1. Levetiracetam in epilepsy & beyond.pptx

levitaracetam in epilepsy

1. Levetiracetam in Epilepsy & Beyond

2. Outline Introduction Epilepsy Treatment: Challenges Levetiracetam in Epilepsy Management: Current Indications Favorable Features Recent Clinical Data Summary

3. Goals of Antiepileptic Therapy

4. Therapeutic Challenges in Epilepsy An antiepileptic drug should ideally possess all of the following: Good efficacy 1 and safety profiles 2 Broad spectrum of activity 1 Immediate seizure control 3 Favorable pharmacokinetics 4 Positive impact on quality of life 5 Demonstrable efficacy in elderly patients 6 Trinka E. Acta Neurol Scand . 2012:126:10-18. http:// effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and reports /? productid=463&pageaction=displayproduct Rosenow F, et al. J Neurol Neurosurg Psychiatry . 2012;83(11):1093-1098. Patsolas PN. Pharmacol Therapeut . 2000;85(2):77-85. Marson AG, et al. Lancet . 2007;369(9566):1000-1015. Arif H, etal . Arch Neurol . 2010;67(4):408-415.

5. Levetiracetam Approved Indications: Adjunctive therapy: epilepsy Partial-onset seizures with or without secondary generalisation in epilepsy patients aged 1 month and older (US, EU) Myoclonic seizure in patients aged 12 years and older with juvenile myoclonic epilepsy (US, EU) Primary generalised tonic-clonic seizures in patients aged 12 years and older with refractory idiopathic generalised epilepsy ( EU ) Monotherapy: epilepsy Partial-onset seizures with or without secondary generalisation in patients aged 16 years and older (EU)

6. Levetiracetam Favorable Features: Broad spectrum of antiepileptic activity and expanding indications As an ‘add-on’ drug it improves level of seizure control and is easier to add to existing antiepileptic therapy as compared with several other AEDs Eminently suitable as an 'add-on' AED in the treatment of POS (simple or complex) because of the following virtues: Rapid onset of effect in partial epilepsy patients refractory to treatment significantly more proportion of seizure-free patients as of the first day of treatment Also approved for monotherapy use

7. Levetiracetam Favorable Features: The antiepileptic efficacy is sustained over the long term, with no evidence of development of tolerance Comparable or better patient retention rates than lamotrigine, topiramate, gabapentin, and vigabatrin Also safe and effective in children and infants ( ≥ 1 mo) Is tolerated well and side effects are not serious and manageable

8. Levetiracetam Favorable Features: Virtual absence of potential for drug-to-drug interactions with co-administered AEDs / other drugs minimal hepatic drug metabolism low (<10%) plasma protein binding Simple BID dosing and titration The start dose is the usual effective dose of the drug Dosage titration, when required, is simpler and widely spaced (at 2 week intervals) no need to monitor plasma drug levels

9. Levetiracetam in Epilepsy Management: Clinical Data

10. LEV is Efficacious & Well Tolerated in R x -Resistant Pediatric Epileptics Brain Nerve. 2013 Sep;65(9):1083-92. [Efficacy and safety of levetiracetam as adjunctive therapy in Japanese children with uncontrolled partial-onset seizures: multicenter and open-label study (N01223), short term evaluation]. [Article in Japanese] Nakamura H 1 , Osawa M , Yokoyama T , Yoshida K , Suzuki A . Multicenter, open-label, single-armed study (N01223) to evaluate efficacy and safety of add-on LEV in 73 Japanese pediatric (4-15 yr) patients with uncontrolled POS. 14-wk R x with add-on LEV led to 43.2% decrease in POS frequency. Incidence - TEAEs: 82.2% (60/73); ADRs: 56.2% (41/73) Common TEAEs: somnolence, nasopharyngitis , URTI, pyrexia Frequent ADRs (>3%): somnolence, feeling jittery Conclusion: Adjunctive therapy with LEV is clinically efficacious and well tolerated in Japanese children with uncontrolled POS.

