New Drug: Movantik (Naloxegol)

What It Is

Naloxegol (Movantik) is a new oral treatment for opioid-induced constipation. This document reviews pertinent information such as specific indication, mechanism of action, dosing, side effects, and comparisons to similar agents.

How It Works

Naloxegol, a pegylated derivative of naloxone, is a peripherally acting mu-opioid receptor antagonist. It acts locally to inhibit opioid binding in the gastrointestinal (GI) tract. Naloxegol does not appreciably cross the blood-brain barrier. Pegylation of the drug decreases passive permeability and naloxegol is a P-glycoprotein substrate (the P-glycoprotein transport system moves drugs out of cells and it helps to keep drugs from crossing the blood-brain barrier).¹

Indication

Naloxegol is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.¹

How Supplied

Naloxegol is available as 12.5 mg and 25 mg film-coated tablets.¹

Dosage

The recommended dose of naloxegol is 25 mg once daily, taken in the morning on an empty stomach. The dose can be reduced to 12.5 mg once daily for patients who are unable to tolerate the full dose.¹

Patients with CrCl <60 mL/min should start with 12.5 mg once daily. If this dose is well tolerated but ineffective, the dose can be increased to 25 mg once daily. However, increasing the dose might increase the risk of side effects.¹

Adverse Effects

The most common side effects seen in clinical trials of naloxegol were abdominal pain, diarrhea, nausea, flatulence, vomiting, headache, and hyperhidrosis.¹

In clinical trials, symptoms indicating possible opioid withdrawal were seen in less than 1% of patients who received placebo, 1% of those who received naloxegol 12.5 mg, and 3% of those who received naloxegol 25 mg.¹

Drug Interactions

Because naloxegol does not appreciably cross the blood-brain barrier at recommended doses, the potential for interactions with centrally acting opioids is limited.¹

Naloxegol does not appear to inhibit or induce enzymes or transporters such as cytochrome P450, P-glycoprotein, or OATP.¹

Naloxegol is metabolized by CYP3A4 and, as mentioned previously, is a substrate for P-glycoprotein. Use of naloxegol with strong CYP3A4 inhibitors, such as ketoconazole, or strong CYP3A4 inducers, such as rifampin, is contraindicated. The dose of naloxegol should be reduced by 50% if it is used with moderate CYP3A4 inhibitors, such as diltiazem. Grapefruit juice should not be consumed during treatment with naloxegol, due to its moderate to strong inhibition of CYP3A4.¹

Naloxegol should not be used with other opioid antagonists due to the potential for additive effects and a resultant increased risk of opioid withdrawal in patients taking opioids.¹

Contraindications

Naloxegol is contraindicated in patients who have or at risk for GI obstruction, due to an increased risk of perforation.¹

Precautions

Patients who may be at increased risk of GI perforation due to impaired integrity of the GI wall (e.g., peptic ulcer disease, Crohn’s disease, etc) should be monitored for signs and symptoms of perforation during treatment with naloxegol, and the risk-benefit profile should be considered as well.¹

Patients with disruptions to the blood-brain barrier may be at increased risk of opioid withdrawal or reduced analgesia from opioids when taking naloxegol.¹

Patients who are taking methadone as an analgesic may be at higher risk of GI side effects from naloxegol.¹

Use In Pregnancy

Naloxegol is Pregnancy Category C, as there are no adequate and well-controlled studies in pregnant women. However, no adverse effects from naloxegol have been seen in animal embryos. Naloxegol is present in the milk of animals.¹

Note that the use of naloxegol during pregnancy may precipitate opioid withdrawal in the fetus.¹

Manufacturer

AstraZeneca
Wilmington, DE 19850
800-236-9933
www.movantikhcp.com

Commentary

Opioid-induced constipation occurs in most patients who take opioids for chronic pain.² Lifestyle interventions (e.g., fluid and fiber, increased physical activity) and OTC stimulant or osmotic laxatives are typically considered first-line treatments, although there aren’t good data for efficacy of these meds and many patients will not see adequate results.²

