Scemblix

Scemblix 20 mg film-coated tablets: The tablets are pale yellow, round and biconvex with bevelled edges and a diameter of approximately 6.2 mm, unscored, and imprinted with the "Novartis" logo on one side and "20" on the other side.
Each 20 mg film-coated tablet contains 21.62 mg asciminib hydrochloride equivalent to 20 mg asciminib.
Scemblix 40 mg film-coated tablets: The tablets are violet white, round and biconvex with bevelled edges and a diameter of approximately 8.2 mm, unscored, and imprinted with the "Novartis" logo on one side and "40" on the other side.
Each 40 mg film-coated tablet contains 43.24 mg asciminib hydrochloride equivalent to 40 mg asciminib.
Excipients/Inactive Ingredients: 20 mg film-coated tablets: lactose monohydrate, microcrystalline cellulose (E460(i)), hydroxypropyl cellulose (E463), croscarmellose sodium (E468), polyvinyl alcohol (E1203), titanium dioxide (E171), magnesium stearate, talc (E553b), colloidal silicon dioxide, iron oxide (E172, yellow and red), lecithin (E322), xanthan gum (E415).
40 mg film-coated tablets: lactose monohydrate, microcrystalline cellulose (E460(i)), hydroxypropyl cellulose (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).

ATC code: L01EA06.
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-binding 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 harbouring BCR::ABL1 with IC₅₀ values between 1 and 25 nanomolar. In cells expressing the wild-type form or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth with mean IC₅₀ values of 0.61 ± 0.21 nanomolar or 7.64 ± 3.22 nanomolar, respectively.
In mouse xenograft models of CML asciminib dose-dependently inhibited the growth of tumours harbouring either the wild-type form or the T315I mutant form of BCR::ABL1, with tumour regression being observed at doses above 7.5 mg/kg or 30 mg/kg twice daily, respectively.
Cardiac electrophysiology: Scemblix treatment has been 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 leukaemia (ALL) receiving Scemblix 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 the Scemblix 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 efficacy: Newly diagnosed Ph+ CML‑CP: The clinical efficacy and safety of Scemblix in the treatment of patients with newly diagnosed Philadelphia chromosome-positive myeloid leukaemia in chronic phase (Ph+ CML‑CP) were demonstrated in the multicentre, randomised, active-controlled and open-label phase III study ASC4FIRST.
In this study a total of 405 patients were randomised in a 1:1 ratio to receive either Scemblix or investigator-selected tyrosine kinase inhibitors (IS TKIs). Prior to randomisation, the investigator selected the TKI (imatinib or second-generation [2G] TKI) to be used in the event of randomisation in the comparator arm based on patient characteristics and comorbidities. Patients were stratified by EUTOS long-term survival (ELTS) risk group (low, intermediate, high) and pre-randomisation selection of TKI (imatinib or 2G TKI stratum). Patients received either Scemblix or IS TKIs and continued to receive treatment until unacceptable toxicity or treatment failure occurred.
Patients were 36.8% female and 63.2% male with a median age of 51 years (range: 18 to 86 years). Of the 405 patients, 23.5% were aged 65 years or older, while 6.2% were aged 75 years or older. Patients were white (53.8%), Asian (44.4%) and black (1%), and 0.7% were of unknown ethnicity. Demographic characteristics within the imatinib (N=203) and 2G TKI strata (N=202) were as follows: median age: 55 years and 43 years, respectively; ELTS high-risk group: 8.4% and 13.9%, respectively; Framingham group with high risk for cardiovascular disorders: 35.5% and 17.8%, respectively.
Demographic characteristics were balanced between Scemblix and IS TKIs and between both arms within the imatinib and 2G TKI strata.
Of the 405 patients, 200 received Scemblix and 201 received IS TKIs. Of the 201 patients who received IS TKIs, 99 were treated with imatinib, 49 with nilotinib, 42 with dasatinib and 11 with bosutinib. 4 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 Scemblix and 64.3 weeks (range: 1.3 to 103.1 weeks) for patients receiving IS TKIs. By 48 weeks 90% of patients on Scemblix and 80.6% of patients on IS TKIs were still receiving treatment.
The study had 2 primary objectives for the assessment of major molecular response (MMR) at 48 weeks. One primary objective evaluated Scemblix compared to IS TKIs. The other primary objective evaluated Scemblix compared to IS TKIs within the imatinib stratum. A secondary objective evaluated MMR at 48 weeks, with Scemblix having been evaluated compared to IS TKIs within the 2G TKI stratum.
The key efficacy outcomes of ASC4FIRST are summarised in Table 1. (See Table 1.)

