Dose-reducing H2 receptor antagonists in the presence of low glomerular filtration rate: a systematic review of the evidence

J. Manlucu1, M. Tonelli2, J. G. Ray3, A. Papaioannou4, G. Youssef1, H. R. Thiessen-Philbrook1, A. Holbrook5 and A. X. Garg1,6

1 Division of Nephrology and 6 Department of Epidemiology, University of Western Ontario, London, Ontario, 2 Division of Nephrology, University of Alberta, Edmonton, Alberta, 3 Departments of Medicine and Health Policy Management Evaluation, University of Toronto, Toronto, 4 Division of Geriatric Medicine and 5 Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence and offprint requests to: Amit Garg, MD, PhD, London Kidney Clinical Research Unit, Room A01, Westminster Tower, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada. Email: Amit.Garg{at}lhsc.on.ca



   Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. While it is recommended that H2 receptor antagonists (H2RAs) be dose reduced in the presence of low glomerular filtration rate (GFR), in practice such adjustments often do not occur. We reviewed the evidence for this recommendation.

Methods. We searched multiple medical reference databases for relevant cohort studies and randomized clinical trials. Studies that enrolled five or more participants with low GFR who also received at least one unadjusted dose of an H2RA, and who were compared with controls were included. Data were abstracted on study and participant characteristics and drug-related adverse effects. Pharmacokinetic measures were pooled using meta-analysis.

Results. A total of 22 articles were included, comprising 19 unique cohort studies. With declining GFR, there was a significant increase in the area under the curve (AUC) and elimination half-life (t1/2) of the serum drug concentration of H2RAs (P<0.001). Compared with a GFR >80 ml/min/1.73 m2, drug AUC increased by 200% when the GFR was 30 ml/min/1.73 m2, and by 300% when the GFR was 20 ml/min/1.73 m2. In hospitalized patients with low GFR, reducing the interval dose of intravenous H2RA was associated with fewer adverse reactions. The gastro-protective effects of H2RAs were similar with reduced and unadjusted doses.

Conclusions. Reducing the dose of H2RAs in persons with low GFR will decrease drug expenditure and may prevent adverse events, without a change in efficacy. Quality assurance programmes, which improve deficiencies in H2RAs prescribing, appear justified.

Keywords: H2 receptor antagonist; kidney function tests; meta-analysis



   Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
H2 receptor antagonists (H2RAs) are one of the mostly widely prescribed and efficacious drug classes for the prevention of peptic ulcer disease [1], gastro-oesophageal reflux disease [2] and stress-induced ulcers in the critically ill [3]. Despite greater use of proton pump inhibitors, H2RAs use increased from 7 to 26 per thousand persons over the past decade [4]. Both oral and parenteral H2RAs consistently rank high in drug plan and hospital pharmacy expenditures [5,6].

Since they are renally excreted, usual doses of H2RAs may lead to unnecessarily high drug concentrations in patients with low glomerular filtration rate (GFR), which may result in adverse effects such as altered mental status and increased transaminase levels [7,8]. This led manufacturers to recommend dose reductions in patients with low GFR (Table 1). However, in practice, between 25 and 50% of hospitalized patients with low GFR do not receive dose adjustments [6,9]. The reasons for this variance in care are multifactorial, and may stem from a lack of awareness of low GFR or clinician scepticism about the quality of evidence supporting manufacturer's dosing recommendations. We reviewed the pharmacokinetic and clinical evidence for reducing the dose of H2RAs in the presence of low GFR.


