Levetiracetam

Observational studies

The efficacy and tolerability of levetiracetam 1–4 g/day as add-on treatment for refractory epilepsy have been studied in 29 patients with refractory epilepsy [ ]. The most common adverse events were somnolence and weakness, the frequency and severity of which increased with increasing doses.

The efficacy and tolerability of levetiracetam 1–2 g/day as add-on therapy have been studied in 324 patients with refractory partial seizures [ ]. Levetiracetam did not affect the plasma concentrations of other antiepileptic drugs or alter vital signs or laboratory measurements. The most commonly reported adverse reactions in patients taking levetiracetam were weakness, headache, and somnolence.

In a multicenter, prospective, long-term, open study of levetiracetam (500 mg bd increased to 3000 mg/day according to response) in patients with newly diagnosed juvenile myoclonic epilepsy (n = 10) or resistant/intolerant to previous antiepileptic drugs (n = 38) for 19 (range 0.3–38) months, the mean monthly seizure frequency was significantly reduced [ ]. Five patients dropped out, owing to lack of efficacy and pregnancy. Five patients complained of adverse reactions, somnolence in three cases, and nervousness in two. The authors suggested that levetiracetam may become a reasonable alternative to valproate in juvenile myoclonic epilepsy.

The effects of levetiracetam have been studied in 218 patients with epilepsy, of whom 199 were treated for at least 6 months [ ]. There was a significant reduction in the number of seizures after 6 months. There were adverse reactions in 18% and withdrawal was required in 6.4%. The adverse reactions leading to withdrawal were not identified. The most frequent adverse reactions were somnolence (11%), mood changes (5%), and dizziness (4%). There was aggression in 1%.

The effects of levetiracetam 2–3 g/day as either ‘de novo’ (monotherapy; n = 8) or “add-on” therapy (n = 27) have been studied for 12 months in 35 patients (mean age 25 years, 21 women) with different types of generalized epilepsies (juvenile myoclonic epilepsy, severe myoclonic epilepsy of infancy, Lennox–Gastaut syndrome, myoclonic–astatic epilepsy, myoclonic absences, and benign myoclonic epilepsy in infancy) [ ]. In all, 29 patients achieved at least a 50% reduction in seizure frequency, of whom 15 were free from seizures. Six discontinued levetiracetam because of inefficacy or seizure worsening, none because of adverse reactions, which were not described.

In an observational, multicenter a study of levetiracetam as add-on treatment in 251 patients with partial-onset epilepsy for 16 weeks, the starting dose was 1 g/day and doses were adjusted at 2-weekly intervals in steps of 1 g, to a maximum of 3 g/day, based on seizure control and tolerance [ ]. There was a 62% reduction in frequency of partial-onset seizures; 19% of the patients became seizure free and 57% had a reduction in seizure frequency of at least 50%. Most adverse events were mild to moderate and only 10% of events led to withdrawal from the study. The most frequently reported adverse events were weakness in 25%, somnolence in 18%, dizziness in 16%, headache in 14, and depression in 5%.

Levetiracetam by nasogastric tube has been evaluated in six patients with status epilepticus of various types, four of whom were refractory to at least two antiepileptic drugs, including benzodiazepines; all had complete resolution [ ]. Effective doses of oral levetiracetam were 500–3000 mg/day and seizure control was achieved within 12–96 hours. Adverse events were not specified, but there were said to have been no significant adverse events.

The long-term retention rate, efficacy, and safety of levetiracetam have been evaluated in all patients with epilepsy exposed to the drug during its developmental program (n = 1422) [ ]. The retention rate was 60% after 1 year and 32% after 5 years. Seizures were reduced by over 50% in 39% of the patients, and 13% became seizure free for at least 6 months. The commonest treatment-emergent adverse events requiring withdrawal were convulsions (3.4%), somnolence (2.0%), weakness (0.6%), depression (0.6%), dizziness (0.5%), and headache (0.5%). There were no serious hematological or biochemical abnormalities during exposure to levetiracetam. Eight patients died suddenly and unexpectedly, about one death per 300 patient-years, which is within the expected range in patients with refractory epilepsy.

In 2007 and the first part of 2008 more than 30 observational studies of levetiracetam in different populations of patients with epilepsy or other neurological and psychiatric diseases were published.

In a prospective, 16-week, open study, levetiracetam was given as add-on therapy to 1541 adults with treatment-resistant partial seizures [ ]. More than 80% (1346 subjects) completed the study, and 7.5% reported adverse events as the most important reason for withdrawing. The more common adverse reactions were somnolence (19%), fatigue (14%), dizziness (8%), and headache (10%). There were serious adverse events attributed to levetiracetam in 1%.

