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.
- •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.
Abstract
Purpose
Epilepsy affects more than 50 million people worldwide and its management can be complicated by comorbidities such as impaired renal function. To optimize epilepsy control in patients with kidney 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 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 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 in MEDLINE database (1946 to 7th Jan 2019).
Results
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.
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 vigilant about this possibility. In addition, AEDs renal adverse reactions and renal drug interactions should be considered when selecting an AED.
Keywords
1. Introduction
Epilepsy affects more than 50 million people worldwide and is characterized by recurrent unprovoked seizures. One of the main goals of treatment is to improve patient quality of life by optimizing 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 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 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 practical approach to using AEDs in the setting of renal disease will also be provided.
2. Evidence used in this review
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 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*”, “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 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]
].3. What are the effects of AEDs on the kidney?
3.1 AEDs-induced nephrotoxicity
The incidence of AEDs-induced nephrotoxicity is rare - typically reported in less than 1 in 1000 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 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.
Table 1Renally-related adverse reactions and electrolytes abnormalities associated with antiepileptic drugs (AEDs) use.
| Antiepileptic drug | Renally-related adverse reactions and electrolyte abnormalities (frequency, if reported) – From Drug Monographs [ [1] ] 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 nephrocalcinosis [ [35] ,[81] ,[82] ] | |
| Brivaracetam | Hyponatremia ≤ 2 % |
| Carbamazepine | Hyponatremia; edema; fluid retention (1–10 %) |
| Renal failure [ [10] ,[11] ]; interstitial nephritis [83 , 84 , 85 ]; albuminuria; glycosuria; hematuria; oliguria; urinary retention; urinary frequency (<0.01%) | |
| DRESS syndrome with renal involvement [ 3 , 4 , 5 ] | |
| Overdose: Urinary retention; water intoxication; hyponatremia; hypokalemia | |
| Clobazam | UTI (2–5 %) |
| Clonazepam | Dysuria; urinary retention; enuresis; incontinence (rare) |
| Eslicarbazepine acetate | Hyponatremia (<1-2 %) |
| Ethosuximide | Hematuria |
| Reports of nephrotoxicity and nephrotic syndrome [ 29 , 30 , 31 ] | |
| Gabapentin | Hematuria; dysuria, urinary frequency; urinary retention; incontinence; peripheral edema; cystitis (0.1–1 %) |
| 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 %) |
| Lamotrigine | Dysuria; hyperkalemia; peripheral edema (1–2 %) |
| DRESS syndrome with renal involvement [ 86 , 87 , 88 ] | |
| Levetiracetam | Post-marketing reports: hyponatremia; acute kidney injury [ 32 , 33 , 34 ]; hypokalemia; hypomagnesemia [[89] ] |
| Oxcarbazepine | Hyponatremia, UTI (1–5 %) |
| Thirst (up to 2 %) | |
| Urinary frequency (1–2 %) | |
| DRESS (rare) | |
| Perampanel | Hematuria (2 %) |
| UTI (4 %) | |
| Phenobarbital | Oliguria |
| Reports: DRESS with renal involvement [ [90] ]; nephrotoxicity with overdose [[91] ] | |
| Phenytoin | Hypokalemia with fosphenytoin (>1 %) |
| DRESS syndrome with renal involvement [ 6 , 7 , 8 , 9 ] | |
| Reports: interstitial nephritis [ 92 , 93 , 94 , 95 , 96 ] | |
| 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 %) | |
| Primidone | Polyuria; thirst (rare) |
| Rufinamide | Urinary retention; proteinuria (1 %) |
| Urinary frequency; incontinence; dysuria; hematuria; renal stones (0.1–1 %) | |
| Rare: DRESS with renal involvement; renal failure | |
| Stiripentol | Dysuria (5 %) |
| Topiramate | Kidney stones/Renal calculus; urinary frequency (≤ 3 %) |
| Decreased serum bicarbonate (9–25 %); metabolic acidosis [ 97 , 98 , 99 , 100 , 101 , 102 ] | |
| Incontinence; UTI (1–5 %) | |
| Dysuria (≤ 2 %) | |
| Thirst (1–6 %) | |
| Valproic acid/Divalproex sodium | Dysuria; urinary frequency; urinary incontinence; UTI (1–5 %) |
| Reports: AKI [ [12] ]; interstitial nephritis [[13] ]; nephrotic syndrome [[14] ]; Fanconi syndrome [15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ] |
AKI, acute kidney injury; DRESS, drug reaction with eosinophilia and systemic symptoms; UTI, urinary tract infection.
