The US Food and Drug Administration (FDA) has approved methylnaltrexone bromide (Relistor, Salix Pharmaceuticals/Progenics Pharmaceuticals) subcutaneous injection 12 mg/0.6 mL for the treatment of opioid-induced constipation (OIC) in patients taking opioids for noncancer pain.
The drug was approved in the United States in 2008 for the treatment of OIC in patients with advanced illness receiving palliative care, when the response to laxative therapy has not been sufficient.
It is currently the only available peripherally acting mu-opioid receptor antagonist approved for treating OIC by blocking the constipating effects of opioids in the gastrointestinal tract without crossing the blood-brain barrier and interfering with the analgesic effects of opioids, the companies note in a joint statement.
The drug was declined approval for this indication in July of 2012. In the complete response letter, the FDA asked for more data to support the application.
Approval is based on results of a randomized, double-blind, placebo-controlled trial including a total of 312 patients with a history of noncancer pain who were taking opioids for at least 1 month prior to study entry. All had confirmed constipation, defined as less than 3 spontaneous bowel movements per week during the screening period.
Constipation due to opioid use had to be associated with 1 of more of the following, the statement notes: a Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements; straining during, or a sensation of incomplete evacuation after at least 25% of the bowel movements.
The median duration of constipation at baseline was 59 months, the statement notes. The median daily baseline oral morphine equivalent dose was 161 mg. Patients were randomized to receive methylnaltrexone 12 mg or placebo once daily for 4 weeks, followed by an 8-week open-label phase where patients could take medications as needed.
Study results showed that a significantly great proportion of patients taking methylnaltrexone reported having 3 or more spontaneous bowel movements during the 4-week double-blind period vs placebo (59% vs 38%).
After the first dose, 33% of treated patients reported having a spontaneous bowel movement within 4 hours, and approximately 50% had a bowel movement prior to the second dose.
Treatment was well tolerated, and adverse events were consistent with those seen with other studies of the drug in an advanced illness population, the statement adds. The most common side effects were abdominal pain (21%), diarrhea (6%), nausea (9%), and hyperhidrosis (6%). Hot flush, tremor, and chills were also seen.
Methylnaltrexone is contraindicated in patients with known or suspected gastrointestinal (GI) obstruction and those at increased risk of recurrent obstruction, due to the potential for GI perforation, the statement warns. Cases of perforation have been reported in patients with advanced illness in conditions that may be associated with localized or diffuse reduction in the structural integrity of the GI tract, such as peptic ulcer disease, Ogilvie syndrome, diverticular disease, infiltrative GI tract malignancies, or peritoneal metastases.
"Take into account the overall risk-benefit profile when using Relistor in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease)," the statement adds. "Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue Relistor in patients who develop this symptom. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with Relistor and consult their physician."
Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with this drug, the release said. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored closely for adequacy of analgesia and symptoms of opioid withdrawal.
Concomitant use with other opioid antagonists should be avoided because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal, it said.
It may precipitate opioid withdrawal in a fetus and "should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
"Unlike other opioid-related side effects, such as nausea and vomiting, constipation never goes away," said Eugene Viscusi, MD, director of Acute Pain Management, Department of Anesthesiology, at Thomas Jefferson University in Philadelphia, in the companies' statement. "Constipation is one of the side effects for which patients do not develop tolerance with chronic exposure. It can be a significant burden affecting a patient's ability to function adequately."
Patients generally experience a rapid bowel movement following administration of methylnaltrexone, often within 30 minutes, Dr. Viscusi adds. "Unlike laxatives, Relistor offers patients a relatively predictable timed response for a bowel movement. Additionally, most patients describe the sensation like a normal bowel activity. These attributes of treatment with Relistor are tremendous advantages."
The use of the drug beyond 4 months has not been studied in the advanced illness population, the statement said.
Methylnaltrexone is approved for use in over 50 countries worldwide, including the European Union, Canada, and Australia, and applications in additional countries are pending. It is under license to Salix Pharmaceuticals from Progenics Pharmaceuticals.
Full prescribing information for methylnaltrexone can be found at www.salix.com.
Last month, the FDA approved naloxegol (Movantik, AstraZeneca) for the treatment of OIC in adults with chronic noncancer pain.
Last year, it approved another agent, lubiprostone (Amitiza, Sucampo Pharmaceuticals/Takeda Pharmaceuticals USA), the first oral treatment for OIC in adults with chronic noncancer pain.
Cite this: FDA Okays Methylnaltrexone (Relistor ) for Opioid Constipation - Medscape - Sep 30, 2014.