Levetiracetam (Keppra): Evidence-Based Polypharmacy in Two Patients With Epilepsy

Epilepsy is a common long-lasting complaint that necessitates long-term pharmacotherapy with anti-epileptic drugs (AEDs). Around 50% of epileptic patients fail the preliminary AED and about 35% are intractable to pharmacotherapy, emphasizing the continuous need for more effective and better-tolerated drugs. To craft an appropriate pharmacotherapy policy in epileptic patients, an evidence-based pharmacotherapy study could be valuable. The magnitudes of decision for prescription of AEDs are challenging due to the narrow therapeutic window related to the old generation of this category, and also require plenty of awareness related to the seizure as a symptom and epilepsy as a condition. AEDs must include a prescription based on polypharmacy or monotherapy, and the ability to monitor effectiveness or adverse effects (1-7). Monotherapy remains the “gold standard,” because the concurrent prescription of AEDs in patients with epilepsy could cause side effects. Related to the mechanism of action for the first generation of AEDs, such as carbamazepine, phenytoin, sodium valproate, Lamotrigine, clonazepam, and clobazam, two main models could be described by increasing γ -amino butyric acid (GABA) or decreasing excitation due to glutamate. These drugs also act through ionic channels (2-11).

Since 2000, levetiracetam has been marketed as an AED (1). While the exact mechanism of its action in epilepsy is unknown, it seems that modulation of synaptic neurotransmitter release, through binding to the synaptic vesicle protein (SV2A) in the brain, could exhibit a novel mechanism of action. Therefore, levetiracetam acts as a neuromodulator by reducing the release of neurotransmitters. The routes of drug administration could be oral or intravenous. The drug has a urinary route of excretion. Less than 10% of the drug binds to plasma protein. With a mean concentration of 12.9 and 9.5 μg/mL, levetiracetam has a half-life of 6 to 8 hours. The mean plasma concentrations in responders and non - responders were 12.9 and 9.5 μg/mL, respectively (1-16). Due to enzymatic hydrolysis of the acetamide group, the pattern of metabolism is completely different than first-generation AEDs that are cytochrome P450 inducers or inhibitors (3). This paper reports on cases of two epileptic patients with hematological and biochemical changes under treatment of levetiracetam, based on AED polypharmacy.

The United States National Library of Medicine was searched, using three relevant keywords: 1) “levetiracetam in epilepsy,” 2) “keppra in epilepsy,” and 3) “levetiracetam hematological and biochemical side-effects.” A total of 1724 articles (from 1993 - 8 August 2015), 1025 (from 1992 - June 2015), and 30 (from November 2014 - Septembere 2014) were found. Consequently, manuscripts applicable to the pharmacotherapy management of levetiracetam in epilepsy were identified and studied individually.

According to previous publications on pharmacotherapy, using levetiracetam for partial epilepsy, myoclonic seizure in patients with juvenile myoclonic epilepsy, or generalized tonic-clonic seizures in the setting of idiopathic generalized epilepsy might be considered as preliminary or early add-on therapy (1). There are only a few published papers reporting the therapeutic drug monitoring methods of levetiracetam (17). In this study, a 32-year-old male patient had been admitted to the Isfahan/Kashani hospital epilepsy ward in 2011. His first seizure attack was around the age of 6. Since then he had been taking antiepileptic drugs. He stayed for two days in the hospital.

A review of his medication history confirmed that his prescribed pharmacotherapy was based on levetiracetam, 250 mg/B.I.D. in combination with: 1) primidone; 50 mg/T.D.S, 2) phenytoin, 100 mg/T.D.S., and 3) topiramate; 50 mg/T.D.S. Hematological results confirmed a decrease in white blood cell count (WBC; 3400 cells/mcL, versus a normal range of 3500 - 10500 cells/mcL), red blood cell count (RBC; 4.4 mil/mm³ versus a normal value of M: 4.5 - 5.9 mil/mm³), hemoglobin (Hb; 11.8 g/dL versus a normal value of 14 - 17.5 g/dL) and hematocrit (Ht; 36.7% versus a normal value of 41.5% - 50.5%). Another admitted case to the Isfahan/Kashani hospital epilepsy ward (also in 2011) was a 14-year-old female who had her first seizure attack around the age of 7-year-old. Levetiracetam, 250 mg/B.I.D., had been taken with primidone, 50 mg/T.D.S., and sodium-valproate, 200 mg/T.D.S. Hematological results confirmed a decrease in hemoglobin (Hb; 10.4 g/dL versus a normal value of 12.3 - 15.3 g/dL) and hematocrit (Ht; 34% versus a normal value of 35.9% - 44.9%) and an increase in lymphocyte (Lymph; 84 versus a normal value of 20% - 40%). Neither patient was on any additional medications other than the AEDs. Prior to starting the AEDs no effort was made to achieve the level of biochemistry and hematology parameters, therefore the abnormal results reflect the dysfunction prevailing around the time of study.

While previous pharmacokinetic studies show that levetiracetam is usually well tolerated (18), side effects can include sleepiness, faintness, shaking step, exhaustion, management difficulties, headache, discomfort, amnesia, nervousness, bad temper or distress, giddiness, uneasiness, damage of taste, nausea, diarrhea and constipation, gullet aching, and deviations in skin pigmentation. Hopelessness, deliriums, desperate opinions, worse or dissimilar seizures, high fever, marks of contagion, dual image, puffiness of the face, Stevens-Johnson syndrome, and toxic epidermal necrolysis are other serious side effects related to levetiracetam therapy (19).

A previous study confirmed that cytochrome enzyme inducer AEDs like phenytoin and oxcarbazepine are strongly associated with increased levels of total cholesterol, low-density lipoprotein cholesterol, high - density lipoprotein cholesterol, and triglyceride, whereas valproate and levetiracetam showed no significant changes (20). It seems that encephalopathy subsequent to the prescription of levetiracetam should be mentioned as an infrequent incidence. But a recent case report described a patient receiving levetiracetam who was treated with valproic acid for partial seizures and secondary generalization. There was a developing hyperammonemic encephalopathy that improved after withdrawal of the drug (21). Another study related to the Iranian epileptic population confirmed that the efficiency of AEDs pharmacotherapy should be qualified by the close monitoring of AEDs in relation to clinical conditions and laboratory records. Any major alteration in patients’ laboratory archives may necessitate close confirmation of the rapid detection AEDs side-effects (5). In conclusion, this report highlights that levetiracetam with other AEDs might cause significant decreases in hemoglobin, hematocrit, and white blood cell count, as well as an increase in lymphocytes (22-27).