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Drug Interactions between Cordarone and fosphenytoin

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

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Major

amiodarone fosphenytoin

Applies to: Cordarone (amiodarone) and fosphenytoin

MONITOR CLOSELY: Coadministration of amiodarone and phenytoin may alter the plasma concentrations of both drugs. Specifically, phenytoin concentrations may increase due to inhibition of its metabolism via CYP450 2C9 and 2C19 by amiodarone and its active metabolite, N-desethylamiodarone, while amiodarone concentrations may decrease due to induction of its metabolism via CYP450 3A4 by phenytoin. Pharmacokinetic studies in healthy subjects have reported an approximately 40% increase in phenytoin systemic exposure (AUC) following both oral and intravenous administration in combination with amiodarone 200 mg/day. In addition, there have been case reports describing 2- to 4-fold increases in phenytoin levels within 10 days to several weeks after initiation of amiodarone, with some experiencing phenytoin toxicity that required dosing interruption and/or reduction. With respect to phenytoin's effect on amiodarone, data are limited to one pharmacokinetic study of 5 healthy male subjects which reported amiodarone AUCs that were approximately 50% to 70% of those predicted for amiodarone alone. The clinical relevance of these changes are not clear, since AUCs of the active metabolite, N-desethylamiodarone, increased at the same time.

MANAGEMENT: Caution is advised when amiodarone and phenytoin are used together. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation, discontinuation, or change of dosage of amiodarone. Due to the long half-lives of both amiodarone and N-desethylamiodarone, phenytoin levels may be affected for an extended period following discontinuation of amiodarone. Patients should be advised to contact 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. The clinical relevance of the changes in amiodarone pharmacokinetics is uncertain. It may be advisable to monitor for altered therapeutic effects or loss of efficacy of amiodarone during coadministration with phenytoin.

References

  1. Kerin NZ, Aragon E, Faitel K, Frumin H, Rubenfire M (1989) "Long-term efficacy and toxicity of high- and low-dose amiodarone regimens." J Clin Pharmacol, 29, p. 418-23
  2. Lesko LJ (1989) "Pharmacokinetic drug interactions with amiodarone." Clin Pharmacokinet, 17, p. 130-40
  3. Nolan PE, Marcus FI, Karol MD, Hoyer GL, Gear K (1990) "Effect of phenytoin on the clinical pharmacokinetics of amiodarone." J Clin Pharmacol, 30, p. 1112-9
  4. Wilson JS, Podrid PJ (1991) "Side effects from amiodarone." Am Heart J, 121, p. 158-71
  5. Duffull SB, McKenzie SK (1991) "Interaction between amiodarone and phenytoin." Am J Cardiol, 67, p. 328-9
  6. Gore JM, Haffajee CI, Alpert JS (1984) "Interaction of amiodarone and diphenylphydantoin." Am J Cardiol, 54, p. 1145
  7. Nolan PE Jr, Erstad BL, Hoyer GL, Bliss M, Gear K, Marcus FI (1990) "Steady-state interaction between amiodarone and phenytoin in normal subjects." Am J Cardiol, 65, p. 1252-7
  8. Funck-Brentano C, Jacqz-Aigrain E, Leenhardt A, Roux A, Poirier JM, Jaillon P (1991) "Influence of amiodarone on genetically determined drug metabolism in humans." Clin Pharmacol Ther, 50, p. 259-66
  9. McGovern B, Geer VR, LaRaia PJ, et al. (1984) "Possible interaction between amiodarone and phenytoin." Ann Intern Med, 101, p. 650-1
  10. Nolan PE, Marcus FI, Hoyer GL, et al. (1989) "Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers." Clin Pharmacol Ther, 46, p. 43-50
  11. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  12. Ahmad S (1995) "Amiodarone and phenytoin: interaction." J Am Geriatr Soc, 43, p. 1449-50
  13. Levy RH (1995) "Cytochrome P450 isozymes and antiepileptic drug interactions." Epilepsia, 36 Suppl 5, s8-13
  14. (2010) "Product Information. Amiodarone Hydrochloride (amiodarone)." Bedford Laboratories
  15. (2019) "Product Information. Pacerone (amiodarone)." Upsher-Smith Laboratories LLC
View all 15 references

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Drug and food interactions

Major

amiodarone food

Applies to: Cordarone (amiodarone)

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.

References

  1. (2002) "Product Information. Cordarone (amiodarone)." Wyeth-Ayerst Laboratories
  2. Libersa CC, Brique SA, Motte KB, et al. (2000) "Dramatic inhibition of amiodarone metabolism induced by grapefruit juice." Br J Clin Pharmacol, 49, p. 373-8
  3. Meng X, Mojaverian P, Doedee M, Lin E, Weinryb I, Chiang ST, Kowey PR (2001) "Bioavailability of Amiodarone tablets administered with and without food in healthy subjects." Am J Cardiol, 87, p. 432-5

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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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