Scemblix is indicated for the treatment of adult patients with Philadelphia chromosome‑positive chronic myeloid leukaemia in chronic phase (Ph+ CML‑CP) previously treated with two or more tyrosine kinase inhibitors (see section 5.1).

Treatment should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia.

Posology

The recommended dose is 40 mg twice daily at approximately 12‑hour intervals.

Missed dose

If a dose is missed by less than 6 hours, it should be taken and the next dose should be taken as scheduled.

If a dose is missed by more than approximately 6 hours, it should be skipped and the next dose should be taken as scheduled.

Treatment duration

Treatment with asciminib should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

Dose adjustments for adverse reactions

The starting dose is 40 mg twice daily, while the reduced dose is 20 mg twice daily. The dose can be modified based on individual safety and tolerability as shown in Table 1. Asciminib should be permanently discontinued in patients unable to tolerate a dose of 20 mg twice daily.

Table 1       Asciminib dose modification schedule for the management of adverse reactions

Special populations

Elderly

No dose adjustment is required in patients aged 65 years or above.

Renal impairment

No dose adjustment is required in patients with mild, moderate or severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild, moderate or severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Scemblix in paediatric patients aged below 18 years have not been established. No data are available.

Method of administration

Scemblix is for oral use. The film‑coated tablets should be swallowed whole with a glass of water and should not be broken, crushed or chewed.

The tablets should be taken orally without food. Food consumption should be avoided for at least 2 hours before and 1 hour after taking asciminib (see section 5.2).

Myelosuppression

Thrombocytopenia, neutropenia and anaemia occurred in patients receiving asciminib. Severe (NCI CTCAE grade 3 or 4) thrombocytopenia and neutropenia were reported during treatment with asciminib (see section 4.8). Myelosuppression was generally reversible and managed by temporarily withholding treatment. Complete blood counts should be performed every two weeks for 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 dose should be temporarily withheld, reduced or permanently discontinued as described in Table 1 (see section 4.2).

Pancreatic toxicity

Pancreatitis and asymptomatic elevations of serum lipase and amylase, including severe reactions, occurred in patients receiving asciminib (see section 4.8).

Serum lipase and amylase levels should be assessed monthly during treatment with asciminib, 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 elevations are accompanied by abdominal symptoms, treatment should be temporarily withheld and appropriate diagnostic tests should be considered to exclude pancreatitis (see section 4.2).

Based on the severity of serum lipase and amylase elevations, the dose should be temporarily withheld, reduced or permanently discontinued as described in Table 1 (see section 4.2).

QT prolongation

QT prolongation occurred in patients receiving asciminib (see section 4.8).

It is recommended that an electrocardiogram is performed prior to the start of treatment with asciminib, and monitored during treatment as clinically indicated. Hypokalaemia and hypomagnesaemia should be corrected prior to asciminib administration and monitored during treatment as clinically indicated.

Caution should be exercised when administering asciminib concomitantly with medicinal products with known risk of torsades de pointes (see sections 4.5 and 5.1).

Hypertension

Hypertension, including severe hypertension, occurred in patients receiving asciminib (see section 4.8).

Hypertension and other cardiovascular risk factors should be monitored regularly and managed using the standard therapies during treatment with asciminib.

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. HBV carriers who require treatment with asciminib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film‑coated tablet, that is to say essentially “sodium‑free”.

Medicinal products with known risk of torsades de pointes

Caution should be exercised during concomitant administration of asciminib and medicinal products with known risk of torsades de pointes, including, but not limited to, bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide (see section 5.1).

Medicinal products that may decrease asciminib plasma concentrations

Strong CYP3A4 inducers

Co‑administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUC_inf by 15% and increased C_max by 9% in healthy subjects receiving a single asciminib dose of 40 mg.

Caution should be exercised during concomitant administration of asciminib with strong CYP3A4 inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoin or St. John’s wort (Hypericum perforatum), which may result in lower efficacy of asciminib.

Medicinal products 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 40 mg twice daily.

Caution should be exercised during concomitant administration of asciminib with CYP3A4 substrates known to have a narrow therapeutic index, including, but not limited to, the CYP3A4 substrates fentanyl, alfentanil, dihydroergotamine or ergotamine (see section 5.2). Dose adjustment of asciminib 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 40 mg twice daily.

Caution should be exercised during concomitant administration of asciminib with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin (see section 5.2). Dose adjustment of asciminib is not required.

Women of childbearing potential/Contraception

The pregnancy status of women of childbearing potential should be verified prior to starting treatment with asciminib.