View this table:
[in this window]
[in a new window]
 
Table 1. Manufacturer's recommended dose reductions for common H2 receptor antagonists in the presence of reduced glomerular filtration ratea

 


   Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Studies eligible for our review
English language cohort studies and randomized clinical trials were included that met each of the following criteria: (i) enrolled at least five participants with low GFR who received at least one unadjusted dose of H2RA; (ii) included either a control group of five or more persons with either normal GFR (>80 ml/min/1.73 m2) who received a similar medication dose, or lower GFR who received a reduced dose of H2RA; and (iii) reported either H2RA drug pharmacokinetics or a clinical measure of drug efficacy or side effects. The former was represented as either a drug area under the curve (AUC), i.e. the total amount of drug, through time, that is detectable in plasma when administered orally or intravenously (i.v.), or the elimination half-life (t1/2), i.e. the time required for the plasma drug concentration to be decreased by 50%. Studies with end-stage renal disease patients were excluded, given the alteration of H2RA pharmacokinetics by dialysers [10].

Literature search
We searched MEDLINE from 1966 to November 2003 and EMBASE from 1980 to November 2003, using the following terms to identify eligible studies of H2RAs and low GFR: cimetidine, famotidine, nizatidine, ranitidine, kidney diseases and kidney function tests (complete search strategies available from the authors). Supplementary methods of finding relevant studies included speaking to manufacturers, reviewing article reference lists, other references [11–22], the Science Citation Index, and ‘see related articles’ PubMed citations. Citations considered potentially relevant were retrieved. Two physicians (J.M. and A.G.) independently evaluated the eligibility of each study, and disagreements were resolved by consensus.

Data abstraction
One reviewer abstracted data on study and participant characteristics, measures of renal function, drug pharmacokinetic and clinical events. Each study was also evaluated on the proportion of participants lost to follow-up, use of matched controls or adjustment for potential confounders, and masked assessment of underlying renal function, participant health or clinical outcomes. A second reviewer confirmed the accuracy of all abstracted data.

Statistical analysis
The percentage increase in the AUC and t1/2 with low GFR was calculated using a GFR >80 ml/min/1.73 m2 as the referent. Random effects meta-analysis for trend estimation was used to graph the relationship between the percentage increase in AUC and t1/2 with GFR [23]. A relative risk (RR) and 95% confidence interval (CI) were calculated for all adverse clinical events [24]. All analyses were done using SAS version 8.02 and R version 2.0.0.



   Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Finding and selecting studies
Out of 1750 potential citations, 45 full-text articles were retrieved, of which 22 articles describing 19 unique patient groups met our inclusion criteria [25–46]. Reviewer agreement on study eligibility was good but not quantified.

Methodology for assessment of studies
No randomized clinical trial was included in this review as participants with low GFR were either excluded or, when included, were given an adjusted dose of H2RA as per trial protocol [3,47]. Of the 19 cohorts studied, with the exception of one whose controls were individuals with low GFR who received a reduced H2RA dose [46], all controls had normal GFR and received the usual dose of H2RA. Pharmacokinetic studies were conducted in a prospective fashion, and the follow-up of each of these studies was typically 100%. In those studies that assessed clinical outcomes, the proportion of patients lost to follow-up was poorly described. The clinical indication for using H2RAs pre-dated each study, and was made by each participant's physician. Two studies compared relevant baseline characteristics between persons with low GFR and controls [41,46]. Two studies used clinical outcome adjudicators who were masked to renal function and medication dose [39,41]. Only one study used multivariate analysis to assess the adjusted risk of appropriate H2RA dosing [44].

GFR measurement within studies
When described, low GFR was assessed using a nomogram [27], predictive estimators, such as the Jellife, Cockcroft–Gault or Siersbaek–Nielsen equations [28,36,41,45], 24 h urinary creatinine clearance, or more detailed measurements such as ethylenediaminetetraacetic acid (EDTA) or inulin clearance [25,29]. The cut-off points used to define low GFR were inconsistent across studies.

Pharmacokinetic outcomes
The relationship between low GFR and H2RA pharmacokinetics was examined in 16 studies, comprising 452 individuals (Table 2, Figures 1 and 2). These participants typically received a pre-defined dose of H2RA for the sole purpose of evaluating the pharmacokinetic properties of the drug. As illustrated in Table 2 and Figures 1 and 2, there was an increase in both the AUC and t1/2 of H2RAs with incremental reductions in GFR. For example, compared with those with normal GFR, drug AUC increased by 200% when the GFR was 30 ml/min/1.73 m2 and by 300% when the GFR was 20 ml/min/1.73 m2.


