Leaflet SCEMBLIX 100mg film-coated tablets

Scemblix 20 mg film-coated tablets

Scemblix 40 mg film-coated tablets

Scemblix 100 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.

Scemblix 100 mg film-coated tablets

Each film-coated tablet contains 108.10 mg asciminib hydrochloride, equivalent to 100 mg asciminib.

Each film-coated tablet contains 216 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 100 mg film-coated tablets

Light red, round, biconvex film-coated tablets with bevelled edges of approximately 11 mm diameter,debossed with company logo on one side and “100” 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) (see section 5.1).

Scemblix is indicated for the treatment of adult patients with Ph+ CML-CP with the T315I mutationwho are resistant to, intolerant to or ineligible for ponatinib (see section 5.1).

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

Ph+ CML-CP

The recommended total daily dose of asciminib is 80 mg. Asciminib can be taken orally either as80 mg once daily at approximately the same time each day, or as 40 mg twice daily at approximately12-hour intervals (see section 4.4).

Patients switching from 40 mg twice daily to 80 mg once daily should start taking asciminib oncedaily approximately 12 hours after the last twice-daily dose, and then continue at 80 mg once daily.

Patients switching from 80 mg once daily to 40 mg twice daily should start taking asciminib twicedaily approximately 24 hours after the last once-daily dose, and then continue at 40 mg twice daily atapproximately 12-hour intervals.

The decision on the appropriate dosage regimen should be taken at the prescriber’s discretion asnecessary for the benefit of the patient.

Ph+ CML-CP with the T315I mutation in patients resistant to, intolerant to or ineligible for ponatinib

The recommended dose is 200 mg twice daily at approximately 12-hour intervals.

Use of the 100 mg film-coated tablets is restricted to patients with Ph+ CML-CP with the T315Imutation.

Once-daily dosage regimen:

If a dose is missed by less than 12 hours, it should be taken and the next dose should be taken asscheduled.

If a dose is missed by more than approximately 12 hours, it should be skipped and the next doseshould be taken as scheduled.

Twice-daily dosage regimen:

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

Ph+ CML-CP

The starting dose is 80 mg once daily or 40 mg twice daily, while the reduced dose is 40 mg oncedaily or 20 mg twice daily, respectively. The dose can be modified based on individual safety andtolerability as shown in Table 1. Asciminib should be permanently discontinued in patients unable totolerate a dose of 40 mg once daily or 20 mg twice daily.

Ph+ CML-CP with the T315I mutation in patients resistant to, intolerant to or ineligible for ponatinib

The starting dose is 200 mg twice daily, while the reduced dose is 160 mg twice daily. The dose canbe modified based on individual safety and tolerability as shown in Table 1. Asciminib should bepermanently discontinued in patients unable to tolerate a dose of 160 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 starting dose adjustment is required in patients with mild or moderate renal impairment at allrecommended doses and in patients with severe renal impairment at the 80 mg total daily dose. Noclinical data are available in patients with severe renal impairment at the 200 mg asciminib twice dailydose. Therefore, no recommendations for dose adjustment can be given. Caution should be exercisedin patients with severe renal impairment receiving the 200 mg twice daily dose (see sections 4.4and 5.2).

No starting dose adjustment is required in patients with mild or moderate hepatic impairment at allrecommended doses and in patients with severe hepatic impairment at the 80 mg total daily dose. Noclinical data are available in patients with severe hepatic impairment at the 200 mg asciminib twicedaily dose. Therefore, no recommendations for dose adjustment can be given. Caution should beexercised in patients with severe hepatic impairment receiving the 200 mg twice daily dose (seesections 4.4 and 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.

Ph+ CML-CP with the T315I mutation in patients resistant to, intolerant to or ineligible for ponatinib

In patients with Ph+ CML-CP with the T315I mutation treated with the 200 mg twice-daily dose, closemonitoring should be considered since there are uncertainties regarding a potential increase of safetyrisks compared to the 80 mg total daily dose due to the small dataset of 48 patients, of whom 34 had atreatment intensity of >90%.

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 at a total daily dose of 80 mgconcomitantly with medicinal products with known risk of torsades de pointes.

Concomitant administration of asciminib at 200 mg twice daily with medicinal products with a knownrisk of torsades de pointes should be avoided (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.

In the absence of clinical data, caution should be exercised when administering asciminib at 200 mgtwice daily in patients with severe renal impairment (see sections 4.2 and 5.2).

