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Drug Interactions between Di-Phen and fluconazole

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

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Interactions between your drugs

Major

fluconazole phenytoin

Applies to: fluconazole and Di-Phen (phenytoin)

MONITOR CLOSELY: The concomitant use of fluconazole may increase serum hydantoin levels and risk of hydantoin toxicity. The mechanism is inhibition of CYP450 2C9 and 2C19 hepatic metabolism. In 10 healthy male volunteers, a mean increase in phenytoin AUC of 88% (with a range of 16% to 247%) was observed after 4 days of phenytoin administration (200 mg orally per day for 3 days followed by 250 mg IV once) with fluconazole (200 mg orally per day for 16 days) compared to phenytoin administration alone. Repeated concomitant administration of phenytoin (250 mg IV) and fluconazole (200 mg) also resulted in increased phenytoin AUC24 and Cmin by 75% and 128%, respectively.

MANAGEMENT: Close clinical monitoring of patient response, tolerance, and serum hydantoin concentrations is recommended whenever fluconazole is added, discontinued, or the dose changed. Patients should be advised to notify their doctor if they experience symptoms of toxicity (drowsiness, visual disturbances, change in mental status, nausea, or ataxia). A reduction in hydantoin dosage may be necessary.

References

  1. Howitt KM, Oziemski MA (1989) "Phenytoin toxicity induced by fluconazole." Med J Aust, 151, p. 603-4
  2. Mitchell AS, Holland JT (1989) "Fluconazole and phenytoin: a predictable interaction." Br Med J, 298, p. 1315
  3. Grant SM, Clissold SP (1990) "Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses." Drugs, 39, p. 877-916
  4. Lazar JD, Wilner KD (1990) "Drug interactions with fluconazole." Rev Infect Dis, 12 Suppl 3, s327-33
  5. Vincent-Ballereau FN, Patey ON, Lafaix C (1990) "Fluconazole: review and situation among antifungal drugs in the treatment of opportunistic mycoses of human immuno-deficiency virus infections." Pharm Weekbl Sci, 13, p. 45-57
  6. Holechek MJ (1991) "Medication review: fluconazole." ANNA J, 18, p. 585-6
  7. Blum RA, Wilton JH, Hilligoss DM, et al. (1991) "Effect of fluconazole on the disposition of phenytoin." Clin Pharmacol Ther, 49, p. 420-5
  8. Morrow JD (1991) "Fluconazole: a new triazole antifungal agent." Am J Med Sci, 302, p. 129-32
  9. Touchette MA, Chandrasekar PH, Milad MA, Edwards DJ (1992) "Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man." Br J Clin Pharmacol, 34, p. 75-8
  10. Cadle RM, Zenon GJ III, Rodriguez-Barradas MC, Hamil RJ (1994) "Fluconazole-induced symptomatic phenytoin toxicity." Ann Pharmacother, 28, p. 191-5
  11. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  12. (2001) "Product Information. Diflucan (fluconazole)." Roerig Division
  13. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  14. Cerner Multum, Inc. "Australian Product Information."
View all 14 references

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Drug and food interactions

Moderate

phenytoin food

Applies to: Di-Phen (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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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.

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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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