Journal Pre-proof

Managing the Patient with Epilepsy and Renal Impairment

Sherif Hanafy Mahmoud, Xiao Ying Zhou, S. Nizam Ahmed

PII: S1059-1311(20)30047-9
DOI: https://doi.org/10.1016/j.seizure.2020.02.006
Reference: YSEIZ 3659

To appear in: Seizure: European Journal of Epilepsy

Received Date: 14 September 2019

Revised Date: 5 January 2020
Accepted Date: 6 February 2020

Please cite this article as: Hanafy Mahmoud S, Zhou XY, Nizam Ahmed S, Managing the
Patient with Epilepsy and Renal Impairment, Seizure: European Journal of Epilepsy (2020),
doi: https://doi.org/10.1016/j.seizure.2020.02.006

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© 2019 Published by Elsevier.

Managing the Patient with Epilepsy and Renal Impairment

Sherif Hanafy Mahmoud1, BSc (Pharm), MSc, PhD; Xiao Ying Zhou2 ,Pharm D and S. Nizam Ahmed3,

MD, FRCPC

1
Clinical Associate Professor, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta,

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Edmonton, AB, Canada
2
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

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3
Professor of Medicine (Neurology) and Director, Clinical Neurophysiology Laboratory, Division of

Neurology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,

AB, Canada

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Corresponding Author:
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Sherif Hanafy Mahmoud, BSc (Pharm), MSc. , PhD

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta

3-142H Katz Group Centre for Pharmacy and Health Research

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Edmonton, AB, Canada T6G 2E1

Email: smahmoud@ualberta.ca
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Highlights

 Kidney disease in epilepsy patients complicates optimal use of antiepileptic drugs (AEDs).

 Disposition of AEDs can be altered in kidney disease, leading to higher risk of toxicity or therapy

failure.

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  Although AED nephrotoxicity is rare, it is unpredictable. Monitoring is recommended.

 AEDs renal adverse reactions and renal drug interactions are additional factors that need to be

considered.

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Abstract

Purpose: Epilepsy affects more than 50 million people worldwide and its management can be complicated

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by comorbidities such as impaired renal function. To optimize epilepsy control in patients with kidney

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disease, clinicians need to be aware of how antiepileptic drugs (AEDs) are affected by impaired renal

function and how the kidneys are affected by epilepsy management strategies. Herein we present a narrative
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review with systematic literature search to discuss the use of AEDs in patients with renal impairment,

including those undergoing dialysis, as well as the nephrotoxic effects of some AEDs. We finally conclude
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the article by providing practical tips about our approach to using AEDs in the setting of renal disease.

Methods: A literature search targeting epilepsy management in patients with kidney disease was performed
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in MEDLINE database (1946 to 7th Jan 2019).

Results: A total of 1193 articles were found. After duplicate removal, title and abstract screening followed
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by full text screening, a total of 110 references were included in this review. Additional information was

included from drug product monographs.

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Conclusion: The disposition of AEDs can be altered in patients with impaired renal function, leading to a

higher risk of AED toxicity or therapy failure. Renal dosage adjustment and close monitoring is

recommended. Although AED-induced nephrotoxicity is rare, it is unpredictable and clinicians need to

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vigilant about this possibility. In addition, AEDs renal adverse reactions and renal drug interactions should

be considered when selecting an AED.

Keywords: Epilepsy; kidney disease; renal impairment; antiepileptic drugs

Introduction

Epilepsy affects more than 50 million people worldwide and is characterized by recurrent

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unprovoked seizures. One of the main goals of treatment is to improve patient quality of life by optimizing

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the balance between seizure control and side effects of the antiepileptic drugs (AEDs). Although the

majority of patients can be adequately controlled with AEDs, a significant number, estimated to be as high

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as 30% stay uncontrolled with conventional medical treatment. This can be further complicated if a patient

has comorbid impaired renal function given how AEDs are eliminated and how they are affected by
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impaired renal function. The objective of this review is to discuss the use of AEDs in patients with renal

impairment, including those undergoing dialysis, as well as the nephrotoxic effects of some AEDs. A
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practical approach to using AEDs in the setting of renal disease will also be provided.

Evidence Used in this Review

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A literature review was performed targeting epilepsy management in patients with kidney disease.

The database searched was Medline (1946 to 19th May 2017) using limits restricting the search results to
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articles written in English and concerning humans. The search was repeated on 7th January 2019. The search

terms representing AEDs were “anti-seizure*”, “antiseizure*”, “anticonvuls*”, “anti-convuls*”,

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“antiepileptic*”, “anti-epileptic*”, “brivaracetam”, “carbamazepine”, “clobazam”, “clonazepam”,

“eslicarbazepine”, “ethosuximide”, “gabapentin”, “lacosamide”, “lamotrigine”, “levetiracetam”,

“oxcarbazepine”, “perampanel”, “phenobarbital”, “phenytoin”, “fosphenytoin”, “pregabalin”,

“primidone”, “rufinamide”, “stiripentol”, “topiramate, “divalproex”, “valproic acid”, “valproate”,

“vigabatrin”, “zonisamide”, “midazolam”, and “lorazepam”. The search terms representing renal

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impairment were “(Renal or kidney) adj (disease* or failure* or insufficiency or injur* or blood flow or

impairment or function or dysfunction or pain* or toxicit*)” while the search terms representing renal drug-

drug interactions were “(Renal or kidney) adj (elimination or clearance or excretion or transporter inhibition

or inhibition)”. A total of 1193 articles were found. After duplicate removal, title and abstract screening

followed by full text screening, a total of 110 references were included in this review. Additional

information was included from drug product monographs enlisted in the Canadian Compendium of

Pharmaceuticals and Specialties (CPS).1

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What are the effects of AEDs on the kidney?

