Drug interaction between sevelamer and furosemide

Sir,

Sevelamer hydrochloride (Renagel®) is a calcium-free non-absorbable phosphate-binding cationic polymer marketed for the treatment of hyperphosphataemia in patients undergoing renal function replacement [1].

Furosemide is a loop diuretic. Large doses of furosemide have been employed as an adjunct to other therapies in patients with acute and chronic renal failure. In some patients, the use of furosemide may permit a slightly more liberal fluid intake. This is very important for the quality of life of these patients.

A 64-year-old female on haemodialysis thrice weekly started with sevelamer for hyperphosphataemia. Her urine production was 950 ml/day with furosemide 250 mg twice daily. Upon starting sevelamer, 800 mg with breakfast, 800 mg at lunchtime and 1600 mg with dinner, she noticed that her urine production stopped within 24 h after taking the first sevelamer capsule. After sevelamer withdrawal, her urine production increased within 24 h to her previous level. Her urine production stopped again within 24 h after resumption of sevelamer and increased after withdrawal. Unfortunately, we do not know if the patient gained weight or if there were any blood pressure fluctuations during the time the urine production stopped.

At present the patient takes furosemide 500 mg once daily in the morning and sevelamer twice daily 1600 mg at lunch and dinner. Her urine production is stable as before.

Our case provides evidence for an interaction between the loop diuretic furosemide and the phosphate-binding polymer sevelamer, confirmed by rechallenge. The mechanism of the interaction is probably a physical binding of furosemide to sevelamer in the gastrointestinal tract, diminishing the absorption of furosemide. An alternative explanation appears unlikely as sevelamer is not absorbed by the gastrointestinal tract and thus is devoid of any systemic effect.

Previous studies have shown that sevelamer does not affect absorption of digoxin, warfarin, enalapril or metoprolol [2,3]. Sevelamer does affect the bioavailability of ciprofloxacin [4]. Recently Guillen-Anaya reported an interaction between sevelamer and cyclosporin A [5].

The primary amine groups of sevelamer are responsible for the phosphate binding. These amine groups become protonated at physiological pH (pKa = 9.5) [6], are therefore cationic and bind negatively charged phosphate ions. This results in lower serum phosphate concentrations. Furosemide is anionic at physiological pH (pKa = 3.9) [7] and can therefore bind to sevelamer at physiological pH.

We observed that sevelamer can decrease the diuretic action of furosemide when they are administered at the same time. This interaction can be avoided by taking the drugs at different times.

If this interaction occurs, the physician may erroneously conclude that the remaining diuresis has declined and may stop the diuretic therapy prematurely.

The consequences of this interaction have to be explored further in clinical practice.

Conflict of interest statement. None declared.

Hanneke W. H. A. Fleuren1, Yuhan Kho1, Martin M. J. Schuurmans2 and Ernst J. Vollaard1

1 Department of Clinical Pharmacy2 Department of Nephrology Canisius Wilhelmina Hospital Postbus 9015 6500 GS Nijmegen The Netherlands Email: hwha.fleuren{at}cwz.nl

References

  1. Bleyer AJ, Burke SK, Dillon M et al. A comparison of the calcium free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis 1999; 33: 694–701[ISI][Medline]
  2. Burke SK, Amin NS, Incerti C, Plone MA, Lee JW. Sevelamer hydrochloride (Renagel®), a phosphate-binding polymer, does not alter the pharmacokinetics of two commonly used antihypertensives in healthy volunteers. J Clin Pharmacol 2001; 41: 199–205[Abstract/Free Full Text]
  3. Burke SK, Amin NS, Incerti C, Plone MA, Watson N. Sevelamer hydrochloride (Renagel®), a nonabsorbed phosphate-binding polymer, does not interfere with digoxin or warfarin pharmacokinetics. J Clin Pharmacol 2001; 41: 193–198[Abstract/Free Full Text]
  4. Kays MB, Overholser BR, Mueller BA, Moe SM, Sowinski KM. Effects of sevelamer hydrochloride and calcium acetate on the oral bioavailability of ciprofloxacin. Am J Kidney Dis 2003; 42: 1253–1259[CrossRef][ISI][Medline]
  5. Guillen-Anaya MA, Jadoul M. Drug interaction between sevelamer and cyclosporin. Nephrol Dial Transplant 2004; 19: 1939–1940[Free Full Text]
  6. Braunlin W, Zhorov E, Guo A et al. Bile acid binding of sevelamer HCl. Kidney Int 2002; 62: 611–619[CrossRef][ISI][Medline]
  7. Moffat AC (ed.). Clarke's Isolation and Identification of Drugs, 2nd edn. The Pharmaceutical Press, London: 1986




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