Sexually‑active women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with asciminib and for at least 3 days after stopping treatment.

Pregnancy

There are no or limited amount of data from the use of asciminib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Asciminib is not recommended during pregnancy and in women of childbearing potential not using contraception. The patient should be advised of a potential risk to the foetus if asciminib is used during pregnancy or if the patient becomes pregnant while taking asciminib.

Breast‑feeding

It is unknown whether asciminib/metabolites are excreted in human milk. There are no data on the effects of asciminib on the breast‑fed newborn/infant or on milk production. Because of the potential for serious adverse reactions in the breast‑fed newborn/infant, breast‑feeding should be discontinued during treatment and for at least 3 days after stopping treatment with asciminib.

Fertility

There are no data on the effect of asciminib on human fertility. In rat fertility studies, asciminib did not affect reproductive function in male and female rats. However, adverse effects on sperm motility and count were observed in rats at doses of 200 mg/kg/day (see section 5.3). The relevance for humans is not known.

Asciminib has no or negligible influence on the ability to drive and use machines. However, it is recommended that patients experiencing dizziness, fatigue or other undesirable effects (see section 4.8) with a potential impact on the ability to drive or use machines safely should refrain from these activities as long as the undesirable effects persist.

Summary of the safety profile

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminib were musculoskeletal pain (37.1%), upper respiratory tract infections (28.1%), thrombocytopenia (27.5%), fatigue (27.2%), headache (24.2%), arthralgia (21.6%), increased pancreatic enzymes (21.3%), abdominal pain (21.3%), diarrhoea (20.5%) and nausea (20.2%).

The most common adverse reactions of ≥ grade 3 (incidence ≥5%) in patients receiving asciminib were thrombocytopenia (18.5%), neutropenia (15.7%), increased pancreatic enzymes (12.4%), hypertension (8.7%) and anaemia (5.3%).

Serious adverse reactions occurred in 12.4% of patients receiving asciminib. The most frequent serious adverse reactions (incidence ≥1%) were pleural effusion (2.5%), lower respiratory tract infections (2.2%), thrombocytopenia (1.7%), pyrexia (1.4%), pancreatitis (1.1%), non‑cardiac chest pain (1.1%) and vomiting (1.1%).

Tabulated list of adverse reactions

The overall safety profile of asciminib has been evaluated in 356 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases in the pivotal phase III study A2301 (ASCEMBL) and the phase I study X2101. In ASCEMBL, patients received asciminib as monotherapy at a dose of 40 mg twice daily. In X2101, patients received asciminib as monotherapy 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 was 116 weeks (range: 0.1 to 342 weeks).

Adverse reactions from clinical studies (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on 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).

Table 2       Adverse reactions observed with asciminib in clinical studies

Description of selected adverse reactions

Myelosuppression

Thrombocytopenia occurred in 27.5% of patients receiving asciminib, with grade 3 and 4 reactions reported in 6.7% and 11.8% 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 weeks), with median duration of any occurring reaction of 1.71 weeks (95% CI, range: 1.43 to 2 weeks). 2% of patients receiving asciminib permanently discontinued due to thrombocytopenia, while asciminib was temporarily withheld in 12.6% of patients due to the adverse reaction.

Neutropenia occurred in 19.4% of patients receiving asciminib, with grade 3 and 4 reactions reported in 7.3% and 8.4% of patients, respectively. Among the patients with neutropenia ≥ grade 3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 180 weeks), with median duration of any occurring reaction of 1.79 weeks (95% CI, range: 1.29 to 2 weeks). 1.1% of patients receiving asciminib permanently discontinued due to neutropenia, while asciminib was temporarily withheld in 9.6% of patients due to the adverse reaction.

Anaemia occurred in 12.9% of patients receiving asciminib, with grade 3 reactions occurring in 5.3% of patients. Among the patients with anaemia ≥ grade 3, the median time to first occurrence of reactions was 30 weeks (range: 0.4 to 207 weeks), with median duration of any occurring reaction of 0.9 weeks (95% CI, range: 0.43 to 2.14 weeks). Asciminib was temporarily withheld in 0.6% of patients due to the adverse reaction.

Pancreatic toxicity

Pancreatitis occurred in 2.5% of patients receiving asciminib, with grade 3 reactions occurring in 1.1% of patients. All these reactions occurred in the phase I study (X2101). 0.6% of patients receiving asciminib permanently discontinued due to pancreatitis, while asciminib was temporarily withheld in 1.1% of patients due to the adverse reaction. Asymptomatic elevations of serum lipase and amylase occurred in 21.3% of patients receiving asciminib, with grade 3 and 4 reactions occurring in 10.1% and 2.2% of patients, respectively. Of the patients with elevation of pancreatic enzymes, asciminib was permanently discontinued in 2.2% of patients due to the adverse reaction.