Carbamazepine, phenytoin, primidone, and phenobarbital are commonly implicated in drug rash with eosinophilia and systemic symptoms (DRESS). Also known as anticonvulsant hypersensitivity 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 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
, 4
, 5
, 6
, 7
, 8
, 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
, 11
, 12
, 13
, 14
, 15
, 16
, 17
, 18
, 19
, 20
, 21
, 22
, 23
, 24
, 25
, 26
, 27
, 28
, 29
, 30
, 31
, 32
, 33
, 34
].Available literature demonstrates that valproic acid can cause renal proximal tubular dysfunction (Fanconi syndrome) [
15
, 16
, 17
, 18
, 19
, 20
, 21
, 22
, 23
, 24
, 25
, 26
, 27
, 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]
]. Although there is currently not enough evidence to establish causality between 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 reactions are often unpredictable, clinicians need to be vigilant about this possibility.
3.2 AED-induced nephrolithiasis
A few AEDs have been reported to cause nephrolithiasis: topiramate, acetazolamide and zonisamide. The mechanism of topiramate-induced renal stones has been attributed to its weak inhibition 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
, 36
, 37
, 38
, 39
, 40
, 41
, 42
, 43
, 44
, 45
]. Reduction in serum 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 failure in patients using commonly prescribed doses of 250−1000 mg daily [[35]
,46
, 47
, 48
, 49
, 50
, 51
, 52
]. Zonisamide has also been implicated to cause renal stones with a similar mechanism to topiramate and acetazolamide.Risk factors for metabolic acidosis and subsequent nephrolithiasis include administration of these 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.4. What is the effect of renal impairment on the elimination of AEDs?
4.1 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
, 54
, 55
, 56
, 57
]. Other examples include encephalopathy with vigabatrin and levetiracetam [[58]
,[59]
]. Table 2 depicts the disposition (proportion of drug metabolized, renally eliminated, 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.Table 2Disposition, adult dosing considerations of antiepileptic drugs (AEDs) in patients with renal disease.
| Antiepileptic drug | Metabolism (%) | Renal elimination (%) | Protein binding (%) | Dosage range in patients with normal kidney function | Dosing in renal impairment 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 references [73,107,108]. | Dosing in renal replacement therapies 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 references [73,107,108]. |
|---|---|---|---|---|---|---|
| Brivaracetam | Extensive | 5-8 | <18 | 50-200 mg/day | No dosage adjustment needed | HD: No data PD: No data CRRT: No data |
| 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 |
| Clobazam | 98 | Negligible | 85 | 5-80 mg/day | CrCl > 30: No dosage adjustment needed CrCl< 30: Use low initial doses, gradual dose increments under careful observation | HD: No data; hemodialysis has been shown not to markedly affect clobazam concentration based on a case report [ [103] ]PD: No data; Use low initial doses, gradual dose increments under careful observation CRRT: No data; use low initial dose and then titrate |
| Clonazepam | 98 | <2 | 85 | 1.5−20 mg/day | No dosage adjustment needed. Use caution when dosing. | HD: No data PD: No data CRRT: No data |
| Eslicarbazepine | 34 | 66 | <40 | 400-1600 mg/day | CrCl 30-60: Reduce dose by 50 % (200−600 mg/day) CrCl < 30: No data; Use caution; use low initial doses [[ [104] ]]. | HD: No sufficient data; HD removes its metabolites PD: No data; use caution; use low initial doses. CRRT: No data; likely to be significantly removed by CRRT |
| Ethosuximide | 80-90 | 10-20 | negligible | 500−1500 mg/day | CrCl > 30: No dosage adjustment needed CrCl< 30: Use caution; use low initial doses | HD: It gets dialyzed [ [105] ]; No dose adjustment needed; dose after dialysisPD: No sufficient data; a case report suggests significant removal [ [106] ]CRRT: No data; likely to be significantly removed by CRRT |
