Naldemedine Tablets (Symproic) C-II
April 30, 2017 4 minutes read
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A third oral, naltrexone-derived, peripheral acting µ-opioid receptor antagonist (PAMORA) has been approved by the FDA for the treatment of opioid-induced constipation (OIC) in patients with chronic non-cancer pain. Naldemedine is similar to naltrexone, but with the addition of a phenyl oxadiazoyl propyl carboxamide side chain to reduce central nervous system penetration. It is marketed as Symproic.
INDICATION
Naldemedine is indicated for the treatment of OIC in adults with chronic noncancer pain.1
DOSAGE
The recommended dose is 0.2 mg once daily with or without food.1 Patients who have taken opioids for less than four weeks may be less responsive to naldemedine. The drug is available as 0.2 mg tablets.
POTENTIAL ADVANTAGES
Naldemedine has low penetration into the central nervous system because of its lower lipid solubility and its role as the substrate for P-glycoprotein transporter, which increases efflux across the blood-brain barrier.1
POTENTIAL DISADVANTAGES
Most common adverse reactions (compared to placebo) in 12-week studies are abdominal pain (8-11% vs. 2-5%), diarrhea (7% vs. 2-3%), and nausea (4-6% vs. 2-5%).1 Avoid concomitant use with strong CYP3A4 inducers. Like other PAMORAs, naldemedine is a schedule II controlled substance.
COMMENTS
The efficacy of naldemedine was evaluated in two replicate, 12-week, randomized, double-blind, placebo-controlled studies.1 Subjects with noncancer pain met OIC criteria based on the Bowel Movement and Constipation Assessment Diary. This is defined as no more than four spontaneous bowel movements (SBMs) over 14 consecutive days and less than three SBMs in a given week, with at least 25% of the SBMs associated with one or more of the following: staining, hard or lumpy stools, having a sensation of incomplete evacuation, and having a sensation of anorectal obstruction/blockage. Subjects were on a stable opioid regimen at a total daily dose of ≥ 30 mg morphine equivalent for at least four weeks and were not using or agreed to discontinue laxatives. Subjects were randomized to naldemedine (n = 273; n = 276) or placebo (n = 271; n = 274) in the first and second studies, respectively. Treatment response was defined as having at least two SBMs per week and a change from baseline of at least one SBM per week for at least nine out of the 12 weeks and three out of the last four weeks.
The response rates were 48% for naldemedine compared to 35% for placebo in the first study, and 53% compared to 34% in the second study. Absolute treatment differences were 13% and 19%, respectively. The mean increase in frequency of SBMs per week from baseline compared to placebo during the first week was about two. The mean increase in frequency of complete SBM from baseline compared to placebo during the last two weeks of the 12-week treatment period was only about one. Results from a 52-week placebo-controlled study (n = 621) suggest the drug is well tolerated, with common adverse reactions between 6-11%, compared to 3-5% for placebo.3 There are no published comparative studies with other oral naltrexone-derived peripheral acting opioid antagonists. When indirectly comparing placebo-controlled studies of other PAMORAs, the treatment differences appear to be similar across studies.2 For methylnaltrexone, the treatment difference was 13%.4 For naloxegol, differences were 15% and 10% in two studies.5
CLINICAL IMPLICATIONS
OIC is a result of opioid medications binding to the µ-opioid receptors, causing increased fluid absorption and reduced gastrointestinal motility. OIC is a common problem in patients on long-term opioid therapy, and it significantly affects quality of life and increases healthcare use.6-8 Generally, OIC does not respond well to conventional laxatives. For laxative-resistant OIC, there are four PAMORAs and a chloride channel activator (lubiprostone) approved by the FDA. Alvimopan is recommended for hospital use only because of cardiovascular risk. This leaves three modified versions of naltrexone: methyl derivative (methylnaltrexone), pegylated naltrexone (naloxegol), and naldemedine. Although PAMORAs are more effective than placebo, their benefit appears modest as a large percentage of subjects remained constipated at the end of the study.2 With minimal differences in benefit, treatment choice may be determined by price. For a 30-day supply, lubiprostone (24 mcg twice daily) is $420. Methylnaltrexone (three times 150 mg daily) is $1,800, and naloxegol (25 mg daily) is $377. The cost for naldemedine was not available at the time of this review.
REFERENCES
- Symproic Prescribing Information. Shionogi and Purdue Pharma. March 2017.
- Sonu I, Triadafilopoulos G, Gardner JD. Persistent constipation and abdominal adverse events with newer treatments for constipation. BMJ Open Gastroenterol 2016 Jun 20;3(1):e000094. doi: 10.1136/bmjgast-2016-000094. eCollection 2016.
- Healio. COMPOSE III: Naldemedine safe for long-term treatment of OIC. Available at: http://bit.ly/2ogxqht. Accessed April 1, 2017.
- Relistor Prescribing Information. Valeant and Progenic Pharmaceuticals. January 2017.
- Movantik Prescribing Information. AstraZeneca Pharmaceuticals. August 2016.
- Müller-Lissner S, Bassotti G, Coffin B, et al. Opioid-induced constipation and bowel dysfunction: A clinical guideline. Pain Med 2016 Dec 29. pii: pnw255. doi: 10.1093/pm/pnw255. [Epub ahead of print].
- Pergolizzi JV Jr, Raffa RB, Pappagallo M, et al. Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy. Patient Prefer Adherence 2017;11:107-119.
- Hjalte F, Ragnarson Tennvall G, Welin KO, Westerling D. Treatment of severe pain and opioid-induced constipation: An observational study of quality of life, resource use, and costs in sweden. Pain Ther 2016;5:227-236.
Naldemedine is indicated for the treatment of opioid-induced constipation in adults with chronic noncancer pain.
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