11. LEV is Safe & Effective in Children at Risk for Posttraumatic Epilepsy Epilepsia . 2013 Sep;54(9):e135-7. Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy. Pearl PL , McCarter R , McGavin CL , et al. Posttraumatic seizures develop in up to 20% of children following severe TBI. N= 20 children (6-17 yrs) with presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or posttraumatic seizure received LEV 55 mg/kg/day, b.i.d ., for 30 d, starting within 8 h post-injury. 19 / 20 treatment patients were retained; 1 observation patient lost to follow-up Common AEs: Headache, fatigue, drowsiness, irritability No higher incidence of infection, mood changes, or behavior problems Only 1 developed posttraumatic epilepsy (seizures >7 days after trauma) LEV was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at-risk population.

12. Epilepsy Res. 2013 Mar;104(1-2):140-50. Quality of life, anxiety and depression in adult patients after add-on of levetiracetam and conversion to levetiracetam monotherapy. Hagemann A , May TW , Nieder E , et al. Objective: To evaluate impact of switch from LEV add-on therapy to LEV monotherapy on HRQoL , anxiety, depression in adult epileptics. Methods: ( i ) Add-on LEV given to existing AEDs in 140 adult epileptics for 16 wks (ii) 65 patients benefited from add-on LEV (≥50%  in seizure)  converted to LEV monotherapy (16-wk follow-up). Results: Add-on LEV in LEV responders  improved HRQoL , anxiety, depression LEV monotherapy  no further improvement in the above, but + ve effect of add-on LEV on these maintained. Conclusion: The effects were highly related to seizure reduction. LEV Improves HRQoL , Anxiety & Depression in Epileptics

13. LEV is Safe & Effective in Adults and Children at Risk for Posttraumatic Epilepsy Arch Neurol. 2012 Oct;69(10):1290-5. Results of phase 2 safety and feasibility study of treatment with levetiracetam for prevention of posttraumatic epilepsy. Klein P , Herr D , Pearl PL , et al. Open-label, nonrandomized phase 2 study with 2 arms comparing LEV R x vs. observation for LEV safety and LEV trough C p in TBI patients. LEV R x group: N=66 (46 adults; 20 children) with TBI received LEV 55 mg/kg/d for 30 days starting within 8 h post-injury. Observation group: N=60 (40 adults; 20 children) with TBI who reported after 8 h post-injury. Outcome Measures: No. of AEs, mood score, no. of infections, LEV trough C p , PTE. Results: 2 (3%) stopped treatment due to toxicity (somnolence). Commonest AEs: fatigue, headache, somnolence. No difference in mood scores and no. of infections in the 2 groups. Mean trough LEV levels on days 2-30: 19.6-26.7 μg / mL. PTE at 2 years: LEV group: 05/46 adults (10.9%) Observation group: 8 / 40 adults (20.%) ; 1 / 20 children (5%) Conclusion: LEV 55 mg/kg/d (a dose with an antiepileptogenic effect on animals) for TBI patients at risk for PTE is safe and well tolerated, with C p similar to those in animal studies.

14. The HELLO Trial [ Acta Neurochirurgica 2012; 154(2):229-235] SUMMARY Background: Levetiracetam (LEV) is a newer anticonvulsant with a favorable safety profile. There seem to be no relevant drug interactions, and an intravenous formulation is available. Therefore, LEV might be a suitable drug for the perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosurgery. Methods: In this prospective study (NCT00571155) patients with suspected primary brain tumors and tumor-related seizures were perioperatively treated with oral and intravenous LEV up to 4 weeks before and until 4 weeks after a planned neurosurgical procedure .

15. The HELLO Trial [ Acta Neurochirurgica 2012; 154(2):229-235] Table. Patient characteristics

16. The HELLO Trial [ Acta Neurochirurgica 2012; 154(2):229-235] Table. Patient characteristics (Cont’d.)

17. The HELLO Trial [ Acta Neurochirurgica 2012; 154(2):229-235] a as per protocol AED other than LEV were withdrawn not later than 7 days before surgery b including one papillary glioneural tumor Table. Patient characteristics (Cont’d.)