| Gabapentin | 0 | 100 | <10 | 900-3600 mg/day | CrCl 30-59: 400−1400 mg/day CrCl 15-29: 200−700 mg/day CrCl 15: 100−300 mg/day CrCl 10: 100−200 mg/day CrCl <10: use caution; very small doses might be required | HD: Dose based on CrCl + supplemental dose post dialysis (125−350 mg) PD: Initiate dosing as in patients with CrCl <15 CRRT: Initiate dosing as in patients with CrCl 15-50 |
| Lacosamide | 60 | 40 | <15 | 100-600 mg/day | CrCl > 30: No dosage adjustment needed CrCl< 30: 50−300 mg/d | HD: 50−300 mg/d + supplemental dose post dialysis PD: No data CRRT: No sufficient data; likely removed by CRRT; no initial dose adjustment needed |
| Lamotrigine | 90 | 10 | 55 | 50-500 mg/day (based on concomitant medications) | No sufficient data; start at low dose and titrate cautiously | HD: No sufficient data; start at low dose and titrate cautiously; give dose post dialysis. PD: No data; start at low dose and titrate cautiously CRRT: No data; start at low dose and titrate cautiously |
| Levetiracetam | 34 | 66 | <10 | 1000−3000 mg/day | CrCl 50-79: 1000−2000 mg/day | HD: 500−1000 mg/day + supplement al dose post dialysis (250−500 mg) |
| CrCl 30-49: 500−1500 mg/day | PD: Dose for CrCl < 10 | |||||
| CrCl <30: 500−1000 mg/day | CRRT: Significantly removed; suggested dosage 1000 mg q12h | |||||
| Oxcarbazepineb | >50 | 20-30 | 40 | 600-2400 mg/day | CrCl< 30: Initiate at 50 % starting dose (300 mg/day) then titrate cautiously | HD: No data |
| PD: No data | ||||||
| CRRT: No data; possibly removed | ||||||
| Perampanel | >95 | negligible | 95 | 2-12 mg/day | CrCl > 30: No dosage adjustment needed CrCl< 30: No data | HD: 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 CrCl < 10: low dosage might be needed; monitoring serum levels is necessary | HD: Dose before and 50 % dose after HD PD: 50 % of the normal dose CRRT: No sufficient data; no initial dose adjustment is needed; possible significant removal by CRRT |
| Phenytoin | >95 | <5 | 90 | 4-7 mg/kg/day | No initial dosage adjustment needed; monitor free phenytoin, if available | HD: No dosage adjustment needed; monitor free phenytoin, if available; supplemental doses might be needed after dialysis PD: No initial dosage adjustment needed; monitor free phenytoin CRRT: No initial dosage adjustment needed; monitor free phenytoin |
| Pregabalin | Negligible | 90 | Negligible | 150−600 mg/day | CrCl 30-60: 75−300 mg/day CrCl 15-30: 25−150 mg/day CrCl <15: 25−75 mg/day | HD: Dose based on CrCl + supplemental dose post dialysis (25−150 mg) PD: No data; Initiate dosing as in patients 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 24 hours if required | HD: Give dose after dialysis PD: No data CRRT: No data; possibly removed |
| Rufinamide | >90 | 2 | 34 | 400-3200 mg/day | No dosage adjustment needed | HD: Consider dosage adjustment due to possible reduced exposure PD: No data CRRT: No data; possibly not removed |
| Stiripentol | Extensive | Negligible | 99 | 50 mg/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 titration recommended | HD: 100−200 mg/day + supplemental 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 PD: No dosage adjustment needed CRRT: No initial dosage adjustment needed |
| Vigabatrin | Negligible | 85 | Negligible | 1000−3000 mg/day | CrCl 51-80: ↓ dose by 25% CrCl 31-50: ↓ dose by 50% CrCl 10-30: ↓ dose by 75% | HD: Give after dialysis PD: No data 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 references [
[73]
,[107]
,[108]
].4.2 Non-renally eliminated AEDs
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 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
, 61
, 62
]. Monitoring the free fraction of highly plasma protein bound AEDs could be of value in 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 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 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.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
, 64
, 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.4.3 Renal replacement therapies
Patients with end-stage renal disease may utilize various renal replacement therapies (RRT) 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 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.
