Chronic Kidney Disease

Minimizing Risk of Mental Status Changes with H2 Blockers: Dosage Adjustments in Kidney Dysfunction

Timothy H. Self, PharmD, Jerry P. Gilless, MD, and Joanna Q. Hudson, PharmD, BCPS

For the past 35 years, histamine2 blockers (H2 blockers) have continued to have widespread use within the United States. Soon after cimetidine was released, central nervous system (CNS) reactions were reported for this H2 blocker.1-3 The literature reports similar cases for rantidine4-6 and famotidine.7-11 The manufacturer also reports nizatidine-induced CNS reactions.12 A range of CNS reactions, such as confusion, agitation, delirium, hallucinations, and irritability, have been reported.1-12 While these adverse effects are relatively rare, they are well-documented and therefore should be included in the differential.

Recommended Dosage

Mental status changes associated with H2 blockers have usually occurred within the first 2 weeks of treatment. Fortunately, these CNS reactions typically resolve within 3 days of stopping H2 blocker therapy.13 Reactions seem to be more likely in elderly patients, and hospitalized patients may be more susceptible than outpatients. Decreased kidney function, as indicated by increased serum creatinine concentrations, may be a risk factor for CNS reactions, but no clear relationship has been established.13 Nevertheless, standard references consistently recommend a dosage decrease based on estimated creatinine clearance (Table 1).14 

Furthermore, FDA-approved product literature recommends dose reduction for each available H2 blocker in patients with a creatinine clearance <50 mL/min (Table 2).12,15-17 We note that for famotidine, the manufacturer’s recommendation of 20 mg daily is appropriate for most patients with end-stage renal disease (vs 10% of the usual dose14).17,18  Very similar recommendations are found in commonly used drug information applications for smartphones and tablets.

It is also important to note that dosing recommendations for H2 blockers are based on creatinine clearance in mL/min. Reporting of an estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2 has become routine in clinical practice. While use of the eGFR has been advocated for drug dosing, it is important to note that the eGFR should be multiplied by the patient’s body surface in m2 area divided by 1.73 m2 to adjust this value to an estimate in mL/min.19 This is particularly important for individuals at extremes of body size (ie, substantially above or below 1.73 m2).19 

There are consistent recommendations of dose reductions in patients with kidney dysfunction. Many H2 blockers are available over-the-counter, which increases the risk of adverse events in the chronic kidney disease (CKD) population, as well as those with acute kidney injury. Consequently, it is prudent for physicians, pharmacists, and nurse practitioners to recommend the appropriate dose based on the patient’s age and kidney function as well as to educate the CKD population on the lesser-known risks of H2 blockers.

Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center in Memphis and program director of the PGY2 Internal Medicine Pharmacy Residency at Methodist University Hospital.

Jerry P. Gilless, MD, is an assistant professor of general internal medicine at the University of Tennessee Health Science Center in Memphis and a board-certified nephrologist. He is a hospitalist and internal medicine physician at Methodist University Hospital. 

Joanna Q. Hudson, PharmD, BCPS,is an associate professor of clinical pharmacy and medicine (nephrology) at the University of Tennessee Health Science Center in Memphis and a clinical pharmacy specialist in nephrology at Methodist University Hospital. 


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19. National Kidney Disease Education Program. Chronic kidney disease and drug dosing: information for providers. 2010. Accessed October 21, 2014.