AEDs-induced nephrotoxicity

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The incidence of AEDs-induced nephrotoxicity is rare - typically reported in less than 1 in 1000
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patients (≤0.1%) in drug product monographs and infrequently through post-marketing reports – but may

complicate patients’ management. Table 1 depicts the renally related adverse reactions associated with
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AEDs. The precise mechanism leading to nephrotoxicity is unknown, but may be the result of

idiosyncratic hypersensitivity reactions or AEDs’ direct action on the kidneys.

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Carbamazepine, phenytoin, primidone, and phenobarbital are commonly implicated in drug rash

with eosinophilia and systemic symptoms (DRESS). Also known as anticonvulsant hypersensitivity
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syndrome (AHS), DRESS is an idiosyncratic reaction that has been attributed to arene oxide reactive

metabolites.2 Numerous case reports have reported hypersensitivity reactions associated with initiation of
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carbamazepine and phenytoin that have led to multisystem signs and symptoms, such as fever, rash,

lymphadenopathy, eosinophilia and hepatosplenomegaly, which occasionally also involves the kidneys.3-9

Other case reports describe nephrotoxicity secondary to non-hypersensitivity reactions in patients using

carbamazepine, valproic acid, phenobarbital, ethosuximide, gabapentin, lamotrigine, levetiracetam and

injectable lorazepam.10-34

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 Available literature demonstrates that valproic acid can cause renal proximal tubular dysfunction

(Fanconi syndrome).15-28 The mechanisms leading up to renal dysfunction are unclear; however, the direct

effect of valproic acid on mitochondria in the proximal tubules and its accumulation in the kidney have

been suggested.16,19 There is currently not enough evidence to establish causality higher doses of valproic

acid and nephrotoxicity, it has been suggested that longer durations of treatment might lead to Fanconi

syndrome especially in children.16

In summary, AEDs may be involved in rare but occasionally serious nephrotoxicity. As these

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reactions are often unpredictable, clinicians need to be vigilant about this possibility.

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AED-induced nephrolithiasis

A few AEDs have been reported to cause nephrolithiasis: topiramate, acetazolamide and

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zonisamide. The mechanism of topiramate-induced renal stones has been attributed to its weak inhibition
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of the enzyme carbonic anhydrase in the proximal renal tubules. This results in a decrease in renal

reabsorption of bicarbonate and citrate excretion and increased urinary pH.35-45 Reduction in serum
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bicarbonate may result in metabolic acidosis while increased urinary pH and decreased citrate excretion

increase the risk of nephrolithiasis. Similarly, acetazolamide, a carbonic anhydrase inhibitor used rarely

for epilepsy, has been reported to cause renal tubular acidosis, renal colic, nephrolithiasis and acute renal
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failure in patients using commonly prescribed doses of 250-1000 mg daily.35,46-52 Zonisamide has also

been implicated to cause renal stones with a similar mechanism to topiramate and acetazolamide.
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Risk factors for metabolic acidosis and subsequent nephrolithiasis include administration of these
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agents in patients who are older, have reduced kidney or liver function, and/or diabetes.47,48 In addition,

patients on concurrent carbonic anhydrase inhibitors and those with prior kidney stone history are at

increased risk. Close monitoring of renal function and serum biochemistry is advised during topiramate,

acetazolamide and zonisamide initiation and titration.

What is the effect of renal impairment on the elimination of AEDs?

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Renally eliminated AEDs

Levetiracetam, gabapentin, pregabalin, topiramate, eslicarbazepine, lacosamide and vigabatrin are

at least partially renally eliminated (Table 2). Reduced renal clearance leads to prolonged elimination

half-life and accumulation of the parent drug and its metabolites in the body. If the dose of these

medications is not promptly adjusted, there is a higher likelihood of adverse effects. Gabapentin

accumulation is a classic example of AED toxicity in patients with renal impairment, leading to excessive

sedation and frequent emergency room visits.53-57 Other examples include encephalopathy with vigabatrin

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and levetiracetam.58,59 Table 2 depicts the disposition (proportion of drug metabolized, renally eliminated,

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and protein bound) and adult dosing considerations of AEDs in patients with renal disease, where dosage

adjustment is based on the degree of the renal impairment.

Non-renally eliminated AEDs

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Although non-renally eliminated, the pharmacokinetics of several AEDs are altered in renal

disease. The buildup of endogenous uremic substances and hypoalbuminemia secondary to proteinuria
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can lead to reduced protein binding of highly bound (> 90%) AEDs (such as phenytoin and valproic acid),

increasing the pharmacologically active free fraction leading to enhanced response and adverse

reactions.60-62 Monitoring the free fraction of highly plasma protein bound AEDs could be of value in
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patients with uremia and hypoalbuminemia. Unfortunately, free AEDs levels are not widely available and

are more expensive. If free concentrations are not available, clinicians need to interpret total AEDs
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concentrations cautiously in patients with uremia and hypoalbuminemia. Alteration in protein binding

might be clinically significant with initiation of therapies; however, with chronic administration, the
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initial increase in the free fraction will also lead to an increase in the drugs’ volume of distribution and

plasma clearance, often resulting in a clinically insignificant change in the AEDs’ free fraction at steady

state.