View this table:
[in this window]
[in a new window]
 
Table 2. Pharmacokinetic studies of H2 receptor antagonists in relation to estimated glomerular filtration rate

 


View larger version (28K):
[in this window]
[in a new window]
 
Fig. 1. The area under the curve (AUC) after a fixed dose H2 receptor antagonist was higher in patients with lower GFR. Studies with three or more data points are plotted with grey lines, while studies limited to two data points are plotted with grey circles. The pooled best fit line is plotted in black. Study patients with a GFR >80 ml/min/1.73 m2 were the referent.

 


View larger version (28K):
[in this window]
[in a new window]
 
Fig. 2. The elimination half-life (t1/2) after a fixed dose H2 receptor antagonist was higher in patients with lower GFR. Studies with three or more data points are plotted with grey lines, while studies limited to two data points are plotted with grey circles. The pooled best fit line is plotted in black. Study patients with a GFR >80 ml/min/1.73 m2 were the referent.

 
Adverse drug reactions
Among four studies conducted in hospitalized patients with low GFR, the risk of having an adverse drug reaction increased by a factor of 2–4 when the H2RA dose was not reduced for low GFR (Table 3). Most adverse reactions were described as an alteration in mental status, especially among critically ill patients who received an i.v. preparation of the drug. Deterioration in mental status typically improved after the drug was discontinued. It is notable that in one study, two participants were inadvertently rechallenged with a H2RA, which resulted in a similar worsening of their mental status [39].


View this table:
[in this window]
[in a new window]
 
Table 3. Risk of adverse drug reactions among hospitalized patients when H2 receptor antagonist dose was unadjusted vs appropriate for GFR

 
H2RA efficacy
Two cohort studies measured markers of H2RA efficacy in relation to dose reduction in the face of low GFR [29,46]. In the first, gastric pH was continuously monitored for 24 h following the administration of 25 and 50 mg single i.v. doses of ranitidine in patients with varying degrees of GFR [29]. Ranitidine was equally effective in sustaining a raised intragastric pH in each GFR category. In addition, at lower levels of GFR, reduced doses of H2RAs were equally effective at raising intragastric pH compared with standard doses. In a second study of 336 elderly adults living in a nursing home, and whose GFR was <50 ml/min, gastrointestinal symptoms or bleeding did not differ between those who did and did not receive H2RA dose adjustments [46]. In addition, all-cause mortality at 1 year was significantly lower in the dose-adjusted (12%) vs dose-unadjusted (22%) group (P = 0.02).



   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We observed a consistent relationship between H2RA drug kinetics and renal function among several small observational studies. In persons with low GFR, drug-related side effects may be avoided when H2RA doses are reduced.

A major weakness of the current review was the absence of randomized clinical trials that assessed clinical outcomes in relation to H2RA dose adjustments according to GFR. Most participants with low GFR were either excluded from such trials, or were given an adjusted dose of H2RAs as per trial protocol. The observational studies in this review often did not assess, or adjust for, relevant participant characteristics, including age, weight, concurrent medication use and co-morbidity. In many studies, those in the lowest GFR groups were older [25,36,38,43], weighed less [25,28,35,43] and had a smaller volume of distribution than patients with preserved renal function. Furthermore, older participants with low GFR may be more vulnerable to having altered mental status independent of adjusted H2RA use [48]. Together, these may confound the inferred association between lack of H2RA dose adjustment for GFR and adverse outcomes, especially in the absence of masked assessment of drug exposure or toxicity effects. Short-term pharmacokinetic studies included herein did not elucidate whether compensatory mechanisms exist that can facilitate the non-renal metabolism or excretion of H2RA with chronic administration of the drug.