Peripherally acting opioid antagonists (e.g., methylnaltrexone, naloxegol) are another option. These have a minimal risk of counteracting analgesic effects of opioids compared with centrally acting agents such as naltrexone or injectable naloxone. (Note that naloxone undergoes extensive first-pass hepatic metabolism when given orally, so it only binds to a significant degree to opioid receptors in the GI tract. An oral formulation with naloxone for opioid-induced constipation is available in Canada [Targin, extended-release oxycodone/naloxone], but an oral formulation with naloxone approved for opioid-induced constipation is not currently available in the U.S.)⁶ Naloxegol is a new oral agent, and methylnaltrexone (Relistor) is an injectable for subcutaneous administration that is also approved for opioid-induced constipation (in patients with chronic non-cancer pain and those receiving palliative care). Alvimopan (Entereg) is another oral peripherally acting opioid antagonist, but it is only approved for short-term use in post-operative patients.

Naloxegol appears to be effective (i.e., increases spontaneous bowel movements without reducing opioid-related analgesia), and well tolerated for up to one year, in patients with opioid-induced constipation being treated for non-cancer pain.³ In fact, efficacy for increasing bowel movements by at least one per week appears to be comparable whether or not a patient failed laxative therapy and is independent of daily opioid dose.² This benefit was seen in about one more patient for every five to ten treated with naloxegol compared with placebo in phase III clinical studies.²

In comparison with naloxegol, methylnaltrexone has only been studied for short-term treatment (i.e., four weeks). Head-to-head studies of naloxegol and methylnaltrexone have not been performed although efficacy appears to be similar. Naloxegol costs about $10 per day, and methylnaltrexone costs about $70 per day.

Note that discontinuing stimulant or osmotic laxatives is recommended once therapy with a peripherally acting opioid antagonist is started. This was typically done in clinical studies and is recommended in product labeling. However, up to three doses of bisacodyl and an enema were allowed as rescue treatments in patients who failed to have a bowel movement for 72 hours in phase III studies.²

To date, naloxegol has not been adequately studied for treating opioid-induced constipation in patients with cancer pain.

Conclusion

Consider naloxegol as an oral alternative to methylnaltrexone when OTC laxatives and lifestyle interventions (e.g., fluids, fiber, physical activity) aren’t effective for relieving opioid-induced constipation in patients with chronic non-cancer pain. Naloxegol is both more convenient to take than methylnaltrexone (oral vs injectable) and significantly less expensive.

Make sure patients who are taking opioids are also started on a bowel regimen (i.e., an osmotic laxative [PEG 3350, etc] or a stimulant laxative) to prevent constipation.⁴ Adding docusate to a stimulant is widely recommended, but doesn’t seem to be beneficial [Evidence level B; lower quality RCT].⁵ Go to our PL Algorithm, Treatment of Constipation in Adults, for comprehensive information about preventing and treating constipation.

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this PL Detail-Document: Stacy A. Hester, R.Ph., BCPS, Assistant Editor

References

1. Product information for Movantik. AstraZeneca. Wilmington, DE 19850. January 2015.
2. Leonard J, Baker DE. Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother 2015;49:360-5.
3. Garnock-Jones KP. Naloxegol: a review of its use in patients with opioid-induced constipation. Drugs 2015;75:419-25.
4. Weitzel KW, Goode JR. Constipation. In Krinsky DL, Ferreri SP, Hemstreet B, et al, Eds. Handbook of Nonprescription Drugs. 18^th ed. Washington, DC: American Pharmaceutical Association, 2015.
5. Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013;45:2-13.
6. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract 2014;141737.

Cite this document as follows: PL Detail-Document, New Drug: Movantik (Naloxegol). Pharmacist’s Letter/Prescriber’s Letter. June 2015.

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