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The median time to MMR in patients who received Scemblix, IS TKIs, IS TKIs within the imatinib stratum and IS TKIs within the 2G TKI stratum was: 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.
BCR::ABL1 mutations were observed in 4% of patients treated with Scemblix and in 2% of patients treated with IS TKIs.
Pretreated Ph+ CML‑CP: The clinical efficacy and safety of Scemblix in the treatment of patients with Ph+ CML‑CP with treatment failure or intolerance to two or more tyrosine kinase inhibitors were investigated in the multicentre, randomised, active-controlled and open-label phase III study ASCEMBL.
Resistance to the last TKI was defined as: Lack of haematological or cytogenetic response at 3 months; BCR::ABL1 on the International Scale [IS] >10% at 6 months or thereafter; >65% Philadelphia-positive (Ph+) metaphases at 6 months or >35% at 12 months or thereafter; Loss of complete haematological response (CHR), of partial cytogenetic response (PCyR), of complete cytogenetic response (CCyR) or of major molecular response (MMR) at any time; New BCR::ABL1 mutations which potentially cause resistance to the study medicinal product or clonal evolution in Ph+ metaphases at any time.
Intolerance to the last TKI was defined as non-haematological toxicities unresponsive to optimal treatment or as haematological toxicities recurring after dose reduction to the lowest recommended dose.
In this study a total of 233 patients were randomised in a 2:1 ratio and stratified according to major cytogenetic response (MCyR) status at baseline for treatment with either 40 mg Scemblix twice daily (N=157) or 500 mg bosutinib once daily (N=76). There are only limited clinical data on the 80 mg once-daily dosage.
Pharmacological analyses indicate that both dosages have a comparable clinical profile. Patients continued treatment until unacceptable toxicity or treatment failure occurred. Patients with a known T315I and/or V299L mutation at any time prior to study entry were not included in the ASCEMBL study.
Patients with Ph+ CML‑CP previously treated with two or more TKIs were 51.5% female and 48.5% male with a median age of 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 white (74.7%), Asian (14.2%) and black (4.3%). Of the 233 patients, 80.7% and 18% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, respectively. The proportion of patients who had previously received 2, 3, 4, 5 or more prior treatment 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 Scemblix and 30.5 weeks (range: 1 to 239.3 weeks) for patients receiving bosutinib.
The primary endpoint of the study was the MMR rate at 24 weeks and MMR rate at 96 weeks was the key secondary endpoint. MMR rate is defined as a BCR::ABL1 ratio ≤0.1% on the International Scale [IS]. Other secondary endpoints were complete cytogenetic response rate (CCyR) at 24 and 96 weeks, defined as no Philadelphia-positive metaphases in bone marrow with a minimum of 20 metaphases examined.
The most important efficacy results from the ASCEMBL study are summarised in Table 2. (See Table 2.)

