiving Asciminib (Bacrelba) and 30.5 weeks (range: 1 to 239.3 weeks) for patients receiving bosutinib.
The primary endpoint of the study was MMR at 24 weeks and the key secondary endpoint was MMR rate at 96 weeks. MMR is defined as BCR::ABL1 ratio S0.1% by International Scale [IS]. Secondary endpoints were complete cytogenetic response rate (CCyR) at 24 and 96 weeks, defined as no metaphases in bone marrow with a minimum of 20 metaphases examined. The main efficacy outcomes from ASCEMBL are summarized in Table 2. (See Table 2.)

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The predicted MMR rate at 24 weeks for the Asciminib (Bacrelba) 80 mg once-daily dose is comparable to the MMR rate at 24 weeks observed in ASCEMBL with the Asciminib (Bacrelba) 40 mg twice-daily dose, based on exposure-response analysis.
In ASCEMBL, 12.7% of patients treated with Asciminib (Bacrelba) and 13.2% of patients receiving bosutinib had one or more BCR::ABL1 mutation detected at baseline. MMR at 24 weeks was observed in 35.3% and 24.8% of patients receiving Asciminib (Bacrelba) with or without any BCR::ABL1 mutation at baseline, respectively. MMR at 24 weeks was observed in 25% and 11.1% of patients receiving bosutinib with or without any mutation at baseline, respectively. The MMR rate at 24 weeks in patients in whom the randomized treatment represented the third, fourth, fifth or more line of TKI was 29.3%, 25%, and 16.1% in patients treated with Asciminib (Bacrelba) and 20%, 13.8%, and 0% in patients receiving bosutinib, respectively.
The MMR rate at 48 weeks was 29.3% (95% CI: 22.32, 37.08) in patients receiving Asciminib (Bacrelba) and 13.2% (95% CI: 6.49, 22.87) in patients receiving bosutinib.
The Kaplan Meier estimated proportion of patients receiving Asciminib (Bacrelba) and maintaining MMR for at least 120 weeks was 97% (95% CI: 88.64, 99.2).
Ph+ CML-CP harboring the T315I mutation: The clinical efficacy and safety of Asciminib (Bacrelba) in the treatment of patients with Ph+ CML-CP harboring the T315I mutation were assessed in the first in human, multicenter, open-label phase I study X2101.
In this study, a total of 185 patients with Ph+ CML-CP without (N=115) or with (N=70) the T315I mutation received Asciminib (Bacrelba) at doses ranging from 10 to 200 mg twice daily or 80 to 200 mg once daily. Among these, 48 patients with Ph+ CML-CP harboring the T315I mutation received Asciminib (Bacrelba) at a dose of 200 mg twice daily. Patients continued treatment until unacceptable toxicity or treatment failure occurred.
Patients with Ph+ CML-CP harboring the T315I mutation who received Asciminib (Bacrelba) at a dose of 200 mg twice daily were 77.1% male and 22.9% female with median age of 56.5 years (range: 26 to 86 years). Of 48 patients, 33.3% were 65 years or older, while 8.3% were 75 years or older. The patients were Caucasian (47.9%), Asian (25%) and Black (2.1%). Seventy-five percent and 25% of patients had ECOG performance status 0 or 1, respectively. Patients who had previously received 1, 2, 3, 4 and 5 or more TKIs were 16.7%, 31.3%, 35.4%, 14.6% and 2.1%, respectively. The median duration of treatment was 181.7 weeks (range: 2 to 312 weeks).
MMR by 24 weeks was achieved in 42.2% of the evaluable patients (N=45) treated with Asciminib (Bacrelba) (95% CI: 27.7-57.8%).
MMR by 96 weeks was achieved in 48.9% of the evaluable patients (N=45) treated with Asciminib (Bacrelba).
Pharmacokinetics: Absorption: Asciminib is rapidly absorbed, with median maximum plasma levels (T_max) reached 2 to 3 hours after oral administration, independent of the dose. The geometric mean (geoCV%) of C_max at steady state is 1781 ng/mL (23%) and 793 ng/mL (49%) following administration of Asciminib (Bacrelba) at 80 mg once-daily and 40 mg twice-daily doses, respectively. The geometric mean (geoCV%) of C_max at steady state is 5642 ng/mL (40%) following administration of Asciminib (Bacrelba) at 200 mg twice-daily dose. The geometric mean (geoCV%) of AUC_tau is 5262 ng*h/mL (48%) following administration of Asciminib (Bacrelba) at 40 mg twice-daily dose.
PBPK models predict that the asciminib absorption is approximately 100%, while bioavailability is approximately 73%.
Asciminib bioavailability may be reduced by co-administration of oral medicinal products containing hydroxypropyl-β-cyclodextrin as an excipient. Co-administration of multiple doses of itraconazole oral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib, decreased asciminib AUC_inf by 40.2% in healthy subjects.
Food effect: Food consumption decreases asciminib bioavailability, with a high-fat meal having a higher impact on asciminib pharmacokinetics than a low-fat meal. Asciminib AUC is decreased by 62.3% with a high-fat meal and by 30% with a low-fat meal compared to the fasted state, independent of the dose (see Dosage & Administration and Interactions).