QT prolongation

Electrocardiogram QT prolongation occurred in 0.8% of patients receiving asciminib. In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 milliseconds (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.

Hypertension

Hypertension occurred in 18.5% of patients receiving asciminib, with grade 3 and 4 reactions reported in 8.4% and 0.3% of patients, respectively. Among the patients with hypertension ≥ grade 3, the median time to first occurrence of reactions was 14 weeks (range: 0.1 to 156 weeks). Asciminib was temporarily withheld in 0.8% of patients due to the adverse reaction.

Laboratory abnormalities

Decrease in phosphate levels occurred as a laboratory abnormality in 17.9% (all grades) and 6.4% (grade 3/4) of 156 patients receiving asciminib at 40 mg twice daily.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

To report any side effect(s):

·         Saudi Arabia

-          The National Pharmacovigilance Centre (NPC):

o Fax: +966-11-205-7662

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

In clinical studies, asciminib 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.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EA06

Mechanism of action

Asciminib is a 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.

Pharmacodynamic effects

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 engineered to express either 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 tumours harbouring either the wild‑type 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

Asciminib treatment is associated with an exposure‑related prolongation of the QT interval.

The correlation between asciminib concentration and the estimated 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 asciminib 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 asciminib 40 mg twice‑daily dose. See section 4.4.

Clinical efficacy and safety

Ph+ CML‑CP

The clinical efficacy and safety of asciminib in the treatment of patients with Philadelphia chromosome‑positive myeloid leukaemia in chronic phase (Ph+ CML‑CP) with treatment failure or intolerance to two or more tyrosine kinase inhibitors were evaluated in the multicentre, randomised, active‑controlled and open‑label phase III study ASCEMBL. Resistance to last TKI was defined as any of the following: failure to achieve either haematological or cytogenetic response at 3 months; BCR::ABL1 (on the International Scale, IS) >10% at 6 months or thereafter; >65% Ph+ metaphases at 6 months or >35% at 12 months or thereafter; loss of complete haematological response (CHR), partial cytogenetic response (PCyR), complete cytogenetic response (CCyR) or major molecular response (MMR) at any time; new BCR::ABL1 mutations which potentially cause resistance to study medicinal product or clonal evolution in Ph+ metaphases at any time. Intolerance to last TKI was defined as non‑haematological toxicities unresponsive to optimal management, 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 to receive either asciminib 40 mg twice daily (N=157) or bosutinib 500 mg once daily (N=76). Patients with known presence of T315I and/or V299L mutations at any time prior to study entry were not included in ASCEMBL. Patients continued treatment until unacceptable toxicity or treatment failure occurred.

Patients with Ph+ CML‑CP 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 the randomised treatment was 103 weeks (range: 0.1 to 201 weeks) for patients receiving asciminib and 31 weeks (range: 1 to 188 weeks) for patients receiving bosutinib.

Results

The primary endpoint of the study was MMR rate at 24 weeks and the key secondary endpoint was MMR rate at 96 weeks. MMR is defined as BCR::ABL1 IS ratio ≤0.1%. Other secondary endpoints were CCyR rate at 24 and 96 weeks, defined as no Philadelphia‑positive metaphases in bone marrow with a minimum of 20 metaphases examined.

The main efficacy outcomes from the ASCEMBL study are summarised in Table 3.

Table 3       Efficacy results in patients treated with two or more tyrosine kinase inhibitors (ASCEMBL)

The primary and key secondary endpoints were the only ones formally tested for statistical significance according to protocol.

In ASCEMBL, 12.7% of patients treated with asciminib 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 asciminib 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 randomised treatment represented the third, fourth, or fifth or more line of TKI was 29.3%, 25%, and 16.1% in patients treated with asciminib and 20%, 13.8%, and 0% in patients receiving bosutinib, respectively.

The Kaplan‑Meier estimated proportion of patients receiving asciminib and maintaining MMR for at least 72 weeks was 96.7% (95% CI: 87.4, 99.2).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Scemblix in one or more subsets of the paediatric population in CML (see section 4.2 for information on paediatric use).

