Epileptic Disorders
MENUSafety profile of levetiracetam Volume 5, supplément 1, Supplement, May 2003
Auteur(s) : Santiago Arroyo1, Pamela Crawford2
1 Medical College of Wisconsin, Milwaukee, Wisconsin,
USA
2 Department of Neurosciences, York District Hospital,
York, United Kingdom
Introduction
Until about 10 years ago, physicians had limited choices for the control of seizures in patients with epilepsy [1]. However, an ’explosion’ in the development of antiepileptic drugs (AEDs) began in the 1990s and continues today [2]. While these new treatment options offer significant potential benefit to patients with seizure disorders, the risks associated with their use must also be evaluated [3]. Side-effect profiles may differ considerably from one agent to another and represent a major factor in determining choice of treatment. At present, information about the comparative safety of new AEDs is somewhat limited [4]. Continual monitoring is required to establish long-term safety in large numbers of patients with varied demographic and clinical characteristics.
Compared with both classic and newer AEDs, levetiracetam’s (Keppra®1) low incidence of adverse effects results in an unusually high safety margin in animal models reflecting both partial and primary generalized epilepsy [5]. Levetiracetam shows an absence of negative impact on cognitive function in normal and kindled rats, unlike classic AEDs [6].
The objectives of the present review are to summarize information regarding the short- and long-term safety of levetiracetam in controlled clinical trials, present data on the long-term safety of levetiracetam from open-label studies, review the data to support a claim for lack of drug-drug interactions, and summarize limited safety data for levetiracetam in special patient populations (pediatric patients, the elderly, women of childbearing age, and the learning-disabled).
1. Keppra is a registered trademark of UCB S.A.
Safety data from controlled clinical trials
Randomized controlled clinical trials in which levetiracetam was administered in combination with other AEDs or as withdrawal to monotherapy for refractory partial seizures have shown that it is well tolerated [7-13]. The three pivotal trials of levetiracetam were multicenter, double-blind, placebo-controlled studies that included 904 adults with refractory partial seizures with or without secondary generalization who were randomized to treatment with placebo or 1000, 2000, or 3000 mg/day of levetiracetam in conjunction with other AEDs (e.g., carbamazepine, phenytoin, phenobarbital, primidone, clonazepam, valproate, vigabatrin, lamotrigine, and gabapentin) [7-9]. In one of these trials, responders were converted to monotherapy [7]. A fourth study included 119 patients randomized to treatment with placebo or 2000 or 4000 mg/day of levetiracetam as add-on therapy [10].
Vital signs and clinical laboratory values
Levetiracetam had no significant effects on blood pressure,
pulse rate, or electrocardiograms (ECGs) [7-10]. A separate
analysis of the effects of levetiracetam on body weight indicated
that it had no effect on body weight in either male or female
patients [14].
Levetiracetam had minimal or no effects on clinical laboratory
values. Levetiracetam has been associated with slight reductions in
red blood cell counts, hematocrit, and hemoglobin; however, all
values remained within the normal range [13]. Mean white blood cell
(WBC) counts also remained within the standard laboratory normal
range during and after treatment with levetiracetam. Moreover, drug
discontinuation was not necessary in any patient because of
neutropenia [13].
There were no significant changes in blood chemistry associated
with levetiracetam therapy. Most importantly, there were no
statistically significant elevations in liver function tests
(aspartate aminotransferase, alanine aminotransferase, γ-glutamyl
transferase, total bilirubin, or alkaline phosphatase) among
patients who received levetiracetam in placebo-controlled trials
[13].
Adverse events
Adverse events reported most often are summarized in table 1 [11].
