Minimizing Risk of Mental Status Changes with H2 Blockers: Dosage Adjustments in Kidney Dysfunction
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.
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.
1. Schentag JJ, Cerra FB, Calleri G, et al. Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet. 1979;1:177-181.
2. Basavaraju NG, Wolf-Klein G, Sivertone FA, et al. Cimetidine-induced mental confusion in elderly. NY State Med J. 1980;80:1287-1288.
3. Weddington WW Jr, Muelling AE, Moosa HH, et al. Cimetidine toxic reactions masquerading as delirim tremens. JAMA. 1981;245:1058-1059.
4. Price W, Coli L, Brandstetter RD, et al. Ranitidine-associated hallucinations. Eur J Clin Pharmacol. 1985;29:375-376.
5. MacDermott AJ, Insole J, Kaufman B. Acute confusional episodes during treatment with ranitidine. Br Med J. 1987;294:1616.
6. Slugg PH, Haug MT, Pippenger CE. Ranitidine pharmacokinetics and adverse central nervous system reactions. Arch Intern Med. 1992;152:
7. Henann NE, Carpenter DU, Janda SM. Famotidine-associated mental confusion in elderly patients. Drug Intell Clin Pharm. 1988;22:976-978.
8. Odeh M, Oliven A. Central nervous system reactions associated with famotidine: report of five cases. J Clin Gastroenterol. 1998;27:253-254.
9. Rodgers PT, Brengel GR. Famotidine-associated mental status changes. Pharmacotherapy. 1998;18:404-407.
10. Yoshimoto K, Saima S, Echizen H, et al. Famotidine-associated central nervous system reactions and plasma and cerebrospinal drug concentrations in neurosurgical patients with renal failure. Clin Pharmacol Ther. 1994;55:693-700.
11. Catalano G, Catalano MC, Alberts VA. Famotidine-associated delerium. A series of six cases. Psychosomatics. 1996;37:349-355.
12. Axid Product Information. Reliant Pharmaceuticals, Liberty Corner, NJ.
13. Cantu TG, Korek JS. Central nervous system reactions to histamine-2 receptor blockers. Ann Intern Med. 1991;114:1027-1034.
14. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians, 2007.
15. Climetidine. FDA Prescribing Information. www.drugs.com/pro/cimetidine.html. Accessed December 5, 2014.
16. Zantac Product Information. Physicians Desk Reference, 68th ed. Montvale, NJ: PDR Network, LLC; 2014.
17. Pepcid Product Information. Salix Pharmaceuticals, Inc, Raleigh, NC.
18. Redmond AM, Pentapaty N, Weibel J, et al. Use of famotidine in adult patients with end-stage renal disease: assessment of dosing and mental status changes. Am J Med Sci. 2005;330:8-10.
19. National Kidney Disease Education Program. Chronic kidney disease and drug dosing: information for providers. 2010. http://nkdep.nih.gov/resources/CKD-drug-dosing.shtml. Accessed October 21, 2014.