Despite manufacturer recommendations, many clinicians do not reduce the dose of H2RA according to low GFR [6,9]. This may stem from a lack of awareness of low GFR, or scepticism about the benefits of doing so [49]. We found that, with declining GFR, there is an increase in the AUC and elimination t1/2 of the serum concentration of H2RA. While the quality of clinical data was poor, there was a significantly higher risk of adverse drug reactions, such as altered mental status, when H2RA doses were not adjusted for GFR, and a higher associated risk of death in one study of frail elderly adults. Patients with low GFR are at high risk for gastric pathology. However, by reducing the dose of H2RA in persons with low GFR, control of intragastric pH and gastrointestinal symptoms appeared not to be compromised. Taken together, these findings support the practice of reducing H2RAs in patients with low GFR. At the same time, H2RAs may reduce the efficacy of some phosphate-binding agents, such as calcium carbonate [50], which are commonly used to prevent renal hyperparathyroidism in this patient population. They may also predispose patients to nosocomial infections.

With annual global market costs for prescribed H2RAs in excess of US$1 billion, there are enormous potential cost savings to pharmacare programmes by appropriately dosing H2RAs for low GFR [51]. About 5% of non-institutionalized adults have a GFR <60 ml/min [52]—a threshold below which dose adjustment of H2RAs is warranted. The prevalence of low GFR in adults who are hospitalized or living in a long-term care facility is even higher [53]. One study observed a 10% reduction in total drug expenditures when H2RA doses were adjusted for low GFR in elderly adults [55], a finding supported by others [54–57 ]. The largest in-hospital cost savings occurred when the frequency of dosing (and associated labour, material and drug administration costs) was reduced. Certainly, a future cost-effectiveness analysis embedded within a clinical trial could provide the best confirmatory evidence that this is true.

Proton pump inhibitors (PPIs) are hepatically excreted [58] and, since they may be superior to H2RAs in the acute treatment of gastro-oesophageal reflux disease and peptic ulcer disease [59,60], PPIs may be preferred over H2RAs in all patients including those with very low GFR [58]. However, most PPIs are more expensive than H2RAs, and in many jurisdictions they are restricted to use when H2RAs fail. We hypothesize that chronic oral H2RA use, available over the counter in many countries, may be associated with unrecognized side effects in elderly persons who have reduced GFR, recognizing that there are no published data to this effect.

Finally, methods to improve H2RA prescribing in patients with low GFR merit further study. Improved recognition of low GFR in persons prescribed this drug class remains one essential step. Complex algorithms to dose H2RAs may be beneficial [61], but may prove difficult to implement clinically. Computer and pharmacy-based alerts have been used successfully to enhance H2RA prescribing in patients with low GFR [57,62,63]. One such programme was associated with nearly a 50% relative decline in the rate of non-adjusted dosing of H2RAs in persons whose GFR was <50 ml/min [57]. Establishing which intervention is most efficacious and cost saving in improving prescribing for this at-risk segment of the population requires future consideration.