Distribution: Asciminib apparent volume of distribution at steady state is 111 L, based on population pharmacokinetic analysis. Asciminib is mainly distributed to plasma, with a mean blood-to-plasma ratio of 0.58, independent of the dose. Asciminib is 97.3% bound to human plasma proteins, independent of the dose.
Biotransformation/metabolism: Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36%), UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively). PBPK models predict that asciminib biliary secretion via BCRP accounts for 31.1% of its total systemic clearance. Asciminib is the main circulating component in plasma (92. 7% of the administered dose).
Elimination: Asciminib is mainly eliminated via fecal excretion, with a minor contribution of the renal route. Eighty and 11% of the asciminib dose were recovered in the feces and in the urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of [¹⁴C]-labelled asciminib. Fecal elimination of unchanged asciminib accounts for 56. 7% of the administered dose.
The oral total clearance (CL/F) of asciminib is 6.31 L/hour, based on population pharmacokinetic analysis. The accumulation half-life (T½) of asciminib is 5.2 hours at 80 mg total daily dose.
Linearity/non-linearity: Asciminib exhibits a slight dose over-proportional increase in steady-state exposure (AUC and C_max) across the dose range of 10 to 200 mg administered once or twice daily.
The geometric mean average accumulation ratio is approximately 2-fold, independent of the dose. Steady-state conditions are achieved within 3 days at the 40 mg twice-daily dose.
In vitro evaluation of drug interaction potential: CYP450 and UGT enzymes: In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9 and UGT1Al at plasma concentrations reached at a total daily dose of 80 mg. In addition, asciminib reversibly inhibits CYP2C8 and CYP2C19 at plasma concentrations reached at 200 mg twice-daily dose.
Transporters: Asciminib is a substrate of BCRP and P-gp. Asciminib inhibits BCRP, P-gp, OATP1B1, OATP1B3, and OCT1 with Ki values of 24.3, 21.7, 2.46, 1.92, and 3.41 micromolar, respectively. Based on PBPK models, asciminib increases the exposure to P-gp, OATP1B and BCRP substrates (see Interactions). The clinical relevance of the interaction with OCT1 is currently unknown at Asciminib (Bacrelba) 200 mg twice-daily dose.
Multiple pathways: Asciminib is metabolized by several pathways including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secreted by the transporter BCRP.
Medicinal products inhibiting or inducing multiple pathways may alter Asciminib (Bacrelba) exposure.
Asciminib inhibits several pathways including CYP3A4, CYP2C9, OATP1B, P-gp and BCRP. Asciminib (Bacrelba) may increase the exposure of medicinal products, which are substrates of these pathways (see Interactions).
Special populations: Geriatric patients (65 years of age or above): Among the 556 patients receiving Asciminib (Bacrelba) in the ASC4FIRST, ASCEMBL, and X2101 studies, 130 (23.4%) were 65 years of age or older and 31 (5.6%) were 75 years of age or older.
No overall differences in the safety or efficacy of Asciminib (Bacrelba) were observed between patients of 65 years of age or above and younger patients.
Gender/Race/Body weight: Asciminib systemic exposure is not affected by gender, race, or body weight to any clinically relevant extent.
Renal impairment: A dedicated renal impairment study including 6 subjects with normal renal function (absolute glomerular filtration rate [aGFR] ≥90 mL/min) and 8 subjects with severe renal impairment not requiring dialysis (aGFR 15 to <30 mL/min) has been conducted. Asciminib AUC_inf and C_max are increased by 56% and 8%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function, following oral administration of a single 40 mg dose of Asciminib (Bacrelba) (see Dosage & Administration).
Population pharmacokinetics models indicate an increase in asciminib median steady state AUC_0-24h by 11.5% in subjects with mild to moderate renal impairment, compared to subjects with normal renal function.
Hepatic impairment: A dedicated hepatic impairment study including 8 subjects each with normal hepatic function, mild hepatic impairment (Child-Pugh A score 5 to 6), moderate hepatic impairment (Child-Pugh B score 7 to 9) or severe hepatic impairment (Child-Pugh C score 10 to 15) was conducted. Asciminib AUC_inf is increased by 22%, 3% and 66% in subjects with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function, following oral administration of a single 40 mg dose of Asciminib (Bacrelba) (see Dosage & Administration).
