SCEMBLIX 20mg tablets medication leaflet

Scemblix 20 mg film-coated tablets

Scemblix 40 mg film-coated tablets

Scemblix 20 mg film-coated tablets

Each film-coated tablet contains 21.62 mg asciminib hydrochloride, equivalent to 20 mg asciminib.

Each film-coated tablet contains 43 mg lactose monohydrate.

Scemblix 40 mg film-coated tablets

Each film-coated tablet contains 43.24 mg asciminib hydrochloride, equivalent to 40 mg asciminib.

Each film-coated tablet contains 86 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Scemblix 20 mg film-coated tablets

Pale yellow, round, biconvex film-coated tablets with bevelled edges of approximately 6 mmdiameter, debossed with company logo on one side and “20” on the other side.

Scemblix 40 mg film-coated tablets

Violet white, round, biconvex film-coated tablets with bevelled edges of approximately 8 mmdiameter, debossed with company logo on one side and “40” on the other side.

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

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

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

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

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

Treatment with asciminib should be continued as long as clinical benefit is observed or untilunacceptable 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 bemodified based on individual safety and tolerability as shown in Table 1. Asciminib should bepermanently 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

Adverse reaction Dose modification

Thrombocytopenia and/or neutropenia

ANC <1.0 x 109/l and/or PLT Withhold asciminib until resolved to ANC ≥1 x 109/l<50 x 109/l and/or PLT ≥50 x 109/l.

If resolved:

* Within 2 weeks: resume at starting dose.

* After more than 2 weeks: resume at reduced dose.

For recurrent severe thrombocytopenia and/or neutropenia,withhold asciminib until resolved to ANC ≥1 x 109/l and

PLT ≥50 x 109/l, then resume at reduced dose.

Asymptomatic amylase and/or lipase elevation

Elevation >2.0 x ULN Withhold asciminib until resolved to <1.5 x ULN.

* If resolved: resume at reduced dose. If events reoccur atreduced dose, permanently discontinue.

* If not resolved: permanently discontinue. Performdiagnostic tests to exclude pancreatitis.

Non-haematological adverse reactions

Grade 3 or higher1 adverse reactions Withhold asciminib until resolved to grade 1 or lower.

* If resolved: resume at a reduced dose.

* If not resolved: permanently discontinue.

ANC: absolute neutrophil count; PLT: platelets; ULN: upper limit of normal1Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03.

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

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

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

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

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

The tablets should be taken orally without food. Food consumption should be avoided for at least2 hours before and 1 hour after taking asciminib (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Thrombocytopenia, neutropenia and anaemia occurred in patients receiving asciminib. Severe (NCI

CTCAE grade 3 or 4) thrombocytopenia and neutropenia were reported during treatment withasciminib (see section 4.8). Myelosuppression was generally reversible and managed by temporarilywithholding treatment. Complete blood counts should be performed every two weeks for the first3 months of treatment and then monthly thereafter, or as clinically indicated. Patients should bemonitored for signs and symptoms of myelosuppression.

Based on the severity of thrombocytopenia and/or neutropenia, the dose should be temporarilywithheld, 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 asclinically indicated. Patients should be monitored for signs and symptoms of pancreatic toxicity. Morefrequent monitoring should be performed in patients with a history of pancreatitis. If serum lipase andamylase elevations are accompanied by abdominal symptoms, treatment should be temporarilywithheld and appropriate diagnostic tests should be considered to exclude pancreatitis (seesection 4.2).

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

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 withasciminib, and monitored during treatment as clinically indicated. Hypokalaemia andhypomagnesaemia should be corrected prior to asciminib administration and monitored duringtreatment as clinically indicated.

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

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

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

Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virusfollowing administration of other BCR::ABL1 tyrosine kinase inhibitors (TKIs). Patients should betested for HBV infection before the start of treatment with asciminib. HBV carriers who requiretreatment with asciminib should be closely monitored for signs and symptoms of active HBV infectionthroughout therapy and for several months following termination of therapy.

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

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

Medicinal products with known risk of torsades de pointes

Caution should be exercised during concomitant administration of asciminib and medicinal productswith 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

Co-administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUCinf by 15% andincreased Cmax by 9% in healthy subjects receiving a single asciminib dose of 40 mg. Co-administration of a strong CYP3A4 inducer (phenytoin) decreased asciminib AUCinf and Cmax by 34%and 22%, respectively, in healthy subjects receiving a single asciminib dose of 200 mg.

