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Levetiracetam

Open ArchivePublished:July 20, 2018DOI:https://doi.org/10.1016/j.jpainsymman.2018.07.012
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/key

      Off-label use
      b.i.d.
      bis in die, twice per day
      CSCI
      Continuous subcutaneous infusion
      CSF
      Cerebrospinal fluid
      Min
      minute(s)
      PI
      Package insert (USA)
      PO
      Per os, by mouth
      PR
      Per rectum
      IV
      Intravenous
      RCT
      Randomized controlled trial
      SC
      Subcutaneous
      SPC
      Summary of Product Characteristics (UK)
      Class: Anti-epileptic (SV2A ligand).
      Indications: Adjunctive therapy of focal or generalized myoclonic and tonic-clonic seizures; †monotherapy of focal seizures (Authorized in UK); †status epilepticus.

      Pharmacology

      Levetiracetam binds to synaptic vesicle protein SV2A, interfering with the release of the neurotransmitter stored within the vesicle. It gains access after neurotransmitter release as the vesicles are recycled. Thus, it selectively accumulates in, and inhibits, rapidly firing neurons.
      • Klitgaard H.
      • et al.
      Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment.
      Levetiracetam also inhibits potassium and N-type calcium channels.
      • Klitgaard H.
      • et al.
      Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment.
      • Madeja M.
      • et al.
      Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?.
      Levetiracetam is a commonly used first-line choice for seizures in palliative care. Such seizures are generally caused by focal brain lesions and are, thus, focal onset, even if this is obscured by rapid secondary generalization. Efficacy and tolerability compare favorably to other anti-epileptic drugs used in focal seizures, both non-cancer and cancer-related.
      • Nevitt S.J.
      • et al.
      Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
      • Zaccara G.
      • et al.
      Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies?.
      • Lim D.A.
      • et al.
      Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study.
      • Rossetti A.O.
      • et al.
      Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study.
      • Werhahn K.J.
      • et al.
      A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy.
      • Glauser T.
      • et al.
      Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.
      • Vossel K.A.
      • et al.
      Epileptic activity in Alzheimer's disease: causes and clinical relevance.
      It has few drug interactions, can be given IV or SC, and can be used when other anti-epileptics are contra-indicated because of hepatic or cardiac co-morbidities.
      • Karceski S.
      • et al.
      Treatment of epilepsy in adults: expert opinion.
      PR use is also reported; suppositories compounded from levetiracetam tablets produced therapeutic plasma levels.
      • Remi C.
      Personal communication.
      Anti-epileptics should not be used prophylactically in the absence of a history of seizures; in RCTs, they do not reduce the risk.
      • Guerrini R.
      • et al.
      The medical and surgical treatment of tumoral seizures: current and future perspectives.
      Peri-neurosurgical use is a possible exception, but results are conflicting.
      • Weston J.
      • et al.
      Antiepileptic drugs as prophylaxis for post-craniotomy seizures.
      • Dewan M.C.
      • et al.
      The influence of perioperative seizure prophylaxis on seizure rate and hospital quality metrics following glioma resection.
      If used for this indication, prophylactic levetiracetam appears more effective than phenytoin (incidence of seizures 0% vs. 16%).
      • Fuller K.L.
      • et al.
      Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study.
      Although unauthorized, levetiracetam is also used for status epilepticus refractory to benzodiazepines, generally in a dose of 20–30mg/kg given as a single IV bolus. Efficacy appears comparable to fosphenytoin, phenytoin and valproate.
      • Glauser T.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      • Nakamura K.
      • et al.
      Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus.
      • Gujjar A.R.
      • et al.
      Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study.
      • Brigo F.
      • et al.
      Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.
      Trials may have been underpowered to detect clinically significant differences.
      • Brigo F.
      • et al.
      Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.
      Levetiracetam is not effective for neuropathic pain
      • Wiffen P.J.
      • et al.
      Levetiracetam for neuropathic pain in adults.
      or social anxiety disorder.
      • Stein M.B.
      • et al.
      Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial.
      Benefit for bipolar disorder and hot flushes is reported,
      • Zaccara G.
      • et al.
      Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies?.
      • Dunteman E.D.
      Levetiracetam as an adjunctive analgesic in neoplastic plexopathies: case series and commentary.
      • Thompson S.
      • et al.
      Levetiracetam for the treatment of hot flashes: a phase II study.
      but has not been confirmed in an RCT.
      Food affects the rate but not the extent of its PO absorption. It does not bind to plasma proteins. It readily crosses the blood-brain barrier and its CSF halflife is 3 times longer than that for plasma.
      • Patsalos P.N.
      Clinical pharmacokinetics of levetiracetam.
      A third is metabolized predominantly by non-hepatic hydrolysis; the remainder is excreted by the kidneys unchanged.
      Bio-availability ≥95% PO.
      Onset of action <3 days PO.
      Time to peak plasma concentration 1–2h PO.
      Plasma halflife 6–8h.
      Duration of action 24h.