In a retrospective study of 301 patients who had taken levetiracetam since its introduction, 138 (46%) stopped taking it during the 24-month follow-up period; adverse events were responsible for 6% of cases of withdrawal [ ]. The most commonly reported adverse reactions at the time of withdrawal were mood disorders, both activating (14%) and deactivating (13%), tiredness (14%), and sleepiness (8.5%). Behavioral adverse events were more common in patients with mental handicap.

In a prospective, open study, levetiracetam was given as add-on therapy to adults with treatment-resistant partial seizures [ ]. The dose was 500 mg bd initially, increasing to 1500 mg bd in a 4 week titration period, and followed by a 12-week maintenance period. Of 100 patients 92 completed the study and four withdrew because of adverse reactions, the most common of which were somnolence (36%), dizziness (12%), and headache (8%).

Of 379 critically ill patients studied retrospectively, 124 (35%) received levetiracetam 500–4000 mg/day, either orally or via a feeding tube [ ]. The adverse reactions profile of levetiracetam was better than with other antiepileptic drugs, particularly phenytoin. For example, encephalopathy occurred in 40 patients (24%) who received phenytoin and in none who received levetiracetam.

In a retrospective multicenter 4-year study of levetiracetam 8–100 mg/kg/day (mean 39 mg/kg) in 200 children with refractory epilepsies the retention rate was 49% at 1 year [ ]. Adverse events were reported in 24% of the children and in no case were they serious. Emotional lability (7.5%), aggression (6%), depression (3%), and somnolence (2.5%), were the most frequently reported. There were pre-existing behavioral problems in 8%, and less than half of these children had relevant behavioral abnormalities during follow-up.

In a prospective, open, add-on, 26-week study in 33 children aged 4–16 years with refractory epilepsies levetiracetam was given in an initial dose of 10 mg/kg/day and increased at 2-week intervals up to a maximum of 60 mg/kg/day [ ]. The retention rate was 70%. Two children stopped taking levetiracetam because of aggressive behavior. All reported at least one behavioral, sleep-related, cognitive, or physical problem in a standardized adverse reactions questionnaire. The most common complaints were hyperactivity (49%), somnolence (36%), irritability (33%), and aggressive behavior (27%).

In a retrospective study in 81 children aged under 4 years with refractory epilepsies levetiracetam was added to previous therapy in an initial dose of 10 mg/day and increased every week up to a maximum of 62 mg/kg/day [ ]. There was at least one adverse event in 34%, most commonly drowsiness (45%), nervousness (36%), cognitive disturbances (29%), loss of appetite (14%), and sleep disturbances (7%). There were no life-threatening adverse reactions.

In 129 children and adolescents with refractory epilepsy in a prospective, open, long-term study the retention rate among responders after 3 years was 23% [ ]. The rate of adverse reactions, which was similar in patients taking monotherapy or polytherapy, was 40% in all patients. The most frequent adverse reactions during the first 6 months were fatigue (13%), gastrointestinal disorders (13%), and aggressiveness (7.8%). During long-term treatment no new adverse reactions were mentioned by the parents or their caregivers.

In a retrospective analysis of 122 children aged under 4 years, followed for at least 6 months, levetiracetam produced seizure remission in 70 [ ]. Adverse reactions occurred in 34% but required withdrawal in only 16%. The most frequent adverse reactions were irritability or other behavioral disturbances (22%), somnolence (5%), difficulty in sleeping (4%), increased seizure frequency (3.3%), and dizziness (2.5%).

In a retrospective study, eight patients with non-convulsive status epilepticus were given levetiracetam, mostly via nasogastric tube, and titrated from a starting dose of 500/1000 mg bd up to a maximum dose of 2000 mg/day within 2 days [ ]. The authors stressed the excellent tolerability of this drug compared with standard antiepileptic drugs in a similar population of 11 subjects treated with conventional intravenous medications.

In a prospective study in 25 patients with advanced Alzheimer’s disease and new-onset epileptic seizures levetiracetam was given in a dosage of 1000–1500 mg/day [ ]. About 70% were seizure-free for at least 1 year. Four stopped taking levetiracetam because of adverse events.

In two small open studies of the use of levetiracetam for psychiatric diseases in elderly people there were excellent tolerability profiles [ , ].

Comparative studies

In a multicenter, double-blind, non-inferiority, parallel-group comparison of levetiracetam and controlled-release carbamazepine as first treatments in newly diagnosed epilepsy, adults with at least two partial or generalized tonic–clonic seizures were randomly assigned to levetiracetam 500 mg bd (n = 288) or carbamazepine 200 mg bd (n = 291) [ ]. The dosages were increased incrementally to maxima of levetiracetam 1500 mg bd and carbamazepine 600 mg bd. Similar percentages of patients were free of seizures at 6 and 12 months and retention at 12 months was similar in the two groups. Similar proportions of patients in the groups had at least one adverse reaction. However, fewer patients taking levetiracetam group (41/288; 14%) stopping taking therapy because of adverse reactions than those assigned to carbamazepine controlled release (56/291; 19%), although this difference was not significant.

