Koselugo Drug Interactions

Interaction studies have only been performed in healthy adults (aged ≥18 years).
Active substances that may increase selumetinib plasma concentrations: Co-administration with a strong CYP3A4 inhibitor (200 mg itraconazole twice daily for 4 days) increased selumetinib C_max by 19% (90% CI 4, 35) and AUC by 49% (90% CI 40, 59) in healthy adult subjects.
Co-administration with a strong CYP2C19/moderate CYP3A4 inhibitor (200 mg fluconazole once daily for 4 days) increased selumetinib C_max by 26% (90% CI 10, 43) and AUC by 53% (90% CI 44, 63) in healthy adult subjects, respectively.
Concomitant use of erythromycin (moderate CYP3A4 inhibitor) or fluoxetine (strong CYP2C19/CYP2D6 inhibitor) is predicted to increase selumetinib AUC by ~30-40% and C_max by ~20%.
Co-administration with medicinal products that are strong inhibitors of CYP3A4 (e.g., clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (e.g., ticlopidine) should be avoided.
Co-administration with medicinal products that are moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) and CYP2C19 (e.g., omeprazole) should be avoided.
If co-administration is unavoidable, patients should be carefully monitored for adverse events and the selumetinib dose should be reduced (see Dosage & Administration and Table 5).
Active substances that may decrease selumetinib plasma concentrations: Co-administration with a strong CYP3A4 inducer (600 mg rifampicin daily for 8 days) decreased selumetinib C_max by -26% (90% CI -17, -34) and AUC by -51% (90% CI -47, -54).
Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) or moderate CYP3A4 inducers with Koselugo should be avoided.
Active substances whose plasma concentrations may be altered by selumetinib: In vitro, selumetinib is an inhibitor of OAT3. The potential for a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 (e.g., methotrexate and furosemide) cannot be excluded (see Pharmacology: Pharmacokinetics under Actions).
TPGS is a P-gp inhibitor in vitro and it cannot be excluded that it may cause clinically relevant drug interactions with substrates of P-gp (e.g. digoxin or fexofenadine).
The effect of selumetinib on the exposure of oral contraceptives has not been evaluated. Therefore, use of an additional barrier method should be recommended to women using hormonal contraceptives (see Use in Pregnancy & Lactation).
Effect of gastric acid reducing agents on selumetinib: Selumetinib capsules do not exhibit pH dependent dissolution. Koselugo can be used concomitantly with gastric pH modifying agents (i.e. H2-receptor antagonists and proton pump inhibitors) without restrictions, except for omeprazole which is a CYP2C19 inhibitor.
Vitamin E: Koselugo capsules contain vitamin E as the excipient TPGS. Therefore, patients should avoid taking supplemental vitamin E and anticoagulant assessments should be performed more frequently in patients taking concomitant anticoagulant or antiplatelet medicinal products (see Precautions).