Scemblix Drug Interactions

Agents that may affect asciminib plasma concentrations: Strong CYP3A4 inhibitors: The AUC_inf and C_max of asciminib increased by 36% and 19%, respectively, after co-administration of a single dose of 40 mg Scemblix with a strong CYP3A4 inhibitor (clarithromycin). No clinically significant differences in the pharmacokinetics of asciminib were observed after co-administration with itraconazole, which is also a strong CYP3A4 inhibitor.
Physiologically based pharmacokinetic (PBPK) models predict that the co-administration of Scemblix 200 mg twice daily with a strong CYP3A4 inhibitor (clarithromycin) would increase the asciminib AUC_tau and C_max by 77% and 49%, respectively.
Caution is required during co-administration of Scemblix 200 mg twice daily with strong CYP3A4 inhibitors, including, but not limited to, clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir or saquinavir. Scemblix dose adjustment is not required.
Strong CYP3A4 inducers: Co-administration of a strong CYP3A4 inducer (rifampicin) decreased the asciminib AUC_inf by 15% and increased the C_max of asciminib by 9% in healthy subjects receiving a single Scemblix dose of 40 mg.
Co-administration of asciminib 200 mg twice daily with rifampicin would decrease the asciminib AUC_tau and C_max by 63% and 47%, respectively.
Caution is required during co-administration of Scemblix at all recommended doses with strong CYP3A4 inducers, including, but not limited to, carbamazepine, phenobarbital, phenytoin or St. John's wort (Hypericum perforatum). Scemblix dose adjustment is not required.
Imatinib: The asciminib AUC_inf and C_max increase by 108% and 59%, respectively, after co-administration of a single dose of 40 mg Scemblix with imatinib (an inhibitor of BCRP, CYP3A4, UGT2B17 and UGT1A3/4). The changes in exposure are not considered to be clinically significant.
Other agents: No clinically significant differences in the pharmacokinetics of asciminib were observed after co-administration with rabeprazole (acid-reducing agent) and quinidine (P-gp inhibitor).
Agents whose plasma concentrations may be altered by asciminib: CYP3A4 substrates with a narrow therapeutic index: Co-administration of asciminib with a CYP3A4 substrate (midazolam) increased the midazolam AUC_inf and C_max by 28% and 11%, respectively, in healthy subjects receiving 40 mg Scemblix twice daily. PBPK models predict that the co-administration of asciminib at 200 mg twice daily would increase the midazolam AUC_inf and C_max by 88% and 58%, respectively.
Caution is required during co-administration of Scemblix 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 Pharmacology: Pharmacokinetics under Actions). Scemblix dose adjustment is not required.
CYP2C8 substrates: The AUC_inf and C_max of repaglinide (substrate of CYP2C8, CYP3A4 and OATP1B) increased by 8% and 14%, respectively, after co-administration of repaglinide with 40 mg asciminib twice daily. PBPK models predict that the repaglinide AUC_inf and C_max would increase by 12% and 8%, respectively, after co-administration with 80 mg asciminib once daily and by 42% and 25%, respectively, after co-administration with 200 mg asciminib twice daily. PBPK models predict that the AUC_inf and C_max of rosiglitazone (substrate of CYP2C8 and CYP2C9) would increase by 20% and 3%, respectively, after co-administration of rosiglitazone with 40 mg asciminib twice daily. PBPK models predict that the rosiglitazone AUC_inf and C_max would increase by 24% and 2%, respectively, after co-administration of 80 mg asciminib once daily and by 66% and 8% after co-administration of 200 mg asciminib. The changes in exposure are not considered to be clinically significant.
CYP2C9 substrates: Co-administration of asciminib with a CYP2C9 substrate (warfarin) increased the S-warfarin AUC_inf and C_max by 41% and 8%, respectively, in healthy subjects receiving 40 mg Scemblix twice daily. Co-administration of asciminib at 80 mg once daily would be expected to increase the S-warfarin AUC_inf and C_max by 52% and 4%, respectively. Co-administration of asciminib 200 mg twice daily would increase the S-warfarin AUC_inf and C_max by 314% and 7%, respectively.
Caution is required during co-administration of Scemblix at a total daily dose of 80 mg with CYP2C9 substrates known to have a narrow therapeutic index, including, but not limited to, phenytoin or warfarin (see Pharmacology: Pharmacokinetics under Actions). Scemblix dose adjustment is not required.