Placebo-controlled studies

Adverse reactions to an intravenous infusion of ascending doses of levetiracetam (2, 3, 4 g over 15 minutes; 1.5, 2, 2.5 g over 5 minutes) have been evaluated in 48 healthy subjects in a randomized, placebo-controlled study [ ]. Adverse events that occurred after the administration of 4 g over 15 minutes or 2.5 g over 5 minutes were primarily related to the CNS—dizziness 53%; somnolence 33%; fatigue 11%; headache 8.3%—and were consistent with the established profile for the oral formulation.

The effects of levetiracetam 60 mg/kg/day have been studied in children (4–16 years) with treatment-resistant partial-onset seizures in a 14-week, multicenter, randomized, placebo-controlled trial preceded by an 8-week baseline [ ]. There were one or more adverse events in 88% of those who took levetiracetam and 92% of those who took placebo. The most common treatment-related adverse events, which occurred in at least 10% of patients taking levetiracetam, were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, pharyngitis, and nervousness. A similar number of patients in each group required a dosage reduction or withdrew from the study as a result of an adverse event.

Of 25 patients (aged over 6 years) with resistant focal epilepsies undergoing presurgical evaluation randomized to levetiracetam 500–1000 mg bd for 7 days or placebo, one complained of tiredness on day 1, which resolved on day 3; there were no other adverse reactions [ ].

The efficacy and safety of levetiracetam 500–1000 mg bd in controlling partial-onset seizures refractory to other antiepileptic drugs has been assessed in 94 Taiwanese adults aged 16–60 years with refractory partial seizures in a 14-week placebo-controlled multicenter study followed by a 12-week maintenance phase and then long-term, open levetiracetam therapy or a 4-week phase of medication withdrawal [ ]. Levetiracetam reduced weekly frequency of partial seizures by 24% (95% CI = 10, 35) relative to placebo. Adverse events were reported in 34 of 47 patients taking levetiracetam and 32 of 47 taking placebo. The three most common adverse events in those taking levetiracetam and placebo were somnolence (40% and 15%), dizziness (15% and 9%), and headache (11% and 9%). Four patients withdrew because of adverse events: dizziness, a mouth ulcer, and a rash (levetiracetam) and a rash (placebo).

In a 10-week, placebo-controlled, double-blind trial of levetiracetam (mean dose 862 mg/kg/day) in 20 patients with autism aged 5–17 years there was no significant therapeutic effect, and agitation and aggression were reported with levetiracetam and placebo [ ].

In a pooled analysis of safety data from double-blind, placebo-controlled add-on trials of levetiracetam (1–3 g/day) in adults with refractory partial seizures, adverse events occurring in at least 3% of patients and with at least 3% higher incidence in the active treatment group were tiredness (14% vs. 10%), somnolence (15% vs. 10%), dizziness (9% vs. 4%), and common cold or upper respiratory tract infections (13% vs. 7%) [ ]. The proportions of patients requiring withdrawal of treatment or dosage reduction owing to adverse events were 15% with levetiracetam and 12% with placebo. The efficacy and tolerability of levetiracetam monotherapy in refractory partial seizures have been studied in a double-blind, placebo-controlled study in 286 patients [ ]. Adverse events that were more common with levetiracetam and that occurred in more than 5% of cases included weakness, infection, and somnolence. Of 181 patients who took levetiracetam, 36 completed the study compared with only 10 of 105 who took placebo. The tolerability and efficacy of levetiracetam, 2 or 4 g/day, as add-on therapy have been studied in 119 patients with refractory epilepsy [ ]. Somnolence was the most common reason for withdrawal and occurred more often with levetiracetam than placebo, as did weakness. Somnolence was more common with the higher dose, which was not more effective than the lower dose. Nausea, dizziness, and urinary tract infections were also more common with the higher dose. The efficacy and safety of levetiracetam 1 and 3 g/day as adjunctive therapy for refractory partial seizures have been studied in a double-blind, randomized, placebo-controlled trial in 294 patients with uncontrolled partial seizures [ ]. Treatment-associated adverse events that occurred in at least 10% of patients and had incidences higher than placebo were weakness, dizziness, a flu-like syndrome, headache, infection, rhinitis, and somnolence. These events were mostly mild to moderate.