   Acknowledgments
 
We thank Dr Nick Barrowman for statistical advice and help. A.X.G. was supported by a Canadian Institutes of Health Research Clinician Scientist Award. M.T. was supported by an Investigator Award from the Alberta Heritage Foundation for Medical Research.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Taha AS, Hudson N, Hawkey CJ et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996; 334: 1435–1439[Abstract/Free Full Text]
  2. Beck IT, Champion MC, Lemire S et al. The Second Canadian Consensus Conference on the Management of Patients with Gastroesophageal Reflux Disease. Can J Gastroenterol 1997; 11 [Suppl B]: 7B–20B[Medline]
  3. Cook D, Guyatt G, Marshall J et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998; 338: 791–797[Abstract/Free Full Text]
  4. Fisher AA, Le Couteur DG. Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists. Drug Saf 2001; 24: 39–57[ISI][Medline]
  5. Westbrook JI, Duggan AE, McIntosh JH. Prescriptions for antiulcer drugs in Australia: volume, trends, and costs. Br Med J 2001; 323: 1338–1339[Free Full Text]
  6. Dettmer RM, Riley TH, Byfield F, Green PH. The use of intravenous H2-receptor antagonists in a tertiary care hospital. Am J Gastroenterol 1999; 94: 3473–3477[CrossRef][ISI][Medline]
  7. Pearson TF, Pittman DG, Longley JM, Grapes ZT, Vigliotti DJ, Mullis SR. Factors associated with preventable adverse drug reactions. Am J Hosp Pharm 1994; 51: 2268–2272[Abstract]
  8. Sherman DS, Avorn J, Campion EW. Cimetidine use in nursing homes: prolonged therapy and excessive doses. J Am Geriatr Soc 1987; 35: 1023–1027[ISI][Medline]
  9. Segal R, Russell WL, Oh T, Ben Joseph R. Use of i.v. cimetidine, ranitidine, and famotidine in 40 hospitals. Am J Hosp Pharm 1993; 50: 2077–2081[Abstract]
  10. Tsuruoka S, Sugimoto KI, Hayasaka T, Saito T, Fujimura A. Ranitidine clearance during hemodialysis with high-flux membrane: comparison of polysulfone and cellulose acetate hemodialyzers. Eur J Clin Pharmacol 2000; 56: 581–583[CrossRef][ISI][Medline]
  11. Echizen H, Ishizaki T. Clinical pharmacokinetics of famotidine. Clin Pharmacokinet 1991; 21: 178–194[ISI][Medline]
  12. Lin JH. Pharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists. Relationship between intrinsic potency and effective plasma concentrations. Clin Pharmacokinet 1991; 20: 218–236[ISI][Medline]
  13. Roberts CJ. Clinical pharmacokinetics of ranitidine. Clin Pharmacokinet 1984; 9: 211–221[ISI][Medline]
  14. Chremos AN. Clinical pharmacology of famotidine: a summary. J Clin Gastroenterol 1987; 9 [Suppl 2]: 7–12
  15. Krishna DR, Klotz U. Newer H2-receptor antagonists. Clinical pharmacokinetics and drug interaction potential. Clin Pharmacokinet 1988; 15: 205–215[ISI][Medline]
  16. Chremos AN. Pharmacodynamics of famotidine in humans. Am J Med 1986; 81: 3–7
  17. Sawyer D, Conner CS, Scalley R. Cimetidine: adverse reactions and acute toxicity. Am J Hosp Pharm 1981; 38: 188–197[Abstract]
  18. Nazario M. The hepatic and renal mechanisms of drug interactions with cimetidine. Drug Intell Clin Pharm 1986; 20: 342–348[ISI][Medline]
  19. Sax MJ. Clinically important adverse effects and drug interactions with H2-receptor antagonists: an update. Pharmacotherapy 1987; 7: 110S–115S[Medline]
  20. Nicholson AN. Central effects of H1 and H2 antihistamines. Aviat Space Environ Med 1985; 56: 293–298[ISI][Medline]
  21. Epstein CM. Histamine H2 antagonists and the nervous system. Am Fam Physician 1985; 32: 109–112[ISI][Medline]
  22. Gladziwa U, Klotz U. Pharmacokinetics and pharmacodynamics of H2-receptor antagonists in patients with renal insufficiency. Clin Pharmacokinet 1993; 24: 319–332[ISI][Medline]