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 There is also emerging evidence that chronic kidney disease can affect non-renal clearance of

AEDs due to its effect on drug transporters and cytochrome P450 enzymes expression throughout the

body.63-65 This provides further support for closely monitoring patients with renal impairment on non-

renally eliminated AEDs to avoid toxicity due to the complex pharmacokinetic alterations at play.

Renal replacement therapies

Patients with end-stage renal disease may utilize various renal replacement therapies (RRT)

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including hemodialysis (HD), peritoneal dialysis (PD) and continuous renal replacement therapy (CRRT),

which have different effects on AED removal and may warrant dose changes as well as more frequent

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monitoring. It is important to take into consideration the extent of extracorporeal clearance of AEDs, to

avoid the risk of breakthrough seizures due to subtherapeutic AED blood levels.

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Several factors could influence extracorporeal drug removal. The first factor is the molecular
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weight of the drug. Drugs with molecular weight (MW) lower than 500 Daltons can diffuse easily through

the dialysis filters. Given that the MW of all AEDs are less than 400 Dalton, MW is not rate limiting for
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AED removal by dialysis. The second, and most important, factor is protein binding of AEDs. Only the

unbound drug is available for removal by extracorporeal means as the size of the protein bound drug

complex hinders its passage through membranes.66 Thus, drugs that are highly protein bound are less
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likely to be removed by extracorporeal means, including phenytoin and carbamazepine. On the other

hand, AEDs with limited protein binding (such as levetiracetam) can be significantly removed. Factors
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affecting protein binding such as drug interactions, low albumin and renal failure can alter the percentage

of free fraction and therefore can alter the extent of its extracorporeal removal. For example, the unbound
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fractions of phenytoin and valproic acid have been reported to reach up to 40% and 86%, respectively in

critically ill patients with renal failure leading to substantial drug removal by CRRT.67,68 The third factor

influencing extracorporeal elimination is the drug’s volume of distribution (Vd). Owing to extensive tissue

distribution, drugs with high Vd are less available for removal by extracorporeal means compared to drugs

with low Vd. Last, the route of drug elimination is of importance. For AEDs that are mainly renally

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eliminated, such as gabapentin and pregabalin, RRT will have significant contribution to their clearance.69

On the other hand, AEDs that are mainly eliminated by liver metabolism such as phenytoin and valproic

acid, will be minimally impacted by RRT. However, removal of uremic substances following dialysis has

been associated with reduction of the free fraction of the highly protein bound drugs (including

phenytoin) due to reduced competition at the protein binding site potentially leading to breakthrough

seizures.70-72

In addition to drug characteristics, the type of the RRT modality has an influence on the extent of

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AED removal. HD is in an efficient RRT and supplemental AED doses might be needed after the dialysis

runs. Similarly, CRRT might have a significant effect on AED removal and dosing alterations are

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warranted (Table 2).73 On the other hand, PD is less likely to contribute to AED clearance and dosing as

in patients with CrCl < 15 ml/min is recommended.

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Unfortunately, there is not sufficient evidence to provide robust dosing recommendations for all
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AEDs in patients undergoing RRT; however, the pharmacokinetic characteristics of AEDs combined with

the available evidence could be used as a guide for dosing and ongoing monitoring. Suggestions for AED
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dosing in renal replacement therapies are summarized in Table 2.

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What are the renally-related AEDs drug-drug interactions?

It is well known that several AEDs inhibit (valproic acid) or induce (phenytoin, carbamazepine,
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phenobarbital, primidone and topiramate (at high doses)) liver microsomal enzymes, which might alter

the metabolism of concomitantly administered drugs. In addition, AEDs may also be implicated in renally
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related drug interactions that clinicians need to be aware of as they might either result in alteration of

drugs’ renal clearance or aggravation of renal toxicity.

Table 3 summarizes the known renally-related drug interactions of AEDs. Examples of

potentially affected drugs are lithium, high-dose methotrexate (MTX) and metformin when co-

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administered with topiramate, levetiracetam and lamotrigine, respectively. Topiramate might increase the

serum concentration of lithium secondary to alteration of lithium renal clearance and monitoring lithium

levels is recommended.37,74,75 Levetiracetam has been reported to increase MTX serum concentration

secondary to levetiracetam-induced reduction of MTX renal elimination;76,77 however, a retrospective

study conducted in oncology patients reported no significant interaction.78 Finally, lamotrigine may

inhibit the organic cation transporter in the kidney potentially reducing the renal tubular secretion of its

substrates, including metformin.1 Monitoring for metformin adverse effects is recommended.

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In addition to altered renal elimination, clinicians need to be aware that co-administration of some

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drugs may aggravate the nephrotoxic potential or electrolyte imbalance associated with some AEDs

through pharmacodynamic drug interactions. For example, co-administration of acetazolamide,

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zonisamide and/or topiramate may increase the risk of nephrolithiasis and co-administration of diuretics

with carbamazepine and eslicarbazepine may increase the risk of hyponatremia. Although the evidence
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for those interactions is mainly based on case reports and retrospective studies, clinicians should always

consult a drug interaction resource for all patients prescribed AEDs.

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How can control of epilepsy be optimized in a patient with renal impairment?

Renally-eliminated AEDs are not absolutely contraindicated in patients with renal impairment,
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however they need to be used with caution, with appropriate dosing and close follow-up for adverse

effects. Signs of accumulation with AEDs may include CNS changes such as myoclonus, excessive
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somnolence, and ataxia. On the other hand, there can be situations where choosing renally-eliminated

AEDs in renal impairment is preferred or advantageous. To illustrate, in patients receiving chemotherapy,

immunosuppressants, direct oral anticoagulants or antiretroviral therapies, there is a high risk of drug-

drug interactions through cytochrome P450 enzymes induction and/or inhibition with multiple non-

renally eliminated AEDs such as phenytoin, carbamazepine and phenobarbital. This will potentially put

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patients at risk for therapy failure or toxicity. Renally eliminated AEDs, such as levetiracetam, which do

not alter and are not substrates of cytochrome P450 enzymes, have the advantage over non-renally

eliminated AEDs in terms of drug-drug interactions. This makes them better choice in those patient

populations.

