Victor Biton MD
Director, Arkansas Epilepsy Program, Little Rock, Arkansas
Levetiracetam, or ucb L059, was approved by the U.S. Food and Drug Administration in November 1999 as add-on therapy for the treatment of partial seizures in adults, and is marketed under the trade name Keppra (UCB Pharmaceuticals, Hampton, VA). Recommended dosages are 1,000 to 3,000 mg/day, given twice daily. Levetiracetam is the (S)enantiomer of α-ethyl-2-oxo-1 -pyrrolidine acetamide, structurally and pharmacologically a novel compound with respect to other antiepileptic drugs. It is chemically related to piracetam, a drug marketed in Europe for many years.
The toxicity profile of levetiracetam has been characterized after single and repeat intravenous (i.v.) and oral administration in mice, rats, and dogs. Repeat oral administration of levetiracetam in dosages of up to 1,800 mg/kg/day in rats and 1,200 mg/kg/day in dogs is well tolerated. Clinical signs are minimal across studies and species, with the most consistent observations being neuromuscular effects, salivation, and, in dogs, emesis. Only in the rodent were treatment-related changes in the liver and kidney reported; these are species specific and are not of toxicologic concern to humans. Studies in neonatal or juvenile animals do not indicate any greater potential for toxicity compared with adult animals. Investigations involving administration of ucb L057, the major human metabolite, and ucb L060 [the (R)-enantiomer] indicate a low potential for toxicity in animals. Levetiracetam is neither carcinogenic nor mutagenic; although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in mice. As discussed elsewhere in this chapter, the drug is not teratogenic.
The clinical development of levetiracetam began in the early 1980s. Before its approval, comprehensive safety data were obtained in 3,347 subjects exposed to levetiracetam. The primary focus of this review of the safety of levetiracetam is its use in the 1,422 (primarily adult) patients with epilepsy who participated in clinical trials. Overall, the median levetiracetam dosage was 3,000 mg/day, with treatment continuing on average for approximately 1 year, and for up to 8 years. A total of 769 of these patients received levetiracetam 1,000 to 4,000 mg/day in one of four placebo-controlled studies of approximately 6 months' duration (1, 2, 3, 4). The dosage and duration of exposure in placebo-controlled trials are illustrated in Figure 43.1.
Given levetiracetam's structural relationship to piracetam, early development efforts were in diverse indications relating to cognition, anxiety, and prevention of deep vein thrombosis. The dosages used in the 1,559 patients who participated in these studies in general were lower than those in patients with epilepsy, and the durations of treatment were shorter. Three hundred sixty-seven volunteers have participated in clinical pharmacology studies, including geriatric patients and subjects with hepatic or renal impairment. The safety profile in these studies is consistent with that observed in the epilepsy trials.
Levetiracetam has been available for use in the United States since April 2000. It was launched internationally in September 2000. It is estimated that approximately 38,000 patients have used this medication during the first 6 months of commercial use, a 25-fold increase in exposure relative to the investigational stage. To date, no new treatment-related adverse events have been identified during this broader use.
MOST COMMONLY OBSERVED ADVERSE EFFECTS
Adverse events associated with levetiracetam pertain primarily to the central nervous system. In placebo-controlled studies, the most common such events were somnolence, asthenia, and dizziness. Vertigo, although infrequent, occurred in significantly more levetiracetam-treated patients. Headache and accidental injury also were common adverse effects, but occurred with a comparable or
higher frequency before treatment and in placebo-treated patients. The incidence of treatment-emergent adverse events that occurred in at least 3% of the levetiracetam-treated patients is summarized in Table 43.1.
FIGURE 43.1. Dose and duration of exposure to levetiracetam in placebo-controlled studies in patients with epilepsy.
Psychiatric events commonly are reported in patients with epilepsy, often related to the disease itself or the effects of antiepileptic medication. The overall incidence of psychiatric adverse experiences in placebo-controlled studies of levetiracetam in adult patients with epilepsy is within the expected range for patients with epilepsy. Nonpsychotic behavioral symptoms were the most common, occurring in approximately 13% of the patients (compared with 6% in the placebo-treated group). Individual events that were significantly more common with levetiracetam treatment were nervousness, emotional lability, and hostility. Sleep disorders, including abnormal dreams and insomnia, occurred less frequently (4% levetiracetam-treated patients, compared with 3% of placebo-treated patients).
