Clinical Therapeutics/Volume ], Number ], 2014

Levetiracetam as a Possible Contributor to Acute Kidney Injury Danielle C. Spengler, MD; Georgia D. Montouris, MD; and Anna D. Hohler, MD Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts ABSTRACT Purpose: Levetiracetam is an antiepileptic medication that has been reported to be both well-tolerated and effective in treating generalized tonic-clonic, myoclonic, and partial-onset seizures. The adverse effects most commonly reported in tolerability trials include somnolence, fatigue/asthenia, headaches, dizziness, and nausea. However, there have been a few reports suggesting possible detrimental effects of levetiracetam on renal function. Methods: Here we describe the case of a previously healthy 23-year-old female patient who developed acute kidney injury 1 day after the initiation of levetiracetam therapy for new-onset seizures. Findings: Based on the time course of the patient’s rise in serum creatinine and the exclusion of other causes, this case suggests that levetiracetam use contributed to the acute kidney injury. Implications: Levetiracetam is a widely used drug that has been reported to be generally tolerable and effective; however, it has the potential to negatively affect renal function. This potential consequence of therapy should be considered when deciding whether or not to prescribe this medication, and renal function should be monitored during treatment. (Clin Ther. 2014;]:]]]–]]]) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: epilepsy, levetiracetam, medication toxicity, renal failure, seizures.

CASE REPORT A 23-year-old, right-handed female patient presented to the emergency department via ambulance after a witnessed generalized tonic seizure lasting 1 minute. On arrival, she was back to her baseline with a normal neurologic examination. Two hours later she had a tonic-clonic seizure, which again lasted 1 minute. She was given 2 mg of lorazepam and was loaded with 1 g of levetiracetam. The patient’s medical history was significant for episodes of staring, lasting a few seconds at a time.

] 2014

She was not sure when the episodes first began but noted that they had been increasing in frequency in the several months before admission. Her only treatment was an intrauterine device, and she had no known allergies. She reported that consumption of her last alcoholic drink was 3 months before admission, and she denied the use of other drugs. Of note, she reported some recent sleep deprivation and an increase in stress. Family history was significant for a cousin with a history of suspected absence seizures. Magnetic resonance imaging of the brain, without contrast, and electroencephalography were unremarkable. Initial laboratory testing revealed a normal complete blood count, biochemistry, and urinalysis. The patient was admitted to the neurology service and was prescribed levetiracetam 500 mg BID to be started on the following day. The following day, the patient had a markedly elevated creatinine concentration (Table). The nephrology team was consulted to evaluate for rhabdomyolysis secondary to the seizure activity versus medication toxicity. Her creatinine kinase (CK) concentration did not support rhabdomyolysis and instead her rising creatinine was believed to be due to the use of levetiracetam. Levetiracetam treatment was discontinued, phenytoin treatment was initiated, and she received fluids. On hospital day 3, the patient reported myalgias and a decreased appetite. Urinalysis was remarkable only for 1þ blood. A renal ultrasound revealed diffusely increased bilateral renal cortical echogenicity. Fluids were increased, and by hospital day 4, her creatinine had started to improve. Repeated testing at follow-up revealed

Accepted for publication June 2, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.06.002 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

1

Clinical Therapeutics

Table. Laboratory results. BUN, mg/dL

Creatinine, mg/dL

CK, U/L

Urinalysis Results

Treatment

Before admission Day 1 Day 2 Day 2

— — 20 21

0.80 0.77 2.48 2.76

— — — —

— — — Myoglobin negative

Day 3 Day 4 Day 4 Day 8 2 mo after hospitalization

27 22 21 8 8

4.22 3.58 3.23 1.04 0.76

310 935 1368 117 117

1þ Blood — — — —

— — — Stopped levetiracetam — — — — —

Day of Hospital Stay

BUN ¼ blood urea nitrogen; CK ¼ creatine kinase.

that her creatinine concentration had returned to baseline.

DISCUSSION Levetiracetam is an antiepileptic medication that has been reported to be well-tolerated and effective in the treatment of generalized tonic-clonic, myoclonic, and partial-onset seizures. There have been rare reports of patients on levetiracetam treatment developing acute kidney failure.1 This case directly supports a medication-related kidney effect. Since its development, levetiracetam has been praised for its favorable pharmacokinetic profile. Specifically, it has been reported to possess good bioavailability and linear kinetic properties and reaches steady-state concentrations quickly (ie, after 2 days of repeated twicedaily dosing). It does not demonstrate a high degree of protein binding and does not involve the cytochrome P450 system in its metabolism; as a result, it has minimal interactions with other medications.2 Levetiracetam is excreted almost exclusively through the kidneys. One study reported that 66% of the administered dose was found unchanged in the urine and that 27% was eliminated as inactive metabolites after 24 hours.3,4 The renal clearance is directly proportional to creatinine clearance (data on file, UCB Pharma Inc, 1999). Therefore, although its profile is favorable, dosing must be tailored to a patient’s renal function.

