4.1. Therapeutic indications

Scemblix is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph + CML) in chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors, and without a known T315I mutation.

4.2. Posology and method of administration

Treatment with Scemblix should be initiated by a physician knowledgeable in the diagnosis and treatment of patients with chronic myeloid leukaemia.

Posology

The recommended total daily dose of Scemblix is 80 mg. Scemblix can be taken orally either as 80 mg once daily at approximately the same time each day or as 40 mg twice daily at approximately 12-hour intervals.

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

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

Any change in the dosage regimen is at the prescriber's discretion, as necessary for the management of the patient.

Missed dose

Once-daily dosage regimen: If a dose is missed by more than approximately 12 hours, it should be skipped and the next dose should be taken as scheduled.

Twice-daily dosage regimen: If a dose is missed by more than approximately 6 hours, it should be skipped and the next dose should be taken as scheduled.

Treatment duration

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

Dose adjustments for adverse reactions

For the management of adverse reactions, the dose can be reduced based on individual safety and tolerability, as described in Table 1.

If adverse reactions are effectively managed, asciminib may be resumed as described in Table 1. It should be permanently discontinued in patients unable to tolerate a total daily dose of 40 mg.

Table 1 Asciminib dose modification

Starting dose

Reduced dose

Resumed dose

80 mg once daily

40 mg once daily

80 mg once daily

40 mg twice daily

20 mg twice daily

40 mg twice daily

The recommended dosage modification for the management of selected adverse reactions is shown in Table 2.

Table 2 Asciminib dose modification schedule for the management of adverse reactions

Adverse reaction

Dosage modification

Thrombocytopenia and/or neutropenia

ANC <1.0 x 109/l and/or PLT

<50 x 109/l

Withhold asciminib until resolved to ANC ≥1 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 at reduced dose, permanently discontinue.

• If not resolved: permanently discontinue. Perform diagnostic tests to exclude pancreatitis.

Non-haematological adverse reactions

Grade 3 or higher adverse reactions1

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 normal

1Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03.

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

No dose adjustment is required in patients with mild, moderate or severe hepatic impairment (see section 5.2). Since there are no data available in patients with moderate or severe hepatic impairment, caution should be exercised in these patients (see section 4.8 and 5.2).

Paediatric population

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

Method of administration

Scemblix is for oral use. The tablets should be taken orally without food. Food consumption should be avoided for at least 2 hours before and 1 hour after taking asciminib (see sections 4.5 and 5.2).

The film-coated tablets should be swallowed whole with a glass of water and should not be broken, crushed or chewed.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Myelosuppression

Thrombocytopenia, neutropenia and anaemia occurred in patients receiving asciminib. Severe (NCI CTCAE grade 3 or 4) thrombocytopenia and neutropenia were reported during treatment with asciminib (see section 4.8). Myelosuppression was generally reversible and managed by temporarily withholding treatment. Complete blood counts should be performed every two weeks for the first 3 months of treatment and then monthly thereafter, or as clinically indicated. Patients should be monitored for signs and symptoms of myelosuppression.

Based on the severity of thrombocytopenia and/or neutropenia, the dose should be temporarily withheld, reduced or permanently discontinued (see section 4.2).

Pancreatic toxicity

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

Serum lipase and amylase levels should be assessed monthly during treatment with asciminib, or as clinically indicated. Patients should be monitored for signs and symptoms of pancreatic toxicity. More frequent monitoring should be performed in patients with a history of pancreatitis. If serum lipase and amylase elevation are accompanied by abdominal symptoms, treatment should be temporarily withheld and appropriate diagnostic tests should be considered to exclude pancreatitis (see section 4.2).

Based on the severity of serum lipase and amylase elevation, the dose should be temporarily withheld, reduced or permanently discontinued (see section 4.2).

QT prolongation

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

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

Caution should be exercised when administering asciminib concomitantly with medicinal products with a known risk of torsades de pointes, or in patients who have a history of or predisposition for QTc prolongation or uncontrolled or significant cardiac disease including bradycardia (see sections 4.5 and 5.1).

Hypertension

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

Hypertension should be monitored and managed using standard antihypertensive therapy during treatment with asciminib as clinically indicated.

