Levetiracetam adverse effects

Levetiracetam Unknown Loading dose Not recommended due to excessive adverse effects Maintenance dose 1 000-3000 mg/day. Start at 1 000 mg/day and titrate upward as indicated by response Half-life Not established 6-8 hours Apparent volume of distribution 0.5-0.7 L/kg Protein binding less than 10% Primary elimination route 70% renal 30% hepatic Somnolence, dizziness Depression... 

Levetiracetam acts in a manner different to other antiepilepsy drugs. It has a potentially broad spectrum of use but is currently indicated for adjunctive treatment in partial seizures with or without secondary generalisation. It is rapidly and completely absorbed after oral administration, and is effective with twice-daily dosing. Its therapeutic index appears to be high and the commonest of the adverse effects are asthenia, dizziness and drowsiness. 

The clinical pharmacology and adverse effects of some new antiepileptic drugs (ganaxolone, levetiracetam, losi-gamone, pregabalin, remacemide, rufinamide, stiripentol, and zonisamide) have been reviewed (1). 

Levetiracetam is a piracetam derivative used in the treatment of refractory partial seizures. In trials it has shown an excellent tolerability profile. The main dose-related adverse effects are sedation, fatigue, and headache. Other possible adverse effects include dizziness, unsteadiness, diplopia, nausea, infection, memory impairment, and disturbances of mood and behavior, although in controlled trials the incidence of most of these was no greater than with placebo (1). 

The efficacy and tolerability of levetiracetam 1-2 g/day as add-on therapy have been studied in 324 patients with refractory partial seizures (9). Levetiracetam did not affect the plasma concentrations of other antiepileptic drugs or alter vital signs or laboratory measurements. The most commonly reported adverse effects in patients taking levetiracetam were weakness, headache, and somnolence. 

THERAPEUTIC USE TOXICITY The addition of levetiracetam to other antiseizure medications in adults with refractory partial seizures improved control in one clinical trial. Insufficient evidence is available on use of levetiracetam as monotherapy for partial or generalized epilepsy. The drug is well tolerated adverse effects include somnolence, asthenia, and dizziness. 

The short-term effects of intravenous levetiracetam as the treatment of choice for status epilepticus have been evaluated in nine elderly patients (five women median age 78 years) [197 ]. In all but one, intravenous levetiracetam was effective and there were no adverse reactions or changes in electrocardiography or laboratory parameters. 

In a prospective multicenter, open, addon study, 33 children aged 4-16 years with refractory epilepsy were given levetira-cetam in addition to their previous treatment regimen [180. The retention rate was 70% after 26 weeks, with a median levetiracetam dosage of 22 mg/kg/day. Most reported adverse effects were hyperactivity (49%), somnolence (36%), irritability (33%), and aggressive behavior (27%). 

Comparative studies Levetiracetam versus phenytoin Levetiracetam monotherapy has been compared with phenytoin for postoperative control of glioma-related seizures in a randomized pilot study [181 ]. Over 13 months, 29 patients were randomized in a 2 1 ratio to start levetiracetam within 24 hours of surgery or to continue phenytoin therapy. Similar percentages of patients were seizure-free after 6 months of treatment. Reported adverse effects at 6 months were dizziness (0% levetiracetam, 14% phenytoin), difficulty with coordination (0% versus 29%), depression (7% versus 14%), lack of energy or strength (20% versus 43%), insomnia (40% versus 43%), and mood instability (7% versus 0%). No adverse effect resulted in hospitalization or withdrawal from the study. 

Levetiracetam and phenytoin have been retrospectively compared in the prophylaxis of early and late postoperative seizures in 315 patients [182 ]. Levetiracetam (n = 105) was at least as effective as phenytoin ( = 210) and significantly better tolerated. Adverse effects that prompted a change in antiepileptic drug therapy occurred in one patient taking levetiracetam, who had visual hallucinations, compared with 38 patients taking phenytoin (18%). In patients who were followed for at least 1 year and developed epilepsy, levetiracetam also had a higher retention rate. 

Hematologic Thrombocytopenia has been reported in a child [194 ] and an adult with epilepsy [195during treatment with levetiracetam, in one case requiring blood transfusion. The adverse effect occurred within days or weeks and quickly resolved after withdrawal. 

Once-daily adjunctive extended-release levetiracetam 1000 mg/day (n = 70) and adjunctive immediate-release levetiracetam 500 mg bd (n = 204) have been compared in a meta-analysis of three randomized, pla-cebo-controUed, phase III trials in 555 patients aged over 16 years with partial-onset seizures [205 ]. After adjustment for placebo-associated adverse events, immediate-release levetiracetam was associated with statistically more treatment-emergent adverse effects than extended-release levetiracetam across nervous system disorders (risk difference = 18%), psychiatric disorders (risk difference = 11%), and... 

In a retrospective analysis of 118 intravenous infusions of levetiracetam in 15 children with epilepsy, most of whom were aged under 4 years, the following adverse effects were noted during the post-infusion period lethargy n = 2), agitation (1), irritability (1), mild tremors (1), and ataxia (1) no adverse effects required drug withdrawal [207. Three patients had reductions in white blood cell counts within the first 4 days after administration of the first dose of levetiracetam. 