Toxicology: Non-Clinical Safety Data: Asciminib was evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity and phototoxicity studies.
Safety pharmacology: In safety pharmacology studies, asciminib did not have any effect on the central nervous and respiratory systems in rats at doses up to 600 mg/kg/day.
In an in vitro study, asciminib inhibited the human ether-à-go-go-related gene (hERG) channels with an IC₅₀ of 11.4 micromolar. This value translates into a clinical safety margin at least 200-fold, 100-fold, or 30-fold higher when compared to asciminib free C_max in patients at the 40 mg twice-daily, 80 mg once-daily, or 200 mg twice-daily doses, respectively.
Moderate cardiovascular effects (increased heart rate, decreased systolic pressure, decreased mean arterial pressure, and decreased arterial pulse pressure) were observed in in vivo cardiac safety studies in dogs. No QTc prolongation was evident in dogs up to the highest asciminib free exposure of 6.3 micromolar.
Repeat dose toxicity: Repeat dose toxicity studies identified the pancreas, liver, hematopoietic system, adrenal gland, and gastro-intestinal tract as target organs of asciminib.
Pancreatic effects (serum amylase and lipase increases, acinar cell lesions) occurred in dogs at AUC exposures below those achieved in patients on 40 mg twice daily, 80 mg once daily or 200 mg twice daily. A trend towards recovery was observed.
Elevations in liver enzymes and/or bilirubin were observed in rats, dogs, and monkeys. Histopathological hepatic changes (centrilobular hepatocyte hypertrophy, slight bile duct hyperplasia, increased individual hepatocyte necrosis and diffuse hepatocellular hypertrophy) were seen in rats and monkeys. These changes occurred at AUC exposures either equivalent to (rats) or 8- to 18-fold (dogs and monkeys) higher than those achieved in patients on 40 mg twice daily or 80 mg once daily. AUC exposures were below (rats), equivalent (dogs) or approximately 2-fold higher (monkeys) than the exposure in patients on 200 mg twice daily. These changes were fully reversible.
Effects on the hematopoietic system (reduction in red blood cells mass, increased splenic or bone marrow pigment and increased reticulocytes) were consistent with a mild and regenerative, extravascular, hemolytic anemia in all species. These changes occurred at AUC exposures either equivalent to (rats) or 10- to 14-fold (dogs and monkeys) higher than those achieved in patients on 40 mg twice daily or 80 mg once daily. AUC exposures were below (rats), equivalent (dogs) or approximately 2-fold higher (monkeys) than the exposure in patients on 200 mg twice daily. These changes were fully reversible.
Minimal mucosal hypertrophy/hyperplasia (increase in thickness of the mucosa with frequent elongation of villi) was present in the duodenum of rats, at AUC exposures 30-fold or 22-fold higher than those achieved in patients on 40 mg twice daily or 80 mg once daily, respectively. AUC exposure was 4-fold higher than those achieved in patients on 200 mg twice daily. This change was fully reversible.
Minimal or slight hypertrophy of the adrenal gland and mild to moderate decreased vacuolation in the zona fasciculata occurred at AUC exposures either equivalent to (monkeys) or 19- to 13-fold (rats) higher than those achieved in patients on 40 mg twice daily or 80 mg once daily, respectively. AUC exposures were below (monkeys) or 2-fold higher (rats) than the exposure in patients on 200 mg twice daily, respectively. These changes were fully reversible.
Carcinogenicity and mutagenicity: Asciminib did not have mutagenic, clastogenic or aneugenic potential neither in vitro nor in vivo.
In a 2-year rat carcinogenicity study, non-neoplastic proliferative changes consisting of ovarian Sertoli cells hyperplasia were observed in female animals at doses equal to or above 30 mg/kg/day. Benign Sertoli cell tumors in the ovaries were observed in female rats at the highest dose of 66 mg/kg/day. AUC exposures to asciminib in female rats at 66 mg/kg/day were generally 8-fold or 5-fold higher than those achieved in patients at the dose of 40 mg twice daily or 80 mg once daily, respectively, and equivalent to those achieved in patients at the dose of 200 mg twice daily. No asciminib-related neoplastic or hyperplastic findings were noted in male rats at any dose level.
The clinical relevance of these findings is currently unknown.
Reproductive toxicity: For information on reproductive toxicity, see Pregnancy & Lactation.
Phototoxicity: In mice, asciminib showed dose-dependent phototoxic effects starting at 200 mg/kg/day. At the NOAEL of 60 mg/kg/day, exposure based on C_max in plasma was 15-fold, 6-fold or 2-fold higher than the exposure in patients on 40 mg twice daily, 80 mg once daily, or 200 mg twice daily, respectively.