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In the ASCEMBL study 12.7% of patients treated with Scemblix and 13.2% of patients receiving bosutinib had one or more BCR::ABL1 mutations detected at baseline. MMR at 24 weeks was observed in 35.3% and 24.8% of patients receiving Scemblix with or without any BCR::ABL1 mutation at baseline, respectively.
The clinical efficacy and safety of Scemblix in the treatment of patients with Ph+ CML‑CP in whom treatment with a tyrosine kinase inhibitor failed or who did not tolerate such treatment were investigated in a cohort of the ongoing multicentre, single-arm, open-label, phase II dose escalation study ASC2ESCALATE.
The primary endpoint of the study is the MMR rate at 12 months in the second-line cohort (2L).
At the time of the interim analysis, 71 patients had been enrolled in the 2L cohort, with a median duration of Scemblix treatment of 19 weeks (range: 6.1 to 29.6 weeks). The MMR at 24 weeks was achieved in 42.9% of evaluable patients (N=28) in the 2L cohort (95% CI: 24.5% to 62.8%).
Ph+ CML‑CP harbouring a T315I mutation: The clinical efficacy and safety of Scemblix in the treatment of patients with Ph+ CML‑CP harbouring the T315I mutation were investigated in a multicentre, open-label, phase I human 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 Scemblix at doses from 10 to 200 mg twice daily or 80 to 200 mg once daily. 48 of these patients with Ph+ CML‑CP harbouring the T315I mutation received Scemblix at a dose of 200 mg twice daily. The patients continued the treatment until unacceptable toxicity or until treatment failure.
Among the patients with Ph+ CML‑CP with the T315I mutation who received Scemblix at a dose of 200 mg twice daily, 77.1% were male and 22.9% were female with a median age of 56.5 years (range: 26 to 86 years). Of the 48 patients, 33.3% were aged 65 years or older and 8.3% were aged 75 years or older. The patients were white (47.9%), Asian (25%), and black (2.1%). 75% of the patients had an ECOG performance status of 0 and 25% had an ECOG performance status of 1. The proportion of patients who had previously received 1, 2, 3, 4, and 5 or more TKIs was 16.7%, 31.3%, 35.4%, 14.6%, and 2.1%, respectively. The median treatment duration was 181.7 weeks (range: 2 to 312 weeks).
MMR at 24 weeks was achieved in 42.2% of the evaluable patients (N=45) treated with Scemblix (95% CI: 27.7-57.8%).
MMR at 96 weeks was achieved in 48.9% of the evaluable patients (N=45) treated with Scemblix.
Elderly patients: Of the 556 patients treated with Scemblix in the ASC4FIRST, ASCEMBL and X2101 studies, 130 (23.4%) were aged 65 years or older and 31 (5.6%) were aged 75 years or older. No clear overall differences in the efficacy of Scemblix were observed between patients aged 65 years or older and younger patients.
Paediatric population: No studies on safety and efficacy have been performed in children and adolescents aged under 18 years.
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 1,781 ng/ml (23%) and 793 ng/ml (49%) following administration of Scemblix at 80 mg once daily and 40 mg twice daily, respectively. The geometric mean (geoCV%) of C_max at steady state is 5642 ng/ml (40%) following administration of Scemblix at 200 mg twice daily. The geometric mean (geoCV%) of AUC_tau is 5262 ng*h/ml (48%) following administration of Scemblix at 40 mg twice daily. According to model calculations, asciminib absorption is estimated at 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 as oral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib decreased the 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 and C_max are decreased by 62.3% and 68.2%, respectively, with a high-fat meal and by 30% and 34.8%, respectively, with a low-fat meal compared to the fasted state (see Dosage & Administration and Interactions).
Distribution: The apparent volume of distribution of asciminib at steady state is 111 l based on a population pharmacokinetic analysis. Asciminib is mainly distributed in the 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.
Metabolism: Asciminib is primarily metabolised via CYP3A4-mediated oxidation, UGT2B7-mediated glucuronidation and UGT2B17-mediated glucuronidation. Asciminib is the main circulating component in plasma (92.7% of the administered dose).
Elimination: Asciminib is mainly eliminated via the faeces, with only a minor proportion eliminated renally. 80% and 11% of the asciminib dose were recovered in the faeces and urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of [¹⁴C]-labelled asciminib. Faecal elimination of unchanged asciminib accounts for 56.7% of the administered dose. Asciminib is eliminated by biliary secretion via the breast cancer resistant protein (BCRP).
The oral total clearance (CL/F) of asciminib is 6.31 l/hour based on a population pharmacokinetic analysis. The accumulation half-life of asciminib is 5.2 hours at dosages of 40 mg twice daily and 80 mg once daily.
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 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.
Kinetics in special populations: Asciminib systemic exposure is not affected by gender, age (20 to 88 years), ethnicity or body weight (42 to 184 kg) to any clinically relevant extent.
Hepatic impairment: A dedicated hepatic impairment study including 8 participants 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. The asciminib AUC_inf was increased by 22%, 3% and 66% in participants with mild, moderate and severe hepatic impairment, respectively, compared to participants with normal hepatic function following oral administration of a single 40 mg dose of Scemblix (see Dosage & Administration).
Renal impairment: A dedicated renal impairment study including 6 participants with normal renal function (absolute glomerular filtration rate [aGFR] ≥90 ml/min) and 8 participants with severe renal impairment not requiring dialysis (aGFR 15 to <30 ml/min) has been conducted. The asciminib AUC_inf and C_max are increased by 56% and 8%, respectively, in participants with severe renal impairment compared to participants with normal renal function following oral administration of a single 40 mg dose of Scemblix (see Dosage & Administration).
Population pharmacokinetic models show an increase in asciminib median steady-state AUC_0-24h by 11.5% in participants with mild to moderate renal impairment compared to participants with normal renal function.
Toxicology: Preclinical data: Asciminib was evaluated in safety pharmacology, repeated-dose toxicity, genotoxicity, reproductive toxicity and phototoxicity studies.
Safety pharmacology: 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 found in dogs up to the highest free asciminib exposure of 6.3 micromolar.
Repeated-dose toxicity: 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. The AUC exposures were lower (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 the thickness of the mucosa with frequent elongation of villi) occurred 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. The AUC exposure was 4-fold higher than 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. The AUC exposures were lower (monkeys) or 2-fold higher (rats) than the exposure in patients on 200 mg twice daily. These changes were fully reversible.
Carcinogenicity and mutagenicity: Asciminib did not show mutagenic, clastogenic or aneugenic potential in vitro or in vivo.
In a 2-year rat carcinogenicity study non-neoplastic proliferative changes in the form of ovarian Sertoli cell hyperplasia were observed in female animals at a dose of ≥30 mg/kg/day. Benign Sertoli cell tumours in the ovaries were observed in female rats at the highest tested dose of 66 mg/kg/day. AUC exposures to asciminib in female rats at a dosage of 66 mg/kg/day were generally 8-fold or 5-fold higher than in patients who received a dose of 40 mg twice daily or 80 mg once daily, respectively, and are equivalent to those achieved in patients at a dose of 200 mg twice daily. However, no asciminib-related neoplastic or hyperplastic findings were observed in male rats at any dosage.
The clinical relevance of these findings is currently unknown.
Reproductive toxicity: In embryo-foetal 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 organogenesis. In embryo-foetal development studies a slight increase in foetal malformations (anasarca and cardiac malformations) and an increase in visceral and skeletal variants were observed in rats. An increased incidence of resorptions indicative of embryo-foetal mortality and a low incidence of cardiac malformations indicative of teratogenicity were observed in rabbits. In rats, at the foetal NOAEL of 25 mg/kg/day, the AUC exposures were equal to or less than those achieved in patients at the 40 mg twice-daily or 80 mg once-daily doses. At the foetal NOAEL of 25 mg/kg/day, the AUC exposures were lower than those achieved in patients at the 200 mg twice daily dose. In rabbits, at the foetal 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. At the foetal NOAEL of 15 mg/kg/day, the AUC exposures were lower than those achieved in patients at the 200 mg twice daily dose.
Fertility: 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 40 mg twice daily, 80 mg once daily or 200 mg twice daily, respectively.
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.