Several factors could influence extracorporeal drug removal. The first factor is the molecular 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 Da, MW is not rate limiting for 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 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 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 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 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
, 71
, 72
].In addition to drug characteristics, the type of the RRT modality has an influence on the extent of 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 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.Unfortunately, there is not sufficient evidence to provide robust dosing recommendations for all 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 dosing in renal replacement therapies are summarized in Table 2.
5. What are the renally-related AEDs drug-drug interactions?
It is well known that several AEDs inhibit (valproic acid) or induce (phenytoin, carbamazepine, 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 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-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]
,,[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.Table 3Renally related drug-drug interactions associated with antiepileptic drugs.
| Antiepileptic Drug | Interacting Agent | Nature of the Interaction |
|---|---|---|
| Acetazolamide | Salicylate | Two case reports [ [47] ]: Concomitant administration with anti-inflammatory doses of salicylates might result in metabolic acidosis. 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. | |
| Topiramate | Increased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity. | |
| Carbamazepine | Diuretics (e.g. hydrochlorothiazide, furosemide) | Concurrent use with carbamazepine may lead to hyponatremia. |
| 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 , 110 , 111 ] |
| Levetiracetam | Methotrexate | 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. |
| Eslicarbazepine | Diuretics (e.g. hydrochlorothiazide, furosemide) | Concurrent use with eslicarbazepine may lead to hyponatremia. |
| Lamotrigine | Metformin | Lamotrigine might inhibit renal tubular secretion of metformin. Monitoring metformin adverse reactions such as lactic acidosis and gastrointestinal upset is recommended. [ [1] ] |
| 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 % 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] ,,[75] ] |
In addition to altered renal elimination, clinicians need to be aware that co-administration of some drugs may aggravate the nephrotoxic potential or electrolyte imbalance associated with some AEDs through pharmacodynamic drug interactions. For example, co-administration of acetazolamide, 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 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.
6. 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, 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 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 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 agents need to be started, frequent monitoring and/or possible consideration of prophylactic therapies 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 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.7. 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 “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 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 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 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.Table 4Suggested monitoring for antiepileptic drugs (AEDs).