Hepatitis B reactivation

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

Lactose

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

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

Medicinal products that may decrease asciminib plasma concentrations

Strong CYP3A4 inducers

Co-administration of a strong CYP3A4 inducer in healthy subjects decreased asciminib AUCinf by 14.9% and increased 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

Physiologically-based pharmacokinetic (PBPK) models predict that co-administration of asciminib at 80 mg once daily with rifampicin would decrease asciminib AUCtau and Cmax by 52% and 23%.

Caution should be exercised during concomitant administration of asciminib with strong CYP3A inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoin or St. John's wort (Hypericum perforatum). Dose adjustment of asciminib is not required.

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 AUCinf and Cmax by 28% and 11%, respectively, in healthy subjects receiving asciminib 40 mg twice daily. PBPK models predict that co-administration of asciminib at 80 mg once daily would increase midazolam AUCinf and Cmax by 24% and 17%, respectively.

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

CYP2C9 substrates

Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUCinf and Cmax by 41% and 8%, respectively, in healthy subjects receiving asciminib 40 mg twice daily. PBPK models predict that co-administration of asciminib at 80 mg once daily would increase S-warfarin AUCinf and Cmax by 52% and 4%, respectively.

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

Substrates of OATP1B or BCRP

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 healthy subjects. Clinically relevant interactions between Scemblix and OATP1B substrates are unlikely to occur.

Based on physiologically-based pharmacokinetic (PBPK) modelling, caution should be exercised during concomitant administration of asciminib with BCRP substrates, including, but not limited to, sulfasalazine, methotrexate and rosuvastatin. Refer to BCRP substrates' product information.

P5-gp substrates of narrow therapeutic index Based on physiologically-based pharmacokinetic (PBPK) modelling, caution should be exercised during concomitant administration of asciminib with 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.

QT prolongation

Caution should be exercised during concomitant administration of asciminib and medicinal products with a known risk of torsades de pointes, including, but not limited to, bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin or pimozide (see sections 4.4, 4.8 and 5.1).

Drug-food interactions

The bioavailability of asciminib decreases on consumption of food (see sections 4.2 and 5.2).

Hydroxypropyl-β-cyclodextrin as an excipient (e.g., itraconazole oral solution)

Caution should be exercised during concomitant administration of asciminib with hydroxypropyl-β-cyclodextrin containing oral products (see section 5.2).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception

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

Women of childbearing potential should be advised to use effective contraception during treatment with asciminib and for at least 3 days after stopping treatment and to avoid becoming pregnant while receiving asciminib.

Pregnancy

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

Breast-feeding

It is unknown whether asciminib is excreted in human milk. There are no data on the effects of asciminib on the breast-fed newborn/infant or on milk production. Because of the potential for serious adverse reactions in the breast-fed newborn/infant, breast-feeding is not recommended during treatment and for at least 3 days after stopping treatment with asciminib.

Fertility

There are no data on the effect of asciminib on human fertility. In rat fertility studies, asciminib did not affect reproductive function in male and female rats (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The overall safety profile of asciminib has been evaluated in 356 patients with Ph+ CML-in chronic (CP) and accelerated (AP) phases in the pivotal phase III study A2301 (ASCEMBL) and the phase I study X2101. In ASCEMBL, patients received asciminib as monotherapy at a dose of 40 mg twice daily. In X2101, patients received asciminib as monotherapy at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily.

The safety pool (N=356) includes patients receiving asciminib at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily, with 156 patients receiving asciminib at 40 mg twice daily in the pivotal study, and 35 patients receiving 40 mg twice daily and 18 patients receiving 80 mg once daily from study X2101 as a starting dose. In the pooled dataset, the median duration of exposure to asciminib was 167 weeks (range: 0.1 to 349 weeks).

The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminib were 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 asciminib were thrombocytopenia (18.5%), neutropenia (15.7%), increased pancreatic enzymes (12.94%), hypertension (11.2%) and anaemia (5.3%).

Serious adverse reactions occurred in 13.2% of patients receiving asciminib. The most frequent serious adverse reactions (incidence ≥1%) were pleural effusion (2.5%), lower respiratory tract infections (2.2%), thrombocytopenia (1.7%), pyrexia (1.4%), pancreatitis (1.1%), abdominal pain (1.1%), non-cardiac chest pain (1.1%) and vomiting (1.1%). The predicted safety profile of asciminib at the 80 mg once-daily dose is similar to the 40 mg twice-daily dose, based on exposure-safety analysis.