Table 1. Incidence of adverse events occurring in at least 1% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients in placebo-controlled clinical trials [11]
Adverse event |
Levetiracetam | Placebo |
---|---|---|
(N = 769) % |
(N = 439) % |
|
Body as a whole | ||
Asthenia | 15 | 9 |
Headache | 14 | 13 |
Infection | 13 | 8 |
Pain | 7 | 6 |
Digestive system | ||
Anorexia | 3 | 2 |
Nervous system | ||
Amnesia | 2 | 1 |
Anxiety | 2 | 1 |
Ataxia | 3 | 1 |
Depression | 4 | 2 |
Dizziness | 9 | 4 |
Emotional lability | 2 | 0 |
Hostility | 2 | 1 |
Nervousness | 4 | 2 |
Paresthesia | 2 | 1 |
Somnolence | 15 | 8 |
Vertigo | 3 | 1 |
Respiratory system | ||
Cough increased | 2 | 1 |
Pharyngitis | 6 | 4 |
Rhinitis | 4 | 3 |
Sinusitis | 2 | 1 |
Special senses | ||
Diplopia | 2 | 1 |
In controlled clinical trials, 15.0% of patients treated with levetiracetam discontinued therapy or had their dose reduced due to adverse events, versus 11.6% of those who received placebo [11, 12]. The adverse events most commonly associated with discontinuation or dose reduction in patients treated with levetiracetam were somnolence (4.4% versus 1.6% for placebo), convulsions (3.0% versus 3.4%), dizziness (1.4% versus 0%), asthenia (1.3% versus 0.7%), and rash (0% versus 1.1%). The majority of adverse events were mild to moderate in severity. Overall, 14.7% (113/769) of the patients taking levetiracetam and 11.2% (49/439) of those who received placebo experienced severe adverse events. Those events occurring at greater than 0.5% and with an incidence more common in the levetiracetam group were somnolence, 3.1% (0.9% for placebo group); asthenia, 1.6% (0.5% for placebo group); convulsion, 1.6% (1.4% for placebo group); grand mal convulsions, 1.0% (0.9% for placebo group); dizziness, 0.7% (0 for placebo group); depression, 0.7% (0 for placebo group); and personality disorder, 0.5% (0 for placebo group) [12].
Seizure exacerbation
Unexpected exacerbation of seizures can occur during treatment with AEDs [15-18]. Worsening of seizures may occur in patients treated with levetiracetam. Data from placebo-controlled trials have shown that worsening of seizures (increase of > 25%) was seen in 14% of levetiracetam patients, compared to 26% of placebo patients (P < 0.001) [13, 19]. No definite relationship with dose was observed.
Safety from long-term extension studies
While results from short-term clinical trials are essential for
establishing the safety of an AED, they are not powered to provide
information about the occurrence of rare adverse events [20] and
are not of sufficient duration to permit the identification of side
effects that occur only with long-term drug exposure. Thus, data
from long-term, often open-label, evaluations provide an essential
component of the safety profile for any drug product.
Krakow et al. [21] assessed the long-term open-label
efficacy and safety of levetiracetam in 1422 patients who were
followed for up to 5 years. During this period, 15.8% (225) of
patients discontinued levetiracetam due to adverse events, most
often convulsions (3.4%), somnolence (2.0%), asthenia (0.6%),
depression (0.6%), dizziness (0.5%), and headache (0.5%). These
events are similar to those reported in the shorter-term
placebo-controlled studies and support the view that long-term use
of this AED does not appear to be associated with the development
of unexpected adverse events.
Postmarketing surveillance
The spontaneous reporting of adverse events to surveillance
programs such as MEDWATCH is important for determining the safety
profile of any drug, and is particularly useful for revealing
unusual or rare adverse events [22-24]. Such surveillance has
provided safety data for levetiracetam consistent with that
summarized in the preceding sections.
Other tools for measuring reported side effects in clinical use
have revealed a similar profile as well. Sadek and colleagues, of
the University of Pennsylvania School of Medicine in Philadelphia,
analyzed data on behavioral side effects in patients starting
treatment in the Post-marketing Antiepileptic Drug Survey (PADS)
database [25]. The database is a prospective registry that pools
information from 16 epilepsy centers to study patients treated
with new AEDs.
Several small-scale studies report behavioral adverse events
[26-36]. The behavioral adverse event rate from the PADS registry
(N = 288) is nearly identical to that
obtained in the premarketing data. Of 288 patients initiating
levetiracetam therapy who had a mean follow-up of 240 days, 75
(23.8%) reported behavioral problems. Behavioral adverse events led
to the discontinuation of levetiracetam in 27 patients
(8.5%).
Behavioral adverse events in the PADS registry included
irritability in four patients, aggression in five (all of whom were
mentally retarded), depression in 14, anxiety in eight, and mood
swings in three; the type of behavioral problem was unspecified in
five patients (table 2).