Caution should be exercised during concomitant administration of asciminib with strong CYP3A4inducers, 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 AUCinfand Cmax 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 substratesknown to have a narrow therapeutic index, including, but not limited to, the CYP3A4 substratesfentanyl, alfentanil, dihydroergotamine or ergotamine (see section 5.2). Dose adjustment of asciminibis not required.

Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUCinf and

Cmax 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 substratesknown to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin (seesection 5.2). Dose adjustment of asciminib is not required.

Substrates of OATP1B or BCRP

Based on physiologically-based pharmacokinetic (PBPK) modelling, caution should be exercisedduring concomitant administration of asciminib with BCRP substrates, including, but not limited to,sulfasalazine, methotrexate and rosuvastatin. No clinical drug interaction study with BCRP wasperformed.

Co-administration of asciminib at 80 mg once daily with an OATP1B, CYP3A4 and P-gp substrate(atorvastatin) increased atorvastatin AUCinf and Cmax by 14% and 24%, respectively, in healthysubjects. Clinically relevant interactions between Scemblix and OATP1B substrates are unlikely tooccur.

P-gp substrates of narrow therapeutic index

Based on PBPK modelling, caution should be exercised during concomitant administration ofasciminib with P-gp substrates known to have a narrow therapeutic index, including, but not limited todigoxin, dabigatran and colchicine (see section 5.2). Dose adjustment of asciminib is not required.

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

Sexually-active women of childbearing potential should use effective contraception (methods thatresult in less than 1% pregnancy rates) during treatment with asciminib and for at least 3 days afterstopping treatment.

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

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

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

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

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminibwere musculoskeletal pain (38.8%), upper respiratory tract infections (29.5%), fatigue (28.9%),thrombocytopenia (28.1%), headache (26.4%), arthralgia (24.4%), increased pancreatic enzymes(23%), diarrhoea (22.5%), abdominal pain (22.2%), rash (21.6%), hypertension (20.8%) and nausea(20.8%).

The most common adverse reactions of ≥ grade 3 (incidence ≥5%) in patients receiving asciminibwere thrombocytopenia (18.5%), neutropenia (15.7%), increased pancreatic enzymes (12.9%),hypertension (11.2%) and anaemia (5.3%).

Serious adverse reactions occurred in 13.2% of patients receiving asciminib. The most frequentserious adverse reactions (incidence ≥1%) were pleural effusion (2.5%), lower respiratory tractinfections (2.2%), thrombocytopenia (1.7%), pyrexia (1.4%), pancreatitis (1.1%), abdominal pain(1.1%), non-cardiac chest pain (1.1%) and vomiting (1.1%).

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 Istudy X2101. In ASCEMBL, patients received asciminib as monotherapy at a dose of 40 mg twicedaily. In X2101, patients received asciminib as monotherapy at doses ranging from 10 to 200 mg twicedaily and 80 to 200 mg once daily. In the pooled dataset, the median duration of exposure to asciminibwas 167 weeks (range: 0.1 to 439 weeks).

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

Frequency

System organ class Adverse reactioncategory

Very common Upper respiratory tract infection1

Common Lower respiratory tract infection2, influenza

Blood and lymphatic system Very common Thrombocytopenia3, neutropenia4, anaemia5disorders Uncommon Febrile neutropenia, pancytopenia

Immune system disorders Uncommon Hypersensitivity

Metabolism and nutrition Very common Dyslipidaemia6disorders Common Decreased appetite, hyperglycaemia

Nervous system disorders Very common Headache, dizziness

Eye disorders Common Dry eye, vision blurred

Cardiac disorders Common Palpitations

Vascular disorders Very common Hypertension7

Respiratory, thoracic and Very common Dyspnoea, coughmediastinal disorders Common Pleural effusion, non-cardiac chest pain

Pancreatic enzymes increased8, vomiting, diarrhoea,

Very common

Gastrointestinal disorders nausea, abdominal pain9

Common Pancreatitis10

Very common Hepatic enzyme increased11

Common Blood bilirubin increased12

Skin and subcutaneous tissue Very common Rash13, pruritusdisorders Common Urticaria