Asciminib (Bacrelba) is indicated for the treatment of adult patients with: Newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP).
Ph+ CML in CP harboring the T315I mutation.

Treatment with Asciminib (Bacrelba) should be initiated by a physician experienced in the use of anticancer therapies.
Dosage regimen: General target population: Ph+CML-CP: The recommended total daily dose of Asciminib (Bacrelba) is 80 mg. Asciminib (Bacrelba) can be taken orally either as 80 mg once daily at approximately the same time each day, or as 40 mg twice daily at approximately 12-hour intervals.
Patients changing from 40 mg twice daily to 80 mg once daily should start taking Asciminib (Bacrelba) once daily approximately 12 hours after the last twice-daily dose, and then continue at 80 mg once daily.
Patients changing from 80 mg once daily to 40 mg twice daily should start taking Asciminib (Bacrelba) twice daily approximately 24 hours after the last once-daily dose and then continue at 40 mg twice daily at approximately 12-hour intervals.
Any change in the dosage regimen is at the prescriber's discretion, as necessary for the management of the patient.
Ph+ CML-CP harboring the T315I mutation: The recommended dose of Asciminib (Bacrelba) is 200 mg taken orally twice daily at approximately 12-hour intervals.
Treatment with Asciminib (Bacrelba) should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.
Missed dose: Once-daily dosage regimen: If an Asciminib (Bacrelba) dose is missed by more than approximately 12 hours, it should be skipped, and the next dose should be taken as scheduled.
Twice-daily dosage regimens: If an Asciminib (Bacrelba) dose is missed by more than approximately 6 hours, it should be skipped, and the next dose should be taken as scheduled.
Dose modifications: Ph+ CML-CP: For the management of adverse drug reactions, Asciminib (Bacrelba) dose can be reduced based on individual safety and tolerability, as described in Table 3. If adverse drug reactions are effectively managed, Asciminib (Bacrelba) may be resumed as described in Table 3.
Asciminib (Bacrelba) should be permanently discontinued in patients unable to tolerate a total daily dose of 40 mg.
Ph+ CML-CP harboring the T315I mutation: For the management of adverse drug reactions, Asciminib (Bacrelba) dose can be reduced based on individual safety and tolerability, as described in Table 3. If adverse drug reactions are effectively managed, Asciminib (Bacrelba) may be resumed as described in Table 3.
Asciminib (Bacrelba) should be permanently discontinued in patients unable to tolerate a dose of 160 mg twice daily. (See Table 3.)

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The recommended dosage modification for the management of selected adverse drug reactions is shown in Table 4. (See Table 4.)

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Special populations: Renal impairment: No dose adjustment is required in patients with mild, moderate, or severe renal impairment receiving Asciminib (Bacrelba). Caution should be exercised in patients with severe renal impairment receiving Asciminib (Bacrelba) 200 mg twice daily dose (see Pharmacology under Actions).
Hepatic impairment: No dose adjustment is required in patients with mild, moderate, or severe hepatic impairment receiving Asciminib (Bacrelba). Caution should be exercised in patients with severe hepatic impairment receiving Asciminib (Bacrelba) 200 mg twice daily dose (see Pharmacology under Actions).
Pediatric patients {below 18 years): The safety and efficacy of Asciminib (Bacrelba) in pediatric patients (below 18 years) has not been established.
Geriatric patients (65 years of age or above): No dose adjustment is required in patients 65 years of age or above.
Method of administration: Asciminib (Bacrelba) should be taken orally without food. Food consumption should be avoided for at least 2 hours before and 1 hour after taking Asciminib (Bacrelba) (see Interactions and Pharmacology under Actions).
Asciminib (Bacrelba) film-coated tablets should be swallowed whole and should not be broken, crushed, or chewed.

There is limited experience of Asciminib (Bacrelba) overdose. In clinical studies, Asciminib (Bacrelba) has been administered at doses up to 280 mg twice daily with no evidence of increased toxicity. General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose.

None.

