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Drug Interactions between Equaline Acid Reducer and phenytoin

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

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Major

cimetidine phenytoin

Applies to: Equaline Acid Reducer (cimetidine) and phenytoin

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

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Drug and food interactions

Moderate

phenytoin food

Applies to: phenytoin

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

References

  1. Sandor P, Sellers EM, Dumbrell M, Khouw V (1981) "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther, 30, p. 390-7
  2. Holtz L, Milton J, Sturek JK (1987) "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr, 11, p. 183-6
  3. Sellers EM, Holloway MR (1978) "Drug kinetics and alcohol ingestion." Clin Pharmacokinet, 3, p. 440-52
  4. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  5. Doak KK, Haas CE, Dunnigan KJ, et al. (1998) "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy, 18, p. 637-45
  6. Rodman DP, Stevenson TL, Ray TR (1995) "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy, 15, p. 801-5
  7. Au Yeung SC, Ensom MH (2000) "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother, 34, p. 896-905
  8. Ozuna J, Friel P (1984) "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs, 16, p. 289-91
  9. Faraji B, Yu PP (1998) "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs, 30, p. 55-9
  10. Marvel ME, Bertino JS (1991) "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr, 15, p. 316-8
  11. Fleisher D, Sheth N, Kou JH (1990) "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr, 14, p. 513-6
  12. Haley CJ, Nelson J (1989) "Phenytoin-enteral feeding interaction." DICP, 23, p. 796-8
  13. Guidry JR, Eastwood TF, Curry SC (1989) "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med, 150, p. 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM (1987) "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia, 28, p. 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  16. Cerner Multum, Inc. "Australian Product Information."
View all 16 references

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Minor

cimetidine food

Applies to: Equaline Acid Reducer (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 (1982) "Effects of cimetidine on the elimination and actions of ethanol." JAMA, 247, p. 2819-21
  2. Hansten PD (1992) "Effects of H2-receptor antagonists on blood alcohol levels." JAMA, 267, p. 2469

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Minor

cimetidine food

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

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Minor

cimetidine food

Applies to: Equaline Acid Reducer (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 (1990) "Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans." Eur J Clin Pharmacol, 38, p. 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

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