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STUDY SELECTION AND DATA EXTRACTION: All sources evaluated were published in English and included original case reports, letters, and medical record or database reviews that described an interaction between phenytoin and statins or a specific statin.
DATA SYNTHESIS: Primary and tertiary literature describe the decreased efficacy of specific statins secondary to the concomitant use with phenytoin. Limited evidence exists for monitoring patients' phenytoin and cholesterol. However, increased lipid profiles were reported with concomitant use of phenytoin with atorvastatin, simvastatin or lovastatin, which increases cardiovascular risk. Despite the limited evidence, the drug interaction mechanism is likely due to induction of the cytochrome (CYP) 450 enzyme subtypes by phenytoin, which increases metabolism of atorvastatin, simvastatin, lovastatin, and fluvastatin. Four publications were identified, including 3 case reports and 1 retrospective study. Out of three case reports, two described patients with familial hypercholesterolemia who experienced cardiovascular events in temporal relation to increased lipid levels.
CONCLUSIONS: Phenytoin induces CYP450 enzymes which decrease the efficacy of atorvastatin, simvastatin, lovastatin and fluvastatin by increasing their metabolism. The interaction with other statins has not been established. Monitoring of cholesterol levels should be considered in patients taking both agents, especially those with familial hypercholesterolemia, because of the increased cardiovascular risk associated with increased lipid levels. Phenytoin levels were not affected by the interaction, therefore monitoring is not required.
KEY WORDS: drug interactions, phenytoin, hydroxymethylglutaryl-CoA reductase inhibitors, statin
Phenytoin is deemed to interact with statins. What is the mechanism? Is monitoring of phenytoin and cholesterol levels required for patients on both agents?
Phenytoin is an antiepileptic drug which is a substrate of the enzyme cytochromeP450 (CYP) 2C9 and 2C19 subtypes1 and an inducer of the subtypes CYP1A2, 2C9, 2C19 and 3A4.2 Within the class, statins have different pharmacokinetic parameters.3 All statins undergo metabolism via the CYP450 enzyme system, except pravastatin which is metabolized in the liver cytosol.3 The CYP3A4 subtype metabolizes lovastatin, simvastatin, and atorvastatin. Fluvastatin is metabolized mostly by CYP2C9; whereas, rosuvastatin is not extensively metabolized, but has some interaction with CYP2C9.3 Phenytoin and most statins share a common metabolic pathway, however, the clinical implications and the mechanism of the interaction need to be established. We performed an evaluation of the literature to define the mechanism and monitoring of concomitant administration of phenytoin and statins.
Literature describing the potential interaction between phenytoin and statins was reviewed. Relevant literature was identified through a PubMed (Medline) search from 1950 to May 20, 2011 and EMBASE (1980-week 20, 2011) search using the search terms phenytoin, hydroxymethylglutaryl-CoA reductase inhibitors, statin and drug interactions. The articles were limited to use in humans and published in English, mapped to subject headings. Bibliographic was reviewed but did not reveal any additional references. Only primary literature reports for the interaction of phenytoin and statins were included. Four publications were identified, including 3 individual case reports and 1 retrospective study. Table 1 summarizes the literature describing this potential interaction.
The first report of this interaction described a 50-year-old female, diagnosed with familial hypercholesterolemia and taking simvastatin with total cholesterol (TC) of 9.4mmol/l and triglycerides of 1.87mmol/l.4 She was taking valproate for her epilepsy, which was changed to phenytoin. Her TC increased to15.99mmol/l. She claimed that she was compliant with
Table 1. Case Summaries
1 pt case report and kept under review for 1 year
Retrospective insurance claims review (2000 to 2006) comparing enzyme-inducing antiepileptic drugs (EIAEDs)+ statins and non-enzyme-inducing antiepileptic drugs (NEIAEDs)+statins
TC = total cholesterol TG = triglycerides
simvastatin. She denied significant alcohol intake, with no other evidence of this. Successive subsequent changes made to her lipid-lowering regimen included increasing the simvastatin dose, switching to fluvastatin, switching to atorvastatin, and subsequently increasing the atorvastatin dose. Her TC level remained above 10mmol/l throughout. The patient developed angina and coronary angiography revealed significant coronary heart disease. Subsequently, phenytoin was discontinued in two steps and her TC was markedly reduced to 6.24mmol/l.
