Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus


Address correspondence to Charles J. Vecht, Department of Neurology, Medical Center Haaglanden, The Hague, The Netherlands. E-mail:


Purpose: To evaluate the feasibility and safety of intravenous (iv) levetiracetam (LEV) added to the standard therapeutic regimen in adults with status epilepticus (SE), and as secondary objective to assess a population pharmacokinetic (PK) model for ivLEV in patients with SE.

Methods: In 12 adults presenting with SE, 2,500 mg ivLEV was added as soon as possible to standardized protocol, consisting of iv clonazepam and/or rectal diazepam, as needed followed by phenytoin or valproic acid. ivLEV was administered over approximately 5 min, in general after administration of clonazepam, regardless the need for further treatment. During 24-h follow-up, patients were observed for any clinically relevant side-effects. Blood samples for PK analysis were available in 10 patients. A population PK model was developed by iterative two-stage Bayesian analysis and compared to PK data of healthy volunteers.

Results: Eleven patients with a median age of 60 years were included in the per protocol analysis. Five were diagnosed as generalized-convulsive SE, five as partial-convulsive SE, and one as a nonconvulsive SE. The median time from hospital admission to ivLEV was 36 min. No serious side effects could be related directly to the administration of ivLEV. During PK analysis, four patients showed a clear distribution phase, lacking in the others. The PK of the population was best described by a two-compartment population model. Mean (standard deviation, SD) population parameters included volume of distribution of central compartment: 0.45 (0.084) L/kg; total body clearance: 0.0476 (0.0147) L/h/kg; distribution rate constants, central to peripheral compartment (k12): 0.24 (0.12)/h, and peripheral to central (k21): 0.70 (0.22)/h. Mean maximal plasma concentration was 85 (19) mg/L.

Discussion: The addition of ivLEV to the standard regimen for controlling SE seems feasible and safe. PK data of ivLEV in patients with SE correspond to earlier values derived from healthy volunteers, confirming a two-compartment population model.

Status epilepticus (SE) is associated with significant morbidity and mortality (Rosenow et al., 2002). The current medical strategy consists of first-line benzodiazepines followed by phenytoin or valproate, and occasionally by midazolam, thiopental or propofol infusions. Side effects such as respiratory depression caused by the sedative effects of antiepileptic drugs (AEDs), and hypotension or arrhythmias resulting from phenytoin commonly occur. Apart from the administration of benzodiazepines, evidence-based therapy for treatment of later stages of SE hardly exists, and a recent Cochrane study has emphasized the need for more research in this area (Treiman et al., 1998; Aldredge et al., 2001; Prasad et al., 2005). In addition, treatment options for SE are limited because of the small number of AEDs that are suitable for intravenous administration.

Levetiracetam (LEV) is a second generation AED with proven oral efficacy in idiopathic generalized and partial epilepsies (Shorvon et al., 2000; Berkovic et al., 2007, Brodie et al., 2007; Noachtar et al. 2008). Since the introduction in 2006 of an intravenous (iv) formulation, ivLEV has been administered in patients with SE, and the first experiences have recently been described in individual cases and retrospective series (Patel et al., 2006; Farooq et al., 2007, Knake et al., 2007; Schultz-Bonhage et al., 2007). We report the results of a prospective safety trial on the use of add-on ivLEV in patients with acute SE, while maintaining the standard regimen for SE.

Our objective was to evaluate the feasibility and safety of the administration of 2,500 mg add-on ivLEV in adult patients with SE. The secondary objective was to assess an ivLEV pharmacokinetic (PK) population model of patients with SE to support safety data and future studies.


Study design

The study had a prospective, single-center, single-arm, open-label design. Safety of ivLEV was evaluated as add-on therapy in patients with SE. All patients received a single dose of 2,500 mg ivLEV, administered over approximately 5 min. The patients were treated according to the routinely used standardized drug protocol for patients with SE (see Table 1). The study drug could be given at any time in SE treatment, but always as soon as possible after enrolment in the study. After ivLEV administration, patients were observed for 24 h, and clinical data on cardiac and respiratory functions, symptoms of allergic reactions, irritation at the injection site or other signs of potential side-effects were monitored. Necessary work-up was carried out including blood sampling and electrocardiography (ECG) monitoring. If needed for further diagnostics or treatment, computed tomography/magnetic resonance imaging (CT/MR) of the brain and electroencephalography (EEG) measurements were performed as well.

