Atorvastatin with Fosphenytoin Interaction Details
Brand Names Associated with Atorvastatin
- Atorvastatin
- Caduet® (as a combination product containing Amlodipine, Atorvastatin)
- Lipitor®
- Liptruzet® (as a combination product containing Atorvastatin, Ezetimibe)
Brand Names Associated with Fosphenytoin
- Cerebyx®
- Fosphenytoin Injection
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Mar 04, 2024
Interaction Effect
Decreased atorvastatin plasma concentration and decreased atorvastatin efficacy
Interaction Summary
Concomitant use of atorvastatin and phenytoin may result in decreased atorvastatin plasma concentration and decreased therapeutic effect due to induction of CYP3A4-mediated atorvastatin metabolism. In a pharmacokinetic study (n=44) of the concomitant administration of atorvastatin and phenytoin, the AUC and Cmax of atorvastatin was reduced by 54% and 24%, respectively, compared with administration of atorvastatin alone[1]. In a case report, the total cholesterol level increased in a patient treated with simvastatin (another HMG-CoA reductase inhibitor) 3 months after initiating phenytoin. Multiple changes were made to her lipid-lowering regimen, but only after discontinuing phenytoin did her total cholesterol decrease below 10 mmol/L [2]. Therefore, patients receiving concomitant atorvastatin and phenytoin should be monitored for atorvastatin efficacy and atorvastatin dosage adjustment may be necessary [1].
Severity
Moderate
Onset
Delayed
Evidence
Established
How To Manage Interaction
Concomitant use of atorvastatin and phenytoin may result in decreased atorvastatin plasma concentration and exposure, and decreased efficacy[1][2]. Monitor patients for decreased atorvastatin efficacy when atorvastatin and phenytoin are coadministered and adjust atorvastatin dosage as necessary [1].
Mechanism Of Interaction
Induction of CYP3A4-mediated atorvastatin metabolism by phenytoin
Literature Reports
A) In an open-label pharmacokinetic study, coadministration of atorvastatin and phenytoin reduced atorvastatin AUC and Cmax by 54% and 24%, respectively, compared with administration of atorvastatin alone. Healthy subjects (n=44) received atorvastatin 40 mg once daily for 7 days, then on days 8 to 28 all participants received daily atorvastatin 40 mg plus oral phenytoin at a target dose of 4 mg/kg/day. On days 7 and 28, the mean atorvastatin AUC was 63.4 nanogram(ng) x hr/mL (95% CI, 54.3 to 74 ng x hr/mL) and 29.2 ng x hr/mL (95% CI, 24.4 to 35 ng x hr/mL), respectively. The mean atorvastatin Cmax was 12.1 nanogram/mL (21.7 nanomol/L) on day 7, compared with 9.2 nanogram/mL (16.5 nanomol/L) on day 28. When atorvastatin is coadministered with phenytoin, atorvastatin dosage may need to be increased to maintain its exposure [1].
B) A 50-year-old woman was receiving simvastatin 10 mg daily for familial hypercholesterolemia and had a total cholesterol level of 9.4 mmol/L and a triglyceride level of 1.87 mmol/L. Other medications included sodium valproate 200 mg 3 times daily for epilepsy. Her anticonvulsant medication was switched to phenytoin 325 mg daily, and 3 months later her cholesterol had increased to 15.99 mmol/L. Serum activity of gamma-glutamyl transpeptidase, which was in the normal range (5 units/L to 50 units/L) before phenytoin, was also elevated at 175 units/L. Simvastatin was increased to 40 mg in a step-wise manner, with no resolution. Antilipidemic therapy was switched to fluvastatin 40 mg daily and finally to atorvastatin, starting at 10 mg daily and increasing in a step-wise fashion to 80 mg daily. Her cholesterol stayed in excess of 10 mmol/L throughout these changes, while phenytoin levels remained within the therapeutic range. Phenytoin was slowly discontinued, and her total cholesterol decreased to 6.24 mmol/L while gamma-glutamyl transpeptidase returned to normal values [2].
References
1 ) Bullman J, Nicholls A, Van Landingham K, et al: Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers. Epilepsia 2011; 52(7):1351-1358.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
2 ) Murphy MJ & Dominiczak MH: Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med 1999; 75:359-360.
Atorvastatin Overview
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Atorvastatin is used together with diet, weight loss, and exercise to reduce the risk of heart attack and stroke and to decrease the chance that heart surgery will be needed in people who have heart disease or who are at risk of developing heart disease. Atorvastatin is also used to decrease the amount of fatty substances such as low-density lipoprotein (LDL) cholesterol ('bad cholesterol') and triglycerides in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol ('good cholesterol') in the blood. Atorvastatin may also be used to decrease the amount of cholesterol and other fatty substances in the blood in children and teenagers 10 to 17 years of age who have familial heterozygous hypercholesterolemia (an inherited condition in which cholesterol cannot be removed from the body normally). Atorvastatin is in a class of medications called HMG-CoA reductase inhibitors (statins). It works by slowing the production of cholesterol in the body to decrease the amount of cholesterol that may build up on the walls of the arteries and block blood flow to the heart, brain, and other parts of the body.
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Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats with atorvastatin has been shown to prevent heart disease, angina (chest pain), strokes, and heart attacks.
Fosphenytoin Overview
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Fosphenytoin injection is used to treat primary generalized tonic-clonic seizures (formerly known as a grand mal seizure; seizure that involves the entire body) and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Fosphenytoin injection may also be used to control certain type of seizures in people who cannot take oral phenytoin. Fosphenytoin 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.