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Drug Interactions between Di-Phen and triazolam

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

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Interactions between your drugs

Moderate

phenytoin triazolam

Applies to: Di-Phen (phenytoin) and triazolam

MONITOR: Coadministration with some benzodiazepines may alter the serum concentrations of phenytoin. Both increases and decreases have been cited by case reports and pharmacokinetic studies, while a few reported no changes. The exact mechanism of interaction is unknown, and it is uncertain whether other hydantoins are also affected. Phenytoin toxicity has been reported in patients treated with various benzodiazepines, including clobazam, chlordiazepoxide, clonazepam, and diazepam. Conversely, phenytoin may reduce the plasma concentrations of some benzodiazepines by inducing their metabolism via hepatic microsomal enzymes. In one study, pretreatment with phenytoin (4.3 mg/kg/day for 19 days) increased the clearance of clonazepam (0.03 mg/kg single oral dose) by 46% to 58% and decreased its half-life by 31% in eight healthy volunteers. In another study, mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of midazolam (15 mg oral dose) in six epileptic patients treated concomitantly with phenytoin or carbamazepine were 7.4% and 5.7%, respectively, of those observed in seven control subjects who were not receiving enzyme inducers. The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects.

MANAGEMENT: Pharmacologic response and serum hydantoin levels should be monitored more closely whenever a benzodiazepine is added to or withdrawn from therapy, and the hydantoin dosage adjusted as necessary. Patients should be advised to contact their physician if they experience symptoms of hydantoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, or changes in mental status. The potential for diminished or inadequate benzodiazepine effects should be considered during concomitant use with phenytoin.

References

  1. Scott AK, Khir AS, Steele WH, et al. (1983) "Oxazepam pharmacokinetics in patients with epilepsy treated long-term with phenytoin alone or in combination with phenobarbitone." Br J Clin Pharmacol, 16, p. 441-4
  2. Sennoune S, Mesdjian E, Bonneton J, et al. (1992) "Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy." Ther Drug Monit, 14, p. 269-74
  3. Khoo KC, Mendels J, Rothbart M, et al. (1980) "Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam." Clin Pharmacol Ther, 28, p. 368-75
  4. Zifkin B, Sherwin A, Andermann F (1991) "Phenytoin toxicity due to interaction with clobazam." Neurology, 41, p. 313-4
  5. Vajda FJ, Prineas RJ, Lovell RR (1971) "Interaction between phenytoin and the benzodiazepines." Br Med J, 1, p. 346
  6. Shuttleworth E, Wise G, Paulson G (1974) "Choreoathetosis and diphenylhydantoin intoxication." JAMA, 230, p. 1170-1
  7. Saavedra IN, Aguilera LI, Faure E, Galdames DG (1985) "Phenytoin/clonazepam interaction." Ther Drug Monit, 7, p. 481-4
  8. Johannessen SI, Strandjord RE, Munthe-Kaas AW (1977) "Lack of effect of clonazepam on serum levels of diphenylhydantoin, phenobarbital and carbamazepine." Acta Neurol Scand, 55, p. 506-12
  9. Siris JH, Pippenger CE, Werner WL, Masland RL (1974) "Anticonvulsant drug-serum levels in psychiatric patients with seizure disorders. Effects of certain psychotropic drugs." N Y State J Med, 74, p. 1554-6
  10. Kutt H (1975) "Interactions of antiepileptic drugs." Epilepsia, 16, p. 393-402
  11. Backman JT, Olkkola KT, Ojala M, Laaksovirta H, Neuvonen PJ (1996) "Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin." Epilepsia, 37, p. 253-7
  12. Windorfer A Jr, Sauer W (1977) "Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepin and dipropylacetate." Neuropadiatrie, 8, p. 29-41
  13. Murphy A, Wilbur K (2003) "Phenytoin-diazepam interaction." Ann Pharmacother, 37, p. 659-63
View all 13 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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Moderate

triazolam food

Applies to: triazolam

GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

References

  1. (2002) "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn
  2. (2002) "Product Information. Valium (diazepam)." Roche Laboratories
  3. (2001) "Product Information. Halcion (triazolam)." Pharmacia and Upjohn
  4. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  5. Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S (1995) "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther, 58, p. 20-8
  6. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ (1995) "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther, 58, p. 127-31
  7. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
View all 7 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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