Research
Tardive Dyskinesia Risks and Metoclopramide Use Before and After U.S. Market Withdrawal of Cisapride

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ABSTRACT

Objective

To assess risk factors for tardive dyskinesia (TD) in spontaneousreports of metoclopramide and TD and evaluate metoclopramide prescribing patterns before and after withdrawal of cisapride from the market in the United States.

Design

Retrospective and observational analyses.

Setting

International metoclopramide adverse event reports and domesticdrug-use data for the continental United States.

Patients

Users of metoclopramide for 30 days or more who experiencedadverse events reported as TD.

Interventions

Analyses of the Food and Drug Administration AdverseEvent Reporting System (AERS) and IMS HEALTH data.

Main Outcome Measures

Pharmacoepidemiological patterns in AERS reports and utilization data from IMS HEALTH.

Results

The case series comprised 87 reports of primarily older (mean ± SD, 60 ± 22 years) women (67% of all cases). While average metoclopramidedaily dose (33 ± 14 mg) was within recommended product labeling limits,duration of use was considerably longer (753 ± 951 days). Overall, 37% of thereports included concomitant drugs believed to be TD risk factors. Similarly,18% of the reports noted comorbid diseases that are considered risk factors fordevelopment of TD. Metoclopramide utilization decreased following cisapridemarketing in 1993 and increased following cisapride withdrawal in 2000. Themajority (62%) of metoclopramide prescriptions were intended for women.Intended use overall increased with age and was highest in the seventh andeighth decades, with nearly one quarter of all utilization being in persons olderthan 70 years.

Conclusion

Well-described TD risk factors were common in metoclopramide-associated TD reports. Given the cisapride market withdrawal andassociated increased metoclopramide utilization, the incidence of TD mayincrease accordingly. TD risk factors relative to the intended benefit and durationof use should be considered in metoclopramide prescribing.

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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    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.

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