The use of antiepileptic drugs (AEDs) in the presence of renal insufficiency is associated with an increased risk of adverse effects. Knowledge of the mechanisms of elimination of these drugs is crucial when selecting an AED in epilepsy patients with renal impairment (Kuo et al., 2002; Lacerda et al., 2006; Drug Facts and Comparisons, 2007; RxList, n.d.). Drugs that are cleared by the kidneys have different pharmacokinetic properties in the presence of renal failure, and intermittent dialysis can cause significant swings in serum levels, depending on serum levels.
Moreover, renal failure is often accompanied by other medical problems, which can influence drug levels (Kuo et al., 2002). Renal failure is associated with gastroparesis, which slows absorption and bowel edema, which may reduce absorption. There is often a decrease in gut cytochrome P-450 metabolism and P-glycoprotein active transport, which can affect how much of the drug enters the portal circulation. It is also associated with hypoalbuminemia, which may influence free plasma concentrations of AEDs that are highly protein bound. Acidosis may affect albumen-binding affinity as well.
Reduced renal function and hypoalbuminemia lead to accumulation of renally excreted AEDs, such as eslicarbazepine acetate, gabapentin, pregabalin, vigabatrin, and levetiracetam. If there is coexisting impairment of liver function, drugs metabolized by the liver may have altered kinetics as well. AEDs that have low protein binding are largely removed through hemodialysis. Lastly, seizures may be caused by uremia and its associated conditions, such as intracranial hemorrhage, glucose and electrolyte imbalances, dialysis encephalopathy, primary cerebral lymphoma, opportunistic infections, and immunosuppressant toxicity in renal transplant recipients (Kuo et al., 2002).
In patients who require dialysis or in whom dialysis is anticipated, it may be wisest to use drugs that are cleared by hepatic mechanisms rather than eliminated by the kidneys. In addition, AEDs with relatively high levels of protein binding are easier to manage, although they might be less desirable for other properties; a balance must then be struck. Carbamazepine, lamotrigine, benzodiazepines (e.g., clobazam, clonazepam), and rufinamide are preferred when renal failure is present, particularly when dialysis is needed. Therapeutic monitoring of drug levels is important for these patients, and ascertainment of free levels is preferred.
Dosage adjustment in patients with renal impairment depends on renal function and creatinine clearance of the patient (Box 12.1).
Acetazolamide is contraindicated in patients with severe renal disease. It may potentiate acidosis and may cause central nervous system adverse effects in dialysis patients.
No quantitative recommendations are available for patients with renal impairment. Due to the lack of renal excretion of unchanged drug, clobazam doses do not need to be adjusted in renal dysfunction. As, active drug is not excreted by the kidneys, clonazepam doses will not need to be reduced in patients with renal dysfunction. The minimal renal excretion of lorazepam, midazolam and diazepam or any of the active metabolites suggests that dosage adjustment is not needed in patients with renal disease (Anderson & Hakimian, 2014).
No quantitative recommendations are available for patients with renal impairment. As there is minimal excretion of carbamazepine by the kidneys, carbamazepine doses should not need to be reduced in renal dysfunction (Anderson & Hakimian, 2014).
Clearance of eslicarbazepine is decreased in patients with impaired renal function and is correlated with creatinine clearance. Dosage should be modified depending on clinical response and degree of renal impairment. A dose reduction is recommended in patients with renal impairment (creatinine clearance < 60 mL/min). Start treatment at 200 mg once daily. After two weeks, increase dosage to 400 mg once daily, which is the recommended maintenance dosage. Eslicarbazepine is not recommended in patients with creatinine clearance < 30 mL/min. Eslicarbazepine is dialyzable, however, no dosage adjustments have been recommended (Anderson & Hakimian, 2014).
No dosage adjustment is needed in patients with renal dysfunction since only a small percentage of ethosuximide is renally eliminated unchanged (Anderson & Hakimian, 2014).
Dosage adjustment is recommended for patients with creatinine clearance <50 mL/min or patients with end-stage renal disease receiving dialysis treatments. Dosage should be modified depending on clinical response and degree of renal impairment. In patients with renal impairment (CrCL <50 mL/ min or end-stage renal disease on dialysis) the initial dose is 50 mg 3 times daily (150 mg per day) and the maximum dose is 200 mg 3 times daily (600 mg per day). The effect of hemodialysis on ezogabine clearance has not been established.
Felbamate should be used with caution in patients with renal impairment. The starting and maintenance doses should be reduced by one-half in patients with renal impairment.
Dosage adjustment in patients with renal impairment depends on renal function and CrCl of the patient. The following recommendations (Box 12.2) have been made for adults and adolescents >12 years old.
Patients on hemodialysis should receive maintenance doses based on CrCl as indicated for patients with renal impairment. A supplemental dose equal to the daily dose plus 50 mg is recommended after a 4-h hemodialysis session (Anderson & Hakimian, 2014).