A second case report described a 61-year-old male, with a medical history significant for coronary artery disease.5 He was asymptomatic at the time of assessment and had an unremarkable physical examination with no xanthelasmas, xanthomas, carotid or peripheral bruits. The patient was on phenobarbital 200mg/d, phenytoin 500mg/d, aspirin 81mg, and fosinopril 20mg/d. He was compliant with his medications and diet, and denied alcohol abuse. His lipid values were: TC 330mg/dL, LDL 256mg/dL, HDL 38mg/dL, triglycerides (TG) 195mg/dL. Consequently, he was diagnosed with familial hypercholesterolemia and atorvastatin 40mg/d was initiated. After 8 weeks of treatment, his lipid values were repeated with a TC of 287mg/dL, LDL 205mg/dL, HDL 39mg/dL and TG 210mg/dL. The atorvastatin dose was increased, and ezetimibe and niacin were initiated. After ten weeks on triple therapy, his lipids were: TC 246mg/dL, LDL 165mg/dL, HDL 55mg/dL and TG 130mg/dL. Subsequently, the patient suffered an acute coronary event and had a percutaneous transluminal coronary angioplasty. At this time the niacin was discontinued, but was reinitiated two months later secondary to elevated lipid values. Given the lack of response to the triple lipid-lowering therapy and that he had been seizure-free for over 15 years, phenytoin was discontinued. Two months after discontinuation of phenytoin his lipid levels decreased by approximately 50% to the following: TC of 190mg/dL, LDL 110mg/dL, HDL 55mg/dL, and TG 130mg/dL. The patient also remained seizure-free for six months on phenobarbital alone.
A third case report described a 78-year-old female admitted to the emergency department with truncal ataxia secondary to phenytoin toxicity (serum phenytoin 38.6ug/ml).5 She was stabilized for several years on bisoprolol 5mg, bendrofluazide 2.5mg, aspirin 75mg, simvastatin 40mg and phenytoin 300mg daily and her random TC was an average of 5.6mmol/l. On this occasion, history revealed that she had been taking extra phenytoin 300mg daily for one week instead of a bendrofluazide tablet, while continuing simvastatin. This was confirmed by tablet counting. At this time, her TC was 8mmol/l. Phenytoin was held in hospital until the symptoms associated with toxicity resolved but her simvastatin was continued at the same dosage and frequency. Monitoring revealed a gradual decrease in phenytoin and serum cholesterol levels. Her phenytoin level was down to 11.7ug/ml and phenytoin was re-initiated at discharge. Twenty-two days after admission her phenytoin level was in therapeutic range (10-20ug/ml) at 15ug/ml and her cholesterol level was 6.2mmol/l. One year after admission, her phenytoin level was therapeutic at 14.6mg/ml and her cholesterol level 5.6mmol/l.
Due to the minimal evidence regarding the clinical significance of the interaction between phenytoin and statins, retrospective insurance claims were analyzed from the Ingenix Impact (formerly Integrated Healthcare Information System) database from 2000 to 2006.2 Subjects were eligible for the study if they were at least 18 years of age, with at least one diagnosis of epilepsy or non-febrile convulsions; at least two prescription claims for an enzyme-inducing antiepileptic drug (EIAED) or an non-enzyme-inducing antiepileptic drug (NEIAED); at least one prescription claim for atorvastatin, simvastatin, or lovastatin within the 31 days before or after antiepileptic drug (AED) initiation; and at least one additional prescription claim for any one of these statins during the follow-up period. A total of 1118 subjects were eligible for analysis. Phenytoin was the most frequently initiated AED in the EIAED+statin group (71.96%), while gabapentin (57%) as the most frequently initiated AED in the NEIAED+statin group. Compared to the NEIAED, subjects initiating an EIAED were more likely to have an increase in statin dose (OR = 1.36; P = 0.0499), increased mean LDL cholesterol level greater than 100 mg/dL (OR = 41.22; P = 0.0058) and increased LDL levels during the follow-up period (+26.61 mg/dL; P = 0.0019).