Table 1.   Standardized treatment protocol of SE at study site
TherapyDoseRoute and mode of administration
  1. Alt., alternative; iv, intravenous; L.D., loading dose; S.I., short infusion; C.I., continuous infusion.

 Diazepam5–10 mgRectal/iv
 Alt.: Midazolam2.5–5 mgBuccal/iv
First line
 Clonazepam1 mgiv: repeated doses (every 5 min)
Second line
 Phenytoin15–20 mg/kgiv: L.D. (20 min)
 Alt.: Valproic acid500–1,500 mgIv: L.D. (20 min)
Third line
 ClonazepamUp to 50 mg/24 hiv: C.I.
 Alt.: MidazolamL.D.: 0.1 mg/kg
C.I.: 1–5 μg/kg/min
iv: L.D. followed by C.I.
Fourth line
 PropofolL.D.: 1–3 mg/kg
C.I.: 4–12 mg/kg/h
iv: L.D., followed by C.I.
 Alt.: ThiopentalL.D.: 10 mg/kg
S.I.: 20 mg/kg
C.I.: 2.5 mg/kg/h
iv: L.D. (5 min), followed by S.I. (20 min) and C.I. Controlled by serum levels

Written informed consent was obtained from the accompanying husband/wife or an authorized relative before study entry. If not, written informed consent was obtained from the patient afterward. When consent was refused, data were excluded from analysis. This study design was reviewed and approved by the governmental accredited Regional Medical Ethics Committee (METC) South-West Holland, The Netherlands. Study medication, levetiracetam solution for iv use, was provided by UCB Pharma (Breda, The Netherlands). Before administration ivLEV was added to a 100-ml pouch of 0.9% sterile saline solution (Viaflow; Baxter, Leiden, The Netherlands). If needed during ivLEV administration, additional clonazepam was given through the Y-site of the catheter (Uges et al., 2007).

Study population

The study was open for men and women older than 18 years old with all different types of SE (Shorvon, 2001). The “operational” definition of Lowenstein was used to establish the presence of SE: 5 min or more of continuous seizures or two or more discrete seizures between which there was incomplete recovery of consciousness (Lowenstein et al., 1999). SE was established clinically, except for nonconvulsive types of SE, which needed to be confirmed by EEG before enrolment. Patients without clear information on the duration of seizure activity, but still seizing at the time of hospital admission, were assumed to comply with the inclusion criteria. Excluded from the study were women of childbearing potential, who were not confident about a potential pregnancy, patients already taking more than 2,000 mg LEV daily, and patients with a known allergy for LEV.

Pharmacokinetic assessments

Blood samples were drawn to determine serum levels of LEV to determine pharmacokinetics of ivLEV. Sample times used in the study were based on an optimal sampling calculation (MwPharm, version 3.60; Mediware, Groningen, The Netherlands) using one-compartment LEV pharmacokinetics for oral administration (Patsalos, 2004). During protocol preparation no information was available on pharmacokinetics of ivLEV. Samples were drawn before; immediately after; and at 1, 5, and 20 h after ivLEV dosing. All LEV samples were analyzed with a validated analytical high-performance liquid chromatography (HPLC) method with diode array detection at 205 nm. Limit of detection of this assay was 0.7 mg/L; and the coefficient of variation was 4.9% at 2.1 mg/L, 3.4% at 10.1 mg/L, and 3.9% at 80.0 mg/L. Population PK parameters: total body clearance (Cl), distribution rate constants (k12, k21), maximal plasma concentration (Cmax), and volume of distribution of the central compartment (Vc) were estimated by an iterative two-stage Bayesian analysis procedure (MwPharm, Mediware BV, Groningen, the Netherlands). Individual patients’ PK parameters: total volume of distribution (Vt), total body clearance (Cl), and terminal elimination half-life (T1/2) were calculated by fitting the population model to the individual data.