TABLE 43.1. MOST COMMON ADVERSE EXPERIENCES IN PLACEBO-CONTROLLED EPILEPSY TRIALS: LIMITED TO THOSE REPORTED BY ≥3.0% LEVETIRACETAM-TREATED ADULT PATIENTS AND OCCURRING MORE OFTEN THAN WITH PLACEBO
Adverse events reflective of cognition (such as amnesia, confusion, and thinking abnormal) occurred in 3% to 4% of patients, regardless of treatment group. Although an infrequent event, significantly more levetiracetam-treated patients reported amnesia (2%, compared with <1% in placebo-treated patients).
A significantly higher incidence of infections was observed in the levetiracetam-treated patients (approximately 13%, compared with 7% of patients in the placebo group). These were primarily mild infections, such as common colds and upper respiratory infections, and did not interrupt treatment. There was not an increase in the incidence of other infections. The underlying cause is unclear and the symptoms were not related to changes in white blood cell or neutrophil counts.
Few patients discontinued double-blind treatment as a result of an adverse event (11% of levetiracetam-treated patients and 8% of placebo-treated patients). For the levetiracetam-treated group, the most frequent reasons for dose reduction or discontinuation were somnolence, dizziness, asthenia, and headaches. Convulsions also were a frequent cause, 3% in both treatment groups. Table 43.2 describes
the incidence of adverse experiences resulting in 0.5% or more patients in the levetiracetam treatment group discontinuing or having a dose reduction.
TABLE 43.2. ADVERSE EXPERIENCES THAT RESULTED IN ≥0.5% LEVETIRACETAM-TREATED PATIENTS DISCONTINUING OR HAVING A DOSE REDUCTION
Clinical Laboratory and Other Objective Studies
In the double-blind, placebo-controlled studies, levetiracetam treatment did not affect any of the five parameters of liver functions that were measured. These included aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, total bilirubin, and alkaline phosphatase. No effects were found on any other serum biochemistry parameter. There were no treatment-related effects on hematology parameters. Although there were statistically significant differences noted between the levetiracetam and placebo treatment groups, with lower hemoglobin, hematocrit, and neutrophil count in patients receiving levetiracetam, the magnitudes of change were not clinically meaningful. Furthermore, abnormalities were not associated with clinical consequences.
TABLE 43.3. ADVERSE EXPERIENCES BY RANDOMIZED DOSE IN PLACEBO-CONTROLLED EPILEPSY TRIALS: LIMITED TO THOSE OCCURRING IN ≥3.0% OF LEVETIRACETAM PATIENTS OVERALL, AND OCCURRING MORE OFTEN THAN WITH PLACEBO
There were no treatment-related effects noted on physical or neurologic examination. Similarly, vital sign measurements did not reveal any treatment-related effects. Specifically with respect to body weight, there was no statistically significant change from baseline in the levetiracetam treatment group.
Electrocardiograms were obtained on 567 patients who received levetiracetam and 298 patients who received placebo in the double-blind, placebo-controlled epilepsy studies. There was no apparent effect of levetiracetam on the PR, QRS, or QTC intervals.
In the recommended adult dosage range, 1,000 to 3,000 mg/day, there is no clear dose-response relationship for adverse events. Adverse events occurring in 3% or more of patients in placebo-controlled studies are summarized by dosage in Table 43.3; only those events occurring more often among levetiracetam-treated patients are included. In
the clinical pharmacology studies in healthy volunteers encompassing dosages up to 5,000 mg, somnolence and asthenia were dose related. In the placebo-controlled clinical trials in patients with epilepsy, the incidences of somnolence and nausea were higher at the highest dosage studied, 4,000 mg/day. However, these patients were randomized directly to this dosage without uptitration as is recommended.