  23. Shi JQ, Copas JB. Meta-analysis for trend estimation. Stat Med 2004; 231: 3–19[CrossRef]
  24. Gardner M, Altman D. Statistics with Confidence. BMJ Publications, London; 1994: 51–52
  25. Dixon JS, Borgcostanzi JM, Langley SJ, Lacey LF, Toon S. The effect of renal-function on the pharmacokinetics of ranitidine. Eur J Clin Pharmacol 1994; 46: 167–171[ISI][Medline]
  26. Aronoff GR, Bergstrom RF, Bopp RJ, Sloan RS, Callaghan JT. Nizatidine disposition in subjects with normal and impaired renal function. Clin Pharmacol Ther 1988; 43: 688–695[ISI][Medline]
  27. Ilett KF, Nation RL, Tjokrosetio R, Thompson WR, Oh TE, Cameron PD. Pharmacokinetics of ranitidine in critically ill patients. Br J Clin Pharmacol 1986; 21: 279–288[ISI][Medline]
  28. Inotsume N, Nishimura M, Fujiyama S et al. Pharmacokinetics of famotidine in elderly patients with and without renal insufficiency and in healthy young volunteers. Eur J Clin Pharmacol 1989; 36: 517–520[CrossRef][ISI][Medline]
  29. Koch KM, Liu M, Davis IM, Shaw S, Yin Y. Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment. Eur J Clin Pharmacol 1997; 52: 229–234[CrossRef][ISI][Medline]
  30. McIsaac RL, Koch KM, Lewis JH. Ranitidine pharmacokinetics and central nervous system. Arch Intern Med 1994; 154: 342–3, 347
  31. Lameire N, Rosenkranz B, Maass L, Brockmeier D. A pharmacokinetic study of roxatidine acetate in chronic renal failure. Drugs 1988; 35 [Suppl 3]: 48–52
  32. Larsson R, Erlanson P, Bodemar G et al. The pharmacokinetics of cimetidine and its sulphoxide metabolite in patients with normal and impaired renal function. Br J Clin Pharmacol 1982; 13: 163–170[ISI][Medline]
  33. Larsson R, Bodemar G, Norlander B. Oral absorption of cimetidine and its clearance in patients with renal failure. Eur J Clin Pharmacol 1979; 15: 153–157[CrossRef][ISI][Medline]
  34. Lin JH, Chremos AN, Yeh KC, Antonello J, Hessey GA. Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man. Eur J Clin Pharmacol 1988; 34; 41–46[CrossRef][ISI][Medline]
  35. Maples HD, James LP, Stowe CD et al. Famotidine disposition in children and adolescents with chronic renal insufficiency. J Clin Pharmacol 2003; 43: 7–14[Abstract/Free Full Text]
  36. McFayden ML, Folb PI, Miller R, Keeton GR, Marks IN. Pharmacokinetics of ranitidine in patients with chronic renal failure. Eur J Clin Pharmacol 1983; 25: 347–351[CrossRef][ISI][Medline]
  37. Redolfi A, Borgogelli E, Lodola E. Blood level of cimetidine in relation to age. Eur J Clin Pharmacol 1979; 15: 257–261[CrossRef][ISI][Medline]
  38. Schentag JJ, Cerra FB, Calleri GM, Leising ME, French MA, Bernhard H. Age, disease, and cimetidine disposition in healthy subjects and chronically ill patients. Clin Pharmacol Ther 1981; 29: 737–743[ISI][Medline]
  39. Schentag JJ, Cerra FB, Calleri G, DeGlopper E, Rose JQ, Bernhard H. Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet 1979; 1: 177–181[CrossRef][ISI][Medline]
  40. Schentag JJ. Cimetidine-associated mental confusion: further studies in 36 severely ill patients. Ther Drug Monit 1980; 2: 133–142[ISI][Medline]
  41. Slugg PH, Haug MT III, Pippenger CE. Ranitidine pharmacokinetics and adverse central nervous system reactions. Arch Intern Med 1992; 152: 2325–2329[Abstract]
  42. Takabatake T, Ohta H, Yamamoto YS et al. Pharmacokinetics of TZU-0460, a new H2-receptor antagonist, in patients with impaired renal function. Eur J Clin Pharmacol 1986; 30: 709–712[CrossRef][ISI][Medline]
  43. Takabatake T, Ohta H, Maekawa M et al. Pharmacokinetics of famotidine, a new H2-receptor antagonist, in relation to renal function. Eur J Clin Pharmacol 1985; 28: 327–331[CrossRef][ISI][Medline]
