Is cimetidine associated with neutropenia?

Background: Cimetidine is perceived as sufficiently safe that it is being considered for over-the-counter use. However, because of residual concerns about cimetidine-induced neutropenia, a study was conducted to evaluate this association.

Methods: A population-based, case-control study was undertaken using a large database with Medicaid data from six states. Cases were defined as patients hospitalized with a discharge diagnosis of neutropenia. Medical records were sought to validate the diagnoses of neutropenia and to characterize the severity of disease. Four controls were randomly selected for each case, matched for age, sex, state, and year of diagnosis. The frequency of exposures to cimetidine in the 30 days prior to hospital admission in the cases was compared to that in the identical time periods in the controls.

Results: When investigators simultaneously controlled for multiple, potentially confounding variables by using conditional logistic regression, the odds ratio associated with the use of cimetidine was 1.2 (P = 0.33), with a one-sided upper 95% confidence limit of 2.6 for all patients over 20 years of age, and 0.6 (P = 0.30) with a one-sided upper 95% confidence limit of 3.1 for validated cases over 12 years of age. Neither a dose-response relationship was evident (P = 0.899 and P = 0.716, respectively, when excluding the nonusers, or P = 0.245 and P = 0.215, respectively, when including the nonusers). From these data, one can exclude the occurrence of hospitalization with neutropenia or agranulocytosis due to cimetidine occurring more often than once in every 116,000 patients and once in every 573,000 patients receiving a 6-week course of the drug, respectively.

Conclusion: If there is an association between cimetidine and neutropenia, it appears to be very small.