Naloxegol

Naloxegol is a PEGylated derivative of naloxone that acts as a peripherally acting mu-opioid receptor antagonist (PAMORA). It reverses opioid effects in the gut without reversing central analgesia and is used for opioid-induced constipation in adults who respond inadequately to laxatives.

Classification. Peripherally acting mu-opioid receptor antagonist.

Mechanism. Competitively blocks mu-opioid receptors in the gastrointestinal tract. The polyethylene glycol moiety makes it a substrate of P-glycoprotein, limiting entry across the intact blood brain barrier.

Pharmacodynamics. Restores gastrointestinal motility and secretion reduced by opioids. Laxation often occurs within 6 to 12 hours of the first dose.

Pharmacokinetics. Absorbed rapidly, peaking in about 2 hours; a high-fat meal increases absorption. Half-life 6 to 11 hours. Protein binding 4% to 10%.

Metabolism. CYP3A4 substrate and P-glycoprotein substrate. Excreted mostly in faeces, about 16% in urine.

Adult oral doses.

Opioid-induced constipation in adults with inadequate response to laxatives.

• 25 mg once daily in the morning.

• Take on an empty stomach, 1 hour before or 2 hours after the first meal.

• Reduce to 12.5 mg once daily if 25 mg is not tolerated.

• Stop other maintenance laxatives before starting; a rescue laxative may be used after 3 days without a bowel movement.

Dose adjustments.

• CrCl under 60 mL/min: start at 12.5 mg once daily; increase to 25 mg if tolerated.

• Moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin): 12.5 mg once daily.

• Mild to moderate liver impairment (Child-Pugh A and B): no adjustment.

• Severe liver impairment (Child-Pugh C): avoid.

• Dialysis: use 12.5 mg with caution.

Children. Not established.

Contraindications.

• Known or suspected gastrointestinal obstruction, or risk of recurrent obstruction.

• Concurrent strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir).

• Hypersensitivity.

Common adverse effects. Abdominal pain (most common), diarrhoea, nausea, flatulence, headache and sweating.

Serious adverse effects.

• Gastrointestinal perforation, particularly with diverticular disease, peptic ulcer, Crohn disease, gastrointestinal malignancy or infiltrative disease; stop for severe, persistent or worsening abdominal pain.

• Opioid withdrawal symptoms (sweating, chills, diarrhoea, anxiety, irritability), more likely when the blood brain barrier is disrupted (brain tumour, multiple sclerosis, recent head injury) and with methadone.

• Severe diarrhoea.

Major interactions.

• Strong CYP3A4 inhibitors: contraindicated.

• Moderate CYP3A4 inhibitors: reduce the dose.

• CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): reduce efficacy; avoid.

• Grapefruit juice: raises levels; avoid.

• Other opioid antagonists: avoid.

• Other laxatives: stop maintenance laxatives before starting.

Special groups.

• Pregnancy: avoid; may precipitate opioid withdrawal in the foetus.

• Breastfeeding: avoid; possible opioid withdrawal in the breastfed infant.

• Children: not established.

• Older adults: no adjustment.

• Kidney impairment: reduce the starting dose when CrCl is under 60 mL/min.

• Liver impairment: avoid in severe impairment.

• Regional: limited availability and high cost in East Africa; lifestyle measures and conventional laxatives remain first-line.

Formulations. Tablets 12.5 mg and 25 mg.

Administration.

• Swallow whole in the morning on an empty stomach.

• Tablets may be crushed and mixed in water and given by nasogastric tube if swallowing is difficult.

• Avoid grapefruit juice.

Baseline. Exclude obstruction and perforation risk; kidney function; review CYP3A4 interactions and laxative use.

Monitoring.

• Bowel movements and abdominal pain, particularly in the first week.

• Opioid withdrawal symptoms and pain control.

• Kidney function if impairment is known.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for severe abdominal pain, opioid withdrawal, perforation or when the opioid is stopped.

Referral and escalation. Urgent imaging and surgical review for severe abdominal pain, fever or peritonism. Palliative care or pain specialist input if withdrawal affects analgesia.