| Antiepileptic drug | Symptoms monitoring | Suggested reference range [ [73] ,[108] ] | Laboratory and other investigations |
|---|---|---|---|
| Brivaracetam |
| NERF | LFT CBC Renal function |
| Carbamazepine |
| 20−50 μmol/L | Electrolytes LFT CBC Renal function Eye examinations |
| Clobazam |
| 0.03-0.3 mg/L | LFT CBC Renal function |
| Clonazepam |
| 0.02–0.07 mg/L | CBC LFT |
| Eslicarbazepine |
| NERF | Serum sodium LFT Renal function |
| Ethosuximide |
| 280−700 μmol/L | LFT CBC Renal function |
| Gabapentin |
| 12–117 μmol/L | Renal function |
| Lacosamide |
| 40–80 μmol/L | ECG in patients at risk of cardiac disorders or on concomitant medications that prolong the PR-interval |
| Lamotrigine |
| 10–60 μmol/L | LFT CBC Renal function |
| Levetiracetam |
| 12–46 mg/L | CBC SCr Electrolytes |
| Oxcarbazepine |
| 12–140 μmol/L (of monohydroxy metabolite) | LFT CBC Renal function |
| Perampanel |
| 515−2800 nmol/L | |
| Phenobarbital |
| 43–170 μmol/L | CBC LFT |
| Phenytoin |
| 40−80 μmol/L Monitoring free phenytoin is recommended in patients with renal failure (reference range 4−8 μmol/L) | LFT CBC Renal function |
| Pregabalin |
| NERF | |
| Primidone |
| 5–10 mg/L | CBC LFT |
| Rufinamide |
| NERF | |
| Stiripentol |
| NERF | CBC LFT |
| Topiramate |
| 15–60 μmol/L | Serum bicarbonate Renal Eye examinations |
| Valproic acid/Divalproex sodium |
| 350−700 μmol/L | LFT CBC Renal function If hyperammonemia issuspected, monitor serum ammonia levels |
| Vigabatrin |
| Vigabatrin plasma concentrations are not helpful as they are not correlated to therapeutic activity | CBC Periodic visual field examination |
CBC, complete blood count; LFT, liver function test; NERF, no established reference range.
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 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 tips that we have found useful when managing our patients in the Epilepsy Clinic:
- 1Start 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.
- 2Instead 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 preferences and discuss this balance with each patient.
- 3Less may be more. Periodically re-evaluate the efficacy of prescribed medication(s). Even with medically refractory epilepsy, some patients will be better off on less rather than more medications.
- 4The AED levels are just a guideline. Do not alter the dose of the AED solely based on numbers. Always consider the clinical correlation.
- 5Share 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.
8. 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.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
None.
Acknowledgements
The authors would like to thank Dr. Jill Hall for reviewing the manuscript and providing valuable feedback. The authors would like to thank Janice Kung (librarian) for her guidance in the literature search process for this review.
References
CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).
- Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk.J Clin Invest. 1988; 82: 1826-1832
- Carbamazepine-induced acute granulomatous interstitial nephritis.Clin Nephrol. 2002; 57: 310-313
- Severe multisystemic hypersensitivity reaction to carbamazepine including dyserythropoietic anemia.Ann Pharmacother. 1999; 33: 571-575
- Generalized pustulosis and severe tubulointerstitial nephropathy as manifestations of carbamazepine hypersensitivity syndrome.Acta Derm Venereol. 2002; 82: 374-376
- Reversible renal failure and myositis caused by phenytoin hypersensitivity.Jama. 1976; 236: 2773-2775
- Early-onset phenytoin toxicity mimicking a renopulmonary syndrome.Eur Respir J. 1998; 11: 501-503
- Levetiracetam following liver and kidney failure in late-onset anticonvulsant hypersensitivity syndrome.J Clin Neurosci. 2014; 21: 859-860
- Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome and hepatitis induced by phenytoin.Int J Dermatol. 2014; 53: 490-493
