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Drug Interactions between Busulfex and phenytoin

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

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Moderate

phenytoin busulfan

Applies to: phenytoin and Busulfex (busulfan)

MONITOR: Limited data suggest that coadministration with phenytoin may decrease the plasma concentrations of busulfan. The proposed mechanism is phenytoin induction of busulfan conjugation via glutathione-S-transferase. The product labeling of busulfan states that concurrent use with phenytoin can increase busulfan's clearance by 10 to 15% or more. A study in 17 patients receiving oral busulfan (1 mg/kg four times daily for 4 days) for myeloablative conditioning prior to bone marrow transplantation compared diazepam (n=10) and phenytoin (n=7) for seizure prophylaxis. In the phenytoin group, busulfan's elimination half-life decreased by 23%, clearance increased by 19%, and systemic exposure (AUC) decreased by 16% between the first and last dose of busulfan. There was also a continuous decrease in the steady-state level of busulfan in 4 of the patients. By contrast, no changes in busulfan pharmacokinetics were observed in the diazepam group. Another study reported an approximately 21% increase in busulfan oral clearance associated with phenytoin use in a group of 64 adults and 12 children receiving busulfan conditioning. However, not all published data support an interaction. One group of investigators studied busulfan clearance in 24 patients receiving intravenous busulfan with clonazepam and found no significant change in clearance when compared to historical data collected for 127 patients treated with phenytoin. Additionally, a large cohort study of 2155 patients, 1460 treated with phenytoin or fosphenytoin and 695 treated with alternative anti-epileptic medications, found no difference in regimen-related toxicities between the two groups.

MANAGEMENT: Because busulfan crosses the blood brain barrier and may induce seizures, anticonvulsants are typically employed prophylactically when high-dose busulfan is given for myeloablative conditioning. Some manufacturers recommend that all patients receiving high-dose busulfan be premedicated with phenytoin, in which case the recommended dosing may already have taken this potential interaction into account. These manufacturers further suggest that use of other anticonvulsants may result in higher busulfan exposure, potentially increasing the risk of veno-occlusive disease, seizures, and other serious adverse effects. By contrast, some product labeling as well as some medical literature recommends using a benzodiazepine or a non-enzyme inducing anticonvulsant instead of phenytoin, to avoid this potential interaction and/or to avoid side effects or toxicities associated with phenytoin. Regardless of which anticonvulsant is used, plasma busulfan levels and patient monitoring for the development of toxicity in accordance with product labeling as well as relevant local institutional and/or national guidelines is recommended.

References

  1. Fitzsimmons WE, Ghalie R, Kaizer H "The effect of hepatic enzyme inducers on busulfan neurotoxicity and myelotoxicity." Cancer Chemother Pharmacol 27 (1990): 226-8
  2. Hassan M, Oberg G, Bjorkholm M, Wallin I, Lindgren M "Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics." Cancer Chemother Pharmacol 33 (1993): 181-6
  3. "Product Information. Myleran (busulfan)." Prasco Laboratories PROD (2001):
  4. Sandstrom M, Karlsson MO, Ljungman P, et al. "Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients." Bone Marrow Transplant 28 (2001): 657-664
  5. "Product Information. Busulfex (busulfan)." ESP Pharma Inc (2004):
  6. Carreras E, Cahn JY, Puozzo C, et al. "Influence on Busilvex pharmacokinetics of clonazepam compared to previous phenytoin historical data." Anticancer Res 30 (2010): 2977-84
  7. "Product Information. Lyfgenia (lovotibeglogene autotemcel)." bluebird bio (2023):
  8. "Product Information. Casgevy (exagamglogene autotemcel)." Vertex Pharmaceuticals (2023):
  9. Vertex Pharmaceuticals (Europe) Limited "Casgevy 4-13 x 10Exp6 cells/mL dispersion for infusion https://www.medicines.org.uk/emc/product/15296" (2024):
  10. "Product Information. Busulfan (busulfan)." Armas Pharmaceuticals, Inc. (2019):
  11. "Product Information. Busulfan (busulfan)." Tillomed Laboratories Ltd (2020):
  12. "Product Information. Busulfan (Accord) (busulfan)." Accord Healthcare Pty Ltd 1.0 (2019):
  13. "Product Information. Busulfan (busulfan)." Sterimax Inc (2017):
  14. Germeraad RS, Demandt AMP, Rouhl RPW "Phenytoin as seizure prophylaxis in hematopoietic stem cell transplantation with busulfan conditioning. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9441567/" (2024):
  15. Farhan S, Neme K, Mikulandric N, et al. "Phenytoin versus levetiracetam for busulfan-induced seizure prophylaxis and hematopoietic stem cell transplantation outcomes." Transplant Cell Ther 20 (2014): S221
  16. mccune js, Wang T, Bo-Subait K, et al. "Association of antiepileptic medications with outcomes after allogeneic hematopoietic cell transplantation with busulfan/cyclophosphamide conditioning." Biol Blood Marrow Transplant 25 (2019): 1424-31
  17. "Product Information. Lenmeldy (atidarsagene autotemcel)." Orchard Therapeutics (2024):
View all 17 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 "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther 30 (1981): 390-7
  2. Holtz L, Milton J, Sturek JK "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr 11 (1987): 183-6
  3. Sellers EM, Holloway MR "Drug kinetics and alcohol ingestion." Clin Pharmacokinet 3 (1978): 440-52
  4. "Product Information. Dilantin (phenytoin)." Parke-Davis PROD (2001):
  5. Doak KK, Haas CE, Dunnigan KJ, et al. "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy 18 (1998): 637-45
  6. Rodman DP, Stevenson TL, Ray TR "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy 15 (1995): 801-5
  7. Au Yeung SC, Ensom MH "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother 34 (2000): 896-905
  8. Ozuna J, Friel P "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs 16 (1984): 289-91
  9. Faraji B, Yu PP "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs 30 (1998): 55-9
  10. Marvel ME, Bertino JS "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr 15 (1991): 316-8
  11. Fleisher D, Sheth N, Kou JH "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr 14 (1990): 513-6
  12. Haley CJ, Nelson J "Phenytoin-enteral feeding interaction." DICP 23 (1989): 796-8
  13. Guidry JR, Eastwood TF, Curry SC "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med 150 (1989): 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia 28 (1987): 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  16. Cerner Multum, Inc. "Australian Product Information." O 0
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.

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