Musculoskeletal and

Very common Musculoskeletal pain14, arthralgiaconnective tissue disorders

General disorders and

Very common Fatigue15, oedema16, pyrexia17administration site conditions

Electrocardiogram QT prolonged, blood creatine

Investigations Commonphosphokinase increased1 Upper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, pharyngitis andrhinitis.2 Lower respiratory tract infections include: pneumonia, bronchitis and tracheobronchitis.3 Thrombocytopenia includes: thrombocytopenia and platelet count decreased.4 Neutropenia includes: neutropenia and neutrophil count decreased.5 Anaemia includes: anaemia, haemoglobin decreased and normocytic anaemia.6 Dyslipidaemia includes: hypertriglyceridaemia, blood cholesterol increased, hypercholesterolaemia, bloodtriglycerides increased, hyperlipidaemia and dyslipidaemia.7 Hypertension includes: hypertension and blood pressure increased.8 Pancreatic enzymes increased includes: lipase increased, amylase increased and hyperlipasaemia.9 Abdominal pain includes: abdominal pain and abdominal pain upper.10 Pancreatitis includes: pancreatitis and pancreatitis acute.11 Hepatic enzymes increased includes: alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyltransferase increased, transaminases increased and hypertransaminasaemia.12 Blood bilirubin increased includes: blood bilirubin increased, bilirubin conjugated increased andhyperbilirubinaemia.13 Rash includes: rash, rash maculopapular and rash pruritic.14 Musculoskeletal pain includes: pain in extremity, back pain, myalgia, bone pain, musculoskeletal pain, neckpain, musculoskeletal chest pain and musculoskeletal discomfort.15 Fatigue includes: fatigue and asthenia.16 Oedema includes: oedema and oedema peripheral.17 Pyrexia includes: pyrexia and body temperature increased.

Thrombocytopenia occurred in 28.1% of patients receiving asciminib, with grade 3 and 4 reactionsreported 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 6.14 weeks (range: 0.14 to64.14 weeks), with median duration of any occurring reaction of 2 weeks (95% CI, range: 1.43 to2 weeks). 2.5% of patients receiving asciminib permanently discontinued due to thrombocytopenia,while asciminib was temporarily withheld in 12.4% of patients due to the adverse reaction.

Neutropenia occurred in 19.7% of patients receiving asciminib, with grade 3 and 4 reactions reportedin 7.3% and 8.4% of patients, respectively. Among the patients with neutropenia ≥ grade 3, the mediantime to first occurrence of reactions was 6.14 weeks (range: 0.14 to 180.1 weeks), with medianduration of any occurring reaction of 2 weeks (95% CI, range: 1.43 to 2.14 weeks). 1.7% of patientsreceiving asciminib permanently discontinued due to neutropenia, while asciminib was temporarilywithheld in 9.3% of patients due to the adverse reaction.

Anaemia occurred in 13.2% 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 ofreactions was 30.43 weeks (range: 0.43 to 207 weeks), with median duration of any occurring reactionof 0.86 weeks (95% CI, range: 0.29 to 1.71 weeks). Asciminib was temporarily withheld in 0.6% ofpatients 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 receivingasciminib permanently discontinued due to pancreatitis, while asciminib was temporarily withheld in1.4% of patients due to the adverse reaction. Asymptomatic elevations of serum lipase and amylaseoccurred in 23% of patients receiving asciminib, with grade 3 and 4 reactions occurring in 10.4% and2.5% of patients, respectively. Of the patients with elevation of pancreatic enzymes, asciminib waspermanently discontinued in 2.2% of patients due to the adverse reaction.

Electrocardiogram QT prolongation occurred in 1.1% 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 QTcFwith more than 60 ms QTcF increase from baseline.

Hypertension occurred in 20.8% of patients receiving asciminib, with grade 3 and 4 reactions reportedin 11% and 0.3% of patients, respectively. Among the patients with hypertension ≥ grade 3, themedian time to first occurrence of reactions was 29.21 weeks (range: 0.14 to 365 weeks). Asciminibwas temporarily withheld in 0.8% of patients due to the adverse reaction.

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 at 40 mg twice daily.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, asciminib has been administered at doses up to 280 mg twice daily with noevidence of increased toxicity.

General supportive measures and symptomatic treatment should be initiated in cases of suspectedoverdose.

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

Asciminib is a potent inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.

In vitro, asciminib inhibits the tyrosine kinase activity of ABL1 at mean IC50 values below3 nanomolar. In patient-derived cancer cells, asciminib specifically inhibits the proliferation of cellsharbouring BCR::ABL1 with IC50 values between 1 and 25 nanomolar. In cells engineered to expresseither the wild-type or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth withmean 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 tumoursharbouring either the wild-type or the T315I mutant form of BCR::ABL1, with tumour regressionbeing observed at doses above 7.5 mg/kg or 30 mg/kg twice daily, respectively.