Scemblix is indicated for the treatment of adult patients with: newly diagnosed or c-abl tyrosine kinase inhibitor-pretreated Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in chronic phase (CP) (see Pharmacology: Pharmacodynamics: Clinical efficacy under Actions); Ph+ CML-CP harbouring a T315I mutation.

Treatment with Scemblix should be initiated by a physician experienced in the use of anticancer therapies.
Usual dosage: Ph+ CML-CP: The recommended total daily dose of Scemblix is 80 mg. Scemblix 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 who are switched from 40 mg twice daily to 80 mg once daily should start taking Scemblix once daily approximately 12 hours after the last twice-daily dose and then continue at 80 mg once daily.
Patients who are switched from 80 mg once daily to 40 mg twice daily should start taking Scemblix twice daily approximately 24 hours after the last once-daily dose and then continue at 40 mg twice daily at approximately 12-hour intervals (see Pharmacology: Pharmacodynamics: Clinical efficacy under Actions).
Ph+ CML-CP harbouring a T315I mutation: The recommended dose of Scemblix is 200 mg taken orally twice daily at approximately 12-hour intervals.
Treatment duration: Scemblix treatment should be continued as long as a clinical benefit is observed or until unacceptable toxicity occurs.
Dose modification due to adverse effects/interactions: Ph+ CML-CP: For the management of adverse drug reactions of Scemblix, the dose can be reduced based on individual safety and tolerability as described in Table 3. If the adverse drug reactions are effectively managed, treatment with Scemblix may be resumed as described in Table 3.
Scemblix should be permanently discontinued in patients unable to tolerate a total daily dose of 40 mg.
Ph+ CML-CP harbouring a T315I mutation: For the management of adverse drug reactions of Scemblix, the dose can be reduced based on individual safety and tolerability as described in Table 3. If the adverse drug reactions are effectively managed, treatment with Scemblix may be resumed as described in Table 3.
Scemblix 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 dose modification for the management of selected adverse drug reactions is shown in Table 4. (See Table 4.)