Consideration of the propensity to and previous history of renal adverse reactions and toxicities is

very important in AED selection. For example, in patients who are at high risk of renal stones, alternative

AEDs other than topiramate, zonisamide, and acetazolamide should be considered. However, if these

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agents need to be started, frequent monitoring and/or possible consideration of prophylactic therapies

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such as potassium citrate supplementation are recommended. Another example, in patients with prior

history of DRESS should not be started with another AEDs that could be implicated with DRESS because

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the risk of cross reactivity could be as high as 80%.79 Choice of an AED that is less implicated with

DRESS such as valproic acid is favored in this scenario.

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What are the monitoring considerations of AEDs in patients with renal disease?

Patients with seizures and epilepsy treated with AEDs need to be monitored regularly for the two
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“CAs” (Control and Complications of the disease; Adherence and Adverse reactions of the drugs).80

Adherence to the AED regimen is essential for maintaining therapeutic concentration of the drug and
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avoidance of poor seizure control. Second, regular monitoring of seizure control is important to determine

the appropriateness of the AED regimen and if there is a need for regimen adjustment. Third, monitoring
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for progression of the illness and the presence of new comorbidities. For example, the presence of new

onset renal impairment might mandate alteration of the AED drug regimen to maintain seizure control.

Monitoring AED adverse reactions is essential to maintain safety. This involves patient’s self-monitoring

for common adverse reactions and laboratory testing such as serum creatinine, electrolytes, complete

blood count, and liver and thyroid function tests. Monitoring AED plasma concentrations might be used

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to guide dose adjustments using therapeutic drug monitoring. However, it is important to mention that

reference ranges are mainly based on retrospective studies and expert opinion and seizure control may be

achieved with drug concentrations outside of the suggested reference range without any adverse reactions.

AED levels are helpful in guiding therapy in patients with renal disease given the altered

pharmacokinetics of drugs and the possible use of RRTs. For AEDs that are highly protein bound,

measuring the free fraction would be of greater value than total concentration, if available. Table 4

summarizes the suggested monitoring for individual AEDs.

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Practical considerations when prescribing AEDs: The ultimate goal of treating patients with epilepsy is

to improve their quality of life. This goal is achieved by tailoring a plan for each individual patient

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considering their body habitus, occupation, coexisting medical conditions, plans for pregnancy and

interactions with other prescribed or over the counter medications. We would like to share some practical
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tips that we have found useful when managing our patients in the Epilepsy Clinic:
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1. Start low and go slow. If there is no rush do not rush. If a patient is not having very frequent seizures

consider starting very low on AEDs and gradually increase the dose based on patient tolerance rather

than a preconceived dosing schedule.

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2. Instead of chasing seizures, focus on patient quality of life. Some patients would rather live with few

non-disabling seizures a month than experience constant side effects every day. Consider patient
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preferences and discuss this balance with each patient.

3. Less may be more. Periodically re-evaluate the efficacy of prescribed medication(s). Even with
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medically refractory epilepsy, some patients will be better off on less rather than more medications.

4. The AED levels are just a guideline. Do not alter the dose of the AED solely based on numbers.

Always consider the clinical correlation.

5. Share care. Select the best AED(s) with the patient after an informed discussion of benefits and risks.

Try not to impose a medication just because it is recommended in evidence summaries.

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Conclusion

Patients with seizures and epilepsy treated with AEDs might have superimposing comorbidities

like renal disease that might further complicate their management. To optimize epilepsy control in these

patients, clinicians need to be aware of how AEDs are affected by impaired renal function and how the

kidneys are affected by epilepsy management.

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Declarations of interest: none

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Funding: This research did not receive any specific grant from funding agencies in the public,

commercial, or not-for-profit sectors.

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Acknowledgements
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The authors would like to thank Dr. Jill Hall for reviewing the manuscript and providing valuable

feedback.
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71. Dasgupta A, Abu-Alfa A. Increased free phenytoin concentrations in predialysis serum compared
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72. Frenchie D, Bastani B. Significant removal of phenytoin during high flux dialysis with cellulose
triacetate dialyzer. Nephrology Dialysis Transplantation 1998;13:817-8.
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of the Literature. Clinical Drug Investigation 2017;37:7-23.
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2002;22:340.
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resulting in delayed methotrexate elimination. Ann Pharmacother 2014;48:292-6.

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77. Parentelli AS, Phulpin-Weibel A, Mansuy L, Contet A, Trechot P, Chastagner P. Drug-drug
interaction between methotrexate and levetiracetam in a child treated for acute lymphoblastic leukemia.
Pediatr Blood Cancer 2013;60:340-1.
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Coadministered With Levetiracetam. Ann Pharmacother 2016;50:1016-22.
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pharmaceutical care. Pharmacotherapy 2007;27:1425-39.
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82. Parikh JR, Nolan RL, Bannerjee A, Gault MH. Acetazolamide-associated nephrocalcinosis in a
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83. Eguchi E, Shimazu K, Nishiguchi K, Yorifuji S, Tanaka A, Kuwahara T. Granulomatous interstitial
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Clinical & Experimental Nephrology 2012;16:168-72.
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nephritis. Journal of Pediatrics 1981;98:830-2.

