onal 12 weeks (beyond that observed in Kodiac 4) using descriptive statistics. In this study, naloxegol at doses of 12.5 mg and 25 mg was generally safe and well tolerated as compared with placebo in the treatment of OIC patients with non-cancer-related pain.
In all treatment groups, including placebo, improvements in PAC-SYM domains observed in Kodiac 4 were maintained for patients continuing in Kodiac 7.
Long-term safety and tolerability
Kodiac 8 was a Phase III, 52-week, multi-center, open-label, randomized, parallel group, safety and tolerability study of naloxegol versus usual care in the treatment of OIC in patients with non-cancer-related pain. The primary objective was to assess long-term safety and tolerability for naloxegol 25 mg and to compare with usual care treatment using descriptive statistics.
Eligible patients were randomized in a 2:1 ratio to receive either naloxegol 25 mg daily (qd) or usual care treatment for OIC for 52 weeks. Patients assigned to usual care followed a laxative treatment regimen for OIC determined by the investigator according to best clinical judgment, excluding peripheral mu-opioid receptor antagonists.
Of the 844 patients who were randomized, 61.1% completed the study (defined as completing the 2-week follow-up visit after the 52-week treatment period). Overall 393 and 317 patients had at least 6 and 12 months exposure to naloxegol 25 mg, respectively, in this study, which met the specified exposure requirements.
Long-term exposure to naloxegol 25 mg, up to 52 weeks, was generally safe and well tolerated in the treatment of OIC patients with non-cancer-related pain. During the 52-week treatment period there were no important unexpected differences in the safety and tolerability findings between the naloxegol 25 mg treatment group and the usual care treatment group.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies in opioid induced constipation with Moventig in children and adolescents aged 6 months to 18 years as per Paediatric Investigation Plan (PIP) decision (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following oral administration, naloxegol is absorbed rapidly, with peak concentrations (Cmax) achieved at less than 2 hours. In a majority of subjects, a secondary plasma concentration peak of naloxegol was observed approximately 0.4 to 3 hours after the first peak. Enterohepatic recirculation may be an explanation as extensive biliary excretion was seen in the rat.
Food effects: A high-fat meal increased the extent and rate of naloxegol absorption. The Cmax and area under the plasma concentration-time curve (AUC) were increased by approximately 30% and 45%, respectively.
Naloxegol as a crushed tablet mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to the whole tablet, with a median tmax of 0.75 and 1.50 hours (range 0.23 to 5.02 hours) for the crushed tablet given orally and the crushed tablet given via NG tube, respectively.
Distribution
The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteers ranged from 968 to 2,140 L across dosing groups and studies. Results from a QWBA (Quantitative Whole Body Autoradiography) study in the rat and the lack of antagonism of CNS opiate effects in humans at naloxegol doses less than 250 mg, indicate minimal distribution of naloxegol into th |