Phenytoin induces the activity of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme subtypes, which are responsible for the metabolism of specific statins.2 EIAEDs, such as phenytoin, have been reported to decrease drug serum concentrations of statins, such as atorvastatin and simvastatin, resulting in decreased statin efficacy.2 Specifically, induction of CYP2C9 will decrease fluvastatin levels and induction of CYP3A4 will decrease atorvastatin, simvastatin and lovastatin levels. Another potential mechanism involves phenytoin induction of P-glycoprotein, which effluxes drugs back into the intestine subjecting them to metabolism by CYP enzymes in the intestine. As an inhibitor and substrate of P-glycoprotein, simvastatin levels may be affected, however, there is insufficient information regarding this mechanism and its clinical significance.6
The evidence to support monitoring of phenytoin and cholesterol levels in patients taking concomitant phenytoin and statins has not been established. Considering all reports, lipid levels measured in patients taking phenytoin and atorvastatin or simvastatin decreased by approximately 40-50% upon discontinuation of phenytoin.4-6 Depending on dose, lipid levels were higher (TC >6mmol/l or LDL >100 mg/dL) when phenytoin and the statins involved in the reports were used concomitantly.4-7 Phenytoin levels were not affected by this interaction.4-7
Although, two of the three case reports described patients with familial hypercholesterolemia, which may not be applicable to the general population4-5, higher TC and lower HDL levels are associated with increased risk of cardiovascular disease for all individuals.8 In addition, the prevalence ratio of cardiovascular disorders is 20-40% higher in patients with epilepsy than the nonepilepsy population.9 The two patients with familial hypercholesterolemia and epilepsy experienced cardiovascular events in temporal relation to an elevated lipid profile.4-5
Monitoring and meeting target lipid levels8 and calculating a Framingham risk score (FRS) during concomitant phenytoin and statin therapy could be considered substantial, especially in patients with a familial hypercholesterolemia and/or epilepsy. Despite the data source limitations of the retrospective study, increased LDL levels with EIAEDs and atorvastatin, simvastatin or lovastatin, suggest the need to monitor patients on these agents.7 Monitoring with fluvastatin would be prudent because it is metabolized by CYP2C9; however, since rosuvastatin has some CYP2C9 involvement and pravastatin is not metabolized by CYP enzymes, monitoring may not be considered substantial.5,10 Monitoring allows for modification of drug therapy to meet lipid targets which include: a 50% decrease in LDL if LDL≥5mmol/l and FRS <10%; and LDL<2mmol/l if FRS=10-19% and LDL>3.5mmol/l or if FRS ≥20%.8
In practice, clinicians are aware of the interaction between phenytoin and statins, but the interaction with all statins, monitoring requirement and mechanism is less well established. Evaluation of the primary literature revealed minimal evidence on these topics. However, the effect of phenytoin with atorvastatin, simvastatin, fluvastatin and lovastatin on lipid values was reported.
Because patients with epilepsy have an increased cardiovascular risk, increased lipid levels secondary to the concomitant use of phenytoin and statins in the literature (atorvastatin, simvastatin, lovastatin, fluvastatin), would increase the risk of experiencing a cardiovascular event further. For this reason, monitoring cholesterol levels should be considered in all patients on concomitant therapy with these statins, especially those with familial hypercholesterolemia. Since phenytoin efficacy was not affected by statins, monitoring phenytoin levels should be considered if patients' seizures were not controlled or if patients experience intolerable side effects.
The mechanism of the interaction of statins with phenytoin is not a class effect. There is evidence for phenytoin decreasing the efficacy of atorvastatin, simvastatin, fluvastatin and lovastatin, but not with other statins. In the circumstance that patients are taking phenytoin and a statin, especially those mentioned above, clinicians should try to change phenytoin with a NEIAED like lamotrigine or valproate.
If phenytoin cannot be changed, clinicians should prescribe a statin that is less to interact with phenytoin, such as pravastatin or rosuvastatin. However, monitoring of cholesterol levels should be considered in patients taking phenytoin and any statin, especially those with hypercholesterolemia, because of the limited data on the effect of the concomitant use with all statins.
Providing these safeguards will assist the clinician in safely managing the concomitant use of phenytoin and statins, as well as making appropriate changes to a patient's drug therapy regimen to avoid the interaction and ensure patient safety.