Myelosuppression: Thrombocytopenia, neutropenia, and anemia occurred in patients receiving Asciminib (Bacrelba). Severe (NCI CTCAE grade 3 or 4) thrombocytopenia and neutropenia were reported during treatment with Asciminib (Bacrelba) (see Adverse Reactions). Myelosuppression was generally reversible and managed by temporarily withholding Asciminib (Bacrelba). Complete blood counts should be performed every two weeks for the first 3 months of treatment and monthly thereafter, or as clinically indicated. Patients should be monitored for signs and symptoms of myelosuppression.
Based on the severity of thrombocytopenia and/or neutropenia, the Asciminib (Bacrelba) dose should be reduced, temporarily withheld, or permanently discontinued as described in Table 4 (see Dosage & Administration).
Pancreatic toxicity: Pancreatitis occurred in 11 of 556 (2%) patients receiving Asciminib (Bacrelba), with grade 3 reactions occurring in 6 (1.1%) patients. Asciminib (Bacrelba) was permanently discontinued in 3 (0.5%) patients, while it was temporarily withheld in 6 (1.1%) patients due to pancreatitis. Asymptomatic elevation of serum lipase and amylase occurred in 107 of 556 (19.2%) patients receiving Asciminib (Bacrelba), with grade 3 and 4 reactions occurring in 41 (7.4%) and 11 (2%) of patients, respectively. Asciminib (Bacrelba) was permanently discontinued in 11 (2%) patients due to the asymptomatic elevation of serum lipase and amylase.
Serum lipase and amylase levels should be assessed monthly during treatment with Asciminib (Bacrelba), or as clinically indicated. Patients should be monitored for signs and symptoms of pancreatic toxicity. More frequent monitoring should be performed in patients with a history of pancreatitis. If serum lipase and amylase elevation are accompanied by abdominal symptoms, treatment should be temporarily withheld, and appropriate diagnostic tests should be considered to exclude pancreatitis (see Dosage & Administration).
Based on the severity of serum lipase and amylase elevation, the Asciminib (Bacrelba) dose should be reduced, temporarily withheld, or permanently discontinued as described in Table 4 (see Dosage & Administration).
QT prolongation: Electrocardiogram QT prolongation occurred in 5 of 556 (0.9%) patients receiving Asciminib (Bacrelba) (see Adverse Reactions). In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 ms together with more than 60 ms QTcF increase from baseline and one patient had prolonged QTcF with more than 60 ms QTcF increase from baseline.
It is recommended that an electrocardiogram is performed prior to the start of treatment with Asciminib (Bacrelba) and monitored during treatment as clinically indicated. Hypokalemia and hypomagnesemia should be corrected prior to Asciminib (Bacrelba) administration and monitored during treatment as clinically indicated.
Caution should be exercised when administering Asciminib (Bacrelba) at a total daily dose of 80 mg concomitantly with medicinal products with a known risk of torsades de pointes. Coadministration of Asciminib (Bacrelba) at 200 mg twice daily concomitantly with medicinal products with a known risk of torsades de pointes should be avoided (see Interactions and Pharmacology under Actions).
Hypertension: Hypertension occurred in 88 of 556 (15.8%) patients receiving Asciminib (Bacrelba), with grade 3 and 4 reactions reported in 47 (8.5%) and 1 (0.2%) patients, respectively. Among the patients with hypertension ≥grade 3, the median time to first occurrence of reactions was 21.29 weeks (range: 0.14 to 365 weeks). Asciminib (Bacrelba) was temporarily withheld in 5 (0.9%) patients due to hypertension.
Hypertension should be monitored and managed using standard antihypertensive therapy during treatment with Asciminib (Bacrelba) as clinically indicated.
Hypersensitivity: Hypersensitivity events occurred in 169 of 556 (30.4%) patients receiving Asciminib (Bacrelba), with ≥grade 3 events reported in 8 (1.4%) patients. Patients should be monitored for signs and symptoms of hypersensitivity and appropriate treatment should be initiated as clinically indicated.
Hepatitis B reactivation: Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus following administration of other BCR::ABL1 tyrosine kinase inhibitors (TKIs). Patients should be tested for HBV infection before the start of treatment with Asciminib (Bacrelba). HBV carriers who require treatment with Asciminib (Bacrelba) should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Use in Pregnancy: Embryo-fetal toxicity: Based on findings from animal studies, Asciminib (Bacrelba) can cause fetal harm when administered to a pregnant woman. Pregnant women and females of reproductive potential should be advised of the potential risk to a fetus if Asciminib (Bacrelba) is used during pregnancy or if the patient becomes pregnant while taking Asciminib (Bacrelba). The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Asciminib (Bacrelba). Sexually active females of reproductive potential should use effective contraception during treatment with Asciminib (Bacrelba) and for at least 3 days after the last dose (see Use in Pregnancy & Lactation).

