Prucalopride, a selective 5-HT4 receptor agonist used in the treatment of chronic idiopathic constipation (CIC), exhibits a generally favorable safety profile, according to data pooled from multiple clinical trials and an observational cohort study. The findings offer reassurance regarding the drug's tolerability in a patient population often burdened with gastrointestinal distress.
The analysis incorporates data from six double-blind, placebo-controlled clinical trials involving 2530 patients with CIC. Of these, 1251 received prucalopride 2 mg once daily, while 1279 received placebo. The trials, lasting between 12 to 24 weeks, primarily included female (76%) and white (76%) patients, with a mean age of 47 years (ranging from 17 to 95 years).
Common Adverse Reactions
The most frequently reported adverse reactions in patients treated with prucalopride were headache (19% vs. 9% in placebo), abdominal pain (16% vs. 11%), nausea (14% vs. 7%), and diarrhea (13% vs. 5%). Other less common adverse reactions included abdominal distension, dizziness, vomiting, flatulence, and fatigue. Of those who experienced diarrhea, 70% reported it within the first week of treatment, with 73% of these cases resolving within a few days. Severe diarrhea was reported in 1.8% of prucalopride-treated patients compared to 1% in the placebo group.
For patients who reported headache, 66% experienced onset within the first two days of treatment, with symptoms typically resolving within a few days in 65% of these patients.
Discontinuation Rates
In the clinical trials, 5% of patients receiving prucalopride 2 mg once daily discontinued treatment due to adverse reactions, compared to 3% in the placebo group. Nausea was the most common adverse reaction leading to discontinuation (2% prucalopride vs. 1% placebo), followed by headache (1% prucalopride vs. 1% placebo), diarrhea (1% prucalopride vs. <1% placebo), and abdominal pain (1% prucalopride vs. 1% placebo).
Cardiovascular Safety
An independent adjudication committee evaluated major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, across 28 completed clinical trials. In the double-blind trials, the standardized incidence rate (IR) for MACE was 3.5 per 1000 patient-years in the prucalopride group and 5.2 per 1000 patient-years in the placebo group. Combining double-blind and open-label trials, the IR for MACE was 3.3 per 1000 patient-years for prucalopride.
An observational cardiovascular cohort study using European healthcare databases compared new users of prucalopride (N=5715) to new users of polyethylene glycol 3350 (PEG) (N=29,372). The standardized incidence rate ratio (SIRR) for MACE did not demonstrate an increased risk and excluded a pre-specified safety margin of a three-fold risk of MACE during prucalopride use relative to PEG use.
Suicidal Ideation and Behavior
In double-blind trials, one patient reported a suicide attempt seven days after the end of treatment with prucalopride 2 mg once daily; no such events were reported in the placebo group. In open-label trials, two patients reported a suicide attempt, and another reported suicidal ideation. Completed suicide was reported in two patients previously treated with prucalopride 2 mg or 4 mg; both had discontinued prucalopride at least one month prior to the event. These events warrant careful consideration, although a causal relationship with prucalopride is not definitively established.