      Cautions

      Renal or severe hepatic impairment (dose adjustment required, see below).

      Drug interactions

      Clinically significant interactions are unlikely, however caution is advised with concurrent administration of carbamazepine, methotrexate or phenytoin because of isolated reports of toxicity in some patients.

      Baxter K and Preston CL. Stockley's Drug Interactions. London: Pharmaceutical Press www.medicinescomplete.com (accessed December 2017).

      Undesirable effects

      Very common (>10%): fatigue, drowsiness, headache.
      Common (<10%, >1%): ataxia, hyperkinesis, tremor, dizziness, diplopia, blurred vision, amnesia, abnormal thinking, attention disturbance, behavioural disturbances (emotional lability, irritability, agitation, hostility/aggression, personality disorders), depression, insomnia, anorexia, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, myalgia, rash, pruritus, thrombocytopenia.
      Behavioural disturbances occur in 3–4% of patients with epilepsy but only 0.5% of those being treated for other conditions. Risk factors include a history of aggression or psychiatric disturbance.
      • Dinkelacker V.
      • et al.
      Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases.
      • Cramer J.A.
      • et al.
      A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials.
      Uncommon (<1%, >0.1%): suicidal ideation (0.2%).
      Rare (<0.1%): psychosis, pancreatitis, hepatic failure, acute kidney injury, bone marrow suppression, hyponatremia, extra-pyramidal symptoms, rhabdomyolysis, severe skin reactions.

      Dose and use

      Anti-epileptics have been associated with suicidal ideation: advise patients to report mood or thought disturbance.

      Focal seizures

      • start with 250–500mg PO/IV b.i.d.
      • if starting with 250mg b.i.d., increase automatically after 2 weeks to 500mg b.i.d. (the minimum effective dose in most people)
      • if necessary, increase by 250–500mg b.i.d. every 2 weeks
      • maximum dose 1.5g b.i.d.
      For IV use, dilute the dose in ≥100mL sodium chloride 0.9% or dextrose 5% and infuse over 15min.
      Note. Once daily modified-release PO tablets are available in the USA (see Supply). An oral solution or oral granules (not USA) are available for administration by enteral feeding tubes in some countries; see the PI or SPC for full details.

      Status epilepticus refractory to benzodiazepines

      Some centres use higher starting doses for status epilepticus refractory to benzodiazepines, e.g.:
      • Glauser T.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      • Nakamura K.
      • et al.
      Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus.
      • Gujjar A.R.
      • et al.
      Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study.
      • Brigo F.
      • et al.
      Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.
      • loading dose of 1–2g IV (or 20–30mg/kg up to a maximum of 3g) diluted in 100mL sodium chloride 0.9% or dextrose 5% and infused over 15–30min
      • after 4–8h, start a maintenance dose of 1g PO/IV b.i.d.