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 twicedaily 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.

Ph+ CML-CP

The clinical efficacy and safety of asciminib in the treatment of patients with Philadelphiachromosome-positive myeloid leukaemia in chronic phase (Ph+ CML-CP) with treatment failure orintolerance 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 asany 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 at6 months or >35% at 12 months or thereafter; loss of complete haematological response (CHR), partialcytogenetic response (PCyR), complete cytogenetic response (CCyR) or major molecular response(MMR) at any time; new BCR::ABL1 mutations which potentially cause resistance to study medicinalproduct or clonal evolution in Ph+ metaphases at any time. Intolerance to last TKI was defined asnon-haematological toxicities unresponsive to optimal management, or as haematological toxicitiesrecurring 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 majorcytogenetic 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 V299Lmutations at any time prior to study entry were not included in ASCEMBL. Patients continuedtreatment 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: 19to 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% and18% 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 156 weeks (range: 0.1 to 256.3 weeks) forpatients receiving asciminib and 30.5 weeks (range: 1 to 239.3 weeks) for patients receiving bosutinib.

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 endpointswere CCyR rate at 24 and 96 weeks, defined as no Philadelphia-positive metaphases in bone marrowwith 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)

Asciminib Bosutinib

Difference40 mg 500 mg p-value(95% CI)1twice daily once daily

N=157 N=7612.24

MMR rate, % (95% CI) 25.48 13.16 0.0292(2.19, 22.30)at 24 weeks (18.87, 33.04) (6.49, 22.87)

MMR rate, % (95% CI) 37.58 15.79 21.740.0012at 96 weeks (29.99, 45.65) (8.43, 25.96) (10.53, 32.95)

N=1033 N=62317.30 Not formally

CCyR rate, % (95% CI) 40.78 24.19(3.62, 30.99) testedat 24 weeks (31.20, 50.90) (14.22, 36.74)

CCyR rate, % (95% CI) 39.81 16.13 23.87 Not formallyat 96 weeks (30.29, 49.92) (8.02, 27.67) (10.3, 37.43) tested1 On adjustment for the baseline major cytogenetic response status2 Cochran-Mantel-Haenszel two-sided test stratified by baseline major cytogenetic response status3 CCyR analysis based on patients who were not in CCyR at baseline

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

In ASCEMBL, 12.7% of patients treated with asciminib and 13.2% of patients receiving bosutinib hadone 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 withor without any mutation at baseline, respectively. The MMR rate at 24 weeks in patients in whom therandomised treatment represented the third, fourth, or fifth or more line of TKI was 29.3%, 25%, and16.1% 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 atleast 120 weeks was 97% (95% CI: 88.6, 99.2).

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 informationon paediatric use).

Asciminib is rapidly absorbed, with median maximum plasma level (Tmax) reached 2 to 3 hours afteroral administration, independent of the dose. The geometric mean (geoCV%) of Cmax and AUCtau atsteady state is 793 ng/ml (49%) and 5 262 ng*h/ml (48%), respectively, following administration ofasciminib at the 40 mg twice-daily dose. PBPK models predict that asciminib absorption isapproximately 100%, while bioavailability is approximately 73%.

Asciminib bioavailability may be reduced by co-administration of oral medicinal products containinghydroxypropyl-β-cyclodextrin as an excipient. Co-administration of multiple doses of an itraconazoleoral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose ofasciminib decreased asciminib AUCinf by 40.2% in healthy subjects.

Food consumption decreases asciminib bioavailability, with a high-fat meal having a higher impact onasciminib pharmacokinetics than a low-fat meal. Asciminib AUC is decreased by 62.3% with ahigh-fat meal and by 30% with a low-fat meal compared to the fasted state (see section 4.2).

Asciminib apparent volume of distribution at steady state is 111 litres based on populationpharmacokinetic analysis. Asciminib is mainly distributed to plasma, with a mean blood-to-plasmaratio of 0.58, independent of the dose based on in vitro data. Asciminib is 97.3% bound to humanplasma proteins, independent of the dose.

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).

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 healthysubjects, respectively, following oral administration of a single 80 mg dose of [14C]-labelledasciminib. 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 after 40 mg twice daily, based onpopulation pharmacokinetic analysis. The elimination half-life of asciminib is between 7 and 15 hoursat 40 mg twice daily.

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 achievedwithin 3 days at the 40 mg twice-daily dose.