Pregnancy: Risk summary: Based on findings from animal studies, Asciminib (Bacrelba) can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women to inform a product-associated risk.
Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, fetotoxicity and teratogenicity.
Pregnant women and females of reproductive potential should be advised of the potential risk to a fetus if Asciminib (Bacrelba) is used during pregnancy or if the patient becomes pregnant while taking Asciminib (Bacrelba) (see Precautions).
Data: Animal data: In embryo-fetal development studies, pregnant animals received oral doses of asciminib at 25, 150 and 600 mg/kg/day in rats and at 15, 50 and 300 mg/kg/day in rabbits during the period of organogenesis.
In rats, asciminib was not tolerated in maternal animals at 600 mg/kg/day and resulted in the early termination of the dose group. There was no evidence of asciminib-related embryo-fetal death at doses below or equal to 150 mg/kg/day. A dose-related increase in fetal weights at 25 and 150 mg/kg/day was observed. Fetal variations in the urinary tract and skeleton (skull, vertebral column, and ribs), indicative of changes in the rate of development, were observed primarily at 150 mg/kg/day. A slight increase in the malformation rate (anasarca and cardiac malformations) and some visceral variants indicative of adverse effects on embryo-fetal development were also observed at 150 mg/kg/day. The maternal no-observed-adverse-effect level (NOAEL) was 150 mg/kg/day and the fetal NOAEL was 25 mg/kg/day. At the fetal NOAEL of 25 mg/kg/day, the AUC exposures were equivalent to or below those achieved in patients at the 40 mg twice-daily or 80 mg once-daily doses, respectively. At the fetal NOAEL of 25 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice daily dose.
In rabbits, 300 mg/kg/day caused morbidity in the maternal animals and resulted in the early termination of the dose group. An increased incidence of resorptions, indicative of embryo-fetal mortality, and a low incidence of cardiac malformations, indicative of teratogenicity, were observed at 50 mg/kg/day. There was no effect on fetal growth. The NOAEL for maternal toxicity was 50 mg/kg/day and the fetal NOAEL was 15 mg/kg/day. At the fetal NOAEL of 15 mg/kg/day, the AUC exposures were equivalent to or below those achieved in patients at the 40 mg twice-daily or 80 mg once-daily doses, respectively. At the fetal NOAEL of 15 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice-daily dose.
Lactation: Risk summary: It is not known if asciminib is transferred into human milk after administration of Asciminib (Bacrelba). There are no data on the effects of asciminib on the breastfed child or on milk production.
Because of the potential for serious adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment with Asciminib (Bacrelba) and for at least 3 days after the last dose.
Females and males of reproductive potential: Pregnancy testing: The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Asciminib (Bacrelba).
Contraception: Sexually active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Asciminib (Bacrelba) and for at least 3 days after the last dose.
Infertility: There are no data on the effect of Asciminib (Bacrelba) on human fertility.
In the rat fertility study, asciminib did not affect reproductive function in male and female rats.
A slight effect on male sperm motility and sperm count was observed at doses of 200 mg/kg/day, likely at AUC exposures 19-fold, 13-fold, or 2-fold higher than those achieved in patients at the 40 mg twice-daily, 80 mg once-daily, or 200 mg twice-daily doses, respectively.

Summary of the safety profile: The overall safety profile of Asciminib (Bacrelba) has been evaluated in 556 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases receiving Asciminib (Bacrelba) as monotherapy. It is based on the safety pool of the pivotal phase III study J12301 (ASCAFIRST) (N=200 newly diagnosed Ph+ CML-CP patients), the pivotal phase III study A2301 (ASCEMBL) (N=156 Ph+ CML-CP patients previously treated with two or more TKIs) and the phase I study X2101, including patients with: Previously treated Ph+ CML-CP (N=115), Ph+ CML-CP harboring the T315I mutation (N=70), Ph+ CML-AP (N=15).
The safety pool (N=556) includes patients receiving Asciminib (Bacrelba) at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily. In the pooled dataset, the median duration of exposure to Asciminib (Bacrelba) was 83.29 weeks (range: 0.1 to 439 weeks), with 79.3% of patients exposed for at least 48 weeks and 42.4% of patients exposed for at least 96 weeks, respectively.
The most common adverse drug reactions of any grade (incidence ≥20%) in patients receiving Asciminib (Bacrelba) were musculoskeletal pain (32.9%), thrombocytopenia (28.1%), fatigue (25%), upper respiratory tract infections (23.7%), headache (21.8%), neutropenia (21.6%) and diarrhoea (20%). The most common adverse drug reactions of ≥grade 3 (incidence ≥5%) in patients receiving Asciminib (Bacrelba) were thrombocytopenia (16.5%), neutropenia (13.7%), increased pancreatic enzymes (9.4%) and hypertension (8.6%).
Serious adverse drug reactions occurred in 9.5% of patients receiving Asciminib (Bacrelba).
The most frequent serious adverse drug reactions (incidence ≥1%) were pleural effusion (1.6%), lower respiratory tract infections (1.4%), thrombocytopenia (1.3%), pancreatitis (1.1%) and pyrexia (1.1%).
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical studies (Table 5 and Table 6) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 5.)