- Carbamazepine-induced hepatorenal failure in a child. Pharmacotherapy.The Journal of Human Pharmacology & Drug Therapy. 1999; 19: 667-671
- Severe hepatorenal failure in a child receiving carbamazepine and erythromycin.Eur J Pediatr. 1992; 151: 715
- Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusion-haemodialysis.Eur J Pediatr. 1990; 149: 363-364
- Immunologically mediated chronic tubulo-interstitial nephritis caused by valproate therapy.Nephron. 1996; 72: 328-329
- Collapsing focal segmental glomerulosclerosis as a possible complication of valproic acid.South African Medical JournalSuid-Afrikaanse Tydskrif Vir Geneeskunde. 2007; 97: 388
- Fanconi syndrome caused by valproic acid.Pediatr Neurol. 2010; 42: 287-290
- Renal toxicity induced by valproic acid (Depakene).Pediatr Pathol. 1993; 13: 863-868
- Fanconi syndrome caused by antiepileptic therapy with valproic Acid.Epilepsia. 2004; 45: 868-871
- Reversible Fanconi syndrome associated with valproate therapy.J Pediatr. 1993; 123: 320-322
- Valproic acid: a possible cause of proximal tubular renal syndrome.J Pediatr. 1981; 98: 503-504
- Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome.Pediatr Neurol. 2014; 51: 846-849
- Valproate-induced Fanconi syndrome in a 27-year-old woman.J Gen Intern Med. 2011; 26: 1072-1074
- Anticonvulsants as a cause of Fanconi syndrome.Nephrol Dial Transplant. 1995; 10: 543-545
- Autoimmune haemolytic anaemia and renal Fanconi syndrome caused by valproate therapy.Eur J Pediatr. 2005; 164: 186-187
- Secondary renal Fanconi syndrome caused by valproate therapy.Pediatr Nephrol. 2005; 20: 814-817
- Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate.Pediatr Int. 2016; 58: 1023-1026
- Tubulo-interstitial nephritis caused by sodium valproate.Brain Dev. 2002; 24: 102-105
- Fanconi syndrome caused by sodium valproate: report of three severely disabled children.Eur J Paediatr Neurol. 2002; 6: 165-167
- Renal injury from valproic acid: case report and literature review.Pediatr Neurol. 2002; 27: 318-319
- Nephrotic syndrome associated with ethosuccimide.Am J Dis Child. 1978; 132: 99
- Ethosuximide-associated lupus with cerebral and renal manifestations.Eur J Pediatr. 1998; 157: 780
- Ethosuximide-induced lupus-like syndrome with renal involvement.Intern Med. 1996; 35: 587-591
- Levetiracetam as a possible contributor to acute kidney injury.Clin Ther. 2014; 36: 1303-1306
- Levetiracetam induced interstitial nephritis and renal failure.Pediatr Neurol. 2009; 41: 57-58
- Levetiracetam-induced interstitial nephritis in a patient with glioma.J Clin Neurosci. 2012; 19: 177-178
- Acetazolamide and sodium bicarbonate induced nephrocalcinosis and nephrolithiasis; relationship to citrate and calcium excretion.Arch Intern Med. 1969; 124: 736-740
- Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet.Epilepsia. 2002; 43: 1168-1171
- Topiramate can cause lithium toxicity.J Clin Psychopharmacol. 2004; 24: 565-567
- Alkali replacement raises urinary citrate excretion in patients with topiramate-induced hypocitraturia.Br J Clin Pharmacol. 2016; 81: 131-136
- Patients with and without prior urolithiasis have hypocitraturia and incident kidney stones while on topiramate.Urology. 2011; 77: 295-298
- Topiramate-induced nephrolithiasis.J Endourol. 2002; 16: 229-231
- Topiramate increases biochemical risk of nephrolithiasis.Ann Clin Biochem. 2004; 41: 166-169
- Nephrolithiasis in topiramate users.Urol Res. 2011; 39: 303-307
- Incidence of kidney stones with topiramate treatment in pediatric patients.Epilepsia. 2011; 52: 1890-1893
- Calcium nephrolithiasis induced by topiramate.Arch Esp Urol. 2014; 67: 284-287
- Biochemical and stone-risk profiles with topiramate treatment.Am J Kidney Dis. 2006; 48: 555-563
- Acetazolamide blood concentrations are excessive in the elderly: propensity for acidosis and relationship to renal function.J Clin Pharmacol. 1989; 29: 348-353
- Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function.Br Med J (Clin Res Ed). 1984; 289: 347-348
- Acetazolamide and symptomatic metabolic acidosis in mild renal failure.Br Med J (Clin Res Ed). 1982; 284: 422
- Anticonvulsant-induced rickets associated with renal tubular acidosis and normal level of serum 1,25-dihydroxyvitamin D.Am J Dis Child. 1981; 135: 1140-1142
- Acetazolamide and symptomatic metabolic acidosis in mild renal failure.Br Med J (Clin Res Ed). 1981; 283: 1527-1528
- Renal tubular acidosis and skeletal demineralization in patients on long-term anticonvulsant therapy.J Pediatr. 1975; 87: 202-205
- Acetazolamide and symptomatic metabolic acidosis in mild renal failure.Br Med J (Clin Res Ed). 1982; 284: 1114
- Gabapentin toxicity in patients with chronic kidney disease: a preventable cause of morbidity.Am J Med. 2010; 123: 367-373
- A probable case of gabapentin-related reversible hearing loss in a patient with acute renal failure.Clin Ther. 2008; 30: 1681-1684
- Gabapentin toxicity: an important cause of altered consciousness in patients with uraemia.Emerg Med J. 2008; 25: 178-179
- Gabapentin-induced coma in a patient with renal failure.Hemodial Int. 2006; 10: 168-169
- Gabapentin-induced neurologic toxicities.Pharmacotherapy:The Journal of Human Pharmacology & Drug Therapy. 2005; 25: 1817-1819
- Acute encephalopathy associated with vigabatrin monotherapy in patients with mild renal failure.Neurology. 1998; 51: 314-315
- Levetiracetam accumulation in renal failure causing myoclonic encephalopathy with triphasic waves.Seizure. 2009; 18: 376-378
- Comparison of the serum protein binding of maprotiline and phenytoin in uraemic patients on haemodialysis.Eur J Clin Pharmacol. 1981; 19: 73-77
- Binding of amobarbital, pentobarbital and diphenylhydantoin to blood cells and plasma proteins in healthy volunteers and uraemic patients.Eur J Clin Pharmacol. 1975; 8: 445-453
- Endogenous accumulation products and serum protein binding in uremia.J Lab Clin Med. 1981; 98: 730-740
- Diphenylhydantoin metabolism in uremia.N Engl J Med. 1971; 285: 648-652
- Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: improving Global Outcomes (KDIGO).Kidney Int. 2011; 80: 1122-1137
- Influence of renal function on pharmacokinetics of antiepileptic drugs metabolized by CYP3A4 in a patient with renal impairment.Ther Drug Monit. 2018; 40: 144-147
- Pharmacokinetic assessment in patients receiving continuous RRT: perspectives from the Kidney Health Initiative.Clin J Am Soc Nephrol. 2015; 10: 159-164
- Phenytoin removal by continuous venovenous hemofiltration.Ann Pharmacother. 2013; 47: 1218-1222
- High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy.Ann Pharmacother. 2011; 45: e18
- Pharmacokinetic principles during continuous renal replacement therapy: drugs and dosage.Kidney Int Suppl (2011). 1999; (S24-8)
- Hemodialysis effects on phenytoin pharmacokinetics.Eur J Clin Pharmacol. 2014; 70: 499-500
- Increased free phenytoin concentrations in predialysis serum compared to postdialysis serum in patients with uremia treated with hemodialysis. Role of uremic compounds.Am J Clin Pathol. 1992; 98: 19-25
- Significant removal of phenytoin during high flux dialysis with cellulose triacetate dialyzer.Nephrol Dial Transplant. 1998; 13: 817-818
- Antiepileptic drug removal by continuous renal replacement therapy: a review of the literature.Clin Drug Investig. 2017; 37: 7-23
- Topiramate-induced Lithium toxicity.Cureus. 2017; 9: e1804
- Does topiramate elevate serum lithium levels?.J Clin Psychopharmacol. 2002; 22: 340
- Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.Ann Pharmacother. 2014; 48: 292-296
- Drug-drug interaction between methotrexate and levetiracetam in a child treated for acute lymphoblastic leukemia.Pediatr Blood Cancer. 2013; 60: 340-341