In the absence of clinical data, caution should be exercised when administering asciminib at 200 mgtwice daily in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Potential for lower efficacy with the 80 mg once-daily regimen compared with the 40 mg twice-dailyregimen

Equivalent efficacy of the different posologies has not been formally demonstrated in clinical studies.

Clinical, pharmacokinetic and exposure-response modelling data in patients with Ph+ CML-CPpreviously treated with two or more TKIs suggest that the 40 mg twice-daily dose regimen might bemore effective than the 80 mg once-daily dose regimen (see sections 5.1 and 5.2).

Patients with 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 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 at a total daily dose of80 mg and medicinal products with known risk of torsades de pointes, including, but not limited to,bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide.

Concomitant administration of asciminib 200 mg twice daily with medicinal products with a knownrisk of torsades de pointes should be avoided (see section 5.1).

Medicinal products that may increase asciminib plasma concentrations

Strong CYP3A4 inhibitors

Caution should be exercised during concomitant administration of asciminib at 200 mg twice dailywith strong CYP3A4 inhibitors, including, but not limited to, clarithromycin, telithromycin,troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir orsaquinavir. Dose adjustment of asciminib is not required.

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 at all recommended doseswith strong CYP3A4 inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoinor 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 at all recommended doseswith 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). Doseadjustment of asciminib is 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 at a total daily dose of80 mg with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limitedto, phenytoin or warfarin (see section 5.2). Dose adjustment of asciminib is not required.

Concomitant administration of asciminib at 200 mg twice daily with CYP2C9-sensitive substrates and

CYP2C9 substrates known to have a narrow therapeutic index should be avoided and alternativemedicines should be considered (see section 5.2). If co-administration cannot be avoided, the CYP2C9substrate dose should be reduced. If co-administration with warfarin cannot be avoided, the frequencyof international normalised ratio (INR) monitoring should be increased as the anticoagulant effect ofwarfarin may be enhanced.

Substrates of OATP1B or BCRP

Based on physiologically-based pharmacokinetic (PBPK) modelling, caution should be exercisedduring concomitant administration of asciminib at all recommended doses with BCRP substrates,including, but not limited to, sulfasalazine, methotrexate and rosuvastatin. No clinical drug interactionstudy with BCRP was performed.

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 with narrow therapeutic index

Caution should be exercised during concomitant administration of asciminib at all recommended doseswith P-gp substrates known to have a narrow therapeutic index, including, but not limited to digoxin,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.

Ph+ CML (ASCEMBL, X2101, ASC4FIRST studies)

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminibwere musculoskeletal pain (34.4%), thrombocytopenia (28.1%), fatigue (25.4%), upper respiratorytract infections (24.8%), headache (22.8%), neutropenia (21.8%), arthralgia (20.7%) and diarrhoea(20.7%).

The most common adverse reactions of ≥ grade 3 (incidence ≥5%) in patients receiving asciminibwere thrombocytopenia (16.5%), neutropenia (13.8%), increased pancreatic enzymes (9.4%) andhypertension (9.2%).

Serious adverse reactions occurred in 9.9% of patients receiving asciminib. The most frequent seriousadverse reactions (incidence ≥1%) were pleural effusion (1.6%), lower respiratory tract infections(1.6%), thrombocytopenia (1.3%), pancreatitis (1.1%) and pyrexia (1.1%).

Ph+ CML-CP with the T315I mutation in patients resistant to, intolerant to or ineligible for ponatinib(X2101 study)

The safety dataset for the 200 mg twice-daily dose is limited to 48 patients, of whom 34 had atreatment intensity of >90%.

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminibwere musculoskeletal pain (41.7%), fatigue (35.4%), increased pancreatic enzymes (31.3%), diarrhoea(27.1%), nausea (27.1%), increased hepatic enzymes (25.0%), arthralgia (25.0%), cough (22.9%),thrombocytopenia (20.8%), vomiting (20.8%) and headache (20.8%).

The most common adverse reactions of ≥grade 3 (incidence ≥5%) in patients receiving asciminib wereincreased pancreatic enzymes (22.9%), thrombocytopenia (16.7%), neutropenia (12.5%), increasedhepatic enzymes (10.4%), hypertension (8.3%), anaemia (6.3%), vomiting (6.3%) and abdominal pain(6.3%).