Table 2. Behavioral adverse events reported in postmarketing use database for levetiracetam [25]
Adverse event | Number (%) of patients |
---|---|
(N = 288) | |
Depression | 14 (4.9%) |
Anxiety | 8 (2.8%) |
Aggression | 5 (1.7%) |
Irritability | 4 (1.4%) |
Mood swings | 3 (1.0%) |
Unspecified | 5 (1.7%) |
A history of past psychiatric/behavioral problems/mental
retardation was noted in 51.2% of patients with behavioral adverse
events, versus 49.6% of the total levetiracetam group [25].
Psychiatric symptoms are common in many patients with epilepsy
[37]. Indeed, behavioral disturbances and psychotic reactions
appear to be more prevalent in patients with refractory epilepsy
than in the population at large, and sometimes have been associated
with AED therapy [38]. Therefore, the findings of behavioral
adverse events in randomized, double-blind trials with
levetiracetam are not unexpected. Such reactions can be seen, for
example, when patients with previously intractable epilepsy
suddenly become seizure-free [39]. Older drugs most often
associated with psychobehavioral disturbances in patients with
epilepsy include phenobarbital and phenytoin [40]. Among the newer
agents, vigabatrin, zonisamide, topiramate, and gabapentin appear
to have raised concern regarding psychiatric adverse events [38,
40-44].
In addition to the adverse experiences summarized in table 1, the following have been reported in
patients receiving levetiracetam postmarketing: leukopenia,
neutropenia, pancytopenia, and thrombocytopenia. However, the data
are insufficient to support an estimate of their incidence or to
establish causation.
While postmarketing surveillance safety data must be viewed with
some caution, particularly with respect to the assignment of
causality for reported events [23, 45], the results available to
date for levetiracetam are consistent with the view that long-term
use of this AED in the normal clinical setting is not associated
with the emergence of new and life-threatening adverse events not
observed in shorter-term controlled clinical trials. However, the
total patient exposure to date (197 634 patient-years as
of December 2002) is still not enough to rule out the possibility
of very rare severe idiosyncratic adverse events [24].
Drug-drug interactions
Drug-drug interactions affecting AED metabolism occur often but
may be unpredictable [46]. Treatment with some AEDs is complicated
by the fact that they may induce or inhibit the activity of key
hepatic enzymes that catalyze oxidative reactions important for
drug clearance. Treatment with such drugs can influence both their
own metabolism and that of other medications.
Some of the newer AEDs have a substantially lower potential for
drug-drug interactions than the older AEDs, including phenytoin,
valproate, and carbamazepine. The pharmacokinetic profile of
levetiracetam suggests that it has a very low potential for
clinically significant drug-drug interactions, and this has proven
to be the case. Levetiracetam is not protein bound (< 10%
bound), and its volume of distribution is close to the volume of
intracellular and extracellular water [47]. Sixty-six percent of a
levetiracetam dose is excreted unchanged in urine. The major
metabolic pathway (24% of dose) involves enzymatic hydrolysis of
the acetamide group, which is not hepatic CYP-dependent. The
metabolites of levetiracetam have no known pharmacologic activity
and are also excreted via the kidney [47].
Levetiracetam does not interfere with the metabolism of other
AEDs, and other drugs used to control seizures do not significantly
affect the pharmacokinetic profile of levetiracetam [11, 47].
Studies with agents well known to cause drug interactions (e.g.,
phenytoin, oral contraceptives, digoxin, and warfarin) showed no
evidence of any pharmacokinetic interaction with levetiracetam
[48-51]. Administration of probenecid, an inhibitor of renal
tubular secretion, did not change the pharmacokinetics of
levetiracetam but did reduce the clearance of the primary
metabolite (ucb L057) by 60%. This effect was probably a result of
competitive inhibition of tubular secretion of ucb L057 by
probenicid [11].
Safety in special patient populations
Both children and elderly patients are especially prone to have epilepsy. In both populations, the selection of AEDs has to take into account the different pharmacokinetics and sensitivity to adverse events [52-58]. Women are considered a special patient population because of issues related to contraception, childbirth, and breast-feeding. Finally, the learning-disabled or cognitively impaired also constitute a special patient population. These patients may be particularly vulnerable to the neurotoxic and sedative effects of some AEDs, and inappropriate treatment may exacerbate their intellectual impairment [59].
Pediatric patients
Results from a small-scale study (N = 24)
suggest that levetiracetam may be safe and well tolerated in
pediatric patients with epilepsy [60]. The types and rates of side
effects in children in this study appear generally similar to those
reported in adults.