- Methotrexate elimination when coadministered with levetiracetam.Ann Pharmacother. 2016; 50: 1016-1022
- Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care.Pharmacotherapy. 2007; 27: 1425-1439
- Patient assessment in clinical pharmacy : a comprehensive guide.1 ed. Springer Nature, 2019
- Acetazolamide-induced nephrocalcinosis.Abdom Imaging. 1994; 19: 466-467
- Acetazolamide-associated nephrocalcinosis in a transplant kidney.Transplantation. 1995; 59: 1742-1743
- Granulomatous interstitial nephritis associated with atypical drug-induced hypersensitivity syndrome induced by carbamazepine.Clin Exp Nephrol. 2012; 16: 168-172
- Carbamazepine-induced acute tubulointerstitial nephritis.J Pediatr. 1981; 98: 830-832
- Lithium intoxication due to carbamazepine-induced renal failure.Ann Pharmacother. 2001; 35: 560-562
- Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment.Am J Kidney Dis. 2000; 36: 1034-1040
- Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome.Ann Pharmacother. 1999; 33: 557-559
- Multisystem adverse reaction to lamotrigine.Lancet. 1994; 344: 481
- Hyponatraemia associated with lamotrigine in cranial diabetes insipidus.Lancet. 2000; 356: 656
- A case of tubulo-interstitial nephritis with exfoliative dermatitis and hepatitis due to phenobarbital hypersensitivity.Eur J Pediatr. 1992; 151: 69-72
- Muscle necrosis and calcification in acute renal failure due to barbiturate intoxication.Br Med J. 1966; 2: 214-215
- Phenytoin-induced interstitial nephritis.South Med J. 1981; 74: 1160-1161
- Diphenylhydantoin interstitial nephritis. Roles of cellular and humoral immunologic injury.J Pediatr. 1978; 92: 915-920
- Diphenylhydantoin-induced hypersensitivity reaction with interstitial nephritis.Hum Pathol. 1985; 16: 94-97
- Granulomatous interstitial nephritis after prolonged use of phenytoin.Saudi J Kidney Dis Transplant. 2009; 20: 131-133
- Interstitial nephritis due to phenytoin hypersensitivity.J Pediatr. 1977; 91: 438-441
- Topiramate and severe metabolic acidosis: case report.Arq Neuropsiquiatr. 2005; 63: 532-534
- Hallucinations and comorbid renal tubular acidosis caused by topiramate in a patient with psychiatric history.Gen Hosp Psychiatry. 2013; 35: e3
- Topiramate-induced metabolic acidosis: a case study.Nefrologia. 2012; 32: 403-404
- Topiramate-induced renal tubular acidosis.Am J Med. 2004; 116: 281-282
- Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors.Pharmacogenet Genomics. 2011; 21: 297-302
- Topiramate induces type 3 renal tubular acidosis by inhibiting renal carbonic anhydrase.Nephrol Dial Transplant. 2006; 21: 2995-2996
- Clobazam and N-desmethylclobazam serum concentrations in endstage renal failure and hemodialysis.Ann Pharmacother. 1994; 28: 966-967
- Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate.Int J Clin Pharmacol Ther. 2008; 46: 119-130
- Hemodialysis clearance of ethosuximide in patients with chronic renal disease.Am J Hosp Pharm. 1981; 38: 1757-1760
- Removal of ethosuximide and phenobarbital by peritoneal dialysis in a child.Clin Pharm. 1992; 11: 1030-1031
- American College of physicians.in: Philadelphia P. Drug prescribing in renal failure : dosing guidelines for adults and children.5th ed. American College of Physicians, 2007
- Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies.Epilepsia. 2008; 49: 1239-1276
- Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects.Clin Pharmacol Ther. 1982; 31: 642-649
- The effect of aspirin on valproic acid metabolism.Clin Pharmacol Ther. 1986; 40: 94-100
- Valproic acid toxicity associated with low dose of aspirin and low total valproic acid levels: a case report.J Clin Psychopharmacol. 2009; 29: 509-511
Article info
Publication history
Published online: February 10, 2020
Accepted:
February 6,
2020
Received in revised form:
January 5,
2020
Received:
September 14,
2019
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