In vitro evaluation of drug interaction potential

Asciminib is metabolised by several pathways, including the CYP3A4, UGT2B7 and UGT2B17enzymes, and biliary secreted by the transporter BCRP. Medicinal products inhibiting or inducing the

CYP3A4, UGT and/or BCRP pathways may alter asciminib exposure.

CYP450 and UGT enzymes

In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9 and UGT1A1 at plasma concentrationsreached at a 40 mg twicedaily dose. Asciminib may increase the exposure of medicinal products whichare substrates of CYP3A4/5 and CYP2C9 (see section 4.5).

Asciminib is a substrate of BCRP and P-gp.

Asciminib inhibits BCRP, P-gp and OATP1B with Ki values of 24, 22 and 2 micromolar, respectively.

Based on PBPK models, asciminib may increase the exposure of medicinal products which aresubstrates of P-gp and BCRP transporters.

Gender, race, body weight

Asciminib systemic exposure is not affected by gender, race or body weight to any clinically relevantextent.

A dedicated renal impairment study including 6 subjects with normal renal function (absoluteglomerular filtration rate [aGFR] ≥90 ml/min) and 8 subjects with severe renal impairment notrequiring dialysis (aGFR 15 to <30 ml/min) has been conducted. Asciminib AUCinf and Cmax wereincreased by 56% and 8%, respectively, in subjects with severe renal impairment compared to subjectswith normal renal function, following oral administration of a single 40 mg dose of asciminib (seesection 4.2). Population pharmacokinetic models indicate an increase in asciminib median steady-state

AUC0-24h by 11.5% in subjects with mild to moderate renal impairment, compared to subjects withnormal renal function.

A dedicated hepatic impairment study including 8 subjects each with normal hepatic function, mildhepatic 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 AUCinf wasincreased 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 asingle 40 mg dose of asciminib (see section 4.2).

Safety pharmacology

Moderate cardiovascular effects (increased heart rate, decreased systolic pressure, decreased meanarterial pressure, and decreased arterial pulse pressure) were observed in in vivo cardiac safety studiesin dogs, likely at AUC exposures 12-fold higher than those achieved in patients at the recommendeddose (RD) of 40 mg twice daily.

Pancreatic effects (serum amylase and lipase increases, acinar cell lesions) occurred in dogs at AUCexposures below those achieved in patients at the RD of 40 mg twice daily. A trend towards recoverywas 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 andmonkeys. These changes occurred at AUC exposures either equivalent to (rats) or 12- to 18-fold (dogsand 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 bonemarrow pigment and increased reticulocytes) were consistent with a mild and regenerative,extravascular, haemolytic anaemia in all species. These changes occurred at AUC exposures eitherequivalent to (rats) or 12- to 14-fold (dogs and monkeys, respectively) higher than those achieved inpatients at the RD of 40 mg twice daily. These changes were fully reversible.

Minimal mucosal hypertrophy/hyperplasia (increase in thickness of the mucosa with frequentelongation of villi) was present in the duodenum of rats at AUC exposures 30-fold higher than thoseachieved 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 thezona fasciculata occurred at AUC exposures either equivalent to (monkeys) or 19-fold (rats) higherthan those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.

Asciminib did not have mutagenic, clastogenic or aneugenic potential either in vitro nor in vivo.

In a 2-year rat carcinogenicity study, non-neoplastic proliferative changes consisting of ovarian Sertolicell hyperplasia were observed in female animals at doses equal to or above 30 mg/kg/day. Benign

Sertoli cell tumours 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 higher than thoseachieved in patients at the dose of 40 mg twice daily.

The clinical relevance of these findings is currently unknown.

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

In embryo-foetal development studies, a slight increase in foetal malformations (anasarca and cardiacmalformations) and increased visceral and skeletal variants were observed in rats. Increased incidenceof resorptions indicative of embryo-foetal mortality and a low incidence of cardiac malformationsindicative of teratogenicity were observed in rabbits. In rats, at the foetal no observed adverse effectlevel (NOAEL) of 25 mg/kg/day, the AUC exposures were equivalent to those achieved in patients atthe RD of 40 mg twice daily. In rabbits, at the foetal NOAEL of 15 mg/kg/day, the AUC exposureswere 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. Aslight effect on male sperm motility and sperm count was observed at doses of 200 mg/kg/day, likelyat 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.

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 Cmax in plasma was 15-fold higher than the exposure inpatients 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.

3 years.

Do not store above 25°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.

Scemblix 40 mg film-coated tablets are also available in multipacks containing 180 (3 packs of 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 localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/22/1670/001-005

25 August 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.