SCEMBLIX Film-coated tablet Ref.[50174] Active ingredients: Asciminib

Myelosuppression

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

Based on the severity of thrombocytopenia and/or neutropenia, the dose should be temporarily withheld, reduced or permanently discontinued as described in Table 1 (see section 4.2).

Pancreatic toxicity

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

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

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

QT prolongation

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

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

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

Hypertension

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

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

Hepatitis B reactivation

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

Lactose

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

Sodium

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

Medicinal products with known risk of torsades de pointes

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

Medicinal products that may decrease asciminib plasma concentrations

Strong CYP3A4 inducers

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

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

Medicinal products that may have their plasma concentrations altered by asciminib

CYP3A4 substrates with narrow therapeutic index

Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased midazolam AUC_inf and C_max by 28% and 11%, respectively, in healthy subjects receiving asciminib 40 mg twice daily.

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

CYP2C9 substrates

Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased S-warfarin AUC_inf and C_max by 41% and 8%, respectively, in healthy subjects receiving asciminib 40 mg twice daily.

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

Women of childbearing potential/Contraception

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

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

Pregnancy

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

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

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

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

Tabulated list of adverse reactions

The overall safety profile of asciminib has been evaluated in 356 patients with Ph+ CML in chronic (CP) and accelerated (AP) phases in the pivotal phase III study A2301 (ASCEMBL) and the phase I study X2101. In ASCEMBL, patients received asciminib as monotherapy at a dose of 40 mg twice daily. In X2101, patients received asciminib as monotherapy at doses ranging from 10 to 200 mg twice daily and 80 to 200 mg once daily. In the pooled dataset, the median duration of exposure to asciminib was 116 weeks (range: 0.1 to 342 weeks).

Adverse reactions from clinical studies (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000).

Table 2. Adverse reactions observed with asciminib in clinical studies:

¹ Upper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
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, 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 and transaminases increased.
¹² Blood bilirubin increased includes: blood bilirubin increased, bilirubin conjugated increased and hyperbilirubinaemia.
¹³ Rash includes: rash and rash maculopapular.
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 Pyrexia includes: pyrexia and body temperature increased.
¹⁷ Oedema includes: oedema and oedema peripheral.

Description of selected adverse reactions

Myelosuppression

Thrombocytopenia occurred in 27.5% of patients receiving asciminib, with grade 3 and 4 reactions reported in 6.7% and 11.8% of patients, respectively. Among the patients with thrombocytopenia ≥ grade 3, the median time to first occurrence of reactions was 6 weeks (range: 0.14 to 64 weeks), with median duration of any occurring reaction of 1.71 weeks (95% CI, range: 1.43 to 2 weeks). 2% of patients receiving asciminib permanently discontinued due to thrombocytopenia, while asciminib was temporarily withheld in 12.6% of patients due to the adverse reaction.

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

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

Pancreatic toxicity

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

QT prolongation

Electrocardiogram QT prolongation occurred in 0.8% of patients receiving asciminib. In the ASCEMBL clinical study, one patient had a prolonged QTcF greater than 500 milliseconds (ms) together with more than 60 ms QTcF increase from baseline, and one patient had prolonged QTcF with more than 60 ms QTcF increase from baseline.

Hypertension

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

Laboratory abnormalities

Decrease in phosphate levels occurred as a laboratory abnormality in 17.9% (all grades) and 6.4% (grade ¾) 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 national reporting system listed in Appendix V.

Not applicable.