  44. Ben Joseph R, Segal R, Russell WL. Risk for adverse events among patients receiving intravenous histamine2-receptor antagonists. Ann Pharmacother 1993; 27: 1532–1537[Abstract]
  45. Kowalsky SF, Hamilton RA, Figge HL. Drug usage evaluation: H2-receptor antagonist use in 30 hospitals. Hosp Formul 1991; 26: 725–726[ISI][Medline]
  46. Lackner TE, Heard T, Glunz S, Gann N, Babington M, Malone DC. Gastrointestinal disease control after histamine2-receptor antagonist dose modification for renal impairment in frail chronically ill elderly patients. J Am Geriatr Soc 2003; 51: 650–656[CrossRef][ISI][Medline]
  47. Sirgo MA, Mills R, Euler AR, Walker S. The safety of ranitidine in elderly versus non-elderly patients. J Clin Pharmacol 1993; 33: 79–83[Abstract/Free Full Text]
  48. Cerra FB, Schentag JJ, McMillen M, Karwande SV, Fitzgerald GC, Leising M. Mental status, the intensive care unit, and cimetidine. Ann Surg 1982; 196: 565–570[ISI][Medline]
  49. Papaioannou A, Clarke JA, Campbell G, Bedard M. Assessment of adherence to renal dosing guidelines in long-term care facilities. J Am Geriatr Soc 2000; 48: 1470–1473[ISI][Medline]
  50. Tan CC, Harden PN, Rodger RS et al. Ranitidine reduces phosphate binding in dialysis patients receiving calcium carbonate. Nephrol Dial Transplant 1996; 11: 851–853[Abstract]
  51. Westbrook JI, Duggan AE, McIntosh JH. Prescriptions for antiulcer drugs in Australia: volume, trends, and costs. Br Med J 2001; 323: 1338–1339[Free Full Text]
  52. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003; 41: 1–12[ISI][Medline]
  53. Garg AX, Papaioannou A, Ferko N, Campbell G, Clarke JA, Ray JG. Estimating the prevalence of renal insufficiency in seniors requiring long-term care. Kidney Int 2004; 65: 649–653[CrossRef][ISI][Medline]
  54. Wallenberg BG, Caliendo TM. H2-antagonist dosing in the elderly based on renal function. Ann Pharmacother 1992; 26: 1595[ISI][Medline]
  55. Nolly RJ, Skoutakis VA. Cost considerations of intravenously administered histamine2-receptor antagonists. DICP 1989; 23 [Suppl]: S23–S28[Medline]
  56. Connelly JF. Adjusting dosage intervals of intermittent intravenous ranitidine according to creatinine clearance: a cost-minimization analysis. Hosp Pharm 1994; 29: 992–998[Medline]
  57. Caldwell RD, Davis SK. Use of staff pharmacists to reduce the inappropriate use of parenteral histamine-2 antagonist therapy. Hosp Pharm 1987; 22: 1205–1209[Medline]
  58. Delhotal-Landes B, Flouvat B, Duchier J, Molinie P, Dellatolas F, Lemaire M. Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity. Eur J Clin Pharmacol 1993; 45: 367–371[ISI][Medline]
  59. van Pinxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2001; 4: CD002095[Medline]
  60. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112: 1798–1810[ISI][Medline]
  61. Ebihara A, Ohashi K, Ikeda T et al. Dosage regimen of ranitidine in patients with renal impairment. Int J Clin Pharmacol Res 1989; 9: 1–7[ISI][Medline]
  62. Rind DM, Safran C, Phillips RS et al. Effect of computer-based alerts on the treatment and outcomes of hospitalized patients. Arch Intern Med 1994; 154: 1511–1517[Abstract]
  63. Peterson JP, Colucci VJ, Schiff SE. Using serum creatinine concentrations to screen for inappropriate dosage of renally eliminated drugs. Am J Hosp Pharm 1991; 48: 1962–1964[Abstract]
Received for publication: 29. 3.05
Accepted in revised form: 22. 6.05





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
20/11/2376    most recent
gfi025v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Manlucu, J.
Articles by Garg, A. X.
PubMed
PubMed Citation
Articles by Manlucu, J.
Articles by Garg, A. X.