Study population

In a 10-month inclusion period, 16 patients with SE were identified, of whom 12 received ivLEV according to the protocol. Four were not enrolled because of logistical difficulties, misinterpretation of inclusion criteria, or possible pregnancy. One of the 12 included patients was excluded after completion of the diagnostic workup, as he was later diagnosed as having suffered from stroke, without SE. Table 2 reports patients’ demographics. A total of seven men and four women with a median age of 60 years (range 44–75 years) were included, of whom five had a generalized-convulsive SE, five a partial convulsive SE, and one a nonconvulsive SE. Six of them were known with epilepsy and used AEDs at inclusion. The median time from admission to ivLEV was 36 min (range 15–90 min), with a median duration of clinical SE at inclusion of 60 min (range 10 to more than 240 min). Informed consent was obtained in all patients. Nine patients received ivLEV during or directly after initial first-line benzodiazepine treatment. The other two enrolled in the study at later stages of SE, and subsequently received phenytoin and valproate before ivLEV. In 10 patients, SE was terminated during the 24 h period of the study. One patient died after 9 days because of multiorgan failure without an apparent relation to the administration of ivLEV. Blood samples for PK analysis were obtained in 10 patients. The use of concomitant medication to treat the SE is listed in Table 3.

Table 2.   Patient characteristics
No M/FAge (years)Weight (kg)Type SEDuration clinical SE at start therapyHistory of epilepsyAED historyEtiology SE
  1. FSE, focal status epilepticus; NCSE, nonconvulsive status epilepticus (absence SE); GCSE, generalized convulsive status epilepticus; VPA, valproic acid; LEV, levetiracetam.

1F50125NCSE>6 hNoNoAcute subdural hematoma/alcoholism
2F7550FSE4 hYes + SEVPAStroke
3M7045FSE30–60 minYes + SEVPA, LEVStroke
4M4473GCSE120 minYesVPA, LEVPyramidal tetraparesis
5M5395FSE15 minNoNoMeningoencephalitis
6F6273FSE150 minNoNoStroke
7M4598GCSE45 minYesVPAGlioblastoma
9M5186GCSE60 minYesVPAAlcoholism/dementia
10F60120GCSE10 minNoNoHypomagnesemia/hypocalcaemia
11M6464GCSE20 minNoNoHyponatremia
Table 3.   Medication use and adverse advents
NoMedication used to manage SEAdverse events (first 24 h)Clinical observation (at 24 h)
Benzodiazepine (total dose)Other AEDs (total dose)ivLEV (stage of treatment)aRespiratoryCardiovascularAllergic/reactions at injection site
  1. VPA, valproic acid; PHT, phenytoin; LEV, levetiracetam; CZP, clonazepam; DZP, diazepam; MDZ, midazolam. P, preexistent; NA, no prominent abnormalities.

  2. aStage (line) of treatment during or after which ivLEV is added to therapy. For treatment protocol see Table 1.

 1CZP (6 mg)PHT (1,000 mg), VPA (500 mg)2,500 mg (2)NoNoNoConfusion/disorientation
 2DZP (10 mg)PHT (750 mg), VPA (750 mg)2,500 mg (2)NoArrhythmia (P)NoConfusion/disorientation
 3CZP (2 mg)None2,500 mg (1)Desaturation (75%)NoNoNA
 4DZP (30 mg) CZP (1 mg)PHT (1,400 mg)2,500 mg (1)NoNoNoConfusion/disorientation
 5CZP (5 mg)PHT (1,750 mg)2,500 mg (1)NoNoNoNA
 6DZP (20 mg) CZP (8 mg)PHT (1,000 mg)2,500 mg (1)NoNoNoNA
 7DZP (10 mg)VPA (1,000 mg)2,500 mg (1)NoNoNoNA
 8DZP (10 mg) CZP (1 mg)None2,500 mg (1)NoNoRed faceDisorientation
 9DZP (10 mg), MDZ (5 mg), CZP (4 mg)PHT (1,000 mg)2,500 mg (1)ApneasNoNoDisorientation, restlessness
10CZP (1 mg)None2,500 mg (1)Tube (P)NoNoNA
11CZP (2 mg)None2,500 mg (1)Tube (P)NoNoNA