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In the ASCEMBL study, decrease in phosphate levels occurred as a laboratory abnormality in 17.9% (all grades) and 7.1% (grade 3/4) of 156 patients receiving Asciminib (Bacrelba) at 40 mg twice daily. In the ASCAFIRST study, decrease in phosphate levels based on normal ranges occurred as a laboratory abnormality in 13% (all grades) of 200 patients receiving Asciminib (Bacrelba) at 80 mg once daily. (See Table 6.)

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Decrease in phosphate levels occurred as a laboratory abnormality in 47.9% (all grades) and 8.3% (grade 3/4) of 48 patients receiving Asciminib (Bacrelba) at 200 mg twice daily.
Description of selected adverse drug reactions: Myelosuppression: Thrombocytopenia occurred in 156 of 556 (28.1%) patients receiving Asciminib (Bacrelba), with grade 3 and 4 reactions reported in 39 (7%) and 53 (9.5%) of patients, respectively. Among the patients with thrombocytopenia ≥grade 3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 64.14 weeks) with median duration of any occurring reaction of 1.57 weeks (95% CI, range: 1.14 to 2 weeks). Asciminib (Bacrelba) was permanently discontinued in 11 (2%) patients, while it was temporarily withheld in 70 (12.6%) patients due to thrombocytopenia.
Neutropenia occurred in 120 of 556 (21.6%) patients receiving Asciminib (Bacrelba), with grade 3 and 4 reactions reported in 41 (7.4%) and 35 (6.3%) patients, respectively. Among the patients with neutropenia ≥grade 3, the median time to first occurrence of reactions was 7.07 weeks (range: 0.14 to 180.14 weeks) with median duration of any occurring reaction of 1.86 weeks (95% CI, range: 1.29 to 2 weeks). Asciminib (Bacrelba) was permanently discontinued in 7 (1.3%) patients, while it was temporarily withheld in 52 (9.4%) patients due to neutropenia.
Anaemia occurred in 70 of 556 (12.6%) patients receiving Asciminib (Bacrelba), with grade 3 reactions occurring in 22 (4%) patients. Among the patients with anaemia ≥grade 3, the median time to first occurrence of reactions was 22.21 weeks (range: 0.14 to 207 weeks) with median duration of any occurring reaction of 0.79 weeks (95% CI, range: 0.29 to 1.71 weeks). Asciminib (Bacrelba) was temporarily withheld in 2 (0.4%) patients due to anaemia.