Serious adverse reactions occurred in 12.5% of patients receiving asciminib. The most frequentserious adverse reactions (incidence ≥1%) were abdominal pain (4.2%), vomiting (4.2%), lowerrespiratory tract infections (4.2%), constipation (2.1%), headache (2.1%), non-cardiac chest pain(2.1%) and pleural effusion (2.1%).

The overall safety profile of asciminib has been evaluated in 556 patients with Ph+ CML in chronic(CP) and accelerated (AP) phases in the pivotal phase III study A2301 (ASCEMBL) and the phase Istudy X2101, and with newly diagnosed Ph+ CML-CP in the pivotal phase III study J12301(ASC4FIRST). In ASCEMBL (N=156), patients received asciminib as monotherapy at a dose of40 mg twice daily. In X2101 (N=200), patients received asciminib as monotherapy at doses rangingfrom 10 to 200 mg twice daily and 80 to 200 mg once daily. Of these patients, 48 with the T315Imutation received asciminib 200 mg twice daily. In ASC4FIRST (N=200), patients received asciminibas monotherapy at a dose of 80 mg once daily. In the pooled dataset, the median duration of exposureto asciminib was 123.29 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

System organ class Frequencycategory Adverse reaction

Infections and infestations 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

Endocrine disorders Common Hypothyroidism6

Metabolism and nutrition Very common Dyslipidaemia7disorders 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 Hypertension8

Respiratory, thoracic and Very common Coughmediastinal disorders Common Pleural effusion, dyspnoea, non-cardiac chest pain

Pancreatic enzymes increased9, vomiting, diarrhoea,

Gastrointestinal disorders Very common nausea, abdominal pain10, constipation

Common Pancreatitis11

Hepatobiliary disorders Very common Hepatic enzyme increased

Common Blood bilirubin increased13

Skin and subcutaneous tissue Very common Rash14, pruritusdisorders Common Urticaria

Musculoskeletal and 15connective tissue disorders Very common Musculoskeletal pain , arthralgia

General disorders and Very common Fatigue16administration site conditions Common Oedema17, pyrexia18

Investigations Common Blood creatine phosphokinase increased

Uncommon Electrocardiogram QT prolonged1 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 Hypothyroidism includes hypothyroidism, autoimmune thyroiditis, blood thyroid stimulating hormoneincreased, autoimmune hypothyroidism and primary hypothyroidism.7 Dyslipidaemia includes: hypertriglyceridaemia, blood cholesterol increased, hypercholesterolaemia, bloodtriglycerides increased, hyperlipidaemia and dyslipidaemia.8 Hypertension includes: hypertension and blood pressure increased.9 Pancreatic enzymes increased includes: lipase increased, amylase increased and hyperlipasaemia.10 Abdominal pain includes: abdominal pain and abdominal pain upper.11 Pancreatitis includes: pancreatitis and pancreatitis acute.12 Hepatic enzymes increased includes: alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyltransferase increased, transaminases increased and hypertransaminasaemia.13 Blood bilirubin increased includes: blood bilirubin increased, bilirubin conjugated increased andhyperbilirubinaemia.14 Rash includes: rash, rash maculopapular and rash pruritic.15 Musculoskeletal pain includes: pain in extremity, back pain, myalgia, bone pain, musculoskeletal pain, neckpain, musculoskeletal chest pain and musculoskeletal discomfort.16 Fatigue includes: fatigue and asthenia.17 Oedema includes: oedema and oedema peripheral.18 Pyrexia includes: pyrexia and body temperature increased.

Thrombocytopenia occurred in 28.1% of patients receiving asciminib, with grade 3 and 4 reactionsreported in 7% and 9.5% of patients, respectively. Among the patients with thrombocytopenia≥ grade 3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 64.14 weeks),with median duration of any occurring reaction of 1.57 weeks (95% CI, range: 1.14 to 2 weeks). 2% ofpatients receiving asciminib permanently discontinued due to thrombocytopenia, while asciminib wastemporarily withheld in 12.6% of patients due to the adverse reaction.

Thrombocytopenia occurred in 20.8% of patients with the T315I mutation receiving asciminib, withgrade 3 and 4 reactions reported in 16.7% of patients. Among the patients with thrombocytopenia≥ grade 3, the median time to first occurrence of reactions was 8.36 weeks (range: 1.43 to38.43 weeks), with median duration of any occurring reaction of 4.29 weeks (95% CI, range: 1.71 to5.71 weeks). 2.1% of patients with the T315I mutation receiving asciminib permanently discontinueddue to thrombocytopenia, while asciminib was temporarily withheld in 6.3% of patients due to theadverse reaction.