No dose adjustment is necessary in patients with mild to moderate renal impairment. A maximum dose of 300 mg per day is recommended for patients with severe renal impairment [CrCl less than or equal to 30 mL/min] and in patients with end-stage renal disease. In all renally impaired patients, the dose titration should be performed with caution. Patients with renal impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 (eg, valproate) may have a significant increase in exposure to lacosamide. Dose reduction may be necessary in these patients.
In patients with renal impairment, dosage should be modified depending on clinical response and degree of renal impairment. No quantitative recommendations are available.
Hemodialysis decreases the elimination half-life of lamotrigine. Approximately 20% of lamotrigine present in the body is removed after a standard 4-hour dialysis session (Fillastre et al., 1993). An additional dose of lamotrigine is not needed to maintain therapeutic concentrations (Anderson & Hakimian, 2014). However, adjust dosage schedules to give a normally administered dosage after the hemodialysis session. No quantitative recommendations are available for adjustments.
The following dosage adjustments (Box 12.3) pertain to adults with renal impairment using estimated CrCl. Children with renal impairment also need modified dosages but no quantitative recommendations are available.
If CrCl >30 mL/min, no dosage adjustments have been recommended. However, renal clearance of MHD, the active metabolite, declines linearly with a decrease in creatinine clearance. If CrCl <30 mL/min, renal clearance of MHD is decreased. Therefore, initiate therapy with 50% of the usual starting dose and slowly titrate upward as necessary.
No dosage adjustment is necessary for patients with mild renal impairment. Perampanel can be used in patients with moderate renal impairment with close monitoring. A slower titration may be considered based on clinical response and tolerability. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended.
If CrCl >10 mL/min, no dosage adjustment is needed. If CrCl <10 mL/min, significantly decrease dosage by increasing the interval between the doses to 12 hours or longer. Adjust dosage based on clinical response and serum concentrations. The chronic use of phenobarbital should generally be avoided in patients with renal failure.
Phenobarbital is efficiently removed through hemodialysis. Adjust dosage schedules to give a normally administered dosage after the hemodialysis session. It is better to administer the supplementary dose after hemodialysis.
Peritoneal dialysis (as CAPD) removes phenobarbital by almost 35%–50% (not as efficient as hemodialysis) (Porto et al., 1997). No quantitative recommendations for dose adjustment are available. Some references have suggested that 50% of a normal dose be given after a CAPD session.
If CrCl >10 mL/min, no dosage adjustment is needed. If CrCl <10 mL/min, dosage adjustment and serum concentration monitoring are necessary. Decreased protein binding occurs in uremia, and the unbound (free) fraction of phenytoin may be increased. Dosing adjustments may be required based on serum free phenytoin level monitoring and clinical response.
Dose adjustments are required in patients with renal impairment with CrCl <60 mL/min (Box 12.4). Reduction of pregabalin dose may be required in elderly patients based on CrCl.
Pregabalin is effectively removed through hemodialysis because it has little plasma protein binding. Each 4-hour hemodialysis session removes 50%–60% of the amount of drug present in the circulation in patients on three-times-per-week hemodialysis. For patients undergoing hemodialysis, pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose adjustment, a supplemental (single additional) dose should be given immediately following every 4-hour hemodialysis treatment as follows:
• Patients on the 25 mg/day regimen: Take one supplemental dose of 25 mg or 50 mg.
• Patients on the 25–50 mg/day regimen: Take one supplemental dose of 50 mg or 75 mg.
• Patients on the 50–70 mg/day regimen: Take one supplemental dose of 75 mg or 100 mg.
• Patients on the 75 mg/day regimen: Take one supplemental dose of 100 mg or 150 mg.
Dose adjustments are required in patients with renal impairment with CrCl <50 mL/min (Box 12.5). Monitor clinical response and serum concentrations.
Renally impaired patients (CrCl < 30 mL/min) do not require any special dosage change. Rufinamide pharmacokinetics in patients with severe renal impairment (CrCl <30 mL/min) was similar to that of healthy subjects.
No initial dosage adjustment is required in patients with renal impairment. Adjust dosage according to patient’s response and tolerance.
In adults, if CrCl <70 mL/min, reduce the topiramate dose to one-half of the usual dose. In children, adjustment may be required but should be individualized because clearance rates are higher in children than in adults. Patients with renal impairment may require a longer time than patients with normal renal function to reach steady state with each topiramate dosage adjustment.
In patients with severe renal impairment or renal failure, uremia can cause an increase in the free fraction of the drug, resulting in possible toxicity. Also, unbound valproic acid in the blood may be cleared more rapidly than bound drug. Close monitoring of valproic acid serum concentrations may be warranted to ensure adequate dosage, ensure efficacy, and limit toxicity. A supplemental dose of valproate may be required after hemodialysis in some patients.
There are no published studies on the effect of renal dysfunction on vigabatrin pharmacokinetics. It is recommended that the dose of vigabatrin be reduced by 25%, 50%, or 75% for patients with mild (CrCl 50–80 mL/min), moderate (CrCl 30–50 mL/min), or severe (CrCl 10–30 mL/min) renal dysfunction.
