.1-11.3), compared to when naloxegol was administered alone. Therefore, concomitant use with strong CYP3A4 inhibitors is contraindicated (see section 4.3). Grapefruit juice has been classified as a potent CYP3A4 inhibitor when consumed in large quantities. No data are available on the concomitant use of naloxegol with grapefruit juice. Concomitant consumption of grapefruit juice while taking naloxegol should generally be avoided and considered only in consultation with a healthcare provider (see section 4.3).
Interaction with moderate CYP3A4 inhibitors
In an open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover study to eva luate the effect of multiple doses of diltiazem on the single dose PK of naloxegol, co-administration of diltiazem and naloxegol resulted in a 3.4-fold (90% CI: 3.2-3.7) increase in naloxegol AUC and a 2.9-fold increase in naloxegol Cmax (90% CI: 2.6-3.1), compared to when naloxegol was administered alone. Therefore, a dose adjustment of naloxegol is recommended when co-administered with diltiazem and other moderate CYP3A4 inhibitors (see section 4.2). The starting dose for patients taking moderate CYP3A4 inhibitors is 12.5 mg once daily and the dose can be increased to 25 mg if 12.5 mg is well tolerated by the patient (see section 4.2).
No dosage adjustment is required for patients taking weak CYP3A4 inhibitors.
Interaction with strong CYP3A4 inducers
In an open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, single-dose, crossover study to eva luate the effect of multiple doses of rifampin on the single dose PK of naloxegol, co-administration of rifampin and naloxegol resulted in a 89% (90% CI: 88%-90%) decrease in naloxegol AUC and a 76% decrease in naloxegol Cmax (90% CI: 69%-80%), compared to when naloxegol was administered alone. Therefore, Moventig is not recommended in patients who are taking strong CYP3A4 inducers (see section 4.4).
Interaction with P-gp inhibitors
A double-blind, randomized, 2-part, crossover, single centre study was conducted to eva luate the effect of quinidine on the pharmacokinetics of naloxegol and the effect of the co-administration of naloxegol and quinidine on morphine-induced miosis in healthy volunteers. Co-administration of the P-gp inhibitor quinidine resulted in a 1.4 fold increase in the AUC (90% CI: 1.3-1.5) and a 2.4 fold increase in the Cmax (90% CI: 2.2-2.8) of naloxegol. Co-administration of naloxegol and quinidine did not antagonize the morphine-induced miosis effect, suggesting that P-gp inhibition does not meaningfully change the capacity of naloxegol to cross the blood-brain barrier at therapeutic doses.
As the effects of P-gp inhibitors on the PK of naloxegol were small relative to the effects CYP3A4 inhibitors, the dosing recommendations for Moventig when co-administered with medicinal products causing both P-gp and CYP3A4 inhibition should be based on CYP3A4 inhibitor status - strong, moderate or weak (see sections 4.2, 4.3 and 4.5).
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are limited data from the use of naloxegol in pregnant women.
Studies in animals have shown reproductive toxicity where systemic exposures were several times above the therapeutic exposure level (see section 5.3).
There is a theoretical potential for provoking opioid withdrawal in the foetus with use of an opioid receptor antagonist |