In 12 adults with status epilepticus, intravenous levetiracetam 2500 mg was added as soon as possible to a standardized regimen of intravenous clonazepam and/or rectal diazepam as needed followed by phenytoin or valproic acid no serious adverse effects could be related directly to the administration of levetiracetam [208 ]. 

The possible benefit of pyridoxine (vitamin Bg) in the treatment of levetiracetam-induced behavioral adverse effects has been explored in a questionnaire study in 90 children with epilepsy, 22 of whom started taking pyridoxine after having been taking levetiracetam [213 ]. There was behavioral improvement in nine, no effect in eight, deterioration in four, and an uncertain effect in one. 

Mohamed BP, Prabhakar P. Thrombocytopenia as an adverse effect of levetiracetam therapy in a child. Neuropediatrics 2009 40(5) 243. ... 

Levetiracetam versus CBZ Levetiracetam and CBZ were compared in 106 patients with poststroke seizures. There was no significant difference in seizure control. There were significantly fewer adverse effects with levetiracetam versus CBZ attention deficit, frontal executive functions, and functional scales were significantly worse in the CBZ group [29 ]. A separate randomized unblinded study compared levetiracetam and CBZ as monotherapy for seizures in 992 patients. More adverse effects were reported in the CBZ group, which resulted in more patients discontinuing the study (19% vs 10%) [30 ]. 

Observational studies A phase 111 study evaluated the safety and efficacy of levetiracetam in 217 children and adults with primary generalized seizures. The most common adverse effects reported by >10% participants were headache and nasopharyngitis. The most frequent treatment-associated adverse effects were headache (4.6%), dizziness and depression (both 4.1%). Serious adverse effects related to treatment with levetiracetam 4.6% of patients experienced convulsion, atrial fibrillation, epilepsy, depression, psychosis, schizophrenia, suicidal ideation, erythematous rash, and status epilepticus. One patient each discontinued due to the following adverse effects arrhythmia, convulsions, tremor, aggression, depression, psychosis, and exanthem. One patient with worsening of comorbid schizophrenia committed suicide it had been 43 days since he had last taken levetiracetam at the time [87 -]. 

Drug formulations The safety and efficacy of extended-release levetiracetam was evaluated in a randomized double-blind study at a dose of either 1000 mg/day or 2000 mg/day the most common adverse events were somnolence (21.9%), headache (19.7%), and convulsion (14.9%) [108 ]. Similar adverse effects have been reported with immediate release formulation of levetiracetam. 

In a pooled analysis of safety data from double-bUnd, placebo-controUed 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 versus 10%), somnolence (15 versus 10%), dizziness (9 versus 4%), and common cold or upper respiratory tract infections (13 versus 7%) (11). 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, pla-cebo-controUed study in 286 patients (12). 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 (13). 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 safety of levetiracetam has been assessed in 24 children with uncontrolled partial-onset seizures in an open study (16). The most commonly reported adverse events were headache (33%), infection (33%), anorexia (25%), and somnolence (25%). The adverse events profile of levetiracetam was similar to that seen in adults. Owing to a dispensing error, one patient received an accidental overdose of 71 mg/kg/day, rather than 40 mg/kg/day, during the last 4 weeks of the evaluable phase of the study. No iU effects were reported or observed on examination or laboratory testing, and the patient completed the trial. 

Nervous system The effects of lamotrigine (n=29), levetiracetam (n = 38), and pheno-barbital (n=28) have been evaluated in patients with seizures and Alzheimer s disease in a prospective, randomized, three-arm parallel-group, case-control study with a 4-week dosage adjustment and a 12-month evaluation period [180. The adverse reactions were somnolence (30%) and weakness (13%). Patients treated with lamotrigine showed a slight decline in Mini Mental Test scores and other cognitive scores and scored better on measures of mood. 

Placebo-controlled studies The effects of levetiracetam in alcohol withdrawal syndrome, administered in a fixed dose regimen over 6 days, have been investigated in a prospective, randomized, double-blind, multicenter, placebo-controlled trial in 106 patients [198 ]. There were no significant differences in adverse events and severe adverse events or dropouts between placebo and levetiracetam. 

Placebo-controlled studies The effect of levetiracetam as adjunctive therapy in Chinese patients with refractory partial seizures has been evaluated in a 4-week titration and 12-week maintenance period, randomized, placebo-controlled trial in 56 patients [183. There were adverse events in 23 patients taking levetiracetam and 22 taking placebo. These were generally moderate and no patient withdrew. Levetiracetam was associated with somnolence, dizziness, and agitation in more than 10% of patients. There were no treatment-emergent serious adverse events. 

Psychological In a prospective, open, non-interventional study, objective and subjective cognitive measures were evaluated in 401 patients with epilepsy before and 3 and 6 months after introducing levetiracetam [188 ]. Very good tolerance was reported by 68% and cognitive improvement by 58%. Objective improvement was significant in one-quarter of the patients, while 5-6% deteriorated. Adverse events were reported in 28 patients. Psychotropic effects were reported by 1.5%, tiredness by 0.7%, vegetative symptoms by 1.7%, and increased seizure frequency by 0.7% of patients. 

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