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Drug Interactions between cimetidine and fosphenytoin

This report displays the potential drug interactions for the following 2 drugs:

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Major

cimetidine fosphenytoin

Applies to: cimetidine and fosphenytoin

GENERALLY AVOID: Coadministration with cimetidine may significantly increase the plasma concentrations of phenytoin. The proposed mechanism is cimetidine inhibition of CYP450 2C9 and 2C19, the isoenzymes responsible for the metabolic clearance of phenytoin. In pharmacokinetic studies, cimetidine administered at dosages of 1000 to 1200 mg/day has consistently been found to increase phenytoin plasma levels, with wide intersubject variability ranging from a 13% to almost 300% increase and phenytoin toxicity developing in some. There have also been rare reports of severe and life-threatening thrombocytopenia, agranulocytosis, and cutaneous reactions including toxic epidermal necrolysis in patients receiving phenytoin and cimetidine, with or without glucocorticoids. Whether these events are related to a pharmacokinetic or pharmacodynamic interaction is unknown. Cimetidine at a dosage of 400 mg/day for two weeks did not significantly affect phenytoin serum levels or seizure frequency in a study of nine patients on long-term phenytoin therapy.

MANAGEMENT: The use of cimetidine should generally be avoided in patients treated with phenytoin because safer alternatives exist, such as other H2-receptor antagonists or proton pump inhibitors. These agents (except omeprazole) have demonstrated a lack of interaction with phenytoin in pharmacokinetic studies, and only rare cases of suspected interaction have been reported, if any.