Safety and tolerability

No serious or unequivocal adverse effects could be directly related to the administration of ivLEV in the first 24 h following infusion. Table 4 lists the adverse events noticed in the follow-up period. One patient developed transitional facial flushing shortly after ivLEV infusion. No other signs of allergy or reactions at the injection site were seen in this or any of the other patients. One patient showed some depression of oxygenation (75%). To our knowledge no specific relation could be drawn between administration of ivLEV and this ventilatory depression. Two other patients were already artificially ventilated, and this was initiated before ivLEV administration. No cardiovascular events, such as hypotension (systolic blood pressure <90 mmHg) or arrhythmias, were observed in the first 24-h period after ivLEV. ECG before ivLEV and during the consecutive 24 h did not show any significant alterations. One patient, presenting to the emergency department (ED) with existing atrial fibrillation, did not show worsening or alterations of this cardiac condition after ivLEV administration. During observations at study termination 24 h after ivLEV dosing, SE was terminated clinically in 10 of 11 patients. However, in five of these patients, clinical observations still showed apparent confusional behavior.

Table 4.   Individual pharmacokinetic parameters
NoaM/FAge (years)Weight (kg)Length (cm)Body surface areaBody mass indexSerum creatinine (μg/L)Distribution phase (visual)Individual estimated PK parameters
Cpeak (mg/L)Vtot (L/kg)Cl (L/h)T1/2 (h)
  1. Cpeak, highest measured values directly after administration; NA, not available; Vtot, total volume of distribution; Cl, total body clearance; T1/2, terminal half-life.

  2. aFour excluded from pharmacokinetic (PK) analysis (no blood samples).

 2F75501631.5218.870N95.00.582.19 9.2
 5M531031782.2132.591Y90.20.453.26 9.9
 6F62731701.8425.381Y62.40.744.07 9.2
 7M45981962.3225.585N49.80.514.96 7.0
 8M72821872.0723.4594NNA0.573.58 9.0
 9M51861902.1423.862NNA0.784.74 5.8
11M64641701.7422.145N84.60.532.38 9.8
Mean (SD) 60 (9.7)85 (27)178 (11)2.01 (0.35)26.3 (7.2)75.9 (17.4)0.60 (0.14)3.4 (0.93) 9.7 (2.2)

Pharmacokinetics; population model building

Data on serum levels of LEV were available from 10 patients. In two patients, one and two PK samples, respectively, were not obtained. In two others, an extra blood sample was drawn after cessation of seizures. Data on renal clearance was limited; therefore, renal and metabolic clearance could not be established separately. Clearance was calculated as total body clearance. Inspection of the individual serum concentration–time graphs showed a clear distribution phase in four of the patients (see Fig. 1), whereas in the others this phase could not be visually distinguished. The pharmacokinetics of this population could best be described by a two-compartment population model. Mean (SD) PK parameters of the population were: volume of distribution of the central compartment (Vc) 0.45 (0.084) L/kg, total body clearance (Cl) 0.0476 (0.0147) L/h/kg, distribution rate constants (central to peripheral compartment, k12) 0.24 (0.12)/h, (peripheral to central, k21) 0.70 (0.22)/h, and maximal serum concentration (Cmax) was 85 (19) mg/L.

Figure 1.

Individual serum LEV concentration–time profile of patient 5, showing the apparent distribution phase. Measured LEV serum concentrations are fitted to the population model. The dots display the measured results of the four blood samples of this patient. LEV, levetiracetam.

Pharmacokinetics; individual parameters

Individual PK parameters are presented in Table 4. The sample presenting the highest measured serum concentration is shown. In two patients, the first blood sample was not drawn because of difficulties in blood sampling. The maximal measured serum concentrations were lower than the calculated Cmax (mean 76 mg/L, range 50–95 mg/L). Mean total volume of distribution was 0.60 L/kg (range 0.45–0.88 L/kg). Mean terminal half-life was 9.7 h (range 5.8–13.9 h).