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Patients with hepatic impairment: No dose adjustment is necessary in patients with mild, moderate or severe hepatic impairment receiving Scemblix. Caution is required in patients with severe hepatic impairment receiving Scemblix 200 mg twice daily (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: No dose adjustment is necessary in patients with mild, moderate or severe renal impairment receiving Scemblix. Caution is required in patients with severe renal impairment receiving Scemblix 200 mg twice daily (see Pharmacology: Pharmacokinetics under Actions).
Elderly patients: No dose adjustment is required in patients 65 years of age and over.
Children and adolescents: The safety and efficacy in patients under 18 years of age have not been established.
Late administration: Once-daily dosage regimen: If a dose of Scemblix is more than approx. 12 hours late, it should be skipped and the next one taken as scheduled.
Twice-daily dosage regimen: If a dose of Scemblix is more than approx. 6 hours late, it should be skipped and the next one taken as scheduled.
Method of administration: Scemblix should be taken orally without food. The intake of food should be avoided for at least 2 hours before and 1 hour after taking Scemblix (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Scemblix film-coated tablets must be swallowed whole with a glass of water and should not be broken, crushed or chewed.

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

Hypersensitivity to the active substance or any of the excipients listed under Description.

Myelosuppression: Thrombocytopenia, neutropenia and anaemia have occurred in patients receiving Scemblix. Severe (NCI CTCAE grade 3 or 4) thrombocytopenia and neutropenia have been reported during treatment with Scemblix (see Adverse Reactions). Myelosuppression was generally reversible and was managed by temporarily withholding Scemblix.
A complete blood count should be performed every 2 weeks in the first 3 months of treatment and then 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 Scemblix 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 Scemblix, with grade 3 adverse drug reactions occurring in 6 (1.1%) patients. Scemblix was permanently discontinued in 3 (0.5%) patients, while it was temporarily withheld in 5 (1.1%) patients due to pancreatitis. Asymptomatic elevations of serum lipase and amylase occurred in 107 of 556 (19.2%) patients receiving Scemblix treatment, with grade 3 and 4 adverse drug reactions occurring in 41 (7.4%) and 11 (2%) patients, respectively. Scemblix was permanently discontinued in 11 (2%) patients due to asymptomatic elevation of serum lipase and amylase.
Serum lipase and amylase levels should be assessed monthly during treatment with Scemblix 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 is 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 the serum lipase and amylase elevation, the Scemblix 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 Scemblix treatment (see Adverse Reactions). In the ASCEMBL clinical study one patient had a prolonged QTcF greater than 500 ms together with a more than 60 ms QTcF increase from baseline and one patient had a prolonged QTcF with a more than 60 ms QTcF increase from baseline.
It is recommended that an electrocardiogram is performed prior to the start of treatment with Scemblix and that ECG monitoring is carried out during treatment as clinically indicated. Hypokalaemia and hypomagnesaemia should be corrected prior to Scemblix administration and monitored during treatment as clinically indicated.
Caution is required when co-administering Scemblix at a total daily dose of 80 mg with medicinal products with a known risk of torsades de pointes. Co-administration of Scemblix 200 mg twice daily with medicinal products with a known risk of torsades de pointes should be avoided (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Hypertension: Hypertension occurred in 88 of 556 (15.8%) patients receiving Scemblix treatment, with grade 3 and 4 adverse drug reactions reported in 47 (8.5%) and 1 (0.2%) patients, respectively. Among the patients with ≥ grade 3 hypertension, the median time to first occurrence of adverse drug reactions was 21.29 weeks (range: 0.14 to 365 weeks). Scemblix was temporarily withheld in 5 (0.9%) patients due to hypertension.
Hypertension should be monitored and managed with standard antihypertensive therapy during treatment with Scemblix as clinically indicated.
Hypersensitivity: Hypersensitivity events occurred in 169 of 556 (30.4%) patients receiving Scemblix, 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 Scemblix. HBV carriers who require treatment with Scemblix should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Embryo-foetal toxicity: Based on findings from animal studies, Scemblix can cause foetal harm when administered to a pregnant woman. Pregnant women and women of child-bearing potential should be advised of the potential risk to the foetus if Scemblix is used during pregnancy or if the patient becomes pregnant while taking Scemblix. The pregnancy status of women of child-bearing potential should be verified prior to starting treatment with Scemblix. Sexually active women of childbearing potential should use effective contraception during treatment with Scemblix and for at least 3 days after the last dose (see Use in Pregnancy & Lactation).
Other components: The tablets contain lactose. Patients with the rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, making it practically "sodium-free".
Patients excluded from clinical studies: Patients with severe or uncontrolled medical conditions, including any bleeding disorders, with a history of or risk factors for pancreatitis, or with clinically significant cardiac impairment or cardiac repolarisation abnormalities were not included in clinical studies for asciminib.
Effects on ability to drive and use machines: No relevant studies have been performed. Patients experiencing dizziness, fatigue, nausea, visual impairment or other adverse effects with a potential impact on the ability to drive or use machines should refrain from these activities as long as the adverse effects persist (see Adverse Reactions).