TABLE 43.4. INCIDENCE OF ADVERSE EXPERIENCES BY ONSET: LIMITED TO EVENTS REPORTED IN ≥5.0% OF LEVETIRACETAM-TREATED PATIENTS OVERALL AND OCCURRING MORE OFTEN THAN WITH PLACEBO
Convulsions were more common at the lowest dosages (7% at dosages of 1,000 and 2,000 mg/day, 5% at a dosage of 3,000 mg/day, and 3% at a dosage of 4,000 mg/day). This event does not appear on Table 43.3 because it was more common in placebo-treated patients overall (7%).
Somnolence, asthenia, and dizziness tended to occur early in treatment. Less frequent events that also may occur more often early in the treatment are anorexia, dry mouth, nausea, ataxia, nervousness, abnormal thinking, vertigo, amblyopia, and diplopia. The time course of onset of the side effects that were reported in more than 5% of the patients in the levetiracetam treatment group is described in Table 43.4.
TABLE 43.5. MOST COMMON ADVERSE EXPERIENCES (≥5.0%) WITH ONSET BETWEEN 1 AND 2 YEARS
There are no adverse events that are uniquely associated with long-term treatment. Adverse events with an onset after at least 1 year of treatment are presented in Table 43.5; the table is limited to those events with an incidence of 5% or greater. Clinical laboratory results also were reviewed for evidence of abnormalities associated with long-term treatment. None was identified. There were no apparent longterm effects on body weight.
No demographic or concomitant disease factors have been identified that pose an added risk to the use of levetiracetam. The safety profiles by sex and ethnicity have been compared and no differences have been found. Patients also have been categorized on the basis of other medical diagnoses, including psychiatric diagnoses, and no risk factors have been identified. Clinical pharmacology studies have been conducted in patients with hepatic or renal impairment. The safety profile in these patients is similar to that seen in other patient populations.
Levetiracetam is tolerated well in pediatric patients, but less so than in adult patients. A total of 29 pediatric epilepsy patients between the ages of 5 and 12 years of age have been treated with levetiracetam in open-label studies. The mean dosage was 1,271 mg/day (median of 1,000 mg/day); when body weight is taken into consideration, doses are similar to those used by adults. The types of adverse events reported in children are similar to those reported by adults, but occur with an apparently higher incidence in children.
No clinically meaningful drug interactions have been identified, either on the basis of formal pharmacokinetic interaction studies or on review of the safety profile in the placebo-controlled clinical trials in patients with epilepsy. Pharmacokinetic studies have evaluated interactions between levetiracetam and phenytoin, digoxin, oral contraceptives, warfarin, and probenecid. A population pharmacokinetics
approach also has been used to identify pharmacokinetic interactions with other antiepileptic drugs. Adverse event profiles were reviewed by categorizing patients by concomitant antiepileptic drug and also by the more commonly used concomitant medications.
Levetiracetam is primarily excreted renally by glomerular filtration and active secretion, and hence pharmacokinetic half-life is prolonged in patients with renal impairment. Although no undue adverse events have been observed in the small number of patients with renal impairment studied, dose adjustments are recommended as a precautionary measure for patients with creatinine clearance of less than 60 mL/min.
In animal studies, levetiracetam has been shown to cross the placenta and is present in excreted milk. There is limited experience with the use of levetiracetam in pregnant women, and such use should be considered only in those cases where the benefit clearly outweighs the risk. There were 16 documented pregnancies in women who received levetiracetam during the course of clinical development, 6 of which resulted in live births. All deliveries and infants were characterized as normal; to date, the oldest children (twins) are approximately 7 years of age (delivered in December of 1994). Of the seven abortions (spontaneous, elective, or due to an ectopic pregnancy), one of the fetuses had possible trisomy. Studies in rats at dosages up to 1,800 mg/kg/day have not identified any effects of levetiracetam representing a risk to human fertility. Similarly, maternal treatment during gestation and lactation did not affect survival, growth, and development of the offspring. No fetal abnormalities were noted in the rat teratology studies at dosages up to 3,600 mg/kg/day, although fetal growth was slightly retarded and rib numbers were slightly altered at the highest dose. At this high dose, mild maternal toxicity was noted, as demonstrated by a slightly lower body weight gain at the end of pregnancy. In one of three rabbit teratology studies, there was a twofold increase in incidence of spontaneously occurring abnormalities at 1,800 mg/kg/day, a markedly maternally toxic dose; this was not seen in the other two studies.
