Somnolence levetiracetam

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... 

Somnolence - In controlled trials of patients with epilepsy, 14.8% of levetiracetam-treated patients reported somnolence compared with 8.4% of placebo patients. 

The most frequently reported adverse events associated with the use of levetiracetam in combination with other AEDs were asthenia, dizziness, infection, and somnolence. 

Adverse reactions most commonly associated with discontinuation or dose reduction of levetiracetam in patients with epilepsy include convulsion and somnolence. 

Side effects. Detailed safety studies show that levetiracetam is well tolerated, the most frequent side effects reported being somnolence, asthenia and dizziness. To date, levetiracetam would appear to be a highly effective new antiepileptic drug with an excellent safety and tolerability profile. Few drug interactions have been reported so far. The efficacy and safety of the drug have been established as add-on therapy for refractory partial onset seizures with or without secondary generalization and there is now evidence of its efficacy in monotherapy. 

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 (8). 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 (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. 

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. 

Levetiracetam. Levetiracetam is a new anticonvulsant agent that does not as yet present any drug interactions. Dizziness and somnolence occurred to a statistically significant extent (14.8% versus 8.4% of the placebo patients) (18). This side effect occurred more frequently with patients receiving levetiracetam in combination with other anticonvulsant agents. 

Toxicity effects known to be associated with levetiracetam use include decreased RBC count and hematocrit, decreased neutrophil count, somnolence, asthenia, and dizziness. These toxicities may be associated with blood concentrations in the therapeutic range. Co-administration of cimetidine wiU interfere with the test, producing artifactually increased measurements of levetiracetam. The laboratory can identify the presence of cimetidine, and laboratory reports wiU reflect cimetidine interference if it is detected. 

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 risk of clinically relevant drug interactions is minimal with S-(-)-levetiracetam, because it does not alter the pharmacokinetics of coadministered drugs by inhibition or induction of hepatic enzymes (84). Toxic effects include mild to moderate somnolence, asthenia, ataxia, and dizziness these effects seldom require discontinuance. An increase in the incidence of behavioral abnormalities in children and in adults having a previous history of neuropsychiatric problems has been noted (85). Its use in the elderly or in patients with renal Impairment will require an individualization of dose, and an additional dose is needed after renal dialysis. Levetiracetam was associated with developmental toxicity in the offspring of pregnant animals. 

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. 

In a retrospective evaluation of 130 children with intractable epilepsy who had at least four seizures per month and had been treated with levetiracetam, nine reported mild-to-moderate adverse events, but only five dropped out the reason for discontinuation was excessive irritability in three patients and increased aggressiveness in the other two [201 ]. The most common complaints were irritabUity in 6/130 patients, additional aggressive behavior in two, and somnolence in one. 

Of 176 consecutive hospitalized patients with a first diagnosis of glioma, 82 had seizures and were given levetiracetam 1500-3000 mg/day [202. Transient somnolence was the only mild adverse reaction, and it occurred in four patients. There were no laboratory abnormalities in patients with concomitant chemotherapy. 

In 152 children in an open, long-term study of levetiracetam as adjunctive therapy for partial-onset seizures the mean maintenance dose was 56 mg/kg/day and the median treatment duration was 287 days [204 ]. At least one adverse event was reported in 143 patients (94%) the most common were convulsions (25/152 16%), irritability (19/152 13%), and somnolence (16/152 11%). 

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%). 

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. 

Levetiracetam has been evaluated as add-on therapy in Chinese patients with refractory partial-onset seizures in a multicenter, 4 week titration and 12-week maintenance, double-blind, placebo-controlled trial, in which 206 patients aged 16-70 years were randomized to levetiracetam ( = 103) or placebo ( = 103) [184 ]. Levetiracetam significantly reduced the weekly partial-onset seizure frequency over placebo by 27%. Adverse events, which were of mild-to-moderate intensity, were reported by 65 patients taking levetiracetam and 62 taking placebo. The most common were somnolence (18% levetiracetam and placebo), reduced platelet counts (9.7% versus 9.7%), dizziness (7.8% versus 14%), and headache (3.9% versus 8.7%). 

Drug formulations Extended-release levetiracetam Once-daily extended-release levetiracetam as add-on therapy in relractory partial-onset seizures has been evaluated in a 12 week, double-blind, randomized, placebo-controlled trial in 158 patients [204. There were adverse events in 41 (53%) of those who used extended-release leve-tira-cetam and in 43 (54%) of those who used placebo the most common were somnolence, influenza, irritability, nasopharyngitis, dizziness, and nausea. 

In a retrospective study in 43 patients with various forms of status epilepticus after ineffective treatment with benzodiazepines, intravenous levetiracetam was given as a short infusion of 1000 or 2000 mg [211 ]. Status epilepticus was terminated in 19. There were no severe adverse reactions. Among patients aged over 80, somnolence was reported, which could have been due to benzodiazepines, and/or post-seizure twilight state. There were no metabolic disturbances or interactions. 

An observational study following 66 adults and children treated with levetiracetam after traumatic brain injury found that the most common adverse events were fatigue, headache, and somnolence [90 ]. Mood scores and number of infections did not differ between the treatment and observation groups. Two of the 66 patients stopped treatment due to somnolence. 

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. 

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