Treatment of women of childbearing potential/contraception: The pregnancy status of women of child-bearing potential should be verified prior to starting treatment with Scemblix.
Sexually active women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Scemblix and for at least 3 days after the last dose.
Pregnancy: There are no studies in pregnant women therefore it is not possible to provide statements on a medicinal product-associated risk.
Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, fetotoxicity and malformations (see Pharmacology: Toxicology: Preclinical data under Actions). Asciminib is not recommended during pregnancy and in women of childbearing potential who do not use contraceptives. If Scemblix is used during pregnancy or if the patient becomes pregnant during treatment with Scemblix, the patient must be informed of the potential risk to the foetus (see Precautions).
Breast-feeding: It is unknown whether asciminib or its metabolites are excreted in human milk following administration of Scemblix. There are no data on the effects of asciminib on the breast-fed infant or milk production.
Because of the potential for serious adverse effects in the breast-fed infant, breast-feeding is not recommended during treatment with Scemblix and for at least 3 days after the last dose.
Fertility: There are no data on the effects of Scemblix on human fertility.
In the rat fertility study asciminib did not affect reproductive function in male and female rats (see Pharmacology: Toxicology: Preclinical data: Fertility under Actions).

Summary of the safety profile: The overall safety profile of asciminib was investigated in 556 patients with Ph+ CML. In the pooled data set of the phase III pivotal study J12301 (ASC4FIRST) (N=200 newly diagnosed Ph+ CML‑CP patients) (80 mg once daily dosage), the phase III pivotal study A2301 (ASCEMBL) (N=156 Ph+ CML‑CP patients previously treated with two or more TKIs) (40 mg twice-daily dosage) and the phase I study X2101, the median duration of exposure to asciminib was 83.2 weeks (range: 0.1 to 439 weeks), with 79.3% of patients having been exposed for at least 48 weeks and 42.4% of patients having been exposed for at least 96 weeks.
The most common adverse drug reactions of any grade (incidence ≥20%) in patients receiving Scemblix 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 Scemblix 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 Scemblix.
The most common 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%).
List of adverse drug reactions: Adverse drug reactions are ordered by MedDRA system organ class and frequency according to the following convention: 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 a decrease in phosphate levels occurred as a laboratory abnormality in 17.9% (all grades) and 7.1% (grade 3/4) of 156 patients receiving Scemblix at 40 mg twice daily. In the ASC4FIRST study a decrease in phosphate levels based on the normal range occurred as a laboratory abnormality in 13% (all grades) of 200 patients receiving Scemblix at 80 mg once daily. A decrease in phosphate levels occurred as a laboratory abnormality in 47.9% (all grades) and 8.3% (grade 3/4) of 48 patients who received Scemblix at a dose of 200 mg twice daily.
An increase in potassium as a laboratory abnormality was observed with asciminib in 22.5% (all grades) and 1.3% (grade 3/4) of 556 participants in the asciminib safety pool.
Description of specific adverse effects and additional information: Myelosuppression: Thrombocytopenia occurred in 156 of 556 (28.1%) patients receiving Scemblix, with grade 3 and 4 adverse drug reactions reported in 39 (7%) and 53 (9.5%) patients, respectively. Among the patients with ≥ grade 3 thrombocytopenia the median time to first occurrence of adverse drug reactions was 6 weeks (range: 0.14 to 64.14 weeks) with a median duration of an occurring adverse drug reaction of 1.57 weeks (95% CI, range: 1.14 to 2 weeks). Scemblix 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 Scemblix treatment, with grade 3 and 4 adverse drug reactions reported in 41 (7.4%) and 35 (6.3%) patients, respectively. Among the patients with ≥ grade 3 neutropenia the median time to first occurrence of adverse drug reactions was 7.07 weeks (range: 0.14 to 180.14 weeks) with a median duration of an occurring adverse drug reaction of 1.86 weeks (95% CI, range: 1.29 to 2 weeks). Scemblix 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 Scemblix, with grade 3 adverse drug reactions occurring in 22 (4%) patients. Among the patients with grade ≥3 anaemia the median time to first occurrence of adverse drug reactions was 22.21 weeks (range: 0.14 to 207 weeks) with a median duration of an occurring adverse drug reaction of 0.79 weeks (95% CI, range: 0.29 to 1.71 weeks). Scemblix was temporarily withheld in 2 patients (0.4%) due to anaemia.
Reporting suspected adverse effects after authorisation of the medicinal product is very important. It allows continued monitoring of the risk-benefit ratio of the medicinal product. Healthcare professionals are asked to report any suspected new or serious adverse effects.