Glauser et al. administered levetiracetam to
24 children between 6 and 12 years of age with
treatment-resistant partial-onset seizures [60]. The most commonly
reported adverse events were headache (33%), infection (33%),
anorexia (25%), and somnolence (25%). Two patients experienced
changes in laboratory values (a decrease in red blood cell count
and an elevation in mean corpuscular volume) that were considered
clinically significant. There were no significant effects on
physical or ECG findings. Five patients experienced ≥ 7%
changes in body weight (three increased and two decreased). The
safety profile for levetiracetam appeared similar to that in adult
patients. The similarity of the adverse event profiles for
levetiracetam in adult and pediatric patients is further supported
by recent results from Hovinga et al. [61], who
retrospectively evaluated 77 adults and 27 children
(median age 12 years) treated with this AED. Adverse events
occurred in 56% of the adults and 52% of the children over an
average of approximately 5 months of follow-up. Adverse events
resulted in discontinuation of levetiracetam in 14% of the adults
and 11% of the children. The most common adverse events in the two
groups were somnolence, dizziness, depression, increased seizure
frequency, and cognitive changes, and they occurred with
approximately equal frequency in the two groups.
The elderly
Kraemer and Edrich [32] evaluated safety data for levetiracetam in all patients ≥ 50 years of age who were treated with this AED during clinical development for epilepsy. Their retrospective analysis included 211 patients with a median age of 56 years (range, 50 to 78 years), including 14.7% older than 65. The mean duration of exposure was 697 days (range, 1 to 2409 days), the median dose, 3000 mg/day. At the end of the observation period, 43.6% of patients were still receiving levetiracetam; 19.9% of the patients had discontinued treatment due to adverse events. When these researchers compared the adverse events of the older individuals to those of the total population of patients (1422) who received levetiracetam during the same period, the types and rates of adverse events were generally the same. The adverse events reported most often involved the central nervous system (e.g., somnolence, asthenia, dizziness) and were generally mild in severity. Thus, the safety profile for levetiracetam in older patients is very similar to that in younger adults. No dosing modifications for levetiracetam are required in the elderly except as indicated by their renal function [52].
Women of childbearing age
In women with epilepsy, drug-related issues include the alteration of menstrual cycles, interactions with oral contraceptives, and potential risks to the fetus. As already noted, levetiracetam does not influence the efficacy of oral contraceptives [51, 62]. Due to its recent marketing, its potential for teratogenesis is still unknown. However, preclinical data in animals suggest the potential is low [63]. As with other AEDs, levetiracetam can be used during pregnancy if the potential benefits justify the possible risks. Additional prospective data must be collected to determine the effect of levetiracetam on pregnancy and its outcome. Like many other drugs, levetiracetam is excreted in breast milk. The American Academy of Neurology has issued some recommendations on the issue of breast-feeding while on AEDs [64]. It has been advocated that a risk-benefit analysis should be done with the mother in order to make a decision. In general, breast-feeding is encouraged, unless untoward side effects are observed in the child.
The learning disabled
The safety of levetiracetam in patients with learning disabilities has not been evaluated. Kaplan [65] carried out a retrospective chart review of 28 developmentally delayed and/or mentally retarded patients with epilepsy who were treated with levetiracetam. Only one adverse event (somnolence) was noted. O’Rourke et al. [66] administered levetiracetam as add-on therapy to 18 learning-disabled adults with intractable seizures. Over 3 months of follow-up, one patient discontinued due to an adverse event (postictal psychosis). While very limited, these results suggest that levetiracetam therapy may be safe for this patient group.
Patients with renal impairment
No dosing adjustment is required for levetiracetam in patients with solely hepatic impairment, but dosing must be adjusted in patients with renal impairment based on creatinine clearance.
Conclusions
Levetiracetam is a safe AED for the adjunctive treatment of partial epilepsy. Adverse events are relatively infrequent and usually mild. The most frequent CNS-related adverse events include asthenia, fatigue, dizziness, and somnolence. Levetiracetam has little effect on vital signs or clinical laboratory values. Although there have been some reports of behavioral disturbances in patients taking levetiracetam, the frequency of reported symptoms appears to be low. The tolerability of levetiracetam is maintained over the long term and could extend to pediatric and elderly patients as well as those with learning disabilities.