2

Multiple tolerability and efficacy trials have been performed to study the use of levetiracetam in various patient populations. The adverse events most commonly reported in the literature include somnolence, fatigue/asthenia, headaches, dizziness, and nausea.5–7 The largest of these trials was KEEPER (Levetiracetam Adjunctive Treatment of Partial-Onset Seizures in an Open-Label Community-Based Study),7 which attempted to gather tolerability data on levetiracetam use in a population of 1030 patients with a history of partial-onset seizures in a community-based setting. No renally mediated adverse events were reported in the trial. In 2 other trials,5,6 that monitored patients’ laboratory values during levetiracetam therapy, no significant changes in serum blood urea nitrogen or creatinine concentrations were reported. However, urinalysis revealed blood in 10 of 91 patients who completed 1 of these studies.6 Kidney dysfunction related to levetiracetam has been a rarely reported adverse event. In 1 case reported in the literature, a 17-year-old female patient developed acute renal failure and biopsy-confirmed interstitial nephritis 10 days after the initiation of levetiracetam treatment (250 mg BID, or 10 mg/kg/d) of new-onset partial complex seizures.8 A second case report linked the use of levetiracetam and carbamazepine to autopsy findings of acute tubular necrosis in the kidneys of a 22-year-old woman with a history of seizures. At the time of autopsy, both

Volume ] Number ]

D.C. Spengler et al. drugs were present in the blood at or below their respective therapeutic ranges, and tissue concentrations were consistent with long-term administration.9 A third report documented the case of a 45-year-old male patient with a history of low-grade glioma who developed a high creatinine concentration due to acute renal failure. This finding was attributed to levetiracetam-induced interstitial nephritis. The patient’s dose of the medication had gradually been increased over several months until he was taking 3000 mg/d for persistent dizziness and falls, which had been attributed to seizures. The patient’s renal function improved on discontinuation of the levetiracetam treatment.10 Our patient’s medical history does not suggest a history of conditions predisposing her to renal failure, and her only other treatment at the time of onset was an intrauterine device. A review published in 2002 determined that there are no interactions between oral combination contraceptives, oral progesterone, injectable medroxyprogesterone, or implantable levonorgestrel and levetiracetam.11 Rhabdomyolysis is unlikely to have been the cause of the creatinine elevation in this case. Sources suggest that renal failure caused by rhabdomyolysis is related to CK values 45000 IU/L; our patient’s peak CK value was 1368 U/L. CK typically rises within 12 hours of muscle injury, peaks within 1 to 3 days, and begins to decline by 3 to 5 days. Our patient’s CK value peaked at 4 days after her tonic-clonic seizure activity, which is inconsistent with CK trends in rhabdomyolysis related to seizure activity.12 On the Naranjo Adverse Drug Reaction Probability Scale, this case would have scored a þ3 (þ2 points for the event happening after the drug was administered, and þ1 for the adverse reaction improving after the treatment was discontinued), which categorizes this as a possible adverse drug reaction.13 The reaction was reported to the manufacturer, who stated that no cases of the drug causing renal dysfunction had been reported, and who noted only that the drug should be dose-adjusted in patients with renal impairment (personal communication, Medical Information Department, UCB SA, April 25, 2014). The choice to use levetiracetam, or any medical therapy, should be based on a careful assessment and discussion of the potential risks and benefits of the treatment. Although levetiracetam has generally been reported to be a well-tolerated and effective treatment

] 2014

for epilepsy, it may have potentially dangerous effects on renal function. Patients should be closely monitored for changes in renal function while taking levetiracetam.

ACKNOWLEDGMENTS For this article, case was suggested by Dr. Montouris. Literature search was done by Dr. Spengler. Drs. Spengler and Hohler wrote the manuscript and prepared the Table with input from Dr. Montouris. All authors contributed to manuscript revisions.

CONFLICTS OF INTEREST Dr. Hohler has served as a member of the speakers’ bureau for Teva Pharmaceuticals USA. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

REFERENCES 1. eHealthMe. Real world drug outcomes. http://www. ehealthme.com/. Accessed August 31, 2011. 2. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther. 2000;85: 77–85. 3. Arroyo A, Crawford P. Safety profile of levetiracetam. Epileptic Disord. 2003;Suppl 1:S57–S63. 4. Perruca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide, and tiagabine. Clin Pharmacokinet. 1996;31:29–46. 5. Abou-Khalil B, Hemdal P, Privitera MD. An open-label study of levetiracetam at individualized doses between 1000 and 3000 mg/day in adult patients with refractory epilepsy. Seizure. 2003;12:141–149. 6. Beran RG, Berkovic SF, Black AB, et al. Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial onset seizures: a multicenter, open-label, single-arm study. Epilepsy Res. 2005;63:1–9. 7. Morrell MJ, Leppik I, French J, et al. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res. 2003;54:153–161. 8. Hurwitz KA, Ingulli EG, Krous HF. Levetiracetam induced interstitial nephritis and renal failure. Pediatr Neurol. 2009; 41:57–58. 9. Skopp G, Schmitt HP, Pedal I. Fulminant liver failure in a patient on carbamazepine and levetiracetam treatment associated with status epilepticus. Arch Kriminol. 2006;217: 161–175. 10. Mahta A, Kim RY, Kesari S. Levetiracetam-induced interstitial nephritis in a patient with glioma. J Clin Neurosci. 2012; 19:177–178.

3

Clinical Therapeutics 11. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263–272. 12. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis – an overview for clinicians. Crit Care. 2005;9:158–169. 13. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30: 239–245.

Address correspondence to: Danielle C. Spengler, MD, University of Miami School of Medicine/Jackson Memorial Hospital System, Department of Neurology, 1120 NW 14 street (C215), CRB 1385, Miami, FL 33136. E-mail: [email protected]

4

Volume ] Number ]