Naloxegol (Monograph)

Brand name: Movantik
Drug class: GI Drugs, Miscellaneous
Chemical name: Ethanedioate (1:1) (5α,6α)- 4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-propen-1-yl)-morphinan-3,14-diol
Molecular formula: C₃₄H₅₃NO₁₁•C₂H₂O₄
CAS number: 1354744-91-4

Medically reviewed by Drugs.com on Aug 17, 2023. Written by ASHP.

Introduction

Peripherally acting μ-opiate receptor antagonist.

Uses for Naloxegol

Opiate-induced Constipation

Management of opiate-induced constipation in patients with chronic non-cancer-related pain, including those with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) increases in opiate dosage.

Naloxegol Dosage and Administration

General

• Discontinue all maintenance laxative therapy prior to initiating naloxegol; laxatives may be used as needed if the response to naloxegol is suboptimal after 3 days.

• Changes in analgesic dosing regimen not required prior to initiating naloxegol.

• Patients receiving opiates for <4 weeks may be less responsive to naloxegol.

• Discontinue naloxegol if opiate therapy is discontinued.

Administration

Oral Administration

Administer orally on an empty stomach ≥1 hour before or 2 hours after the first meal of the day.

For patients who cannot swallow tablets whole, crush tablet to a powder, mix with 120 mL of water in a glass, stir the resulting mixture, and administer immediately. To ensure consumption of the entire dose, rinse the glass with 120 mL of water, stir the resulting mixture, and administer immediately.

NG Tube

Flush the NG tube with 30 mL of water using a 60-mL syringe, crush the tablet to a powder and mix with approximately 60 mL of water in a container, draw up the mixture into the 60-mL syringe, and administer through the NG tube. To facilitate delivery of the entire dose, rinse the container with approximately 60 mL of water, draw up the mixture into the same syringe, and use the entire contents of the syringe to flush the NG tube.

Dosage

Available as naloxegol oxalate; dosage expressed in terms of naloxegol.

Adults

Opiate-induced Constipation

Oral

25 mg once daily. If the 25-mg dose is not tolerated, may reduce dosage to 12.5 mg once daily.

If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, reduce dosage to 12.5 mg once daily and monitor for adverse effects. (See Interactions.)

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not required.

Severe hepatic impairment: Avoid use; appropriate dosage not established.

Renal Impairment

Moderate or severe renal impairment or end-stage renal disease (ESRD) (Cl_cr <60 mL/minute): Initial dosage of 12.5 mg once daily. If well tolerated but symptoms of opiate-induced constipation persist, may increase dosage to 25 mg once daily; consider the potential for markedly increased exposure and increased risk of adverse effects. (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No dosage adjustment required based solely on age.

Cautions for Naloxegol

Contraindications

• Patients with known or suspected GI obstruction or at increased risk of recurrent obstruction. (See GI Perforation under Cautions.)

• Concomitant use with potent CYP3A4 inhibitors. (See Interactions.)

• Known serious or severe hypersensitivity reaction to naloxegol or any ingredient in the formulation.

Warnings/Precautions

Opiate Withdrawal

Possible opiate withdrawal. Incidence of adverse GI effects potentially related to opiate withdrawal was higher in patients receiving methadone compared with those receiving other opiates in clinical studies.

Patients with disruptions in the blood-brain barrier may be at increased risk for opiate withdrawal or reduced analgesia; carefully consider risks and benefits of naloxegol in such patients, and monitor these patients for symptoms of opiate withdrawal.

Severe Abdominal Pain and Diarrhea

Severe abdominal pain and/or diarrhea, sometimes resulting in hospitalization, reported. Most cases of severe abdominal pain reported in patients receiving naloxegol dosage of 25 mg daily. Symptoms generally occur within a few days following initiation of therapy.

Monitor patients receiving naloxegol for development of abdominal pain and/or diarrhea. Discontinue naloxegol if severe symptoms occur. If appropriate, can consider reinitiating naloxegol therapy at a dosage of 12.5 mg once daily.

GI Perforation

GI perforation reported with use of methylnaltrexone, another peripherally acting opiate antagonist, in patients with underlying conditions that may be associated with localized or diffuse reduction of structural integrity in the GI tract wall (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative GI tract malignancies or peritoneal metastases). Carefully consider risks and benefits of naloxegol in patients with these conditions or with other conditions that might result in impaired integrity of the GI tract wall (e.g., Crohn’s disease).

Monitor patients receiving naloxegol for development of severe, persistent, or worsening abdominal pain; discontinue the drug if such symptoms occur.

Specific Populations

Pregnancy

Category C.

Use only if potential benefits justify potential risk to fetus. No adequate and well-controlled studies in pregnant women. Because of the immature fetal blood-brain barrier, use of naloxegol during pregnancy may precipitate opiate withdrawal in the fetus. No adverse effects on embryofetal development observed in animal studies.

Lactation

Distributed into milk in rats and absorbed in nursing rat pups; not known whether distributed into human milk. Because of the potential for serious adverse effects, including opiate withdrawal, in nursing infants, discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Slight decreases in AUC possible in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

Effect of severe hepatic impairment (Child-Pugh class C) on naloxegol pharmacokinetics not established; avoid use in severe hepatic impairment.

Renal Impairment

Markedly increased exposure to naloxegol observed in some patients with moderate or severe renal impairment or ESRD. (See Special Populations under Pharmacokinetics.) Risk of adverse effects increases with increasing exposure. Reduced initial dosage recommended in patients with Cl_cr <60 mL/minute. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, hyperhidrosis.