Agents that may affect asciminib plasma concentrations: Strong CYP3A4 inhibitors: The AUC_inf and C_max of asciminib increased by 36% and 19%, respectively, after co-administration of a single dose of 40 mg Scemblix with a strong CYP3A4 inhibitor (clarithromycin). No clinically significant differences in the pharmacokinetics of asciminib were observed after co-administration with itraconazole, which is also a strong CYP3A4 inhibitor.
Physiologically based pharmacokinetic (PBPK) models predict that the co-administration of Scemblix 200 mg twice daily with a strong CYP3A4 inhibitor (clarithromycin) would increase the asciminib AUC_tau and C_max by 77% and 49%, respectively.
Caution is required during co-administration of Scemblix 200 mg twice daily with strong CYP3A4 inhibitors, including, but not limited to, clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Scemblix dose adjustment is not required.
Strong CYP3A4 inducers: Co-administration of a strong CYP3A4 inducer (rifampicin) decreased the asciminib AUC_inf by 15% and increased the C_max of asciminib by 9% in healthy subjects receiving a single Scemblix dose of 40 mg.
Co-administration of asciminib 200 mg twice daily with rifampicin would decrease the asciminib AUC_tau and C_max by 63% and 47%, respectively.
Caution is required during co-administration of Scemblix at all recommended doses with strong CYP3A4 inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoin or St. John's wort (Hypericum perforatum). Scemblix dose adjustment is not required.
Imatinib: The asciminib AUC_inf and C_max increase by 108% and 59%, respectively, after co-administration of a single dose of 40 mg Scemblix with imatinib (an inhibitor of BCRP, CYP3A4, UGT2B17 and UGT1A3/4). The changes in exposure are not considered to be clinically significant.
Other agents: No clinically significant differences in the pharmacokinetics of asciminib were observed after co-administration with rabeprazole (acid-reducing agent) and quinidine (P-gp inhibitor).
Agents whose plasma concentrations may be altered by asciminib: CYP3A4 substrates with a narrow therapeutic index: Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased the midazolam AUC_inf and C_max by 28% and 11%, respectively, in healthy subjects receiving 40 mg Scemblix twice daily. PBPK models predict that the co-administration of asciminib at 200 mg twice daily would increase the midazolam AUC_inf and C_max by 88% and 58%, respectively.
Caution is required during co-administration of Scemblix 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: Pharmacokinetics under Actions). Scemblix dose adjustment is not required.
CYP2C8 substrates: The AUC_inf and C_max of repaglinide (substrate of CYP2C8, CYP3A4 and OATP1B) increased by 8% and 14%, respectively, after co-administration of repaglinide with 40 mg asciminib twice daily. PBPK models predict that the repaglinide AUC_inf and C_max would increase by 12% and 8%, respectively, after co-administration with 80 mg asciminib once daily and by 42% and 25%, respectively, after co-administration with 200 mg asciminib twice daily. PBPK models predict that the AUC_inf and C_max of rosiglitazone (substrate of CYP2C8 and CYP2C9) would increase by 20% and 3%, respectively, after co-administration of rosiglitazone with 40 mg asciminib twice daily. PBPK models predict that the rosiglitazone AUC_inf and C_max would increase by 24% and 2%, respectively, after co-administration of 80 mg asciminib once daily and by 66% and 8% after co-administration of 200 mg asciminib. The changes in exposure are not considered to be clinically significant.
CYP2C9 substrates: Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased the S-warfarin AUC_inf and C_max by 41% and 8%, respectively, in healthy subjects receiving 40 mg Scemblix twice daily. Co-administration of asciminib at 80 mg once daily would be expected to increase the S-warfarin AUC_inf and C_max by 52% and 4%, respectively. Co-administration of asciminib 200 mg twice daily would increase the S-warfarin AUC_inf and C_max by 314% and 7%, respectively.
Caution is required during co-administration of Scemblix at a total daily dose of 80 mg with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin (see Pharmacology: Pharmacokinetics under Actions). Scemblix dose adjustment is not required.
Co-administration of Scemblix 200 mg twice daily with CYP2C9-sensitive substrates and CYP2C9 substrates that are known to have a narrow therapeutic index should be avoided and alternative treatment options should be considered (see Pharmacology: Pharmacokinetics under Actions). If co-administration cannot be avoided, the CYP2C9 substrate dose should be reduced. If co-administration with warfarin cannot be avoided, the frequency of the international normalised ratio (INR) monitoring should be increased, as the anticoagulant effect of warfarin may be enhanced.