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85. Mayan H, Golubev N, Dinour D, Farfel Z. Lithium intoxication due to carbamazepine-induced
renal failure. Annals of Pharmacotherapy 2001;35:560-2.
86. Fervenza FC, Kanakiriya S, Kunau RT, Gibney R, Lager DJ. Acute granulomatous interstitial
nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment.
American Journal of Kidney Diseases 2000;36:1034-40.
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Mylonakis E, Vittorio CC, Hollik DA, Rounds S. Lamotrigine overdose presenting as
anticonvulsant hypersensitivity syndrome. Annals of Pharmacotherapy 1999;33:557-9.
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88. Schaub JE, Williamson PJ, Barnes EW, Trewby PN. Multisystem adverse reaction to lamotrigine.
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89. Mewasingh L, Aylett S, Kirkham F, Stanhope R. Hyponatraemia associated with lamotrigine in
cranial diabetes insipidus. Lancet 2000;356:656.
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90. Sawaishi Y, Komatsu K, Takeda O, et al. A case of tubulo-interstitial nephritis with exfoliative
dermatitis and hepatitis due to phenobarbital hypersensitivity. European journal of pediatrics 1992;151:69-
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91. Clark JG, Sumerling MD. Muscle necrosis and calcification in acute renal failure due to barbiturate
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92. Hoffman EW. Phenytoin-induced interstitial nephritis. Southern medical journal 1981;74:1160-1.
93. Hyman LR, Ballow M, Knieser MR. Diphenylhydantoin interstitial nephritis. Roles of cellular and
humoral immunologic injury. Journal of Pediatrics 1978;92:915-20.
94. Matson JR, Krous HF, Blackstock R. Diphenylhydantoin-induced hypersensitivity reaction with
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interstitial nephritis. Human pathology 1985;16:94-7.

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2009;20:131-3.
96. Sheth KJ, Casper JT, Good TA. Interstitial nephritis due to phenytoin hypersensitivity. Journal of
Pediatrics 1977;91:438-41.
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report. Arquivos de Neuro-Psiquiatria 2005;63:532-4.
98. Cheng M, Wen S, Tang X, Zhong Z. Hallucinations and comorbid renal tubular acidosis caused by
topiramate in a patient with psychiatric history. General hospital psychiatry 2013;35:213.e3.
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Alvarez S. Topiramate-induced metabolic acidosis: a case study. Nefrologia 2012;32:403-4.
100. Izzedine H, Launay-Vacher V, Deray G. Topiramate-induced renal tubular acidosis. American
Journal of Medicine 2004;116:281-2.

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101. Mirza NS, Alfirevic A, Jorgensen A, Marson AG, Pirmohamed M. Metabolic acidosis with
topiramate and zonisamide: an assessment of its severity and predictors. Pharmacogenetics and Genomics
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inhibiting renal carbonic anhydrase. Nephrology Dialysis Transplantation 2006;21:2995-6.
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renal failure and hemodialysis. Annals of Pharmacotherapy 1994;28:966-7.
104. Maia J, Almeida L, Falcao A, et al. Effect of renal impairment on the pharmacokinetics of
eslicarbazepine acetate. International Journal of Clinical Pharmacology & Therapeutics 2008;46:119-30.
105. Marbury TC, Lee CS, Perchalski RJ, Wilder BJ. Hemodialysis clearance of ethosuximide in
patients with chronic renal disease. American Journal of Hospital Pharmacy 1981;38:1757-60.
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peritoneal dialysis in a child. Clinical pharmacy 1992;11:1030-1.
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aspirin and low total valproic acid levels: a case report. J Clin Psychopharmacol 2009;29:509-11.
lP
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Table 1. Renally-related adverse reactions and electrolytes abnormalities associated with antiepileptic drugs (AEDs) use

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Antiepileptic drug Renally-related adverse reactions and electrolyte abnormalities (frequency, if reported) – From Drug Monographs1 and post-marketing
reports (cited within text)
Acetazolamide  Metabolic acidosis (incidence may be as high as 50% in older adults); hypokalemia; renal calculi (<1%)
 Reports of nephrocalcinosis35,81,82

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Brivaracetam  Hyponatremia ≤ 2%

Carbamazepine  Hyponatremia; edema; fluid retention (1-10%)



-p
Renal failure10,11; interstitial nephritis83-85; albuminuria; glycosuria; hematuria; oliguria; urinary retention; urinary frequency (<0.01%)
 DRESS syndrome with renal involvement3-5
 Overdose: Urinary retention; water intoxication; hyponatremia; hypokalemia

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Clobazam UTI (2-5%)

Clonazepam  Dysuria; urinary retention; enuresis; incontinence (rare)

Eslicarbazepine acetate  Hyponatremia (<1-2%)

Ethosuximide

Gabapentin




Hematuria
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Reports of nephrotoxicity and nephrotic syndrome29-31

Hematuria; dysuria, urinary frequency; urinary retention; incontinence; peripheral edema; cystitis (0.1-1%)
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 Renal calculi; renal pain; acute renal failure; anuria; glycosuria; nocturia; pyuria; urgency (<0.1%)
 Post-marketing reports: hyponatremia

Lacosamide  Multi-organ hypersensitivity reactions including nephritis (<0.01%)

 Hyponatremia (<0.01%)
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Lamotrigine  Dysuria; hyperkalemia; peripheral edema (1-2%)

