Journal of the American Pharmacists Association
ResearchTardive Dyskinesia Risks and Metoclopramide Use Before and After U.S. Market Withdrawal of Cisapride
Section snippets
Objectives
We aim to draw attention to the presence of underlying risk factors for TD in spontaneous reports of metoclopramide-associated TD obtained through the Adverse Event Reporting System (AERS) of the MedWatch program of the Food and Drug Administration (FDA). To evaluate possible trends in prescribing patterns associated with cisapride withdrawal, we also assessed metoclopramide-prescribing characteristics drawn from U.S. office-based practices and community pharmacy metoclopramide prescriptions.
Methods
We retrospectively evaluated case reports in the FDA AERS from its inception (1968) through June 2003. This database, described in more detail elsewhere, consists of nearly 3 million spontaneous reports submitted by manufacturers (via regulatory mandate), and clinicians and patients (through the MedWatch program).21,22 Our search criteria included metoclopramide for the drug exposure and “tardive dyskinesia” as the adverse event. We included all case reports regardless of nationality or route
Results
Our query of the AERS database yielded 98 metoclopramide-associated TD reports. Our case series consisted of 87 patients after duplicate reports were eliminated (Table 1). Metoclopramide-associated TD reports were primarily from older (mean ± SD, 60 ± 22 years; range, 11 weeks to 95 years) women (67% of patients). The metoclopramide average daily dose (33 ± 14 mg) was within limits recommended in product labeling. The mean duration of metoclopramide use was notably long (753 ± 951 days; median,
Discussion
In this descriptive analysis of metoclopramide-associated TD reports and metoclopramide prescription trends, we observed that TD risk factors were common in metoclopramide adverse event reports. Risk factors linked to TD observed in this case series were increasing duration of use, increasing age, female gender, and concomitant drug and disease states. Furthermore, prescription trends demonstrated a marked increase in metoclopramide use following cisapride withdrawal. Although precise
Limitations
Spontaneous reports are influenced by well-known biases: underreporting (rates as low as 1% and ranging as high as 13% often depending upon the type and severity of the adverse reaction28), marketing trends, and publication bias. In addition, because of confounding factors, causation cannot be determined in our analysis. However, we did not seek to assign causation but rather to highlight the importance of risk factors—especially potentially modifiable factors such as concomitant drugs and
Conclusion
TD is a rare, serious, and potentially irreversible adverse effect of metoclopramide. TD risk factors are notable in clinical practice and reflected in adverse event reports for metoclopramide. If current prescription trends continue, TD incidence may be expected to increase. Given the paucity of evidence that metoclopramide improves the quality of life, TD risk factors relative to the intended benefit and duration of use should be carefully considered in metoclopramide prescribing.
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2021, Clinics in Geriatric MedicineCitation Excerpt :Although there are an increasing number of medications becoming available for the treatment of gastroparesis, in older adults many medications carry undesired side effects. Cisapride, a 5-HT4 receptor agonist, was initially used for the treatment of gastroparesis, but later removed from the market owing to an increased risk of arrhythmia.72 Bethanechol, a muscarinic receptor agonist, decreases fundic contractions allowing for improved gastric accommodation, as well as increasing pyloric contractility to improve gastric emptying.73
Prokinetic agents for gastroparesis
2020, Gastroparesis: Pathophysiology, Clinical Presentation, Diagnosis and TreatmentGastroesophageal Reflux Disease and Aerodigestive Disorders
2018, Current Problems in Pediatric and Adolescent Health CareCitation Excerpt :However, its efficacy in management of airway symptoms has not been extensively studied. The side effect profile of extrapyramidal symptoms, tardive dyskinesia and torticollis have led to a “black box warning” by the Food and Drug Administration has weighed against the routine use of this medication.129–131 Cisapride promote acetylcholine release from postganglionic nerve endings of the GI myenteric plexus longitudinal tract, and is also an agonist for 5-HT4 and an antagonist for 5-HT5 receptors.
Cystic Fibrosis and gastroesophageal reflux disease
2017, Journal of Cystic FibrosisCitation Excerpt :The efficacy of domperidone (a selective dopamine-2 receptor antagonist) and of metoclopramide (a dopamine-2 receptor antagonist with 5-HT3 receptor antagonist and 5-HT4 receptor agonist effects) in subjects with CF is unknown. Metoclopramide use increases risk for tardive dyskinesia [104]. Erythromycin (frequently as an ethyl succinate-EES) and azithromycin are macrolide antibiotics that also display promotility effects, mediated by their stimulation of motilin receptors on GI smooth muscle [105].
Systematic review and meta-analysis: Gastric electrical stimulation for gastroparesis
2017, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :Although delayed gastric emptying is considered to be the defining feature of gastroparesis, prokinetic agents that target this parameter often provide only limited or even no symptomatic relief. Metoclopramide remains the only medication approved in the United States for the medical management of gastroparesis, but it is associated with common side effects and the risk of tardive dyskinesia (Lavy et al., 1978; Stanley et al., 1979; Shaffer et al., 2004). Motilin agonists effectively accelerate gastric emptying, but studies tracking symptomatic outcomes with these agents have not demonstrated superiority over placebo (McCallum et al., 2007a; Russo et al., 2004; Talley et al., 2001).
Commonly used gastrointestinal drugs
2014, Handbook of Clinical NeurologyCitation Excerpt :A retrospective analysis of 434 patients followed up for TD at a movement disorder clinic revealed that metoclopramide was responsible for 39.4% of cases, and was the second most common medicine to induce TD following haloperidol (Kenney et al., 2008). Withdrawal of cisapride from the US markets in 2000, following reports of its cardiotoxicity, led to a surge of metoclopramide use as a prokinetic and an increase in the incidence of metoclopramide-induced TD (Shaffer et al., 2004; Kenney et al., 2008). Currently, metoclopramide accounts for a third of all reported DIMDs (Pasricha et al., 2006).
See related article on page 659.
Disclosure: The authors declare no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria.
Funding: No direct support was received for this manuscript by U.S. Food and Drug Administration (FDA) employees. The FDA by contractual agreement has access to IMS HEALTH data and conducted independent analyses. Dr. Butterfield’s research is supported by a Research Career Development Award, the Duke Clinical Research Institute, and the Department of Veterans Affairs, Veterans Health Administration, HSR&D Service, through a Veterans Affairs research career development award (RCD-0019-2).
Disclaimer: The views expressed in this manuscript are those solely of the authors and not necessarily the Food and Drug Administration, Duke University School of Medicine or Department of Veterans Affairs.