References

  1. Levine M, Jones MW, Sheppard I "Differential effect of cimetidine on serum concentrations of carbamazepine and phenytoin." Neurology 35 (1985): 562-5
  2. Richards DA "Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine." J Clin Gastroenterol 5 (1983): 81-90
  3. Karlstadt RG, Palmer RH, Shinn AF "Unrecognized drug interactions with famotidine and nizatidine." Arch Intern Med 151 (1991): 610, 614-5
  4. Smith SR, Kendall MJ "Ranitidine versus cimetidine: a comparison of their potential to cause clinically important drug interactions." Clin Pharmacokinet 15 (1988): 44-56
  5. Hetzel DJ, Bochner F, Hallpike JF, et al. "Cimetidine interaction with phenytoin." Br Med J 282 (1981): 1512
  6. Bartle WR, Walker SE, Shapero T "Dose-dependent effect of cimetidine on phenytoin kinetics." Clin Pharmacol Ther 33 (1983): 649-55
  7. Feely J "Interaction of cimetidine with other drugs." South Med J 76 (1983): 753-8
  8. Phillips P, Hansky J "Phenytoin toxicity secondary to cimetidine administration." Med J Aust 141 (1984): 602
  9. Algozzine GJ, Stewart RB, Springer PK "Decreased clearance of phenytoin with cimetidine." Ann Intern Med 95 (1981): 244-5
  10. Bramhall D, Levine M "Possible interaction of ranitidine with phenytoin." Drug Intell Clin Pharm 22 (1988): 979-80
  11. Yue CP, Mann KS, Chan KH "Severe thrombocytopenia due to combined cimetidine and phenytoin therapy." Neurosurgery 20 (1987): 963-5
  12. Humphries TJ "Famotidine: a notable lack of drug interactions." Scand J Gastroenterol Suppl 134 (1987): 55-60
  13. Sorkin EM, Darvey DL "Review of cimetidine drug interactions." Drug Intell Clin Pharm 17 (1983): 110-20
  14. "Product Information. Pepcid (famotidine)." Merck & Co., Inc PROD (2002):
  15. "Product Information. Axid (nizatidine)." Lilly, Eli and Company PROD (2002):
  16. "Product Information. PriLOSEC (omeprazole)." Merck & Co., Inc (2022):
  17. "Product Information. Zantac (ranitidine)." Glaxo Wellcome PROD (2001):
  18. Arbiser JL, Goldstein AM, Gordon D "Thrombocytopenia following administration of phenytoin, dexamethasone and cimetidine: a case report and a potential mechanism." J Intern Med 234 (1993): 91-4
  19. Tse CS, Iagmin P "Phenytoin and ranitidine interaction." Ann Intern Med 120 (1994): 892-3
  20. Bachmann KA, Sullivan TJ, Jauregui L, Reese J, Miller K, Levine L "Drug interactions of h-2-receptor antagonists." Scand J Gastroenterol 29 (1994): 14-9
  21. "Product Information. Prevacid (lansoprazole)." TAP Pharmaceuticals Inc PROD (2001):
  22. Griffin JP "Drug interactions with agents used in the treatment of epilepsy." Adverse Drug React Toxicol Rev 15 (1996): 221-46
  23. Powell JR, Donn KH "Histamine H2-antagonist drug interactions in perspective: mechanistic concepts and clinical implications." Am J Med 77 (1984): 57-84
  24. "Product Information. Aciphex (rabeprazole)." Janssen Pharmaceuticals PROD (2001):
  25. Rafi JA, Frazier LM, Driscoll-Bannister SM, O'Hara KA, Garnett WR, Pugh CB "Effect of over-the-counter cimetidine on phenytoin concentrations in patients with seizures." Ann Pharmacother 33 (1999): 769-74
  26. Karol MD, Locke CS, Cavanaugh JH "Lack of pharmacokinetic interaction between lansoprazole and intravenously administered phenytoin." J Clin Pharmacol 39 (1999): 1283-9
  27. "Product Information. Protonix (pantoprazole)." Wyeth-Ayerst Laboratories PROD (2001):
  28. Steinijans VW, Huber R, Hartmann M, Zech K, Bliesath H, Wurst W, Radtke HW "Lack of pantoprazole drug interactions in man: an updated review." Int J Clin Pharmacol Ther 34 (1996): 243-62
  29. Williams D, Kelly A, Feely J "Drug interactions avoided - a useful indicator of good prescribing practice." Br J Clin Pharmacol 49 (2000): 369-72
  30. "Product Information. Nexium (esomeprazole)." Astra-Zeneca Pharmaceuticals PROD (2001):
  31. Andersson T, HassanAlin M, Hasselgren G, Rohss K "Drug interaction studies with esomeprazole, the (S)-isomer of omeprazole." Clin Pharmacokinet 40 (2001): 523-37
  32. Labenz J, Petersen KU, Rosch W, Koelz HR "A summary of Food and Drug Administration-reported adverse events and drug interactions occurring during therapy with omeprazole, lansoprazole and pantoprazole." Aliment Pharmacol Ther 17 (2003): 1015-1019
  33. Bachmann KA, Sullivan TJ, Jauregui L, Reese JH, Miller K, Levine L "Absence of an inhibitory effect of omeprazole and nizatidine on phenytoin disposition, a marker of CYP2C activity." Br J Clin Pharmacol 36 (1993): 380-2
  34. Khan AY, Kalimuddin MN, Gorman JM "Neuropsychiatric manifestations of phenytoin toxicity in an elderly patient." J Psychiatr Pract 13 (2007): 49-54
  35. Sambol NC, Upton RA, Chremos AN, Lin ET, Williams RL "A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow." Br J Clin Pharmacol 27 (1989): 83-7
  36. Watts RW, Hetzel DJ, Bochner F, Hallpike JF, Hann CS, Shearman DJ "Lack of interaction between ranitidine and phenytoin." Br J Clin Pharmacol 15 (1983): 499-500
  37. Neuvonen PJ, Tokola R, Kaste M "Cimetidine interaction with phenytoin." Br Med J (Clin Res Ed) 283 (1981): 501
View all 37 references

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Drug and food interactions

Minor

cimetidine food

Applies to: cimetidine

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

References

  1. Feely J, Wood AJ "Effects of cimetidine on the elimination and actions of ethanol." JAMA 247 (1982): 2819-21
  2. Hansten PD "Effects of H2-receptor antagonists on blood alcohol levels." JAMA 267 (1992): 2469

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Minor

cimetidine food

Applies to: cimetidine

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

References

  1. "Product Information. Tagamet (cimetidine)." SmithKline Beecham PROD (2001):
  2. Broughton LJ, Rodgers HJ "Decreased systenuc clearance of caffeine due to cimetidine." Br J Clin Pharmacol 12 (1981): 155-9

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Minor

cimetidine food

Applies to: cimetidine

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.

References

  1. Bendayan R, Sullivan JT, Shaw C, Frecker RC, Sellers EM "Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans." Eur J Clin Pharmacol 38 (1990): 165-9

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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