Agents that may increase asciminib plasma concentrations: Strong CYP3A4 inhibitors: Physiologically based pharmacokinetic (PBPK) models predict that co-administration of Asciminib (Bacrelba) at 200 mg twice daily with a strong CYP3A4 inhibitor (clarithromycin) would increase asciminib AUC_tau and C_max by 77% and 49%, respectively. Caution should be exercised during concomitant administration of Asciminib (Bacrelba) 200 mg twice daily with strong CYP3A4 inhibitors including but not limited to clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Dose adjustment of Asciminib (Bacrelba) is not required.
Agents that may decrease asciminib plasma concentrations: Strong CYP3A4 inducers: Co-administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUC_inf by 14.9%, while increasing asciminib C_max by 9% in healthy subjects receiving a single Asciminib (Bacrelba) dose of 40 mg.
PBPK models predict that co-administration of asciminib at 80 mg once daily with rifampicin would decrease asciminib AUC_tau and C_max by 52% and 23%, respectively, while co-administration of asciminib at 200 mg twice daily with rifampicin would decrease asciminib AUC_tau and C_max by 63% and 47%, respectively.
Caution should be exercised during concomitant administration of Asciminib (Bacrelba) at all recommended doses with strong CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, or St. John's wort (Hypericum perforatum). Dose adjustment of Asciminib (Bacrelba) is not required.
Agents that may have their plasma concentrations altered by asciminib: CYP3A4 substrates with narrow therapeutic index: Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased midazolam AUC_inf and C_max by 28% and 11%, respectively, in healthy subjects receiving Asciminib (Bacrelba) 40 mg twice daily.
PBPK models predict that co-administration of asciminib at 80 mg once daily would increase midazolam AUC_inf and C_max by 24% and 17%, respectively, while co-administration of asciminib at 200 mg twice daily would increase midazolam AUC_inf and C_max by 88% and 58%, respectively.
Caution should be exercised during concomitant administration of Asciminib (Bacrelba) at all recommended doses with CYP3A4 substrates known to have a narrow therapeutic index, including, but not limited to, the CYP3A4 substrates fentanyl, alfentanil, dihydroergotamine, or ergotamine (see Pharmacology under Actions). Dose adjustment of Asciminib (Bacrelba) is not required.
CYP2C9 substrates: Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUC_inf and C_max by 41% and 8%, respectively, in healthy subjects receiving Asciminib (Bacrelba) 40 mg twice daily.
PBPK models predict that co-administration of asciminib at 80 mg once daily would increase S-warfarin AUC_inf and C_max by 52% and 4%, respectively, while co-administration of asciminib at 200 mg twice-daily would increase S-warfarin AUC_inf and C_max by 314% and 7%, respectively.
Caution should be exercised during concomitant administration of Asciminib (Bacrelba) at 80 mg total daily with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin (see Pharmacology under Actions). Dose adjustment of Asciminib (Bacrelba) is not required.
Concomitant administration of Asciminib (Bacrelba) at 200 mg twice daily with CYP2C9 sensitive substrates and CYP2C9 substrates known to have a narrow therapeutic index should be avoided and alternative medications should be considered (see Pharmacology under Actions). If co-administration cannot be avoided, the CYP2C9 substrates dose should be reduced. If co-administration with warfarin cannot be avoided, the frequency of international normalized ratio (INR) monitoring should be increased as the anti-coagulant effect of warfarin may be enhanced.
Substrates of OATP1B, of BCRP or of both transporters: PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with an OATP1B substrate (pravastatin) would increase pravastatin C_max by 43% and 63% and AUC_inf by 37% and 51%, respectively, while co-administration of asciminib at 200 mg twice daily would increase pravastatin C_max and AUC_inf by 141% and 137%, respectively.
PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with an OATP1B, CYP3A4 and P-gp substrate (atorvastatin) would increase atorvastatin C_max by 97% and 143% and AUC_inf by 81% and 122%, respectively, while co-administration of asciminib at 200 mg twice daily would increase atorvastatin C_max and AUC_inf by 300% and 326%, respectively.
PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with a BCRP substrate (sulfasalazine) would increase sulfasalazine C_max by 334% and 342% and AUC_inf by 333% and 340%, respectively, while co-administration of asciminib at 200 mg twice daily would increase sulfasalazine C_max and AUC_inf by 353% and 359%, respectively.
PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with a BCRP and OATP1B substrate (rosuvastatin) would increase rosuvastatin C_max by 453% and 530% and AUC_inf by 190% and 202%, respectively, while co-administration of asciminib at 200 mg twice daily would increase rosuvastatin C_max and AUC_inf by 732% and by 311%, respectively.
Caution should be exercised during concomitant administration of Asciminib (Bacrelba) at all recommended doses with substrates of OATP1B, of BCRP or of both transporters, including, but not limited to sulfasalazine, methotrexate, pravastatin, atorvastatin, pitavastatin, rosuvastatin and simvastatin. Refer to OATP1B and BCRP substrates' dose reductions, as recommended in their prescribing information.
Concomitant administration of Asciminib (Bacrelba) at all recommended doses with rosuvastatin should be avoided and alternative statins should be considered. If co-administration cannot be avoided, rosuvastatin dose should be reduced, as recommended in its prescribing information (see Pharmacology under Actions).
P-gp substrates of narrow therapeutic index: PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily with a P-gp substrate (digoxin) would increase digoxin C_max by 30% and 38% and AUC_inf by 20% and 22%, respectively, while co-administration of asciminib at 200 mg twice daily would increase digoxin C_max and AUC_inf by 62% and 40%, respectively.
Caution should be exercised during concomitant administration of Asciminib (Bacrelba) at all recommended doses with P-gp substrates known to have a narrow therapeutic index, including but not limited to digoxin, dabigatran, and colchicine.
QT prolonging agents: Caution should be exercised during concomitant administration of Asciminib (Bacrelba) at 80 mg total daily dose and medicinal products with a known risk of torsades de pointes, including, but not limited to, bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide (see Pharmacology under Actions).
Concomitant administration of Asciminib (Bacrelba) at 200 mg twice-daily dose and medicinal products with a known risk of torsades de pointes should be avoided (see Pharmacology under Actions).
Drug-food interactions: The bioavailability of asciminib decreases on consumption of food (see Dosage & Administration and Pharmacology under Actions).

Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C.
Store in the original package in order to protect from moisture.

Targeted Cancer Therapy

L01EA06 - asciminib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.

Rx