Neutropenia occurred in 21.8% of patients receiving asciminib, with grade 3 and 4 reactions reportedin 7.6% and 6.3% of patients, respectively. Among the patients with neutropenia ≥ grade 3, the mediantime to first occurrence of reactions was 7.14 weeks (range: 0.14 to 180.14 weeks), with medianduration of any occurring reaction of 1.86 weeks (95% CI, range: 1.29 to 2 weeks). 1.3% of patientsreceiving asciminib permanently discontinued due to neutropenia, while asciminib was temporarilywithheld in 9.4% of patients due to the adverse reaction.

Neutropenia occurred in 16.7% of patients with the T315I mutation receiving asciminib, with grade 3and 4 reactions reported in 12.5% of patients. Among the patients with neutropenia ≥ grade 3, themedian time to first occurrence of reactions was 4.14 weeks (range: 0.14 to 16.57 weeks), with medianduration of any occurring reaction of 2.86 weeks (95% CI, range: 1.57 to 4.57 weeks). 2.1% ofpatients with the T315I mutation receiving asciminib permanently discontinued due to neutropenia,while asciminib was temporarily withheld in 2.1% of patients due to the adverse reaction.

Anaemia occurred in 12.9% of patients receiving asciminib, with grade 3 reactions occurring in 4.1%of patients. Among the patients with anaemia ≥ grade 3, the median time to first occurrence ofreactions was 24.14 weeks (range: 0.14 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 0.5% ofpatients due to the adverse reaction.

Anaemia occurred in 10.4% of patients with the T315I mutation receiving asciminib, with grade 3 and4 reactions reported in 6.3% of patients. Among the patients with anaemia ≥ grade 3, the median timeto first occurrence of reactions was 38.43 weeks (range: 24.14 to 131 weeks), with median duration ofany occurring reaction of 0.86 weeks (95% CI, range: 0.14 to NE [not estimable] weeks).

Pancreatic toxicity

Pancreatitis occurred in 2% of patients receiving asciminib, with grade 3 reactions occurring in 1.1%of patients. 0.5% of patients receiving asciminib permanently discontinued due to pancreatitis, whileasciminib was temporarily withheld in 1.1% of patients due to the adverse reaction. Asymptomaticelevations of serum lipase and amylase occurred in 19.8% of patients receiving asciminib, withgrade 3 and 4 reactions occurring in 7.4% and 2% of patients, respectively. Of the patients withelevation of pancreatic enzymes, asciminib was permanently discontinued in 2% of patients due to theadverse reaction.

Pancreatitis occurred in 2.1% of patients with the T315I mutation receiving asciminib. Elevations ofserum lipase and amylase occurred in 31.3% of patients with the T315I mutation receiving asciminib,with grade 3 and 4 reactions occurring in 22.9% of patients. 2.1% of patients with the T315I mutationreceiving asciminib permanently discontinued due to elevation of pancreatic enzymes, while asciminibwas temporarily withheld in 16.7% of patients due to the adverse reaction.

Electrocardiogram QT prolongation occurred in 0.9% 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 17.1% of patients receiving asciminib, with grade 3 and 4 reactions reportedin 9% and 0.2% of patients, respectively. Among the patients with hypertension ≥ grade 3, the mediantime to first occurrence of reactions was 40.14 weeks (range: 0.14 to 365 weeks). Asciminib wastemporarily withheld in 0.9% of patients due to the adverse reaction.

Hypertension occurred in 14.6% of patients with the T315I mutation receiving asciminib, with grade 3and 4 reactions reported in 8.3% of patients. Among the patients with hypertension ≥ grade 3, themedian time to first occurrence of reactions was 32.64 weeks (range: 11.14 to 277.3 weeks), withmedian duration of any occurring reaction of 7.57 weeks (95% CI, range: 2.14 to NE weeks).

In the ASCEMBL study, decrease in phosphate levels occurred as a laboratory abnormality in 17.9%(all grades) and 7.1% (grade 3/4) of 156 patients receiving asciminib at 40 mg twice daily. In the

ASC4FIRST study, decrease in phosphate levels based on normal ranges occurred as a laboratoryabnormality in 20.5% (all grades) of 200 patients receiving asciminib at 80 mg once daily.