The rationale to add ivLEV to SE treatment is based on promising results of its oral use in individual cases (Rossetti & Bromfield, 2005; Rupprecht et al., 2007). Experimental data in animal SE models have also indicated potential for its use in SE. Minutes after the start of SE, γ-aminobutyric acid (GABA) receptor internalization and trafficking takes place, resulting in a serious reduction of response to benzodiazepines. This may subsequently contribute to prolonged disease and pharmacoresistance to benzodiazepines or phenytoin (Chen et al., 2007). LEV’s main target has been identified to be the SV2A receptor (Lynch et al., 2004). Because LEV is also thought to interact with GABAergic transmission and to potentiate benzodiazepine efficacy, it seems rational to add LEV in combination with benzodiazepine administration, particularly at the early phase of SE when the GABA system is most susceptible (Rigo et al., 2002; Mazarati et al., 2004). LEV might thus enhance the anticonvulsive effects of benzodiazepines, be beneficial against phenomena of “acute epileptogenesis” observed during SE, and potentially long-lasting protective effects may reduce the risks of seizure relapse (Glien et al., 2002; Mazarati et al., 2004; Yan et al., 2005; Gibbs et al., 2006). During the conduct of this trial, some reports on ivLEV have become available supporting its use in SE therapy (Patel et al., 2006; Farooq et al., 2007; Knake et al., 2007; Schultz-Bonhage et al., 2007).

The acute presentation of SE requires immediate therapy and intervention, which makes clinical research in SE on an emergency basis difficult to carry out. To ensure minimal interference with established acute care, we chose to administer ivLEV as an add-on to the standard antiepileptic regimen. In this study, Lowenstein’s operational definition of SE was used (Lowenstein et al., 1999). The short time frame in this definition made a rapid inclusion procedure possible, so that after admission to the ED, ivLEV could be added to the treatment regimen with minimal delay. Consequently, the study population was heterogeneous and consisted of established SE cases and so-called early or impending SE cases (Shorvon, 1993; Chen et al., 2007). In addition, early administration of LEV could be beneficial in seizure reduction (Mazarati et al., 2004). Treatment delay is potentially deleterious, as continuation of seizures can substantially affect the outcome (Eriksson et al., 2005). Our intention was to achieve therapeutic LEV levels as soon as possible after onset of SE. Therefore, the highest dose in the shortest time frame demonstrated as safe in healthy volunteers, 2,500 mg infused over 5 min, was selected to administer in this study (Ramael et al., 2006a). Using this approach, we were able to manage the inherent difficulties of studying clinical care in an acute setting, and test its feasibility along with the evaluation of safety of high-dose intravenously administered LEV in different stages of SE.

Most side effects related to ivLEV are signs or symptoms associated with the central nervous system. In studies in healthy volunteers and patients with partial seizures, the occurrence of somnolence, dizziness, headache, and fatigue were most commonly observed. The onset of symptoms was observed within the first 4 h after ivLEV administration, although dizziness, the most profound side effect, already started during or shortly after infusion. Most side effects lasted <8 h, except for some individualistic prolonged cases of somnolence and dizziness (Ramael et al., 2006a,b; Baulac et al., 2007). As might be expected with SE, most patients showed postictal drowsiness. The relatively mild side effects of ivLEV as mentioned in the earlier trials, if present in these patients, could not be distinguished from postictal symptoms. However, in the case of SE, mild or transient side effects are acceptable if therapy favors long-term outcome. The combination of high serum LEV levels with the administration of benzodiazepines did not seem to result in serious ventilatory depression, a common and major side effect of initial SE treatment. In addition, no cardiovascular events, a major side effect of phenytoin therapy, were observed. In one patient, signs of an allergic reaction, indicated by redness of the face, were noticed. Shortly after the infusion, this condition normalized. No additional adverse reaction or influence on final outcome was observed. A remarkable observation was a confused mental state in five patients at the 24 h evaluation after clinical termination of SE. It was unclear whether this long period was related to the administered investigational drug or caused by SE including its underlying etiology, or other concomitantly administered drugs. These symptoms were most prominent in the patients with the longest SE episodes, supporting the influence of SE. Nevertheless, prolonged confusion could not be excluded as a side effect of high-dose LEV. The occurrence of possibly enhanced postictal disorientation or confusion did not seem to have an adverse effect on final outcome.

In this small population, 10 of 11 patients did recover from their SE. In addition, 3 of these 10 experienced prolonged epileptic activity or seizures during the 24-h follow-up period. Nevertheless, the efficacy of ivLEV was not the goal of our study and it would be inappropriate to emphasize.