 DRESS syndrome with renal involvement86-88

Levetiracetam  Post-marketing reports: hyponatremia; acute kidney injury32-34; hypokalemia; hypomagnesemia89

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Oxcarbazepine  Hyponatremia, UTI (1-5%)

 Thirst (up to 2%)
 Urinary frequency (1-2%)
 DRESS (rare)

Perampanel  Hematuria (2%)

 UTI (4%)

18
 Phenobarbital  Oliguria
 Reports: DRESS with renal involvement90; nephrotoxicity with overdose91

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Phenytoin  Hypokalemia with fosphenytoin (>1%)
 DRESS syndrome with renal involvement6-9
 Reports: interstitial nephritis92-96

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Pregabalin  Hypokalemia, hyperuricemia; urinary frequency/incontinence; dysuria; hematuria; kidney calculus; nephritis; albuminuria; pyuria (0.1-1%)
 Hypercalcemia; hyperkalemia; hypocalcemia; hypomagnesemia; uremia; hypernatremia; hypophosphatemia; AKI; nocturia; polycystic
kidney disease; renal pain; pyelonephritis; renal stones (< 0.1%)

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Primidone  Polyuria; thirst (rare)

Rufinamide  Urinary retention; proteinuria (1%)

 Urinary frequency; incontinence; dysuria; hematuria; renal stones (0.1-1%)

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 Rare: DRESS with renal involvement; renal failure

Stiripentol  Dysuria (5%)

Topiramate 




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Kidney stones/Renal calculus; urinary frequency (≤ 3%)
Decreased serum bicarbonate (9-25%); metabolic acidosis97-102
Incontinence; UTI (1-5%)
Dysuria (≤ 2%)
Thirst (1-6%)
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Valproic acid/Divalproex  Dysuria; urinary frequency; urinary incontinence; UTI (1-5%)
sodium  Reports: AKI12; interstitial nephritis13; nephrotic syndrome14; Fanconi syndrome15-28

AKI, acute kidney injury; DRESS, drug reaction with eosinophilia and systemic symptoms; UTI, urinary tract infection.
ur
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Table 2. Disposition, adult dosing considerations of antiepileptic drugs (AEDs) in patients with renal disease

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Antiepileptic drug Metabolism Renal Protein Dosage range in Dosing in renal impairmenta Dosing in renal replacement therapiesa
(%) elimination binding patients with
(%) (%) normal kidney

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function
Brivaracetam Extensive 5-8 <18 50-200 mg/day No dosage adjustment needed HD: No data
PD: No data
CRRT: No data

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Carbamazepine 99 1-3 75-90 400-1200 mg/day No dosage adjustment needed HD: No dosage adjustment needed; give
after dialysis
PD: No dosage adjustment needed
CRRT: No dosage adjustment needed

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Clobazam 98 Negligible 85 5-80 mg/day CrCl > 30: No dosage adjustment needed HD: No data; hemodialysis has been
CrCl< 30: Use low initial doses, gradual shown not to markedly affect clobazam
dose increments under careful concentration based on a case report103

lP observation PD: No data; Use low initial doses,

gradual dose increments under careful
observation
CRRT: No data; use low initial dose and
then titrate
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Clonazepam 98 <2 85 1.5-20 mg/day No dosage adjustment needed. Use HD: No data
caution when dosing. PD: No data
CRRT: No data

Eslicarbazepine 34 66 <40 400-1600 mg/day CrCl 30-60: Reduce dose by 50% HD: No sufficient data; HD removes its
ur

(200-600 mg/day) metabolites

CrCl < 30: No data; Use caution; use low PD: No data; use caution; use low initial
initial doses104 doses.
CRRT: No data; likely to be significantly
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removed by CRRT

Ethosuximide 80-90 10-20 negligible 500-1500 mg/day CrCl > 30: No dosage adjustment needed HD: It gets dialyzed105; No dose
CrCl< 30: Use caution; use low initial adjustment needed; dose after dialysis
doses PD: No sufficient data; a case report
suggests significant removal106
CRRT: No data; likely to be significantly
removed by CRRT

20
Antiepileptic drug Metabolism Renal Protein Dosage range in Dosing in renal impairmenta Dosing in renal replacement therapiesa
(%) elimination binding patients with
(%) (%) normal kidney

of
function
Gabapentin 0 100 <10 900-3600 mg/day CrCl 30-59: 400-1400 mg/day HD: Dose based on CrCl + supplemental
CrCl 15-29: 200-700 mg/day dose post dialysis (125-350 mg)
CrCl 15: 100-300 mg/day PD: Initiate dosing as in patients with

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CrCl 10: 100-200 mg/day CrCl <15
CrCl <10: use caution; very small doses CRRT: Initiate dose as in patients with
might be required CrCl 15-50

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Lacosamide 60 40 <15 100-600 mg/day CrCl > 30: No dosage adjustment needed HD: 50-300 mg/d + supplemental dose
CrCl< 30: 50-300 mg/d post dialysis
PD: No data
CRRT: No sufficient data; likely

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removed by CRRT; no initial dose
adjustment needed

Lamotrigine 90 10 55 50-500 mg/day No sufficient data; start at low dose and HD: No sufficient data; start at low dose
(based on titrate cautiously and titrate cautiously; give dose post

lP concomitant
medications)
dialysis.
PD: No data; start at low dose and titrate
cautiously
CRRT: No data; start at low dose and
titrate cautiously
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Levetiracetam 34 66 <10 1000-3000 CrCl 50-79: 1000-2000 mg/day HD: 500-1000 mg/day + supplemental
mg/day CrCl 30-49: 500-1500 mg/day dose post dialysis (250-500 mg)
CrCl <30: 500-1000 mg/day PD: Dose for CrCl < 10
CRRT: Significantly removed; suggested
dosage 1000 mg q12h
ur

