Newer Antiepileptic Drugs in Patients With Renal Failure

Abstract and Introduction

Abstract

Seizures and chronic kidney disease are both common and often coexist. Treating seizures in patients with renal failure, including those on dialysis, is a challenge that is frequently encountered, especially in the inpatient setting. For the newer antiepileptic drugs, there are limited data available, so an understanding of how each drug is affected by kidney disease and dialysis is critical in order to make rational choices qualitatively (which drug) and quantitatively (dosing). Generally, newer (second-generation) antiepileptic drugs are associated with fewer systemic side effects and drug–drug interactions, so they tend to be preferred in this population. The landscape of antiepileptic drugs is constantly evolving, with new compounds being released on a regular basis. Thus, several new agents have become available since the last review of this topic (in 2006) and these are the ones discussed here. Most require dosage adjustment according to the degree of renal failure, and most require extra doses after dialysis.

Introduction

Epilepsy has a prevalence of 1%, the lifetime prevalence of a single seizure is approximately 9%, and seizures are also common in renal failure. Seizures occur in approximately 30% of patients with uremic encephalopathy.^[1] Therefore, the use of antiepileptic drugs (AEDs) in patients with chronic kidney disease (CKD) is a common problem in neurological practice, to which the clinical neurologist is sure to be confronted, in both inpatient and outpatient settings. There are few data and systematic reviews on the use of AEDs in patients with renal failure, including patients on dialysis.^[2] In addition, the landscape of available AEDs is constantly evolving, with new drugs being added to the market on a regular basis. In the absence of data, often the management will rely on a good understanding of the drug's metabolism or 'dialysability'.

This article will focus on the agents that have become available since the last review of this topic,^[2] which include vigabatrin, rufinamide, lacosamide, pregabalin, ezogabine, eslicarbazepine, brivaracetam, perampanel and clobazam.

This review is meant as a practical guide to help clinicians (internists, nephrologists and neurologists) in this relatively common situation. We will first review the general principles of drug treatments in patients with CKD, and then turn to individual AEDs (summarized in Table 1), with an emphasis on recently released and soon to be available compounds. Many AEDs are indicated for conditions other than seizures (e.g., gabapentin and pregabalin for chronic pain, topiramate and valproate for migraine, and lamotrigine for bipolar disease), but these indications are less 'acute' than seizures, so the main focus here will be for the purpose of seizure control.

Table 1. Summary of recommended antiepileptic drug doses for patients with renal impairment.
Drug	Molecular weight	CrCl (ml/min)				HD dose
Drug	Molecular weight	50–80	30–50	>10 to <30	<15	HD dose
Vigabatrin	129.2	25% decrease	50% decrease	75% decrease		Up to 60% removed; replace based on clinical judgment or dose after
Rufinamide	238.2	No change	No change	No change		Supplement 30% of dose
Lacosamide	250.3	No change	No change	Max dose 300 mg/day		Up to 50% replacement dose
Ezogabine	303.3	No change	Initiate 50 mg t.i.d., max 200 mg t.i.d.	Initiate 50 mg t.i.d., max 200 mg t.i.d.		Not established
Eslicarbazepine	296.3	No change	400 mg QOD × 2 weeks then 400 mg daily; 600 mg daily max	400 mg QOD × 2 weeks then 400 mg daily; 600 mg daily max		Not established, metabolites are removed
Perampanel	349.4	Not established	Not established	Not established		Not established
Clobazam	300.7	No change	No change	No change		Not affected by HD
Pregabalin	159.2	600 mg/day max dose^†	300 mg/day max dose^‡	150 mg/day^§	75 mg/day max dose	Replacement dose 25–150 mg

^†CrCl = >60 ml/min.
^‡CrCl = 30–60 ml/min.
^§CrCl = 15–30 ml/min.
CrCl: Creatinine clearance; HD: Hemodialysis; Max: Maximum; QOD: Every other day; t.i.d.: Three times daily.

Sidebar

Key Issues

Pharmacokinetics and pharmacodynamic properties of a parent drug and its active or inactive metabolites are greatly affected in patients with kidney disease and its resulting uremia. Hemodialysis (HD)-related factors also alter drug clearance.
Vigabatrin: in patients with renal impairment the dose should be decreased based on creatinine clearance. The effect of dialysis on vigabatrin clearance has not been adequately studied.
Rufinamide: patients with a creatinine clearance less than 30 ml/min do not require dosage adjustments. HD may reduce plasma concentrations by approximately 30%.
Lacosamide: no dose adjustment is considered necessary in patients with mild or moderate renal impairment. A maximum dose of 300 mg/day should not be exceeded in patients with severe renal impairment or in patients with end-stage renal disease. A supplemental dose of up to 50% following HD should be considered.
Pregabalin: for patients with renal failure, the pregabalin daily dose should be adjusted based on creatinine clearance. A supplemental dose should be administered immediately following each HD treatment.
Ezogabine (retigabine): a single-dose study shows that ezogabine exposure is increased and plasma and renal clearance are decreased as the severity of renal impairment increases. The effect of HD on ezogabine clearance has not been adequately established.
Eslicarbazepine: systemic exposure to antiepileptic drugs is increased in patients with mild-to-moderate renal impairment. The dose of eslicarbazepine should be reduced in patients with a creatinine clearance less than or equal to 50 ml/min. Patients may require supplemental doses after HD.
Brivaracetam: the pharmacokinetic profile of brivaracetam is unaltered in patients with impaired renal function or by HD.
Perampanel: the use of perampanel in patients with altered renal function has not been studied.
Clobazam: dosage adjustment should not be necessary in patients with impaired renal function.

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