      Subcutaneous administration

      Levetiracetam can be given †SC b.i.d., diluted in 100mL sodium chloride 0.9% and infused over 30min.
      • Lopez-Saca J.M.
      • et al.
      Repeated use of subcutaneous levetiracetam in a palliative care patient.
      The dose is the same PO/SC/IV.
      Levetiracetam can also be given by †CSCI diluted with either water for injection or sodium chloride 0.9% when necessary.
      • Sutherland A.E.
      • et al.
      Subcutaneous levetiracetam for the management of seizures at the end of life.
      • Remi C.
      • et al.
      Continuous subcutaneous use of levetiracetam: a retrospective review of tolerability and clinical effects.
      • Ryan S.
      • et al.
      The use of additional antiepileptic drugs with subcutaneous levetiracetam for the management of seizures at the end of life: a case series.
      • Wells G.H.
      • et al.
      Continuous subcutaneous levetiracetam in the management of seizures at the end of life: a case report.
      By CSCI, although there are no formal laboratory compatibility data, levetiracetam is reported to be visually compatible in clinical use with diamorphine (not USA), haloperidol, scopolamine butylbromide (not USA), levomepromazine (methotrimeprazine; not USA), metamizole (dipyrone; not UK or USA), methadone, metoclopramide, midazolam, morphine sulfate, oxycodone or ranitidine. Generally, sodium chloride 0.9% is used as diluent and local skin reactions occur in about 5% of patients.
      • Remi C.
      • et al.
      Continuous subcutaneous use of levetiracetam: a retrospective review of tolerability and clinical effects.
      • Murray-Brown F.L.
      • Stewart A.
      Remember Keppra: seizure control with subcutaneous levetiracetam infusion.
      Munich University Hospital
      Syringe driver compatability database.
      Palliativedrugs.com Ltd. Syringe Driver Survey Database.
      Alternative SC/CSCI anti-epileptics include lacosamide, midazolam, phenobarbital and valproate.
      • Remi C.
      • et al.
      Subcutaneous use of lacosamide.
      • O'Connor N.
      • et al.
      Sodium Valproate as a continuous subcutaneous infusion: a case series.

      Renal impairment

      Because levetiracetam is largely excreted unchanged by the kidneys, the dose should be reduced in patients with renal impairment (Table 1).
      Table 1Dose adjustment for levetiracetam in renal impairment
      for patients weighing <50kg, the UK SPC recommends dosing on a mg/kg basis
      Creatinine clearance (mL/min/1.73m2)
      based on the Cockroft-Gault formula adjusted for body surface area
      Usual maintenance dose
      for immediate-release PO/IV products; modified-release products permit the total daily dose to be given once daily.
      (mg)
      >80500–1,500 b.i.d.
      50–80500–1,000 b.i.d.
      30–49250–750 b.i.d.
      <30250–500 b.i.d.
      a for patients weighing <50kg, the UK SPC recommends dosing on a mg/kg basis
      b based on the Cockroft-Gault formula adjusted for body surface area
      c for immediate-release PO/IV products; modified-release products permit the total daily dose to be given once daily.
      If on peritoneal dialysis or hemodialysis:
      • give 750mg PO/IV on the first day of treatment and 500–1,000mg once daily thereafter
      • consider giving a 250–500mg supplementary dose immediately after each hemodialysis session or timing the daily dose after the dialysis session.

      Hepatic impairment

      Because metabolism is non-hepatic and the drug is not protein-bound, there is no need to reduce the dose in hepatic impairment, unless there is associated renal impairment (see Table 1).

      Stopping levetiracetam

      Reduce by a maximum of 500mg b.i.d. every 2–4 weeks to avoid rebound seizures.

      Supply

      Levetiracetam (non-proprietary)
      Tablets 250mg, 500mg, 750mg, 1g, 28 days @ 750mg b.i.d. = $28.
      Oral solution (sugar-free) 100mg/mL, 28 days @ 750mg b.i.d. = $30.
      Injection (concentrate for dilution and use as an intravenous infusion) 100mg/mL, 5mL vial = $6.
      Modified-release once daily products
      Tablets m/r 500mg, 750mg, 28 days @ 1.5g once daily =$220.