Oxcarbazepineb >50 20-30 40 600-2400 mg/day CrCl< 30: Initiate at 50% starting dose HD: No data
(300 mg/day) then titrate cautiously PD: No data
CRRT: No data; possibly removed
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Perampanel >95 negligible 95 2-12 mg/day CrCl > 30: No dosage adjustment needed HD: No data
CrCl< 30: No data PD: No data
CRRT: No data; less likely to be
removed
Phenobarbital 75 25 20-45 2-3 mg/kg/day CrCl > 10: No initial dosage adjustment HD: Dose before and 50% dose after HD
CrCl < 10: low dosage might be needed; PD: 50% of the normal dose
monitoring serum levels is necessary CRRT: No sufficient data; no initial dose
adjustment is needed; possible significant
removal by CRRT

21
 Antiepileptic drug Metabolism Renal Protein Dosage range in Dosing in renal impairmenta Dosing in renal replacement therapiesa
(%) elimination binding patients with
(%) (%) normal kidney

of
function
Phenytoin >95 <5 90 4-7 mg/kg/day No initial dosage adjustment needed; HD: No dosage adjustment needed;
monitor free phenytoin, if available monitor free phenytoin, if available;
supplemental doses might be needed after

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dialysis
PD: No initial dosage adjustment needed;
monitor free phenytoin
CRRT: No initial dosage adjustment

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needed; monitor free phenytoin
Pregabalin Negligible 90 Negligible 150-600 mg/day CrCl 30-60: 75-300 mg/day HD: Dose based on CrCl + supplemental
CrCl 15-30: 25-150 mg/day dose post dialysis (25-150 mg)
CrCl <15: 25-75 mg/day PD: No data; Initiate dosing as in patients

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with CrCl <15
CRRT: No data; likely to be significantly
removed by CRRT

Primidone 40-60 40-60 10-30 250-2000 mg/day Avoid if possible; administer dose every HD: Give dose after dialysis

Rufinamide >90 2
lP 34 400-3200 mg/day
24 hours if required

No dosage adjustment needed

PD: No data
CRRT: No data; possibly removed

HD: Consider dosage adjustment due to

possible reduced exposure
na
PD: No data
CRRT: No data; possibly not removed
Stiripentol Extensive Negligible 99 50mg/kg/day No dosage adjustment needed HD: No data
PD: No data
CRRT: No data; possibly not removed
Topiramate 50 50 13-41 200-400 mg/day CrCl <70: 100-200 mg/ day; slower HD: 100-200 mg/day + supplemental
ur

titration recommended dose post dialysis (50-100 mg)

PD: 100-200 mg/day
CRRT: No data; possibly removed
Valproic/Divalproex >93 <7 80-90 15-60 mg/kg/day No dosage adjustment needed HD: No dosage adjustment needed
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PD: No dosage adjustment needed

CRRT: No initial dosage adjustment
needed
Vigabatrin Negligible 85 Negligible 1000-3000 CrCl 51-80:  dose by 25% HD: Give after dialysis
mg/day CrCl 31-50:  dose by 50% PD: No data
CrCl 10-30:  dose by 75% CRRT: No data; dose based on CrCl 10-
50
a, monitor AED blood levels if available; b, pharmacokinetic parameters are for the for the active monohydroxymetabolite; CrCl, creatinine clearance in ml/min to be calculated

using Cockcroft-Gault method; CRRT, continuous renal replacement therapy; HD, intermittent hemodialysis; PD, peritoneal dialysis; Adapted from references73,107,108.

22
Table 3. Renally related drug-drug interactions associated with antiepileptic drugs

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Antiepileptic Interacting Agent Nature of the Interaction
Drug
Acetazolamide Salicylate Two case reports47: Concomitant administration with anti-inflammatory doses of salicylates might result in metabolic acidosis.

ro
The mechanism of the interaction is unclear; however, it may be related to salicylate-induced reduction in acetazolamide protein
binding and renal clearance.

Zonisamide Increased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.

-p
Topiramate Increased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.

Carbamazepine Diuretics (e.g. Concurrent use with carbamazepine may lead to hyponatremia.
hydrochlorothiazide,

re
furosemide)

Valproic acid Salicylates Concomitant administration of salicylates might increase the free fraction of valproic acid secondary to displacement of valproic
acid from protein binding. This might result in increased adverse reactions to valproic acid. 109-111

Levetiracetam Methotrexate

lP
Levetiracetam (LEV) might increase methotrexate (MTX) serum concentration secondary to LEV-induced reduction of
methotrexate renal elimination. Few cases of high dose MTX toxicity in patients concurrently treated with LEV have been
reported.76,77 However, in a retrospective study conducted in oncology patients has reported no significant interaction. 78
Monitoring serum MTX is recommended.
na
Eslicarbazepine Diuretics (e.g. Concurrent use with eslicarbazepine may lead to hyponatremia.
hydrochlorothiazide,
furosemide)

Lamotrigine Metformin Lamotrigine might inhibit renal tubular secretion of metformin. Monitoring metformin adverse reactions such as lactic acidosis
and gastrointestinal upset is recommended.1
ur

Procainamide Lamotrigine might inhibit renal tubular secretion of procainamide. Monitoring procainamide adverse reactions is
recommended.1
Topiramate Hydrochlorothiazide Higher incidence of hypokalemia when topiramate was combined with hydrochlorothiazide compared to either drug alone (61%
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vs 27-29%, respectively).1

Acetazolamide Increased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.