In the X2101 study, decrease in phosphate levels occurred as a laboratory abnormality in 47.9% (allgrades) and 8.3% (grade 3/4) of 48 patients receiving asciminib at 200 mg twice daily.

Increases in ALT, AST and bilirubin levels occurred as laboratory abnormalities in 50%, 37.5% and25% (all grades) of 48 patients receiving asciminib at 200 mg twice daily, respectively. Among thesepatients, increased ALT ≥ grade 3 events and increased AST ≥ grade 3 events were reported in 8.3%and 2.1% of patients, respectively.

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, 3.64 ms (upper bound of 90% CI: 4.68 ms) for the80 mg once daily dose and 5.37 ms (upper bound of 90% CI: 6.77 ms) for the 200 mg twice-daily dose(see section 4.4).

Newly diagnosed Ph+ CML-CP

The clinical efficacy and safety of asciminib in the treatment of patients with newly diagnosed

Philadelphia chromosome-positive myeloid leukaemia in chronic phase (Ph+ CML-CP) wereevaluated 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 asciminib orinvestigator-selected tyrosine kinase inhibitors (IS TKIs). Prior to randomisation, the investigatorselected the TKI (imatinib or second-generation [2G] TKI) to be used in the event of randomisation inthe comparator arm, based on patient characteristics and comorbidities. Patients were stratifiedaccording to European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) risk group(low, intermediate, high) and pre-randomisation selection of TKI (imatinib or 2G TKI stratum).

Patients continued 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 Caucasian (53.8%), Asian (44.4%), Black (1%) and 0.7% unknown. The demographiccharacteristics 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.

The demographic characteristics were balanced across asciminib and IS TKIs, as well as across thetwo arms within the imatinib and 2G TKI strata.

Of the 405 patients, 200 received asciminib, while 201 received IS TKIs. Of the 201 patients whoreceived IS TKIs, 99 were treated with imatinib, 49 with nilotinib, 42 with dasatinib and 11 withbosutinib. Four patients did not receive any treatment.

The median duration of the randomised treatment was 26.6 months (range: 0.16 to 35.58 months) forpatients receiving asciminib and 25 months (range: 0.3 to 34.53 months) for patients receiving

IS TKIs. By 96 weeks, 81.6% of patients on asciminib and 60.3% of patients on IS TKIs were stillreceiving treatment.

The study had multiple primary objectives assessing major molecular response (MMR) at 48 weeks.

One primary objective evaluated asciminib compared to IS TKIs. The other primary objectiveevaluated asciminib compared to IS TKIs within the imatinib stratum. The key secondary objectiveevaluated MMR at 96 weeks for asciminib compared both to IS-TKIs and to IS-TKIs within theimatinib stratum. Secondary objectives evaluated MMR at 48 and 96 weeks for asciminib compared to

IS TKIs within the 2G TKI stratum.

The main efficacy outcomes from the ASC4FIRST study are summarised in Table 3.

Table 3 Efficacy results in newly diagnosed Ph+ CML-CP patients (ASC4FIRST)

IS TKIs1

Asciminib 80 mg 100-400 mg once or twice daily

Imatinib 2G TKIs Differenceonce daily All patients 2 p-value(N=204) stratum stratum (95% CI)(N=102) (N=102)

MMR rate, % (95% CI) at 48 weeks

All patients 67.66 49.02 18.88 3(N=201) (60.72, 74.07) (41.97, 56.10) (9.59, 28.17) <0.001

Imatinib stratum 69.31 40.2 29.55 4(N=101) (59.34, 78.10) (30.61, 50.37) (16.91, 42.18) <0.0012G TKIs stratum 66 57.84 8.17 Not(N=100) (55.85, 75.18) (47.66, 67.56) (-5.14, 21.47) formallytested

MMR rate, % (95% CI) at 96 weeks

All patients 74.13 51.96 22.42 3(N=201) (67.50, 80.03) (44.87, 58.99) (13.55, 31.29) <0.001

Imatinib stratum 76.24 47.06 29.68 4(N=101) (66.74, 84.14) (37.10, 57.20) (17.57, 41.79) <0.0012G TKIs stratum 72 56.86 15.14 Not(N=100) (62.13, 80.52) (46.68, 66.63) (2.32, 27.95) formallytested