In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults and children with generalized epilepsies, who had tonic–clonic seizures despite stable doses of one or two antiepileptic drugs, were randomized to levetiracetam (target dose 3000 mg/day for adults; 60 mg/kg/day for children; n = 80) or placebo (n = 84), and a 4-week titration period was followed by a 20-week evaluation period [ ]. Levetiracetam produced a significantly greater reduction in seizure frequency. Adverse events caused withdrawal of therapy in 1.3% of patients compared with 4.8% on placebo, but the proportion of patients who had adverse reactions was similar in the two groups (72% with levetiracetam and 68% with placebo). Psychiatric disorders were the most common drug-related adverse reactions, in about 23% of patients treated with levetiracetam and 14% with placebo. Fatigue (10% levetiracetam vs. 6.0% placebo), somnolence (5.1% vs. 4.8%), headache (5.1%, vs. 3.6%), and irritability (5.1% vs. 1.2%) were reported in more than 5% of patients.

Adolescents and adults with idiopathic generalized epilepsy, who had myoclonic seizures (juvenile myoclonic epilepsy or juvenile absence epilepsy) despite antiepileptic drug monotherapy, were randomized to levetiracetam 3000 mg/day (n = 60) or placebo (n = 60) in a multicenter, double-blind, placebo-controlled trial [ ]. Two patients taking levetiracetam and one patient taking placebo withdrew because of adverse events and similar numbers of patients in each groups had at least one adverse event. Somnolence was reported in those taking levetiracetam during up-titration.

In 22 children with tics, levetiracetam (maximum dose 30 mg/kg/day) or placebo were given for 4 weeks in a crossover, double-blind, randomized, placebo-controlled trial with a 2-week washout period between treatments [ ]. Adverse reactions observed during treatment with levetiracetam included irritability, hyperkinesia (only during the escalation phase), insomnia, sadness, tiredness, verbal aggression, reduced school participation, anxiousness, and headache.

Cardiovascular

In a randomized, placebo- and active-controlled, four-way crossover study in 52 healthy adult subjects there were no clinically important changes in the QT _c interval after a single dose of levetiracetam 1000 or 5000 mg [ ].

Respiratory

Interstitial pneumonitis has been attributed to a low dose of levetiracetam in a 9-year-old girl who had a history of epilepsy, cerebral palsy, mental retardation, asthma, and repeated hospitalizations for presumed aspiration pneumonia [ ].

Nervous system

In a study of levetiracetam up to 50 mg/kg/day for cerebellar tremor in multiple sclerosis, three of 14 patients dropped out because of somnolence, fatigue, and agitation in one patient each [ ].

In a study of levetiracetam up to 2 g/day for cervical dystonia, four of 10 patients dropped out because of vomiting, drowsiness, myalgia, and lack of efficacy [ ].

In nine patients with Parkinson’s disease complicated by levodopa-induced dyskinesia, levetiracetam was not well tolerated. It worsened the Parkinsonian symptoms, caused intolerable somnolence, and worsened dyskinesia in most patients [ ].

In 16 patients with chronic psychosis complicated by tardive dyskinesia, levetiracetam 60 mg/kg/day was well tolerated, except in one patient with excessive drowsiness [ ].

In nine patients with Huntingdon’s disease, levetiracetam up to 3 g/day improved the chorea, but two developed Parkinsonism, one on day 41 at a dose of 500 mg/day, the other after 4 months and a dose of 3 g/day [ ]. Symptoms included tremor at rest, increased rigidity, bradykinesia, and imbalance, stooped axial posture, and hypophonia. In both cases the symptoms of Parkinsonism resolved after withdrawal of levetiracetam. Concurrent medications were olanzapine, donepezil, paroxetine, trazodone, furosemide, oxybutynin, and gabapentin in one patient and alprazolam, risperidone, and celecoxib in the other. The same authors reported one case of chorea treated with levetiracetam without adverse reactions [ ].

In a pilot study of 15 patients undergoing alcohol withdrawal treatment, eight were treated with polytherapy including diazepam and levetiracetam, the latter in a maximum dose of 2 g/day. Mild sedation was reported in three patients and one had mild pruritus [ ].

In a small open trial in 16 patients with frequent attacks of migraine with aura levetiracetam 1 g/day for 6 months significantly reduced the number of attacks, and in seven patients, the attacks were completely abolished after 3 months [ ]. Levetiracetam was generally well tolerated; six patients complained of slight dizziness, nervousness, and somnolence.

A 28-year-old man with idiopathic epilepsy and generalized seizures developed an encephalopathy characterized by a slowing of electroencephalographic background activity, increased seizure frequency, and worsening of neuropsychological findings after starting treatment with levetiracetam 3000 mg/day, which had been added to valproate 2000 mg/day [ ]. The reactions resolved after levetiracetam withdrawal.

A 5-year-old girl, with a drug-resistant symptomatic focal epilepsy developed status gelasticus after levetiracetam was added to oxcarbazepine and diazepam [ ].