eme
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4.9 Overdose
Doses of naloxegol up to 1,000 mg were administered in healthy volunteers in clinical studies. A potential CNS effect (reversal of opioid-induced miosis, as measured by pupillometry) was observed in 1 volunteer in the 250 mg group and 1 volunteer in the 1,000 mg group. In a clinical study of patients with OIC, a daily dose of 50 mg was associated with an increased incidence of intolerable gastrointestinal effects (primarily abdominal pain).
No antidote is known for naloxegol and dialysis was noted to be ineffective as a means of elimination in a clinical study in patients with renal failure.
If a patient on opioid therapy receives an overdose of naloxegol, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms or reversal of central analgesic effect. In cases of known or suspected overdose of naloxegol, symptomatic treatment as well as monitoring of vital functions should be performed.
Paediatric population
The use of naloxegol in the paediatric population has not been studied.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists
ATC code: A06AH03
Mechanism of action and pharmacodynamic effects
Naloxegol is a PEGylated derivative of the mu-opioid receptor antagonist naloxone. PEGylation reduces naloxegol's passive permeability and also renders the compound a substrate for the P-glycoprotein transporter. Due to poorer permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is minimal.
In vitro studies demonstrate that naloxegol is a full neutral antagonist at the mu-opioid receptor. Naloxegol acts by binding to mu-opioid receptors in the GI tract targeting the underlying causes of OIC (i.e. reduced GI motility, hypertonicity and increased fluid absorption resulting from long-term opioid treatment).
Naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.
Clinical efficacy and safety
The efficacy and safety of naloxegol was established in two replicate double-blind, placebo-controlled studies in patients with OIC and non-cancer related pain (Kodiac 4 and Kodiac 5). Patients taking a minimum of 30 morphine equivalent units (meu) of opioids per day for at least 4 weeks before enrolment and self-reported OIC were eligible. OIC was confirmed through a two week run in period and defined as < 3 spontaneous bowel movements (SBMs) per week on average with constipation symptoms associated with at least 25% of bowel movements. Patients were prohibited from using laxatives other than bisacodyl rescue laxative if they had not had a bowel movement for 72 hours. SBM was defined as a bowel movement without rescue laxative taken within the past 24 hours. Patients with mean Numeric Rating Scale (NRS) pain scores equal to or higher than 7 were not studied due to the risk of confounding the efficacy result as a result of uncontrolled pain. Patients who had a QTcF >500 msec at screening, had a recent history of myocardial infarction within 6 months before randomization, had sympt