Co-administration of Scemblix 200 mg twice daily with CYP2C9-sensitive substrates and CYP2C9 substrates that are known to have a narrow therapeutic index should be avoided and alternative treatment options should be considered (see Pharmacology: Pharmacokinetics under Actions). If co-administration cannot be avoided, the CYP2C9 substrate dose should be reduced. If co-administration with warfarin cannot be avoided, the frequency of the international normalised ratio (INR) monitoring should be increased, as the anticoagulant effect of warfarin may be enhanced.
Substrates of OATP1B or BCRP: Co-administration of 80 mg asciminib once daily with an OATP1B, CYP3A4 and P‑gp substrate (atorvastatin) increased the atorvastatin AUC_inf and C_max by 14% and 24%, respectively, in healthy subjects. Clinically relevant interactions between Scemblix at all recommended doses and OATP1B substrates are unlikely to occur.
Using PBPK models it is predicted that co-administration of asciminib at a dosage of 40 mg twice daily or 80 mg once daily with a BCRP substrate (sulfasalazine) would increase the sulfasalazine C_max by 334% and 342% and AUC_inf by 333% and 340%, respectively, while co-administration of asciminib 200 mg twice daily would increase the sulfasalazine C_max and AUC_inf by 353% and 359%, respectively.
Using PBPK models it is predicted that co-administration of asciminib at a dosage of 40 mg twice daily or 80 mg once daily with a substrate of BCRP and OATP1B (rosuvastatin) would increase the rosuvastatin C_max by 453% and 530% and AUC_inf by 190% and 202%, respectively, while co-administration of asciminib 200 mg twice daily would increase the rosuvastatin C_max and AUC_inf by 732% and 311%, respectively.
Caution is required if Scemblix at all recommended doses is co-administered with substrates of BCRP, including, but not limited to, sulfasalazine, methotrexate, and rosuvastatin. Refer to the dose reductions for OATP1B and BCRP substrates recommended in their prescribing information.
Co-administration of Scemblix at all recommended doses with rosuvastatin should be avoided and other statins should instead be considered. If co-administration cannot be avoided, the rosuvastatin dose should be reduced as per the recommendations in its prescribing information.
P-gp substrates with a narrow therapeutic index: PBPK models predict that co-administration of asciminib at 40 mg twice daily and 80 mg once daily doses with a P-gp substrate such as digoxin would increase the maximum plasma concentration (C_max) of digoxin by 30% and 38% and the area under the concentration-time curve (AUC_inf) by 20% and 22%, respectively, while co-administration of asciminib 200 mg twice daily would increase the digoxin C_max and AUC_inf by 62% and 40%, respectively.
Caution is required during co-administration of Scemblix at all recommended doses with P-gp substrates known to have a narrow therapeutic index such as digoxin, dabigatran and colchicine.
QT-prolonging agents: Caution is required during co-administration of Scemblix at a total daily dose of 80 mg and medicinal products with a known risk of torsades de pointes, including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone or moxifloxacin.
Co-administration of Scemblix 200 mg twice daily and medicinal products with a known risk of torsades de pointes should be avoided (see Pharmacology: Pharmacokinetics under Actions).
Interactions with food: The bioavailability of asciminib decreases on consumption of food (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
In vitro evaluation of the potential for drug interactions: CYP450 and UGT enzymes: In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9 and UGT1A1 at plasma concentrations reached at a total daily dose of 80 mg. In addition, asciminib reversibly inhibits CYP2C8 and CYP2C19 at plasma concentrations achieved with a twice daily dose of 200 mg.
Transporters: Asciminib is a substrate of BCRP and P-gp. Asciminib inhibits BCRP, P-gp, OATP1B1, OATP1B3 and OCT1 with Ki values of 24.3, 21.7, 2.46, 1.92 and 3.41 in the micromolar range, respectively. Based on information from PBPK models, asciminib increases exposure to substrates of OATP1B and BCRP.
Co-administration of Scemblix with a medicinal product that is a P-gp substrate may lead to a clinically relevant increase in the plasma concentrations of P-gp substrates, with minimal concentration changes possibly leading to severe toxicities. The clinical relevance of the interaction with OCT1 is currently unknown with the twice daily dose of Scemblix 200 mg.
Multiple metabolic pathways: Asciminib is metabolised by several pathways, including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secretion by the transporter BCRP.
Medicinal products that inhibit or induce multiple metabolic pathways may alter Scemblix exposure.
Asciminib inhibits several metabolic pathways, including CYP3A4, CYP2C9, OATP1B, P-gp and BCRP. Therefore, Scemblix may increase the exposure to medicinal products that are substrates of these metabolic pathways.