Levetiracetam dosing

Levetiracetam Dosing Adjustment Regimen for Patients with Impaired Renal Function ... 

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... 

Pharmacokinetics Absorption is rapid, with peak plasma concentrations occurring in approximately 1 hour following oral administration in fasted subjects. Steady state is achieved after 2 days of multiple twice/day dosing. Levetiracetam is not extensively metabolized. The plasma half-life in adults is approximately 7 hours. Levetiracetam is eliminated from the systemic circulation by renal excretion. 

Renal function impairment Take caution in dosing patients with moderate and severe renal impairment and patients undergoing hemodialysis. Reduce dosage in patients with impaired renal function receiving levetiracetam, and give supplemental doses to patients after dialysis (see Actions and Administration and Dosage). 

Elderly No overall differences in safety were observed between subjects 65 years of age or older and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the efficacy of levetiracetam in these patients. Because elderly patients are more likely to have decreased renal function, take care in dose selection it may be useful to monitor renal function. 

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

Specific myoclonic syndromes are usually treated with valproate an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine valproate is the drug of choice followed by lamotrigine and topiramate. 

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. 

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 1-4 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. 

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... 

Four patients with refractory epilepsy taking carbamaze-pine were given added levetiracetam and developed central nervons system effects (ataxia, diplopia, nystagmns) suggestive of carbamazepine toxicity (18). Rednction in the dose of carbamazepine resolved the symptoms in three cases. Carbamazepine and carbamazepine-epoxide blood concentrations were not altered dnring levetiracetam co-medication. Thns, a pharmacodjmamic interaction between carbamazepine and levetiracetam is likely. 

Betts T, Waegemans T, Crawford P. A multicentre, double-bUnd, randomized, parallel group study to evaluate the tolerabiUty and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000 9(2) 80-7. 

Levetiracetam (Keppra) is approved for adjunctive therapy and treatment of partial onset seizures in adults with epilepsy. Levetiracetam is 100% bioavaflable. Once absorbed, it is <10% bound to protein and has a volume of distribution of 1.0 L/kg. Following an oral dose, it reaches maximum... 

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. 

In a randomised, double-blind, placebo-controlled study in 42 healthy subjects stabilised on warfarin, levetiracetam 1 g twice daily for 7 days had no significant effect on the pharmaeokineties of R- or 5-warfarin and the INRs were not signifieantly altered. No warfarin dose adjustments would therefore be expeeted to be needed on eoneurrent use. 

Information about the concurrent use of oxcarbazepine and other antiepi-lepties is limited, but growing. The overall picture seems to be that, oxcarbazepine is a less potent enzyme inducer than carbamazepine, and therefore it does not markedly affect the serum levels of other antiepilep-ties. If oxearbazepine is substituted for carbamazepine, be aware that drug levels of some other antiepileptics may rise. High oxcarbazepine doses may inerease phenytoin levels, and the manufacturer notes that a decrease in the phenytoin dose may be required. The clinical relevance of the modest reductions in lamotrigine levels is uncertain. For mention of modestly reduced levetiracetam levels, see Levetiracetam + Other antiepileptics , p.543. 

Hepatotoxicity was reported in a 43-year-old man who had been recently diagnosed with a malignant brain tumor (glioblastoma). The man had consumed 20 ml daily of noni juice for 2 weeks and was also taking levetiracetam twice daily (Stadlbauer et al. 2008). Hepatotoxicity was reported in a 33-year-old woman who had consumed several doses of noni (amount unspecified) over a period of several weeks (Lopez-Cepero Andrada et al. 2007). 

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. 

In a retrospective chart review of children taking higher than usual doses of levetiracetam for 1.5 years, 32 (age range 1-9 years) took a median dosage of levetiracetam of 146 mg/kg/day (range 70-275 mg/kg/day) [203 ] the median maximum serum trough concentration was 43 mg/1 (range 20-121 mg/1). All but one took one or more... 

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 six neonates (body weight over 2000 g, gestational age over 30 weeks) in a prospective pilot study on the use of oral levetiracetam as monotherapy in the treatment of neonatal seizures the dose was increased by 10 mg/kg day over 3 days [206 ]. There were no clear adverse events during the study. There was mild sedation during titration in one neonate taking concomitant phenobarbital. 

Skin A 46-year-old woman with a malignant brain tumor developed a reticular eruption after the initial postoperative dose of 1000 mg/day was increased to 2000 mg/day [216 ]. The adverse reaction recurred on rechallenge when the dose of levetiracetam was slowly titrated to 1500 mg/day. 

Hulhoven R, Rosillon D, Bridson WE, Meeus MA, Salas E, Stockis A. Effect of levetiracetam on cardiac repolarization in healthy subjects a single-dose, randomized, placebo- and active-controlled, fourway crossover study. Clin Ther 2008 30 (2) 260-70. 

Obeid M, Pong AW. Efficacy and tolerability of high oral doses of levetiracetam in children with epilepsy. Epilepsy Res 2010 91(1) 101-5. 

Beswick TC, Cohen JB. Dose-related levetiracetam-induced reticulated drug eruption. J Drugs Dermatol 2010 9(4) 409-10. 

Intravenous levetiracetam The safety of rapid intravenous loading doses (20, 40, and 60 mg/kg corresponding to maximum doses of 1000, 2000, and 3000 mg) of levetiracetam has been prospectively evaluated in healthy subjects and patients with epilepsy [206 ]. There were no significant effects on blood pressure or electrocardiography and no local infusion site reactions. 

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 a retrospective analysis of 36 patients who received intravenous levetiracetam for refractory status epilepticus [209 ] a median dose of 3000 mg/day (range 1000-9000) was used as a loading bolus or by continuous pump infusion. Status epilepticus was terminated in 69% of patients. None had cardiac dysrhythmias or significantly reduced blood pressure, or required an increase in the dose of catecholamines. Two patients had nausea and vomiting during levetiracetam loading, leading to aspiration pneumonia in one. 

In a retrospective chart study of 34 patients with status epilepticus who were given intravenous levetiracetam, the median loading dose of levetiracetam was 1000 mg and the maintenance dosage was 500-1500 mg/12 hours (median 1000 mg/12 hours) [212 ]. Status epilepticus stopped in a clear temporal relation to drug infusion in 71% of patients and there were no serious adverse events. 

Her dose of phenobarbital was increased to 90 mg/day and she again became seizure-free. Lamotrigine had to be withdrawn because of a rash. Levetiracetam was started and at a dose of 500 mg bd the dose of phenobarbital was tapered again at a slower rate. However, she had complex partial seizures again when she was taking phenobarbital 30 mg/day and levetiracetam 750 mg bd. The dose of levetiracetam was increased to 1000 mg bd, but complex partial seizures continued while the dose of phenobarbital was being tapered and for 3 weeks after withdrawal. No further seizures occurred during the next 24 months. 

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