Absorption

Asciminib is rapidly absorbed, with median maximum plasma level (Tmax) reached 2 to 3 hours after oral administration, independent of the dose. The geometric mean (geoCV%) of Cmax and AUCtau at steady state is 793 ng/ml (49%) and 5262 ng*h/ml (48%), respectively, following administration of asciminib at the 40 mg twice‑daily dose. PBPK models predict that 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 an itraconazole oral solution containing hydroxypropyl‑β‑cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib decreased asciminib AUCinf 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 (see section 4.2).

Distribution

Asciminib apparent volume of distribution at steady state is 111 litres 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 based on in vitro data. Asciminib is 97.3% bound to human plasma proteins, independent of the dose.

Biotransformation

Asciminib is primarily metabolised via CYP3A4‑mediated oxidation, and UGT2B7‑ and UGT2B17‑mediated glucuronidation. Asciminib is the main circulating component in plasma (92.7% of the administered dose).

Elimination

Asciminib is mainly eliminated via faecal excretion, with a minor contribution of the renal route. Eighty and 11% of the asciminib dose were recovered in the faeces and in the 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 breast cancer‑resistant protein (BCRP).

The oral total clearance (CL/F) of asciminib is 6.31 l/hour, based on population pharmacokinetic analysis. The elimination half‑life of asciminib is 5.2 hours at 40 mg twice daily.

Linearity/non‑linearity

Asciminib exhibits a slight dose over‑proportional increase in steady‑state exposure (AUC and Cmax) across the dose range of 10 to 200 mg administered once or twice daily.

The geometric mean accumulation ratio is approximately 2‑fold. 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 UGT1A1 at plasma concentrations reached at a 40 mg twice‑daily dose.

Transporters

Asciminib is a substrate of BCRP and P‑gp.

Asciminib inhibits BCRP and P‑gp with Ki values of 24.3 and 21.7 micromolar, respectively.

Multiple pathways

Asciminib is metabolised by several pathways, including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secreted by the transporter BCRP. Medicinal products inhibiting or inducing CYP3A4, UGT and BCRP pathways may alter asciminib exposure.

Special populations

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 were 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 (see section 4.2). Population pharmacokinetic 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 5‑6), moderate hepatic impairment (Child‑Pugh B score 7‑9) or severe hepatic impairment (Child‑Pugh C score 10‑15) was conducted. Asciminib AUC_inf was 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 (see section 4.2).

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, likely at AUC exposures 12‑fold higher than those achieved in patients at the recommended dose (RD) of 40 mg twice daily.

Repeat dose toxicity

Pancreatic effects (serum amylase and lipase increases, acinar cell lesions) occurred in dogs at AUC exposures below those achieved in patients at the RD of 40 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 12‑ to 18‑fold (dogs and monkeys, respectively) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.

Effects on the haematopoietic system (reduction in red blood cell mass, increased splenic or bone marrow pigment and increased reticulocytes) were consistent with a mild and regenerative, extravascular, haemolytic anaemia in all species. These changes occurred at AUC exposures either equivalent to (rats) or 12‑ to 14‑fold (dogs and monkeys, respectively) higher than those achieved in patients at the RD of 40 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 higher than those achieved in patients at the RD of 40 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‑fold (rats) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.

Carcinogenicity and mutagenicity

Asciminib did not have mutagenic, clastogenic or aneugenic potential either in vitro nor in vivo. Carcinogenicity studies have not been conducted with asciminib.

Reproductive toxicity

Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity.

In embryo‑foetal development studies, a slight increase in foetal malformations (anasarca and cardiac malformations) and increased visceral and skeletal variants were observed in rats. 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 no observed adverse effect level (NOAEL) of 25 mg/kg/day, the AUC exposures were equivalent to those achieved in patients at the RD of 40 mg twice daily. In rabbits, at the foetal NOAEL of 15 mg/kg/day, the AUC exposures were equivalent to those achieved in patients at the RD of 40 mg twice daily.

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 higher than those achieved in patients at the RD of 40 mg twice daily.

A pre‑ and postnatal developmental toxicity study was not performed.

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 higher than the exposure in patients at the RD of 40 mg twice daily.

Scemblix 20 mg and 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

Lecithin (E322)

Xanthan gum (E415)

Iron oxide red (E172)

Scemblix 20 mg film‑coated tablets only

Iron oxide yellow (E172)

Scemblix 40 mg film‑coated tablets only

Iron oxide black (E172)

Not applicable.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Scemblix is supplied in PCTFE/PVC/Alu blisters containing 10 film‑coated tablets.

The following pack sizes are available:

Packs containing 20 or 60 film‑coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.