Amiodarone with Phenytoin Interaction Details
Brand Names Associated with Amiodarone
- Amiodarone
- Cordarone®
- Pacerone®
Brand Names Associated with Phenytoin
- Dilantin®
- Phenytek®
- Phenytoin
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Feb 27, 2024
Interaction Effect
Increased phenytoin exposure and an increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor)
Interaction Summary
Concomitant use of amiodarone and phenytoin has resulted in increased exposure to phenytoin[1][2] and phenytoin toxicities [3]. Monitor phenytoin levels when coadministration is required. Drug interactions may persist for weeks to months after discontinuation of amiodarone [4] and the interaction may take weeks to occur, due to delayed onset of action of amiodarone. Consider evaluating serum phenytoin once or twice weekly for the first 4 to 6 weeks after initiation of amiodarone in a patient stabilized on phenytoin therapy, and continue regular monitoring for 3 months following dose stabilization [3]. Phenytoin dosage reductions may be needed when amiodarone therapy is added in patients stabilized on phenytoin therapy [1].
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Concomitant use of amiodarone and phenytoin may increase steady-state levels of phenytoin. Monitor phenytoin levels when coadministration is required. Drug interactions may persist for weeks to months after discontinuation of amiodarone[4], and manifestations of the interaction may take weeks to occur, due to the delayed onset of action of amiodarone. Consider evaluating a serum phenytoin level once or twice weekly for the first 4 to 6 weeks after initiation of amiodarone in a patient stabilized on phenytoin therapy, and continue regular monitoring for 3 months following dose stabilization [3]. Phenytoin dosage reductions may be needed when amiodarone therapy is added in patients stabilized on phenytoin therapy [1].
Mechanism Of Interaction
Decreased phenytoin metabolism
Literature Reports
A) The mean AUC of phenytoin was significantly increased from 245 to 342 mg x hr/L with administration of phenytoin base 5 mg/kg IV after 3 weeks of oral amiodarone hydrochloride 200 mg/day (190 mg amiodarone base) to healthy adult male subjects in a pharmacokinetic study (N=7). A corresponding decrease in mean phenytoin clearance (1.57 to 1.17 L/hr) and increase in half-life (16.1 to 22.6 hours) was observed. No significant differences in Vd at steady state or unbound fraction of phenytoin were observed during the coadministration [2].
B) Signs of phenytoin toxicity developed 2 weeks after initiation of amiodarone therapy for cardiac arrhythmia in a 73-year-old man who had been stable on phenytoin extended-release capsules 400 mg/day for treatment of seizure secondary to a cerebral vascular accident. Amiodarone was titrated over 22 days from 200 mg orally 3 times daily at initiation to a maintenance dose of 200 mg 4 times daily. Phenytoin levels were 59 mcmol/L (normal range, 40 to 80 mcmol/L) 5 days after initiation of amiodarone. The patient developed an unsteady gait, drowsiness, confusion, disorientation, and memory loss between days 16 and 26. Phenytoin levels had increased to 122 mcmol/L by day 28. Phenytoin was reduced to a dose of 200 mg/day and symptoms resolved. By day 33, the phenytoin level was 65 mcmol/L. The patient was stabilized on a phenytoin dose of 200 mg/day and amiodarone 800 mg/day [3].
C) The mean phenytoin AUC was significantly increased from 208 to 292 mg x hr/L with concomitant administration of amiodarone in healthy adult male subjects during a pharmacokinetic study (N=7). Amiodarone 200 mg/day orally (190 mg of amiodarone base) was taken for 4 1/2 weeks, then phenytoin base 2 to 4 mg/kg orally was coadministered for 14 days. Serum phenytoin concentrations increased significantly with mean Cmax changing from 10.75 mcg/mL at baseline to 14.26 mcg/mL and the mean concentration at 24 hours increasing from 6.67 to 10.27 mcg/mL. Average oral clearance of phenytoin declined from 1.29 L/hr to 0.93 L/hr, an average 28% decrease. No effects on protein binding of phenytoin were observed [1]
References
1 ) Nolan PE Jr, Erstad BL, Hoyer GL, et al: Steady-state interaction between amiodarone and phenytoin in normal subjects. Am J Cardiol 1990; 65(18):1252-1257.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
2 ) Nolan PE Jr, Marcus FI, & Hoyer GL: Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers. Clin Pharmacol Ther 1989; 46:43-50.
3 ) Shackleford EJ & Watson FT: Amiodarone--phenytoin interaction. Drug Intell Clin Pharm 1987; 21(11):921.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
4 ) Product Information: CORDARONE(R) oral tablets, amiodarone oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadephia, PA, 2018.
Amiodarone Overview
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Amiodarone is used to treat and prevent certain types of serious, life-threatening ventricular arrhythmias (a certain type of abnormal heart rhythm when other medications did not help or could not be tolerated. Amiodarone is in a class of medications called antiarrhythmics. It works by relaxing overactive heart muscles.
Phenytoin Overview
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Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.