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Drug Interactions between Phenytoin Sodium, Extended Release and Sulfatrim Pediatric

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

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Interactions between your drugs

Major

trimethoprim phenytoin

Applies to: Sulfatrim Pediatric (sulfamethoxazole / trimethoprim) and Phenytoin Sodium, Extended Release (phenytoin)

MONITOR CLOSELY: Coadministration with trimethoprim may increase the serum concentrations of phenytoin. The proposed mechanism is inhibition by trimethoprim of the CYP450 2C9-mediated metabolism of phenytoin. Although trimethoprim is primarily a CYP450 2C8 inhibitor, it may demonstrate some CYP450 2C9 inhibition at higher concentrations. Moreover, trimethoprim is frequently given in combination with sulfamethoxazole, which can also inhibit CYP450 2C9 as well as displace phenytoin from protein binding sites resulting in increased free concentrations of phenytoin. In one study, administration of a single intravenous dose of phenytoin to healthy volunteers receiving trimethoprim 320 mg/day for 7 days resulted in a 30% decrease in metabolic clearance and a 51% increase in the half-life of phenytoin. However, administration with sulfamethoxazole-trimethoprim (SMX-TMP) did not result in an increased magnitude of interaction, with phenytoin metabolic clearance decreasing by 27% and half-life increasing by 39%. Sulfamethoxazole alone produced a small but significant increase in phenytoin half-life without a corresponding fall in metabolic clearance. There have been isolated case reports describing symptoms of phenytoin toxicity following the concomitant use of SMX-TMP. In a population-based, case-control study of a cohort of Ontario (Canada) residents aged 66 years of age or older treated with phenytoin over a 17-year period, investigators reported a greater than twofold increase in the risk of phenytoin toxicity following a prescription of SMX-TMP among 796 case patients who had been hospitalized for phenytoin toxicity. No such risk was observed with amoxicillin. Concomitant use of phenytoin and SMX-TMP may also be associated with an increased risk of Stevens-Johnson syndrome (SJS). In a retrospective longitudinal study using SJS-related mortality cases between 1999 and 2008 from the National Health Insurance database in Taiwan, investigators reported that phenytoin and SMX-TMP were among various drug combinations that were administered one month before the patients' deaths. Finally, a case of acute fulminant hepatic failure resulting in death was reported in a 60-year-old woman who was treated with phenytoin and SMX-TMP. The patient was also receiving cimetidine, which may have contributed to increased phenytoin levels.

MANAGEMENT: Caution is advised when phenytoin is prescribed with trimethoprim or sulfamethoxazole-trimethoprim. Pharmacologic response and serum phenytoin levels should be monitored more closely whenever trimethoprim or SMX-TMP is added to or withdrawn from therapy, and the phenytoin dosage adjusted as necessary. Patients should be advised to notify their physician if they experience signs and symptoms of phenytoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, and changes in mental status. Alternative antibiotics should be considered in elderly patients treated with phenytoin when possible.

References

  1. Dasgupta A, Dennen DA, Dean R, McLawhon RW "Displacement of phenytoin from serum protein carriers by antibiotics: studies with ceftriaxone, nafcillin, and sulfamethoxazole." Clin Chem 37 (1991): 98-100
  2. Wilcox JB "Phenytoin intoxication and cotrimoxazole." N Z Med J 94 (1981): 235-6
  3. "Product Information. Bactrim (sulfamethoxazole-trimethoprim)." Roche Laboratories (2022):
  4. Hansen JM, Kampmann JP, Siersback-Nielsen K, et al. "The effect of different sulfonamides on phenytoin metabolism in man." Acta Med Scand Suppl 624 (1979): 106-10
  5. Gillman MA "Phenytoin toxicity and co-trimazole." Ann Intern Med 102 (1985): 559
  6. "Product Information. Dilantin (phenytoin)." Parke-Davis PROD (2001):
  7. Komatsu T, Yamazaki H, Asahi S, Gillam EMJ, Guengerich FP, Nakajima M, Yokoi T "Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol: Roles of cytochromes P4502C9, 2C19, and 3A4." Drug Metab Disposition 28 (2000): 1361-8
  8. Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ "Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively." Drug Metab Dispos 30 (2002): 631-635
  9. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  10. Cerner Multum, Inc. "Australian Product Information." O 0
  11. Antoniou T, Gomes T, Mamdani MM, Juurlink DN "Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a population-based study." Br J Clin Pharmacol 71 (2011): 544-9
  12. Hines LE, Murphy JE "Potentially harmful drug-drug interactions in the elderly: a review." Am J Geriatr Pharmacother 9 (2011): 364-77
  13. Cerner Multum, Inc. "Canadian Product Information." O 0 (2015):
  14. "Product Information. Trimethoprim (trimethoprim)." Teva Pharmaceuticals USA (2016):
  15. Ilario MJ, Ruiz JE, Axiotis CA "Acute fulminant hepatic failure in a woman treated with phenytoin and trimethoprim-sulfamethoxazole." Arch Pathol Lab Med 124 (2000): 1800-3
View all 15 references

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Minor

sulfamethoxazole phenytoin

Applies to: Sulfatrim Pediatric (sulfamethoxazole / trimethoprim) and Phenytoin Sodium, Extended Release (phenytoin)

Sulfamethoxazole may displace phenytoin from serum protein binding sites. Increases in free phenytoin may occur. Some investigators have recommended monitoring free phenytoin plasma levels if this combination must be used.

References

  1. Dasgupta A, Dennen DA, Dean R, McLawhon RW "Displacement of phenytoin from serum protein carriers by antibiotics: studies with ceftriaxone, nafcillin, and sulfamethoxazole." Clin Chem 37 (1991): 98-100
  2. Lumholtz B, Siersbaek-Nielsen K, Skovsted L, Kampmann J, Hansen JM "Sulfamethizole-induced inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism." Clin Pharmacol Ther 17 (1975): 731-4
  3. Hansen JM, Kampmann JP, Siersback-Nielsen K, et al. "The effect of different sulfonamides on phenytoin metabolism in man." Acta Med Scand Suppl 624 (1979): 106-10

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Drug and food interactions

Moderate

phenytoin food

Applies to: Phenytoin Sodium, Extended Release (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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Moderate

sulfamethoxazole food

Applies to: Sulfatrim Pediatric (sulfamethoxazole / trimethoprim)

MONITOR: Two cases have been reported in which patients on sulfamethoxazole-trimethoprim therapy, after consuming beer, reported flushing, heart palpitations, dyspnea, headache, and nausea (disulfiram - alcohol type reactions). First-generation sulfonylureas have been reported to cause facial flushing when administered with alcohol by inhibiting acetaldehyde dehydrogenase and subsequently causing acetaldehyde accumulation. Since sulfamethoxazole is chemically related to first-generation sulfonylureas, a disulfiram-like reaction with products containing sulfamethoxazole is theoretically possible. However, pharmacokinetic/pharmacodynamic data are lacking and in addition, the two reported cases cannot be clearly attributed to the concomitant use of sulfamethoxazole-trimethoprim and alcohol.

MANAGEMENT: Patients should be alerted to the potential for this interaction and although the risk for this interaction is minimal, caution is recommended while taking sulfamethoxazole-trimethoprim concomitantly with alcohol.

References

  1. Heelon MW, White M "Disulfiram-cotrimoxazole reaction." Pharmacotherapy 18 (1998): 869-70
  2. Mergenhagen KA, Wattengel BA, Skelly MK, Clark CM, Russo TA "Fact versus fiction: a review of the evidence behind alcohol and antibiotic interactions." Antimicrob Agents Chemother 64 (2020): e02167-19

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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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