LESS COMMON, BUT CLINICALLY RELEVANT ADVERSE EVENTS
Less common, but clinically significant adverse events observed during treatment with levetiracetam include psychotic events and allergic reactions.
Twenty-three patients (0.7%) receiving levetiracetam in all studies reported delusions, hallucinations, manic reactions, paranoid reaction, or psychotic depression. Nineteen of those 23 patients participated in the epilepsy studies. In approximately one-half of the patients, these events required dose reduction or discontinuation from therapy. During the initial postmarketing use, the types of psychiatric events spontaneously reported were abnormal behavior, aggression, anger, autoaggression, anxiety, confusion, depressed mood, depression, hallucinations, hostility, irritability, mood alteration, nervousness, and restlessness.
Allergic reactions are not commonly associated with this treatment. In placebo-controlled trials, there was no difference between levetiracetam and placebo in the incidence of rashes, urticaria, and other dermatologic manifestations of allergy (6% of patients in each treatment group). In all 3,347 patients exposed to levetiracetam during the development program, only 7 cases of severe allergic events occurred. Eleven patients discontinued levetiracetam therapy owing to an allergic event, and in most cases the event resolved on discontinuation. No allergic reactions have been spontaneously reported during the initial period of commercialization.
To date, taking into consideration the initial 6 months of commercial use, no other rare but serious events have been identified.
POTENTIALLY LIFE-THREATENING ADVERSE EVENTS
The overall mortality rate associated with epilepsy is two to three times that of the general population. No adverse events associated with levetiracetam use have been identified, either during the course of clinical development or subsequent to marketing, that represent an added life-threatening risk.
Nine levetiracetam-treated patients with epilepsy died who had otherwise been in good health. The deaths were not attributed to seizures or to any other medical cause and therefore are consistent with a syndrome known as sudden and unexplained death in epilepsy patients (SUDEP). The overall SUDEP rate, 3.7, is lower than that for placebo-treated patients (6.8), and is similar to that seen in similar drug development programs such as lamotrigine, gabapentin, and tiagabine.
Eleven suicide attempts and one successful suicide were reported during clinical trials with patients with epilepsy receiving levetiracetam. Approximately one-half of these patients reported a previous history of psychiatric problems. This incidence is similar to that seen with other newer antiepileptic drugs.
MANIFESTATIONS AND MANAGEMENT OF OVERDOSE
Oral dosages of levetiracetam up to 5,000 mg/kg/day in the mouse and rat were not lethal and were associated with only
transient clinical signs. In dogs, emesis is a dose-limiting effect. Single-dose escalation to 2,000 mg/kg orally in monkeys resulted in transient behavioral observations indicative of central nervous system depression, nausea, and emesis; all signs disappeared within 24 hours.
There have been no true toxic overdoses with levetiracetam. The highest known dosage of levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, no adverse sequelae were reported. Consistent with its primarily renal excretion, levetiracetam has been shown to be efficiently removed by hemodialysis. Although there is no clinical experience in overdose, this may be a useful option in the management of such cases should clinical symptoms warrant.
Levetiracetam is well tolerated and without significant risks when used as add-on treatment in patients with partial seizures. There are no significant side effects when treatment is initiated at clinically efficacious doses. The overall incidence of adverse events is low, with the most commonly reported events being transient somnolence, asthenia, and dizziness. Nonpsychotic psychiatric events such as nervousness, emotional lability, and hostility also are associated with levetiracetam treatment. These events occur infrequently; however, approximately one-half of the patients experiencing these events required a dose reduction or discontinuation of levetiracetam. More rarely, psychotic events may occur. Allergic reactions are uncommon. Levetiracetam is notable for its lack of effect on clinical laboratory parameters and its lack of drug interactions. No adverse events have been identified that are specific to long-term use. Levetiracetam is not teratogenic, and based on limited clinical experience, no birth defects have been reported.