Zonisamide Increased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.

Lithium Topiramate might increase the serum concentration of lithium secondary to alteration of lithium renal clearance. Monitoring
serum lithium is recommended when topiramate is initiated or discontinued or with dose changes.37,74,75

23
 of
Table 4. Suggested monitoring for antiepileptic drugs (AEDs).

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Antiepileptic drug Symptoms monitoring Suggested reference Laboratory and other investigations
range73,108
Brivaracetam  For all AEDs, monitor for seizure frequency, hypersensitivity NERF LFT
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms CBC
of suicidal ideations Renal function

-p
Carbamazepine  For all AEDs, monitor for hypersensitivity reactions, 20-50 µmol/L Electrolytes
drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal LFT
ideations CBC

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 Hematologic reactions e.g. bleedings Renal function
 Behavioral changes Eye examinations

Clobazam  For all AEDs, monitor for seizure frequency, hypersensitivity 0.03-0.3mg/L LFT

Clonazepam




lP
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms
of suicidal ideations
Behavioral changes and signs of dependence
Any changes in respiratory status

For all AEDs, monitor for seizure frequency, hypersensitivity 0.02–0.07 mg/L
CBC
Renal function

CBC
na
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms LFT
of suicidal ideations
 Behavioral changes and signs of dependence
 Any changes in respiratory status
ur

Eslicarbazepine  For all AEDs, monitor for seizure frequency, hypersensitivity NERF Serum sodium
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms LFT
of suicidal ideations Renal function
 Visual disturbances
Jo

Ethosuximide  For all AEDs, monitor for seizure frequency, hypersensitivity 280-700 µmol/L LFT
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms CBC
of suicidal ideations Renal function

Gabapentin  For all AEDs, monitor for seizure frequency, hypersensitivity 12–117 µmol/L Renal function
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms
of suicidal ideations

24
Lacosamide  For all AEDs, monitor for seizure frequency, hypersensitivity 40–80 µmol/L ECG in patients at risk of cardiac
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms disorders or on concomitant
of suicidal ideations medications that prolong the PR-

of
 Symptoms of AV block (e.g. slow or irregular pulse, headache) interval
Lamotrigine  For all AEDs, monitor for seizure frequency, hypersensitivity 10–60 µmol/L LFT
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms CBC
Renal function

ro
of suicidal ideations
 Closely monitor for dermatological reactions

Levetiracetam  For all AEDs, monitor for seizure frequency, hypersensitivity 12–46 mg/L CBC
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms SCr

-p
of suicidal ideations
 Behavioral and psychiatric changes

Oxcarbazepine  For all AEDs, monitor for seizure frequency, hypersensitivity 12–140 µmol/L (of Electrolytes

re
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms monohydroxy metabolite) LFT
of suicidal ideations CBC
Renal function

Perampanel

Phenobarbital



lP
For all AEDs, monitor for seizure frequency, hypersensitivity
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms
of suicidal ideations
Behavioral and psychiatric changes

For all AEDs, monitor for seizure frequency, hypersensitivity

515-2800 nmol/L

43–170 µmol/L CBC

na
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms LFT
of suicidal ideations
 Behavioral changes
 Cognitive function
ur

Phenytoin  For all AEDs, monitor for seizure frequency, hypersensitivity 40-80 µmol/L LFT
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms Monitoring free phenytoin is CBC
of suicidal ideations recommended in patients with Renal function
 Cognitive function renal failure (reference range

Jo

Gingival hyperplasia 4-8 µmol/L)

Pregabalin  For all AEDs, monitor for seizure frequency, hypersensitivity NERF
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms
of suicidal ideations
 Weight gain and edema
 Visual disturbances

25
 Primidone  For all AEDs, monitor for seizure frequency, hypersensitivity 5–10 mg/L CBC
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms LFT
of suicidal ideations

of
 Behavioral changes and signs of dependence
 Any changes in respiratory status
Rufinamide  For all AEDs, monitor for seizure frequency, hypersensitivity NERF

ro
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms
of suicidal ideations

Stiripentol  For all AEDs, monitor for seizure frequency, hypersensitivity NERF CBC
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms LFT

-p
of suicidal ideations
 Behavioral and psychiatric symptoms
 Growth rate in children

re
Topiramate  For all AEDs, monitor for seizure frequency, hypersensitivity 15–60 µmol/L Serum bicarbonate
reactions, drowsiness, dizziness, fatigue, ataxia and symptoms Renal function
of suicidal ideations
 Weight loss Eye examinations

Valproic
acid/Divalproex



temperature

lP
Hydration status: sweating changes or increased body

Cognitive function

For all AEDs, monitor for seizure frequency, hypersensitivity

reactions, drowsiness, dizziness, fatigue, ataxia and symptoms
350-700 µmol/L LFT
CBC
na
sodium of suicidal ideations Renal function
 Weight gain If hyperammonemia is suspected,
 Motor and cognitive function monitor serum ammonia levels

Vigabatrin  For all AEDs, monitor for seizure frequency, hypersensitivity Vigabatrin plasma CBC
ur

reactions, drowsiness, dizziness, fatigue, ataxia and symptoms concentrations are not helpful Periodic visual field examination
of suicidal ideations as they are not correlated to
 Weight gain therapeutic activity
 Visual disturbances
Jo

CBC, complete blood count; LFT, liver function test; NERF, no established reference range.

26