      References

        • Klitgaard H.
        • et al.
        Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment.
        Epilepsia. 2016; 57: 538-548
        • Madeja M.
        • et al.
        Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?.
        Neuropharmacology. 2003; 45: 661-671
        • Nevitt S.J.
        • et al.
        Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
        Cochrane Database of Systematic Reviews. 2017; 12: CD011412
        • Zaccara G.
        • et al.
        Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies?.
        Acta Neurologica Scandinavica. 2006; 114: 157-168
        • Lim D.A.
        • et al.
        Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study.
        Journal of Neuro-oncology. 2009; 93: 349-354
        • Rossetti A.O.
        • et al.
        Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study.
        Neuro-oncology. 2014; 16: 584-588
        • Werhahn K.J.
        • et al.
        A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy.
        Epilepsia. 2015; 56: 450-459
        • Glauser T.
        • et al.
        Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.
        Epilepsia. 2013; 54: 551-563
        • Vossel K.A.
        • et al.
        Epileptic activity in Alzheimer's disease: causes and clinical relevance.
        Lancet Neurology. 2017; 16: 311-322
        • Karceski S.
        • et al.
        Treatment of epilepsy in adults: expert opinion.
        Epilepsy and Behavior. 2005; 7: S1-S64
        • Remi C.
        Personal communication.
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        • et al.
        The medical and surgical treatment of tumoral seizures: current and future perspectives.
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        • et al.
        Antiepileptic drugs as prophylaxis for post-craniotomy seizures.
        Cochrane Database of Systematic Reviews. 2015; : CD007286
        • Dewan M.C.
        • et al.
        The influence of perioperative seizure prophylaxis on seizure rate and hospital quality metrics following glioma resection.
        Neurosurgery. 2017; 80: 563-570
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        • et al.
        Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study.
        Epilepsia. 2013; 54: 45-57
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        • et al.
        Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
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        • et al.
        Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus.
        Medicine. 2017; 96: e7206
        • Gujjar A.R.
        • et al.
        Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study.
        Seizure. 2017; 49: 8-12
        • Brigo F.
        • et al.
        Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.
        Epilepsy and Behavior. 2016; 64: 110-115
        • Wiffen P.J.
        • et al.
        Levetiracetam for neuropathic pain in adults.
        Cochrane Database of Systematic Reviews. 2014; 7: CD010943
        • Stein M.B.
        • et al.
        Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial.
        Journal of Clinical Psychiatry. 2010; 71: 627-631
        • Dunteman E.D.
        Levetiracetam as an adjunctive analgesic in neoplastic plexopathies: case series and commentary.
        Journal of Pain and Palliative Care Pharmacotherapy. 2005; 19: 35-43
        • Thompson S.
        • et al.
        Levetiracetam for the treatment of hot flashes: a phase II study.
        Supportive Care in Cancer. 2008; 16: 75-82
        • Patsalos P.N.
        Clinical pharmacokinetics of levetiracetam.
        Clinical Pharmacokinetics. 2004; 43: 707-724
      1. Baxter K and Preston CL. Stockley's Drug Interactions. London: Pharmaceutical Press www.medicinescomplete.com (accessed December 2017).

        • Dinkelacker V.
        • et al.
        Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases.
        Epilepsy Behaviour. 2003; 4: 537-547
        • Cramer J.A.
        • et al.
        A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials.
        Epilepsy Behaviour. 2003; 4: 124-132
        • Lopez-Saca J.M.
        • et al.
        Repeated use of subcutaneous levetiracetam in a palliative care patient.
        Journal of Pain and Symptom Management. 2013; 45: e7-e8
        • Sutherland A.E.
        • et al.
        Subcutaneous levetiracetam for the management of seizures at the end of life.
        BMJ Supportive and Palliative Care. 2018; 8: 129-135
        • Remi C.
        • et al.
        Continuous subcutaneous use of levetiracetam: a retrospective review of tolerability and clinical effects.
        Journal of Pain and Palliative Care Pharmacotherpy. 2014; 28: 371-377
        • Ryan S.
        • et al.
        The use of additional antiepileptic drugs with subcutaneous levetiracetam for the management of seizures at the end of life: a case series.
        Palliative Medicine. 2016; 30: NP262
        • Wells G.H.
        • et al.
        Continuous subcutaneous levetiracetam in the management of seizures at the end of life: a case report.
        Age and Ageing. 2016; 45: 321-322
        • Murray-Brown F.L.
        • Stewart A.
        Remember Keppra: seizure control with subcutaneous levetiracetam infusion.
        BMJ Supportive and Palliative Care. 2016; 6: 12-13
        • Munich University Hospital
        Syringe driver compatability database.
        Palliative medicine department, 2017 (Available from)
      2. Palliativedrugs.com Ltd. Syringe Driver Survey Database.
        (Accessed May, 2018)
        • Remi C.
        • et al.
        Subcutaneous use of lacosamide.
        Journal of Pain Symptom Management. 2016; 51: e2-e4
        • O'Connor N.
        • et al.
        Sodium Valproate as a continuous subcutaneous infusion: a case series.
        Journal of Pain and Symptom Management. 2017; 54: e1-e2