NALOXEGOL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NALOXEGOL (NALOXEGOL).
Naloxegol is a PEGylated derivative of naloxone, a mu-opioid receptor antagonist. As a peripherally acting mu-opioid receptor antagonist (PAMORA), it binds to and inhibits mu-opioid receptors in the gastrointestinal tract, reducing opioid-induced constipation without crossing the blood-brain barrier to affect central analgesia.
| Metabolism | Primarily metabolized by CYP3A4. Naloxegol is also a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily fecal (approximately 66%) and renal (approximately 33%) as unchanged drug; <1% as metabolites. |
| Half-life | Terminal elimination half-life is approximately 11-13 hours in patients with normal renal function; may be prolonged in severe renal impairment. |
| Protein binding | Plasma protein binding is approximately 95-97%; primarily bound to albumin. |
| Volume of Distribution | Approximately 0.35-0.55 L/kg; indicates distribution mainly into extracellular fluid. |
| Bioavailability | Oral bioavailability is approximately 5-7% due to extensive first-pass metabolism and low systemic absorption. |
| Onset of Action | Oral: Within 6-12 hours after a single dose; peak effect may require multiple doses over several days. |
| Duration of Action | Sustained improvement in bowel function with daily dosing; continued effect for at least 4 weeks in clinical trials. |
| Molecular Weight | 210.27 |
25 mg orally once daily in the morning, with or without food; may increase to 50 mg once daily if tolerated and needed.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR >=30 mL/min/1.73 m2). Not recommended for severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Not recommended for moderate or severe hepatic impairment (Child-Pugh B or C). |
| Pediatric use | Safety and efficacy not established in pediatric patients (<18 years). |
| Geriatric use | No specific dose adjustment required; initiate at 25 mg once daily and monitor for tolerability, given potential for increased sensitivity. |
| 1st trimester | Insufficient human data; animal studies show no teratogenicity at clinically relevant doses. Use only if benefit outweighs risk. |
| 2nd trimester | Insufficient human data; avoid unless necessary. |
| 3rd trimester | Insufficient human data; risk of preterm labor theoretically possible due to μ-opioid receptor antagonism. Avoid near term. |
Clinical note
Comprehensive clinical and safety monograph for NALOXEGOL (NALOXEGOL).
| Placental transfer | Low molecular weight (210.27 Da) suggests potential for placental transfer; no human data on extent. |
| Breastfeeding | Excretion into human milk unknown; low molecular weight suggests possible transfer. Caution advised. |
| Lactation Rating |
■ FDA Black Box Warning
None.
| Serious Effects |
Known hypersensitivity to naloxegolGastrointestinal obstructionConcurrent use with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole)
| Precautions | Gastrointestinal perforation: Cases reported; discontinue if symptoms develop. Avoid use in patients with known or suspected GI obstruction or at increased risk of perforation., Opioid withdrawal: Symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning may occur due to peripheral mu-opioid receptor blockade in patients with disruption of blood-brain barrier., Severe abdominal pain and diarrhea: May occur, particularly in patients with underlying GI disorders., Drug interactions: Avoid use with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole). Use with caution with moderate CYP3A4 inhibitors and P-gp inhibitors., Not for use in patients with chronic cancer pain requiring frequent opioid dose escalation or in those with OIC from non-cancer pain not related to prior cancer. |
| Food/Dietary | Take on an empty stomach; avoid high-fat meals as they decrease absorption significantly. Grapefruit juice increases naloxegol exposure and should be avoided. |
Loading safety data…
| L3 (Moderately Safe) |
| Teratogenic Risk | No adequate human data; in animal studies, no evidence of teratogenicity at exposures up to 190 times the human AUC at 25 mg/day. Risk cannot be excluded; use only if potential benefit justifies risk. First trimester: limited data; second/third trimester: unknown. |
| Fetal Monitoring | Monitor for opioid withdrawal in mother (e.g., elevated blood pressure, tachycardia, GI symptoms) and, if applicable, fetal distress (e.g., reduced fetal movement, nonreassuring fetal heart rate patterns). No specific fetal monitoring required otherwise. |
| Fertility Effects | No human data on fertility. In animal studies, no adverse effects on male or female fertility at exposures up to 190 times the human AUC. |
| Clinical Pearls | Administer on an empty stomach at least 1 hour before or 2 hours after a meal to maximize absorption. Does not interfere with opioid analgesia at the mu receptor due to peripheral action. Use with caution in patients with severe renal impairment (eGFR <30 mL/min); reduce dose to 12.5 mg once daily. Monitor for signs of gastrointestinal perforation, especially in patients with structural bowel disorders. |
| Patient Advice | Take this medication on an empty stomach at least 1 hour before or 2 hours after eating a meal. · Avoid drinking grapefruit juice while taking naloxegol as it can increase side effects. · Do not take this medication if you have a bowel blockage or history of stomach or bowel surgery. · Tell your doctor if you are taking strong CYP3A4 inhibitors such as ketoconazole or clarithromycin. · Common side effects include abdominal pain, diarrhea, nausea, and headache. Contact your doctor if you experience severe or persistent symptoms. |