Because zonisamide is excreted by the kidneys, patients with renal impairment or renal disease should be treated with caution. Slower titration and more frequent monitoring may be required. No quantitative recommendations are available.
Recommended Antiepileptic Drugs in Epilepsy Patients With Renal Failure
1. Generalized epilepsies: Clobazam, ethosuximide, lamotrigine, rufinamide (in patients with Lennox-Gastaut syndrome)
2. Focal epilepsies: Carbamazepine, clobazam, lamotrigine, phenytoin
Note: Seizures are a serious complication of hemodialysis in people with epilepsy. They may occur within the first 24 hours of beginning dialysis and are usually tonic-clonic. Preexisting hypertension and the use of dialyzable anticonvulsant drugs are associated with dialysis-related seizures. They may be due to the removal of these drugs at a time when metabolic stress induces seizures.
In one pediatric study, phenobarbital was given at a dosage of 5 mg/kg/day orally twice daily to prevent dialysis-associated seizures. Also, diazepam (0.5 mg/kg orally) was administered 30 minutes before each dialysis session in some patients. Patients receiving diazepam prophylaxis had significantly fewer seizures than those with no treatment or patients receiving phenobarbital alone. Therefore, administration of oral diazepam, a nondialyzable anticonvulsant drug, 30 minutes before each dialysis, may help prevent seizure recurrence (Sonmez et al., 2000).
Urinary Adverse Effects of Antiepileptic Drugs (Lacerda et al., 2006; Drug Facts and Comparisons, 2007; RxList, n.d.)
Carbonic anhydrase inhibitors are sulfonamide derivatives that have caused crystalluria and sulfonamide-like nephrotoxicity characterized by renal tubular obstruction, hematuria, dysuria, and oliguria. An increase in calcium excretion can cause nephrolithiasis. Patients with preexisting hypercalcemia develop renal calculi most frequently.
Urinary side effects include increased urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, and renal failure. Albuminuria, glycosuria, and microscopic deposits in the urine have also been observed. Antidiuretic effects and hyponatremia have been reported. Carbamazepine may rarely cause interstitial nephritis or other renal diseases. Occasional monitoring of renal parameters or urinalysis has been recommended.
Because of the increased risk of urinary retention on ezogabine (in about 2% of the patients), urologic symptoms should be carefully monitored. Urinary retention was generally reported within the first 6 months of treatment, but was also observed later. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms prior to and during treatment with ezogabine may be appropriate. Hydronephrosis is a rare adverse effect in patients taking ezogabine. Dysuria and hematuria have been reported as adverse effects of ezogabine.
Crystalluria and urolithiasis have been reported with felbamate. Urinary tract infection and lowered blood urea nitrogen levels have been reported as a result of felbamate therapy.
Dysuria, hematuria, increased urinary frequency, urinary tract pain, polyuria, and renal calculus have been reported as adverse effects of oxcarbazepine.
No significant urinary adverse effects have been reported. Reports of interstitial nephritis are rare.
Phenytoin rarely causes renal complications. Glomerulonephritis, interstitial nephritis, proteinuria, and nephrotic syndrome have been reported.
There are reports of increased urinary frequency and urinary incontinence with pregabalin. However, causality between pregabalin and these adverse events has not been definitively established.
Urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, and incontinence have infrequently been reported as adverse effects of rufinamide.
Nephrolithiasis, hematuria, increased urinary frequency, dysuria, and urinary incontinence have been reported as adverse effects of topiramate.
Increases in serum creatinine and blood urea nitrogen have been reported. Nephrolithiasis has been reported in some patients. Other infrequent adverse reactions affecting the urinary system in zonisamide-treated patients include dysuria, hematuria, nocturia, polyuria, urinary frequency, urinary incontinence, urinary retention, and urinary urgency. Rare adverse reactions include albuminuria, bladder pain, and bladder calculus.
Zonisamide, topiramate, and acetazolamide, which all have carbonic anhydrase-inhibiting properties, are associated with a modest increase in the incidence of renal stones due to reduced urinary citrate excretion and increased urinary pH. Zonisamide is associated with a 4% incidence of renal stones. Approximately 1.5% of patients treated with topiramate developed kidney stones compared with the annual 0.5% incidence of renal stones in the general population. Men are at higher risk for kidney stones, and the association has also been reported for children treated with topiramate. The analyzed stones are mainly composed of calcium phosphate (Kuo et al., 2002). The ketogenic diet may also be associated with renal stones (Kossoff et al., 2002).
In general, increasing fluid intake and urine output can help reduce the risk of stone formation in patients taking zonisamide, topiramate, or acetazolamide or those on the ketogenic diet, particularly in patients with predisposing factors (Kossoff et al., 2002). If there is marked benefit with therapy with one of these drugs, and drugs that do not cause nephrolithiasis have not proved effective, the development of renal calculi is not an absolute indication to discontinue the treatment (Richards et al., 2005).
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