Microsoft word - levetiracetamcfu1005final _2_.doc

Criteria for Use of Levetiracetam (Keppra®)
VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel The following recommendations are based on current medical evidence and expert opinion from clinicians. The content of the document is dynamic and will be revised as new clinical data becomes available. The purpose of this document is to assist practitioners in clinical decision-making, to standardize and improve the quality of patient care, and to promote cost-effective drug prescribing. The clinician should utilize this guidance and interpret it in the clinical context of the individual patient situation. Indication for therapy
Patient with one of the following conditions:
Patient diagnosed with localization-related epilepsy (producing simple or complex partial seizures with or without secondary generalization) Incomplete seizure control requiring adjunctive therapy Incomplete seizure control intolerant of first-line antiepileptic drugs(phenytoin, carbamazepine, Concurrent therapy with a drug that is a CYP450 substrate, inducer or inhibitor and has a narrow
Dosing
Levetiracetam is available as 250 mg, 500 mg, and 750 mg tablets and 100mg/ml oral solution. Levetiracetam may be administered without regards to food. Initiate levetiracetam at 250 mg BID. After 2 weeks increase to 500 mg BID. If needed, additional dosing increments of 500-1000 mg/day every 2 weeks can be implemented, to a maximum recommended daily dose of 3000 mg or to maximum clinically tolerated dose. Adjust dose according to renal function, as follows: Creatinine Clearance(ml/min) Dose(mg) Interval(hours) >80 500-1500 12
50-80 500-1000 12
30-49 250-750 12
<30 250-500 12
On dialysis 500-1000 24
(250-500 mg supplemental dose post dialysis recommended)
Adverse Effects
Use of levetiracetam has been associated with neuropsychiatric adverse events, such as somnolence, fatigue, coordination difficulties, and behavioral abnormalities The most common adverse events associated with levetiracetam use are asthenia (15%), somnolence (15%), headache (14%), infection (13%), dizziness (9%), and pain (7%). These adverse events appear to occur predominantly during the first 4 weeks of treatment with levetiracetam. Monitoring
Therapy with levetiracetam does not require monitoring of blood levels, white blood cell counts or liver function tests There are no reported significant drug interactions, thus concurrent therapy with levetiracetam would not be expected to necessitate dose changes in other agents. Contraindications
Off Label Uses
October 2005 Updated versions may be found at http://www.pbm.va.gov or http://vaww.pbm.va.gov