Drug Interactions

Principally metabolized by CYP3A isoenzymes. Did not inhibit CYP1A2, 2C9, 2C19, 2D6, or 3A4 nor substantially induce CYP 1A2, 2B6, or 3A4 at clinically relevant concentrations in vitro; not expected to alter metabolic clearance of drugs metabolized by these enzymes.

Substrate, but not clinically important inhibitor, of P-glycoprotein (P-gp).

Does not substantially inhibit breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1 or 3, organic cation transporter (OCT) 2, or organic anion transport protein (OATP) 1B1 or 1B3.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Increased plasma naloxegol concentrations and increased risk of adverse effects. Concomitant use contraindicated.

Moderate CYP3A4 inhibitors: Increased plasma naloxegol concentrations and increased risk of adverse effects. Avoid concomitant use; if concomitant use cannot be avoided, reduce naloxegol dosage to 12.5 mg once daily and monitor for adverse effects.

Weak CYP3A4 inhibitors: Clinically important interaction not expected. No dosage adjustment required.

Potent CYP3A4 inducers: Decreased plasma naloxegol concentrations and possible decreased naloxegol efficacy. Concomitant use not recommended.

Specific Drugs and Foods

Naloxegol Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract, with peak concentration attained less than 2 hours after oral administration. Secondary peak generally observed approximately 0.4–3 hours after the first peak, suggesting enterohepatic circulation.

When crushed tablet is mixed in water and administered orally or through an NG tube, median time to peak plasma concentration is 0.75 or 1.5 hours, respectively, and plasma concentrations are comparable to those attained following oral administration of intact tablet.

Peak plasma concentration and AUC increase in dose-proportional or almost dose-proportional manner.

Food

High-fat meal increases extent and rate of absorption (peak plasma concentration and AUC increased by approximately 30 and 45%, respectively).

Special Populations

Hepatic impairment: AUC decreased slightly in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

Renal impairment with Cl_cr <60 mL/minute (moderate or severe renal impairment, ESRD not requiring dialysis): Pharmacokinetic profile in most patients similar to that in healthy individuals. However, marked (up to tenfold) increase in exposure observed in some patients with moderate or severe renal impairment or ESRD; reason for increased exposure unknown.

ESRD requiring dialysis: Plasma concentrations similar to concentrations in healthy individuals whether drug administered before or after hemodialysis.

Age: Peak concentration and AUC increased by approximately 45 and 54%, respectively, in healthy geriatric Japanese individuals compared with younger individuals.

Race: Peak concentration increased by approximately 30% in Asians compared with Caucasians. AUC and peak concentration reduced by approximately 20 and 10%, respectively, in black individuals compared with Caucasians.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

CNS penetration expected to be negligible at recommended dosage.

Plasma Protein Binding

Approximately 4%.

Elimination

Metabolism

Extensively metabolized, principally via CYP3A isoenzymes; undergoes N-dealkylation, O-demethylation, oxidation, and shortening of the polyethylene glycol (PEG) chain.

Elimination Route

Excreted principally in feces (68%, approximately 16% of which is unchanged drug) and to lesser extent in urine (16%).

Half-life

6–11 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Peripherally acting μ-opiate receptor antagonist; covalent conjugate of naloxone and PEG.

• Blocks μ-opiate receptors in the GI tract, thereby reversing opiate-induced constipating effects (e.g., slowing of GI motility and transit).

• Conjugation with PEG decreases passive permeability of the drug across the blood-brain barrier and renders naloxegol a substrate for P-gp, which results in increased efflux across the blood-brain barrier. CNS penetration expected to be negligible at recommended dosages, limiting the potential for interference with centrally mediated opiate analgesia.

• Exhibits antagonist effects at μ- and δ-opiate receptors and weak partial agonist activity at κ-opiate receptors, but has highest affinity for μ-receptors; affinity for μ-receptors is approximately 20-fold lower than that of naloxone.

Advice to Patients

• Importance of reading the manufacturer's medication guide before beginning treatment and each time the prescription is refilled.

• Importance of discontinuing all maintenance laxative therapy prior to initiation of naloxegol. Laxatives may be used as needed if response to naloxegol is suboptimal after 3 days.

• Importance of taking naloxegol on an empty stomach ≥1 hour before or 2 hours after the first meal of the day. If the patient cannot swallow the tablets intact or the drug must be administered through an NG tube, importance of crushing the tablets, mixing with water, and administering according to the manufacturer's instructions.

• Importance of informing clinician if therapy is not tolerated, as dosage adjustment may be appropriate.

• Importance of informing clinician if opiate analgesics are discontinued, since naloxegol should be discontinued if opiates are discontinued.

• Potential for symptoms consistent with opiate withdrawal (e.g., sweating, chills, diarrhea, abdominal pain, anxiety, irritability, yawning) to occur. Inform methadone-treated patients that they may be more likely than patients receiving other opiates to experience adverse GI effects that may be related to opiate withdrawal.

• Potential for severe abdominal pain and/or diarrhea to occur following initiation of therapy; importance of discontinuing naloxegol and contacting clinician if such severe symptoms occur.

• Possible risk of GI perforation. Importance of discontinuing naloxegol and promptly seeking medical attention if unusually severe, persistent, or worsening abdominal pain occurs.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise women that naloxegol use during pregnancy may precipitate fetal opiate withdrawal because the fetal blood-brain barrier is immature. Advise women not to breast-feed while receiving the drug because of the potential for opiate withdrawal in nursing infants.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (especially those that alter CYP3A4 activity), as well as any concomitant illnesses. Advise patients to avoid consumption of grapefruit or grapefruit juice and to inform their clinician when they initiate or discontinue any concomitant drug therapy.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• Which drugs cause opioid-induced constipation?

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