Substrates of OATP1B or BCRP: Co-administration of 80 mg asciminib once daily with an OATP1B, CYP3A4 and P‑gp substrate (atorvastatin) increased the atorvastatin AUC_inf and C_max by 14% and 24%, respectively, in healthy subjects. Clinically relevant interactions between Scemblix at all recommended doses and OATP1B substrates are unlikely to occur.
Using PBPK models it is predicted that co-administration of asciminib at a dosage of 40 mg twice daily or 80 mg once daily with a BCRP substrate (sulfasalazine) would increase the sulfasalazine C_max by 334% and 342% and AUC_inf by 333% and 340%, respectively, while co-administration of asciminib 200 mg twice daily would increase the sulfasalazine C_max and AUC_inf by 353% and 359%, respectively.
Using PBPK models it is predicted that co-administration of asciminib at a dosage of 40 mg twice daily or 80 mg once daily with a substrate of BCRP and OATP1B (rosuvastatin) would increase the rosuvastatin C_max by 453% and 530% and AUC_inf by 190% and 202%, respectively, while co-administration of asciminib 200 mg twice daily would increase the rosuvastatin C_max and AUC_inf by 732% and 311%, respectively.
Caution is required if Scemblix at all recommended doses is co-administered with substrates of BCRP, including, but not limited to, sulfasalazine, methotrexate, and rosuvastatin. Refer to the dose reductions for OATP1B and BCRP substrates recommended in their prescribing information.
Co-administration of Scemblix at all recommended doses with rosuvastatin should be avoided and other statins should instead be considered. If co-administration cannot be avoided, the rosuvastatin dose should be reduced as per the recommendations in its prescribing information.
P-gp substrates with a narrow therapeutic index: PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily doses with a P-gp substrate such as digoxin would increase the maximum plasma concentration (C_max) of digoxin by 30% and 38% and the area under the concentration-time curve (AUC_inf) by 20% and 22%, respectively, while co-administration of asciminib 200 mg twice daily would increase the digoxin C_max and AUC_inf by 62% and 40%, respectively.
Caution is required during co-administration of Scemblix at all recommended doses with P-gp substrates known to have a narrow therapeutic index such as digoxin, dabigatran and colchicine.
QT-prolonging agents: Caution is required during co-administration of Scemblix at a total daily dose of 80 mg and medicinal products with a known risk of torsades de pointes, including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone or moxifloxacin.
Co-administration of Scemblix 200 mg twice daily and medicinal products with a known risk of torsades de pointes should be avoided (see Pharmacology: Pharmacokinetics under Actions).
Interactions with food: The bioavailability of asciminib decreases on consumption of food (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
In vitro evaluation of the potential for drug interactions: CYP450 and UGT enzymes: In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9 and UGT1A1 at plasma concentrations reached at a total daily dose of 80 mg. In addition, asciminib reversibly inhibits CYP2C8 and CYP2C19 at plasma concentrations achieved with a twice daily dose of 200 mg.
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 in the micromolar range, respectively. Based on information from PBPK models, asciminib increases exposure to substrates of OATP1B and BCRP.
Co-administration of Scemblix with a medicinal product that is a P-gp substrate may lead to a clinically relevant increase in the plasma concentrations of P-gp substrates, with minimal concentration changes possibly leading to severe toxicities. The clinical relevance of the interaction with OCT1 is currently unknown with the twice daily dose of Scemblix 200 mg.
Multiple metabolic pathways: Asciminib is metabolised by several pathways, including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secretion by the transporter BCRP.
Medicinal products that inhibit or induce multiple metabolic pathways may alter Scemblix exposure.
Asciminib inhibits several metabolic pathways, including CYP3A4, CYP2C9, OATP1B, P-gp and BCRP. Therefore, Scemblix may increase the exposure to medicinal products that are substrates of these metabolic pathways.

Incompatibilities: Not applicable.

Do not store above 30°C. Store in the original container 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.

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