Tabulated list of adverse reactions

Adverse reactions from clinical studies (Table 3) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category are defined as: 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 3 Adverse reactions observed with asciminib in clinical studies

System organ class

Frequency category

Adverse reaction

Infections and infestations

Very common

Upper respiratory tract infection1

Common

Lower respiratory tract infection2, influenza

Blood and lymphatic system disorders

Very common

Thrombocytopenia3, neutropenia4, anaemia5

Uncommon

Febrile neutropenia, pancytopenia

Immune system disorders

Uncommon

Hypersensitivity

Metabolism and nutrition disorders

Very common

Dyslipidaemia6

Common

Decreased appetite

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 mediastinal disorders

Very common

Dyspnoea, cough

Common

Pleural effusion, non-cardiac chest pain

Gastrointestinal disorders

Very common

Pancreatic enzymes increased8, vomiting, diarrhoea, nausea, abdominal pain9, constipation

Common

Pancreatitis10

Hepatobiliary disorders

Very common

Hepatic enzyme increased11

Common

Blood bilirubin increased12

Skin and subcutaneous tissue disorders

Very common

Rash13, pruritis

Common

Urticaria

Musculoskeletal and connective tissue disorders

Very common

Musculoskeletal pain14, arthralgia

General disorders and administration site conditions

Very common

Fatigue15, oedema16, pyrexia17

Investigations

Common

Electrocardiogram QT prolonged, blood creatine phosphokinase increased

1 Upper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.

2 Lower respiratory tract infections includes: 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, blood triglycerides 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 and hyperbilirubinaemia.

13 Rash includes: rash, rash maculopapular and rash pruritic.

14 Musculoskeletal pain includes: pain in extremity, back pain, myalgia, bone pain, musculoskeletal pain, neck pain, 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.

Description of selected adverse reactions

Myelosuppression

Thrombocytopenia occurred in 28.1% patients receiving asciminib, with grade 3 and 4 reactions reported in 6.7% and 11.8% of patients, respectively. Among the patients with thrombocytopenia ≥ grade 3, the median time to first occurrence of reactions was 6.14 weeks (range: 0.14 to 64.14 weeks) with median duration of any occurring reaction of 2 weeks (95% CI, range: 1.43 to 2 weeks). Of the patients with thrombocytopenia, 2.5% permanently discontinued asciminib, while asciminib was temporarily withheld in 12.4% patients due to the adverse reaction.

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

Anaemia occurred in 13.2% patients receiving asciminib, with grade 3 reactions occurring in 5.3% of patients. Among the patients with anaemia ≥ grade 3, the median time to first occurrence of reactions was 30.43 weeks (range: 0.43 to 207 weeks) with median duration of any occurring reaction of 0.86 weeks (95% CI, range: 0.29 to 1.71 weeks). Of the patients with anaemia, asciminib was temporarily withheld in 0.6% of patients due to the adverse reaction (see section 4.4).

Pancreatic toxicity

Pancreatitis occurred in 2.5%m of patients receiving asciminib, with grade 3 reactions occurring in 1.1% of patients. All these reactions occurred in the phase I study (X2101). Of the patients with pancreatitis, 0.6% permanently discontinued asciminib, while asciminib was temporarily withheld in 1.4% of patients due to the adverse reaction. Asymptomatic elevations of serum lipase and amylase occurred in 23% of patients receiving asciminib, with grade 3 and 4 reactions occurring in 10.4% and 2.5% patients, respectively. Of the patients with elevation of pancreatic enzymes, asciminib was permanently discontinued in 2.2% of patients due to the adverse drug reaction. (see section 4.4)

QT prolongation

Electrocardiogram QT prolongation occurred in 1.1% patients receiving asciminib. In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 ms together with more than 60 ms QTcF increase from baseline, and another patient had prolonged QTcF with more than 60 ms QTcF increase from baseline. (See sections 4.4, 4.5 and 5.1).

Hypertension

Hypertension occurred in 20.8% of patients receiving asciminib, with grade 3 and 4 reactions reported in 11% and 0.3% patients, respectively. Among the patients with hypertension ≥ grade 3, the median time to first occurrence of reactions was 29.21 weeks (range: 0.14 to 365 weeks). Of the patients with hypertension, asciminib was temporarily withheld in 0.8% of patients due to the adverse reaction (see section 4.4).

Laboratory abnormalities

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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is limited experience of asciminib overdose. In clinical studies, asciminib has been administered at doses up to 280 mg twice daily with no evidence of increased toxicity.

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