Abbreviations: MMR, major molecular response (BCR::ABL1IS ≤0.1%); IS TKIs, investigator-selected tyrosine kinaseinhibitors; 2G TKIs, second-generation tyrosine kinase inhibitors; PRS TKI, pre-randomisation selection of TKI.1 IS TKIs include imatinib (400 mg once daily) and 2G TKIs, i.e. nilotinib (300 mg twice daily), dasatinib (100 mg oncedaily) or bosutinib (400 mg once daily).2 Estimated using a common risk difference stratified by PRS TKI and baseline ELTS risk groups.3 Adjusted p-value using a Cochran-Mantel-Haenszel 1-sided test stratified by PRS TKI and baseline ELTS risk groups.4 Adjusted p-value using a Cochran-Mantel-Haenszel 1-sided test stratified by baseline ELTS risk groups.

The median time to MMR in patients who received asciminib, IS TKIs, IS TKIs within the imatinibstratum 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 to 60.0 weeks) and 36.1 weeks(95% CI: 24.4 to 48.1 weeks), respectively.

MMR rates at 96 weeks by ELTS risk group in patients receiving asciminib, IS TKIs, IS TKIs withinthe imatinib stratum, and IS TKIs within the 2G TKIs stratum were: 80.3%, 64.8%, 62.5% and 67.2%for low risk, respectively; 66.1%, 35.1%, 23.3% and 48.2% for intermediate risk, respectively; 60.9%,22.7%, 12.5% and 28.6% for high risk, respectively.

By 96 weeks, MR4.0 achieved by patients receiving asciminib, IS TKIs, IS TKIs within the imatinibstratum, and IS TKIs within the 2G TKIs stratum was: 52.7%, 34.3%, 28.4% and 40.2%, respectively.

By 96 weeks, MR4.5 achieved by patients receiving asciminib, IS TKIs, IS TKIs within the imatinibstratum and IS TKIs within 2G TKIs stratum was: 36.3%, 21.6%, 15.7% and 27.5%, respectively.

The hazard ratio of time to discontinuation of study treatment due to adverse events (TTDAE) forpatients receiving asciminib versus 2G TKIs and asciminib versus imatinib is 0.46 (95% CI: 0.215,0.997) and 0.38 (95% CI: 0.178, 0.818), respectively. The probability of discontinuation due to AEsduring the first 24 months of treatment was 5.5% (95% CI: 2.9, 9.3), 13.1% (95% CI: 7.4, 20.6) and12.7% (95% CI: 7.1, 20) for patients receiving asciminib, imatinib and 2G TKIs, respectively.

Ph+ CML-CP previously treated with two or more TKIs

ASCEMBL

The clinical efficacy and safety of asciminib in the treatment of patients with Ph+ CML-CP withtreatment failure or intolerance to two or more tyrosine kinase inhibitors were evaluated in themulticentre, randomised, active-controlled and open-label phase III study ASCEMBL. Resistance tolast TKI was defined as any of the following: failure to achieve either haematological or cytogeneticresponse at 3 months; BCR::ABL1 (on the International Scale, IS) >10% at 6 months orthereafter; >65% Ph+ metaphases at 6 months or >35% at 12 months or thereafter; loss of completehaematological response (CHR), partial cytogenetic response (PCyR), complete cytogenetic response(CCyR) or major molecular response (MMR) at any time; new BCR::ABL1 mutations whichpotentially cause resistance to study medicinal product or clonal evolution in Ph+ metaphases at anytime. Intolerance to last TKI was defined as non-haematological toxicities unresponsive to optimalmanagement, or as haematological toxicities recurring after dose reduction to the lowest recommendeddose.

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 previously treated with two or more TKIs were 51.5% female and 48.5%male, with median age 52 years (range: 19 to 83 years). Of the 233 patients, 18.9% were 65 years orolder, 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 priorlines 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 4.

Table 4 Efficacy results in Ph+ CML-CP patients previously treated with two or moretyrosine kinase inhibitors (ASCEMBL)

Asciminib Bosutinib40 mg 500 mg Differencetwice daily once daily (95% CI)1 p-value

N=157 N=76

MMR rate, % (95% CI) 25.48 13.16 12.24 0.0292at 24 weeks (18.87, 33.04) (6.49, 22.87) (2.19, 22.30)

MMR rate, % (95% CI) 37.58 15.79 21.74 2at 96 weeks (29.99, 45.65) (8.43, 25.96) (10.53, 32.95) 0.001

N=1033 N=623

CCyR rate, % (95% CI) 40.78 24.19 17.30 Not formallyat 24 weeks (31.20, 50.90) (14.22, 36.74) (3.62, 30.99) tested

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).

