Product
Relistor
Approval Date
April 24, 2008
Release Date
Early June
Company
Progenics/Wyeth
Class
Peripherally acting mu-opioid receptor antagonist
Indication
Subcutaneous injection for the treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.
Active Ingredient
methylnaltrexone bromide
Marketing Strategy/Execution
Call it opioid-induced constipation (OIC) or, if you prefer, opioid-induced bowel dysfunction (OBD); the condition that often results in patients who are taking opioids to manage late-stage illness could turn out to be a small but lucrative market. Wyeth and Progenics, which co-market Relistor, have it all to themselves — for the time being, anyway. How does the drug work? Painkillers such as morphine are often prescribed on a continuous basis for palliative care but can interfere with normal bowel function. Once-a-day, injectable Relistor (methylnaltrexone) is designed to block opioids from relaxing intestinal muscles. Nurses and other attendants who care for hospice patients or the critically ill could use the drug to better control their patients’ bowel movements. The drug is cleared for use only after front-line treatments, like Ex-Lax, are tried. Wyeth, selling Relistor worldwide, is the sole player in the OIC/OBD market. Entereg, being developed by Adolor and GlaxoSmithKline, is in Phase III but was placed under clinical hold at the FDA due to adverse events.
Also in the Pipeline (courtesy of Adis R&D Insight)
No competitor compounds in phase III or pre-registration, US
Recent MM&M Coverage
Product News
Pharmacology
The use of opioid analgesics can lead to constipation due to their effect on intestinal smooth muscle and their interference with normal bowel elimination function. Methylnaltrexone bromide is a mu-opioid receptor antagonist that has limited ability to cross the blood-brain barrier. It blocks the effects of opioids in peripheral tissues, including the GI tract, mitigating their constipating effects without interfering with their centrally-mediated analgesia.
Clinical Trials
The results of two placebo-controlled studies demonstrated the efficacy and safety of Relistor in treating opioid-induced constipation. The studies involved 287 patients with advanced illness (eg, incurable cancer, end-stage COPD, heart failure, Alzheimer’s disease, AIDS). Before screening, patients had been receiving palliative opioid therapy and had opioid-induced constipation. They were on a stable opioid regimen for at least 3 days before randomization. The first study compared single doses of the study drug (0.15mg/kg or 0.3mg/kg) to placebo in a double-blind phase that was followed by an open-label 4-week period in which Relistor was used as needed. The primary endpoint was the proportion of patients with rescue-free laxation within 4 hours of the double-blind dose of the study drug. Patients given either dose of Relistor had a significantly higher rate of laxation than those given placebo.
In the second trial, either the study drug or placebo was given every other day for 2 weeks. During the first week, patients received either Relistor 0.15mg/kg or placebo. In the second week, the dose could be increased to 0.3mg/kg if needed (=2 rescue-free laxations up to day 8). Patients given the study drug had a higher rate of laxation within 4 hours of the first dose than those given placebo, and they had significantly higher rates of laxation within 4 hours after at least two of the first four doses. The laxation response rate was shown to be consistent from the first dose to the 7th dose over the 2-week period.
There was no relationship seen between baseline opioid doses and the laxation response in patients given Relistor. Daily opioid use did not change substantially in either the patients given the study drug or those given placebo, and there was no relevant changes in pain scores from baseline between the groups. Open-label extension studies indicate that the drug maintains its effectiveness for up to 4 months of treatment.
Adverse Reactions
Abdominal pain, flatulence, nausea, dizziness, diarrhea.
Adults
Give by SC inj in upper arm, abdomen, or thigh once every other day as needed (max 1 dose/24hrs); rotate inj sites. <38kg or >114kg: 0.15mg/kg. 38– <62kg: 8mg. 62–114kg: 12mg. Severe renal impair-ment (CrCl<30mL/min): reduce dose by 1/2.
Children
Not recommended.
Contraindications
Mechanical GI obstruction (known or suspected).
Precautions
Reevaluate if severe or persistent diarrhea occurs. Peritoneal catheterization. Bowel movement may occur within 30min of dosing. Pregnancy (Cat.B). Nursing mothers.