References

1. Gajwani P, Forsthoff A, Muzina D, Amann B, Gao K, Elhaj O, Calabrese JR, 2. Grunze H. Antiepileptic drugs in mood-disordered patients. Epilepsia. 2005;46 Suppl 4:38-44. 3. Post RM, Altshuler LL, Frye MA, Suppes T, McElroy SL, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder.J Clin Psychiatry. 2005 Mar;66(3):370-4. 4. Kaufman KR. Monotherapy treatment of bipolar disorder with levetiracetam. Epilepsy Behav. 2004 5. Yatham LN. Newer anticonvulsants in the treatment of bipolar disorder. J Clin Psychiatry. 2004;65 Suppl 6. Grunze H, Langosch J, Born C, Schaub G, Walden J. Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design. J Clin Psychiatry. 2003 Jul;64(7):781-4. 7. Braunig P, Kruger S. Levetiracetam in the treatment of rapid cycling bipolar disorder. J Psychopharmacol. 8. Goldberg JF, Burdick KE.Levetiracetam for acute mania. Am J Psychiatry. 2002 Jan;159(1):148. 9. Striano P, Manganelli F, Boccella P, Perretti A, Striano S. Levetiracetam in patients with cortical myoclonus: A clinical and electrophysiological study. Mov Disord. 2005 Aug 2; [Epub ahead of print] 10. Lim LL, Ahmed A. Limited efficacy of levetiracetam on myoclonus of different etiologies. Parkinsonism 11. Magaudda A, Gelisse P, Genton P. Antimyoclonic effect of levetiracetam in 13 patients with Unverricht- Lundborg disease: clinical observations. Epilepsia. 2004 Jun;45(6):678-81. 12. Crest C, Dupont S, Leguern E, Adam C, Baulac M. Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients. Neurology. 2004 Feb 24;62(4):640-3. 13. Recio MV, Hauser RA, Louis ED, et al. Chorea in a patient with cerebral palsy: Treatment with leviteracetam. Movement Disorders 2005;20(6):762-764. 14. Zesiewicz TA, Louis ED, Sullivan KL, et al. Substantial improvement in a Meige’s Syndrome patient with levetiracetam treatment. Movement Disorders 2004;19(12):1518-1521. 15. Schauer R, Singer M, Saltuari L, Kofler M. Suppression of cortical myoclonus by levetiracetam. Mov 16. Frucht SJ, Louis ED, Chuang C, Fahn S. A pilot tolerability and efficacy study of levetiracetam in patients with chronic myoclonus. Neurology. 2001 Sep 25;57(6):1112-4. 17. Chatterjee A, Louis ED, Frucht S. Levetiracetam in the treatment of paroxysmal kinesiogenic choreoathetosis. Movement Disorders 2002;17(3):614-615. 18. Frediani F. Anticonvulsant drugs in primary headaches prophylaxis. Neurol Sci. 2004 Oct;25 Suppl 19. Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache. 2004 Mar;44(3):238-43. 20. Guay DR. Oxcarbazepine, topiramate, zonisamide, and levetiracetam: potential use in neuropathic pain. Am J Geriatr Pharmacother. 2003 Sep;1(1):18-37. 21. Price MJ. Levetiracetam in the treatment of neuropathic pain: three case studies. Clin J Pain. 2004 Jan- 22. Rowbotham MC, Manville NS, Ren J. Pilot tolerability and effectiveness study of levetiracetam for postherpetic neuralgia. Neurology. 2003 Sep 23;61(6):866-7. 23. Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, et al. Clinical effectiveness, tolerability and cost- effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess. 2005 Apr;9(15):1-157, iii-iv. 24. Bergey GK. Initial treatment of epilepsy: special issues in treating the elderly. Neurology. 2004 Nov 25. Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004;43(11):707-24. 26. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T,et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment ofrefractory epilepsy: report of the Therapeutics and Technology AssessmentSubcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004 Apr 27;62(8):1261-73. October 2005 Updated versions may be found at http://www.pbm.va.gov or http://vaww.pbm.va.gov 27. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology AssessmentSubcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004 Apr 27;62(8):1252-60. 28. Nash EM, Sangha KS. Levetiracetam.Am J Health Syst Pharm. 2001 Jul 1;58(13):1195-9. 29. Alsaadi Tm, Shatzel A, Marquez AV, et al. Clinical experience of levetiracetam montherapy for adults with epilepsy :1 year follow up study. Seizure 2005;14:139-142. 30. Alsaadi TM, Koopmans S, Apperson M, Farias S. Levetiracetam monotherapy for elderly patients with 31. Cohen J.Levetiracetam monotherapy for primary generalised epilepsy.Seizure. 2003 Apr;12(3):150-3. 32. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia. 2000 Oct;41(10):1276-83. October 2005 Updated versions may be found at http://www.pbm.va.gov or http://vaww.pbm.va.gov Table 1: Evidence for Off Label Use of Levetiracetam
Myoclonus/Dystonia
Evidence rating III-I
Open label trial of 8 patients over a one year period. One patient with posthypoxic myoclonus improved. The other seven did not improve or worsened. Case report, 16yo male with posthypoxic myoclonus. Improved clinical condition and allowed patient to enter rehab therapy. Case report, 38 yo female with paroxysmal kinesiogenic choreoathetosis. Resolution of attacks however patient ceased therapy due to sedation and palpitations. Case report, 56 yo female with Meige’s syndrome. Minimal improvement with gabapentin, clorazepate and Botulinum toxin A. Levetiracetam 500 mg TID improved blepharospasm and oral dystonia. Case report, 35 yo female with cerebral palsy. Open label trial in 6 patients with progressive myoclonic epilepsy. Three patients with marked improvement, 3 patients with no improvement or worsening. Open label trial in eight patients with chronic myoclonus. Two patients discontinued therapy. Three patients experience significant reductions in their myoclonus scores. Retrospective review of 13 patients with Unverricht-Lundborg disease. Eight patients had measurable improvement on their myoclonus scores. Bipolar Disorder
Evidence rating III-I
Case report. 21 yo female , failed 15 psychotropics. Patient improved over one year of followup. Ten patients with bipolar disease in acute mania. Used as add on therapy with haloperidol 5-10mg/day. Used an on-off design, levetiracetam till day 14, then remove and reintroduce at day 21. Seven of ten patients were responders at day 28 of the trial. Case report 42 yo male. Previously treated with lithium, divalproex, carbamazepine and SSRI. Modest improvement but significant sedation and nausea which caused DC of agents. No recurrence of mania for 6 weeks on levetiracetam 2500 mg/day Open label adjunctive treatment of 34 patients [ depression(13), mania (7) and cycling (14)]. The 16 patients with manic symptoms showed improvement in 2 weeks, four showed intervening periods of moderate to marked exacerbation. Migraine
Evidence Rating II-2 C ( for pediatric use)
Retrospective review of 19 pediatric patients. Eliminated headache in 10 patients, less severe headache reported in 7 patients no effect in 2 patients. Pain
Evidence rating III C
Case series of three patients, 67 yo male, 75 yo male and 55 yo female. All showed improvement on levetiracetam. Summary report of five case series of levetiracetam in various neuropathic pain syndromes. 48% to 60% of patients improved on therapy- outcomes were measured by visual analog scales, pain score or patient rating. Monotherapy for
Evidence Rating II-2 B
epilepsy
Alsaadi 200429
Retrospective review of 46 patients over a one year period. At 1 year 45% of patients were seizure free. Retrospective review of 14 elderly patients. Eight patients became seizure free by six months Case report of three patients with primary generalized epilepsy. Patients became seizure free for at least 6 months on levetiracetam 1250-3000 mg/day Randomized adjunctive therapy trial where responder patients(N=86) then underwent withdrawal to monotherapy. A responder rate of 52.9% with a mean reduction in seizure frequency by 74% October 2005 Updated versions may be found at http://www.pbm.va.gov or http://vaww.pbm.va.gov
TABLE 2: Quality of Evidence [QE]
Well designed controlled trial without randomization Well designed cohort or case-control analytic study Multiple time series, dramatic results of uncontrolled experiment Opinion of respected authorities, case reports, expert committees. TABLE 3: Grade the Recommendation
A strong recommendation that the intervention is always indicated and acceptable A recommendation that the intervention may be useful/effective A recommendation that the intervention may be considered A Recommend that a procedure may be considered not useful / effective, or may be harmful. Insufficient evidence to recommend for or against – the clinician will use their clinical judgment October 2005 Updated versions may be found at http://www.pbm.va.gov or http://vaww.pbm.va.gov

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