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.

The FDA has approved a highly selective serotonin 5-HT4 receptor agonist to treat chronic idiopathic constipation (CIC) in adults. Previously approved members of this pharmacologic class, cisapride and tegaserod, were withdrawn from the market because of higher risks of potential adverse cardiovascular events. Prucalopride has been available in Europe for 10 years. It is marketed as Motegrity.

INDICATIONS

Prucalopride is indicated for the treatment of CIC in adults.1

DOSAGE

The recommended dose is 2 mg once daily.1 For patients with severe renal impairment (creatinine clearance < 30 mL/min), the dose is 1 mg once daily. The tablets may be taken without regard to food. Prucalopride is available as 1 mg and 2 mg tablets.

POTENTIAL ADVANTAGES

Prucalopride offers a drug from a different class and different mechanism of action for the treatment of CIC.

POTENTIAL DISADVANTAGES

The long-term efficacy, particularly in the elderly, has not been established. The most frequently reported adverse reactions (compared to placebo) were headache (19% vs. 9%), abdominal pain (16% vs. 11%), nausea (14% vs. 7%), and diarrhea (13% vs. 5%).1

Asian patients reported a higher frequency of diarrhea compared to non-Asian patients but lower frequency of other adverse events.2 There is a warning on the label for increased risk of suicidal ideation and behavior.1

COMMENTS

Prucalopride is a selective 5-HT4 agonist that results in the stimulation of colonic peristalsis, increasing bowel motility.1 Its efficacy was evaluated in six double-blind, placebo-controlled, randomized trials that all included subjects with CIC.1,2 Five studies lasted 12 weeks each, while the other lasted 24 weeks.

Eligible subjects had a history of chronic constipation (fewer than three spontaneous bowel movement [SBMs] per week) that resulted in a feeling of complete evacuation (CSBM) and one or more of these symptoms: lumpy or hard stools, sensation of incomplete evacuation, or straining at defecation for more than 25% of bowel movements in the preceding three months. Symptoms had to begin more than six months prior to screening. Most subjects were white women, mean age 47 ± 16 years, with a mean duration of constipation of 16 ± 15 years. Subjects were randomized to prucalopride (2 mg daily if age < 65 years and 1 mg with the option to titrate to 2 mg if age ≥ 65 years). Treatment response was defined as an average of ≥ 3 CSBMs per week over the 12-week treatment period.

Five of the six studies revealed statistical advantage for prucalopride, with responder rates ranging from 19-38% vs. 10-18% for placebo. Absolute percent treatment differences ranged from 10-23%. The authors of the 24-week study did not observe statistical difference at either 12 or 24 weeks.3,4 An integrated analysis of the six studies showed an overall response rate of 27.8% vs. 13.2% for placebo.5

Because of the risk of cardiovascular events with a previous member of the same pharmacologic class (tegaserod), cardiovascular safety was assessed with nonclinical data and postmarket pharmacoepidemiologic observational data — mainly European data, since the drug was approved in 2009. Prucalopride showed no significant QTc prolongation, no platelet aggregation, and no evidence of increased risk (excluding a prespecified safety margin of three-fold risk) of major adverse cardiovascular events.1,3

CLINICAL IMPLICATIONS

CIC is a common disorder that is more common in women, older individuals, and those of lower socioeconomic status.6 Treatment of CIC includes a fiber supplement, osmotic and stimulant laxatives, a 5-HT4 receptor agonist, or a prosecretory agent.6 Currently, prucalopride is the only approved 5-HT4 receptor agonist. Plecanatide and linaclotide are guanylate cyclase-C agonists, and lubiprostone is a chloride channel activator. These agents act by stimulating chloride secretion. Response rates (from placebo) were modest and ranged from 8-17%.7,8 Furthermore, not all available therapies are either effective or tolerated in all patients.3

There are no available comparisons between prucalopride and the other agents. Studies that include laxative-resistant patients would be particularly useful. Only placebo-controlled studies are available; treatment difference between drug and placebo using similar efficacy endpoints appeared to be similar.3 The cost for prucalopride was not available at the time of this review.

REFERENCES

  1. Shire US Inc. Motegrity Prescribing Information, December 2018. Available at: https://bit.ly/2ExaDa6. Accessed Jan. 9, 2019.
  2. Omer A, Quigley EMM. An update on prucalopride in the treatment of chronic constipation. Therap Adv Gastroenterol 2017;10:877-887.
  3. U.S. Food and Drug Administration. FDA Briefing Document. Gastrointestinal Drug Advisory Committee Meeting. Available at: https://bit.ly/2sjwgCU. Accessed Jan. 9, 2019.
  4. Müller-Lissner S, et al. A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. Neurogastroenterol Motil 2010;22:991-998, e255.
  5. Garnock-Jones KP. Prucalopride: A review in chronic idiopathic constipation. Drugs 2016;76:99-110.
  6. Ford AC, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109 (Suppl 1):S2-26; quiz S27.
  7. Allergan Inc. Linzess Prescribing Information, January 2017. Available at: https://bit.ly/2qZKeei. Accessed Jan. 9, 2019.
  8. Synergy Pharmaceuticals Inc. Trulance Prescribing Information, January 2017. Available at: https://bit.ly/2VG0PjB. Accessed Jan. 9, 2019.