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Drug Interactions between mephenytoin and ticlopidine

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

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Interactions between your drugs

Moderate

ticlopidine mephenytoin

Applies to: ticlopidine and mephenytoin

MONITOR: The coadministration with ticlopidine may increase the plasma concentrations and pharmacologic effects of phenytoin. The proposed mechanism is ticlopidine inhibition of CYP450 2C19, one of the isoenzymes responsible for the metabolic clearance of phenytoin. There have been case reports of patients stabilized on phenytoin therapy who developed central nervous system toxicity one to several weeks following the addition of ticlopidine, subsequently requiring discontinuation of ticlopidine or reductions of phenytoin dosage. A pharmacokinetic study conducted in six patients as well as a case report involving dechallenge and rechallenge with ticlopidine confirm an interaction. Data are lacking for other hydantoin anticonvulsants. However, based on their structural and pharmacologic similarities to phenytoin, the possibility of some of the same interactions should be considered.

MANAGEMENT: Given their narrow therapeutic index, caution is advised if phenytoin or other hydantoins must be used concomitantly with ticlopidine. Hydantoin levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of ticlopidine in patients who are stabilized on their anticonvulsant regimen. Patients should be advised to contact their physician if they develop signs of phenytoin toxicity such as ataxia, dizziness, nausea, vomiting, and visual disturbances.

References (10)
  1. (2001) "Product Information. Ticlid (ticlopidine)." Syntex Laboratories Inc
  2. Riva R, Cerullo A, Albani F, Baruzzi A (1996) "Ticlopidine impairs phenytoin clearance: a case report." Neurology, 46, p. 1172-3
  3. Rindone JP, Bryan G (1996) "Phenytoin toxicity associated with ticlopidine administration." Arch Intern Med, 156, p. 1113
  4. Privitera M, Welty TE (1996) "Acute phenytoin toxicity followed by seizure breakthrough from a ticlopidine-phenytoin interaction." Arch Neurol, 53, p. 1191-2
  5. Klaassen SL (1998) "Ticlopidine-induced phenytoin toxicity." Ann Pharmacother, 32, p. 1295-8
  6. Donahue S, Flockhart DA, Abernethy DR (1999) "Ticlopidine inhibits phenytoin clearance." Clin Pharmacol Ther, 66, p. 563-8
  7. Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA (2000) "In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6." Br J Clin Pharmacol, 49, p. 343-51
  8. Giancarlo GM, Venkatakrishnan K, Granda BW, vonMoltke LL, Greenblatt DJ (2001) "Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine." Eur J Clin Pharmacol, 57, p. 31-6
  9. Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D (2001) "Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19." Biochemistry, 40, p. 12112-22
  10. Donahue SR, Flockhart DA, Abernathy DR, Jae-Wook Ko (1997) "Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19." Clin Pharmacol Ther, 62, p. 572-7

Drug and food interactions

Moderate

ticlopidine food

Applies to: ticlopidine

ADJUST DOSING INTERVAL: The bioavailability and gastrointestinal tolerance of ticlopidine is enhanced by food.

MANAGEMENT: Patients may be advised to take ticlopidine with meals.

References (1)
  1. (2001) "Product Information. Ticlid (ticlopidine)." Syntex Laboratories Inc
Moderate

mephenytoin food

Applies to: mephenytoin

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 (16)
  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."

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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