Currently, only PK data on ivLEV from phase I studies in healthy volunteers are available (Ramael et al., 2006a,b; Snoeck et al., 2007). To evaluate safety with the PK data in this study, some comments on the ivLEV PK in our SE population and the healthy volunteers were made. Clearly, one of the weaknesses of assessing a PK population model in a small group of patients is the limited number of samples that can be collected. Especially in an acute setting as SE in an ED, a full PK profile with frequent sampling would be difficult to obtain. To accrue a maximum of information with a limited number of samples, an optimal sampling scheme was designed. This sampling model was based upon an LEV one-compartment PK model for oral administration, because at the time of designing our study, no iv pharmacokinetics were yet available. Based on the model, the optimal (limited) sampling consisted of samples drawn before; immediately after; and at 1, 5, and 20 h post administration of ivLEV. Unfortunately, only the blood sample drawn immediately after administration occurred in the later identified distribution phase. The clinical setting also contributed to blood-sampling delay in some patients. As a result, data on distribution and maximal serum concentrations are limited. In healthy volunteers, a clear distribution phase has been observed in only a subset of the subjects, and these data are used to compose a two-compartment PK model (Snoeck et al., 2007). In our population, this phenomenon was also observed. A possible explanation may be that all patients have a distribution phase but, in some patients, the distribution equilibrium is reached too fast to enable a visible distribution phase. In addition, in our cohort, this phase may not be detected, because of a lack of samples within the first hour after administration. Although only four patients visually showed a distribution phase, ivLEV in SE can probably best be described by a two-compartment PK model. Data from all 10 evaluable patients, regardless of the presence of a distribution phase, have been used to parameterize this model. This resulted in a model matching best the SE population, as was our intention.

Despite the limitations of our data, the strength of this study is that for the first time, prospectively collected PK data on ivLEV in SE are now available. In our population, the administration of 2,500 mg LEV as a rapid infusion led to maximal measured serum levels of 76 (SD 17) mg/L. Based on predictions made by fitting the population model to our data, mean maximal serum (Cmax) level at the end of the administration would be 85 (SD 19) mg/L. These levels correspond to the mean level of 94 (SD 34) mg/L, as was observed in healthy volunteers receiving a similar dose (Ramael et al., 2006a).

The SE population baseline characteristics (Table 2) differ at several points from healthy volunteers (Snoeck et al., 2007). The main differences, besides the presence of SE, were age and body weight. Our study population was older [61 (SD 10) years vs. 38 (SD 9) years], heavier, and had a wider range in bodyweight [85 (SD 27) kg vs. 71 (SD 12) kg]. In our study, some obese [body mass index (BMI) = 38] and malnourished (BMI = 16) patients were included, in contrast to the ivLEV phase I trials, but more reflective of variety expected in clinical practice. Mean clearance was lower in our population; 0.0476 (0.0147) L/h/kg versus 0.0586 (0.0016) L/h/kg. Because LEV is predominantly renally excreted, the lower clearance could possibly be explained by a decrease in renal function resulting from advanced age (Wetzels et al., 2007). Impairment of renal perfusion during SE could also be a contributing factor.

Nevertheless, the ivLEV SE population PK model that was derived from our patients was comparable to the earlier described model in healthy volunteers. Observed differences could be attributed to our patients’ characteristics as weight, age, and impaired renal function. As ivLEV PK seems to be similar in SE patients and healthy volunteers, no differences in drug-exposure–related adverse events were expected.

In conclusion, ivLEV added to the standard therapeutic regimen in patients with SE seems feasible, also in an acute ED setting. No serious adverse effects were seen, and results correspond well to safety data observed in phase I trials in ivLEV. These data suggest that a dose of 2,500 mg LEV can be safely administered iv in a 5-min period as add-on to regular SE treatment. The population PK parameters of our cohort were comparable to PK parameters in healthy volunteers, supporting a comparable side-effect profile in both groups. These results justify further clinical investigations on the effectiveness of ivLEV in SE.


This study was supported by an unrestricted educational grant from UCB Pharma, Inc.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of interest: The authors received an unrestricted educational grant from UCB Pharma Inc. to support this study. None of the authors have any other conflicts of interest to disclose.