ASC4OPT

The clinical efficacy and safety of asciminib 40 mg twice daily and 80 mg once daily in patients with

Ph+ CML-CP previously treated with two or more TKIs were evaluated in a multicentre, open-labelphase III, treatment optimisation study A2302 (ASC4OPT). In this study 169 patients wererandomised 1:1 to either 40 mg twice daily (n=85) or 80 mg once daily (n=84). The primary objectivewas to estimate overall MMR of asciminib at 48 weeks. Results are shown in Table 5.

Table 5 Efficacy results in Ph+ CML-CP patients previously treated with two or moretyrosine kinase inhibitors (ASC4OPT)

Asciminib40 mg twice Asciminib Asciminibdaily and 40 mg 80 mg Difference80 mg once twice daily once daily (95%CI)2 p-valuedaily

N=169 N=85 N=84

MMR rate, % (95% 38.46 42.35 34.52 -7.83 Not formally

CI)1 at 48 weeks (31.09, 46.24) (31.70, 53.55) (24.48, 45.69) (-22.45, 6.79) tested1 Clopper-Pearson 95% CI for response rates2 Unstratified Wald 95% CI

Ph+ CML-CP with the T315I mutation in patients resistant to, intolerant to or ineligible for ponatinib

The clinical efficacy and safety of asciminib in the treatment of patients with Ph+ CML-CP with the

T315I mutation were assessed in the first-in-human, multicentre, open-label phase I study X2101.

This study included patients with Ph+ CML-CP with the T315I mutation who received asciminib atdifferent doses. Patients (N=48) with Ph+ CML-CP with the T315I mutation received asciminib at adose of 200 mg twice daily. Of these 48 patients, 29 were previously treated with ponatinib and 19were ponatinib-naive. Patients continued treatment until unacceptable toxicity or treatment failureoccurred.

Patients with Ph+ CML-CP with the T315I mutation who received asciminib at a dose of 200 mgtwice daily (N=48) were 77.1% male and 22.9% female, with median age 57 years (range: 26 to86 years). Of these 48 patients, 33.3% were 65 years or older, while 8.3% were 75 years or older.

Patients were Caucasian (47.9%), Asian (25%) and Black (2.1%). Seventy-five percent and 25% had

ECOG performance status 0 or 1, respectively. Patients who had previously received 1, 2, 3, 4 and 5 ormore prior lines of TKIs were 16.7%, 31.3%, 35.4%, 14.6% and 2.1%, respectively. The medianduration of treatment was 181.7 weeks (range: 2 to 312 weeks).

Major molecular response (MMR) is defined as BCR::ABL1 IS ratio ≤0.1%. The MMR rate of theevaluable patients (N=45) treated with asciminib by week 24 was 30.8% (90% CI: 16.3%, 48.7%) forthe patients previously treated with ponatinib (N=26). MMR by 96 weeks was achieved in 34.6% ofthe patients previously treated with ponatinib.

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, AUCtau and Cminat steady state is 793 ng/ml (49%), 5 262 ng*h/ml (48%) and 263 ng/ml (68%), respectively, followingadministration of asciminib at the 40 mg twice-daily dose. The geometric mean (geoCV%) of Cmax,

AUCtau and Cmin at steady state is 1 781 ng/ml (23%), 15 112 ng*h/ml (28%) and 193 ng/ml (40%),respectively, following administration of asciminib at 80 mg once-daily dose. The geometric mean(geoCV%) of Cmax, AUCtau and Cmin at steady state is 5 642 ng/ml (40%), 37 547 ng*h/ml (41%) and2 715 ng/ml (58%), respectively, following administration of asciminib at the 200 mg twice-dailydose. PBPK models predict that asciminib absorption is approximately 100%, while bioavailability isapproximately 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 a high-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 theadministered 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 7 l/hour after a total daily dose of 80 mg, based onpopulation pharmacokinetic analysis. The elimination half-life of asciminib is between 7 and 15 hoursat a total daily dose of 80 mg.

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.

Evaluation of the exposure-response relationship for 40 mg twice-daily and 80 mg once-dailyregimens

Based on exposure-response modelling from study A2302 (ASC4OPT) in patients with Ph+ CML-CPpreviously treated with two or more TKIs, a 3% numerically higher MMR rate at week 48 waspredicted for 40 mg twice daily (42.6% [95% CI: 38.4, 46]) than for 80 mg once daily(39.6% [95% CI: 35.4, 43]) (see sections 4.4 and 5.1).

