Leitlinien & Arzneimittelsicherheit

HOS-099841 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile Ph+ CML (ASCEMBL, X2101, ASC4FIRST studies) The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminib were musculoskeletal pain (34.4%), thrombocytopenia (28.1%), fatigue (25.4%), upper respiratory tract 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 asciminib were thrombocytopenia (16.5%), neutropenia (13.8%), increased pancreatic enzymes (9.4%) and hypertension (9.2%). Serious adverse reactions occurred in 9.9% of patients receiving asciminib. The most frequent serious adverse 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 a treatment intensity of >90%. The most common adverse reactions of any grade (incidence ≥20%) in patients receiving asciminib were 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 were increased pancreatic enzymes (22.9%), thrombocytopenia (16.7%), neutropenia (12.5%), increased hepatic 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 frequent serious adverse reactions (incidence ≥1%) were abdominal pain (4.2%), vomiting (4.2%), lower respiratory tract infections (4.2%), constipation (2.1%), headache (2.1%), non-cardiac chest pain (2.1%) and pleural effusion (2.1%). Tabulated list of adverse reactions 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 I study 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 of 40 mg twice

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HOS-099837 · has-contraindication-information · PDF-Seite 5

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

HOS-099836 · has-indication-information · PDF-Seite 3

Scemblix is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic 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 mutation who are resistant to, intolerant to or ineligible for ponatinib (see section 5.1).

HOS-099839 · has-interaction-information · PDF-Seite 7

Medicinal products with known risk of torsades de pointes Caution should be exercised during concomitant administration of asciminib at a total daily dose of 80 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 known risk 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 daily with strong CYP3A4 inhibitors, including, but not limited to, clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Dose adjustment of asciminib is not required. Medicinal products that may decrease asciminib plasma concentrations Strong CYP3A4 inducers Co-administration of a strong CYP3A4 inducer (rifampicin) decreased asciminib AUCinf by 15% 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. Caution should be exercised during concomitant administration of asciminib at all recommended doses 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 AUCinf and 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 doses 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 Cm

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HOS-099840 · has-pregnancy-information · PDF-Seite 8

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. 8

HOS-099838 · has-warning-information · PDF-Seite 5

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, close monitoring should be considered since there are uncertainties regarding a potential increase of safety risks compared to the 80 mg total daily dose due to the small dataset of 48 patients, of whom 34 had a treatment intensity of >90%. 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). 5 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

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