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 twice-daily dose. Asciminib may increase the exposure of medicinal productswhich are substrates of CYP3A4/5 and CYP2C9 (see section 4.5). In addition, asciminib reversiblyinhibits CYP2C8 and CYP2C19 at plasma concentrations reached at a 200 mg twice-daily dose.

Asciminib is a substrate of BCRP and P-gp.

Asciminib inhibits BCRP, P-gp, OATP1B and OCT1 with Ki values of 24, 22, 2 and 3 micromolar,respectively. Based on PBPK models, asciminib may increase the exposure of medicinal productswhich are substrates of P-gp and BCRP transporters. The clinical relevance of the interaction with

OCT1 is currently unknown at an asciminib 200 mg twice-daily dose.

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 (seesections 4.2 and 4.4). Population pharmacokinetic models indicate an increase in asciminib mediansteady-state AUC0-24h by 11.5% in subjects with mild to moderate renal impairment, compared tosubjects with normal 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 sections 4.2 and 4.4).

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, 8-fold or 1.7-fold higher than those achieved in patients atthe recommended dose (RD) of 40 mg twice daily, 80 mg once daily or 200 mg twice daily,respectively.

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, 80 mg once daily or200 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 andmonkeys. These changes occurred at AUC exposures either equivalent to (rats) or 8- to 18-fold (dogsand monkeys) higher than those achieved in patients at the RD of 40 mg twice daily or 80 mg oncedaily. AUC exposures were below (rats), equivalent to (dogs) or approximately 2-fold higher than(monkeys) those achieved in patients at the RD of 200 mg twice daily. These changes were fullyreversible.

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 8- to 14-fold (dogs and monkeys) higher than those achieved in patients at the

RD of 40 mg twice daily or 80 mg once daily. AUC exposures were below (rats), equivalent to (dogs)or approximately 2-fold higher than (monkeys) those achieved in patients at the RD of 200 mg twicedaily. 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- or 22-fold higher thanthose achieved in patients at the RD of 40 mg twice daily or 80 mg once daily, respectively. AUCexposures were 4-fold higher than those achieved in patients at the RD of 200 mg twice daily. Thischange 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 higher than(rats) those achieved in patients at the RD of 40 mg twice daily or at AUC exposures either equivalentto (monkeys) or 13-fold higher than (rats) those at the RD of 80 mg once daily. AUC exposures werebelow (monkeys) or 2-fold higher than (rats) those achieved in patients at the RD of 200 mg twicedaily. 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- or 5-fold higher thanthose achieved in patients at the RD of 40 mg twice daily, or 80 mg once daily, respectively, andequivalent to those achieved in patients at the RD of 200 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 or below those achieved inpatients at the RD of 40 mg twice daily or 80 mg once daily, respectively, and below those achieved inpatients at the RD of 200 mg twice daily. In rabbits, at the foetal NOAEL of 15 mg/kg/day, the AUCexposures were equivalent to or below those achieved in patients at the RD of 40 mg twice daily or80 mg once daily, respectively, and below those achieved in patients at the RD of 200 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-, 13- or 2-fold higher than those achieved in patients at the RD of 40 mg twicedaily, 80 mg once daily or 200 mg twice daily, respectively.

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-, 6- or 2-fold higher than theexposure in patients at the RD of 40 mg twice daily, 80 mg once daily or 200 mg twice daily,respectively.

Scemblix 20 mg, 40 mg and 100 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 and 100 mg film-coated tablets only

Iron oxide black (E172)

Not applicable.

Scemblix 20 mg and 40 mg film-coated tablets3 years.

Scemblix 100 mg film-coated tablets2 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 (20 mg and 40 mg film-coated tablets) or PA/alu/PVC/alu(100 mg film-coated tablets) blisters containing 10 film-coated tablets.

The following pack sizes are available:

Scemblix 20 mg film-coated tablets

Packs containing 20 or 60 film-coated tablets.

Scemblix 40 mg film-coated tablets

Packs containing 20 or 60 film-coated tablets.

Multipacks containing 180 (3 packs of 60) film-coated tablets.

Scemblix 100 mg film-coated tablets

Packs containing 60 or 120 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/1/22/1670/001-007

25 August 2022

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

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