18. The HELLO Trial [ Acta Neurochirurgica 2012; 154(2):229-235] SUMMARY (Cont’d.) Findings: 30 patients with brain tumor-related seizures and intended neurosurgery were included. Three patients did not undergo the scheduled surgery after enrolment and two patients were lost for follow-up. Therefore, 25 patients were fully evaluable . After initiation of therapy with LEV 100% of the patients were seizure-free in the pre-surgery phase (3 days up to 4 weeks before surgery), 88% in the 48 h post-surgery phase and 84% in the early follow-up phase (48 h to 4 weeks post surgery). Treatment failure even after dose escalation to 3000 mg/day occurred in 3 patients . No serious adverse events related to the treatment with LEV occurred.

19. The HELLO Trial [ Acta Neurochirurgica 2012; 154(2):229-235] SUMMARY (Cont’d.) Conclusion: Our data show the feasibility and safety of oral and intravenous LEV in the perioperative treatment of tumor-related seizures . Although this was a single arm study, the efficacy of LEV appears promising. Considering the side effects and interactions of other anticonvulsants, LEV seems to be a favorable option in the perioperative treatment of brain tumor-related seizures.

20. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Abstract Background: Strokes are the leading cause of epileptic seizures in adults and account for 50% of seizures in those over the age of 65 years. The use of antiepileptic drugs to prevent recurrent poststroke seizures is recommended. Methods: 128 patients with poststroke seizures were randomly allocated to treatment with either levetiracetam (LEV) or sustained-release carbamazepine (CBZ) in a multicenter randomized open-label study. After a titration study phase (2 weeks), the optimal individual dose of trial medication was determined and treatment was continued for another 52 weeks. The primary endpoint was defined as the proportion of seizure-free patients; the secondary endpoints were: evaluation of time recurrence to the first seizure, EEG tracings, cognitive functions and side effects.

21. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Figure. Discontinuation/completion summary (all treated patients).

22. EpIC Project [ Cerebrovasc Dis 2012;34:282–289]

23. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Abstract (Cont’d.) Results: Of 128 patients, 22 discontinued the trial prematurely; thus a total of 106 patients (52 treated with LEV and 54 treated with CBZ) were included in the analysis. The results of the study were as follows: no significant difference in number of seizure-free patients between LEV and CBZ (p = 0.08); time to the first recurrence tended to be longer among patients on LEV; there was no correlation between the therapeutic effect and the EEG findings in either treatment group; LEV caused significantly fewer (p = 0.02) side effects than CBZ; attention deficit, frontal executive functions and functional scales (Activities of Daily Living and Instrumental Activities of Daily Living indices) were significantly worse in the CBZ group.

24. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Table. Number and percentage of seizure-free patients and abnormal EEG at V0 and V3

25. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Table. Number of patients with AEs who received either LEV or CBZ

26. Figure. Kaplan-Meier curves estimate of the percentage of seizure-free patients receiving sustained-release CBZ or LEV. Time was calculated as the difference in weeks between the visit at which the crisis was diagnosed and the baseline visit (V 0 ). Seizure-free patients were defined as ‘censored’ at the last observation time. EpIC Project [ Cerebrovasc Dis 2012;34:282–289]

27. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Table. Neuropsychological findings with daily activities at baseline (V0) and end (V3) of the study in the two groups

28. EpIC Project [ Cerebrovasc Dis 2012;34:282–289] Abstract (Cont’d.) Conclusions: This trial suggests that LEV may be a valid alternative to CBZ in poststroke seizures , particularly in terms of efficacy and safety . In addition, our results show that LEV has significant advantages over CBZ on cognitive functions . This trial also indicates that LEV in monotherapy is a safe and effective therapeutic option in elderly patients who have suffered epileptic seizures following a stroke .

29. LEV vs. LTG: LaLiMo Trial J Neurol Neurosurg Psychiatry. 2012 Nov;83(11):1093-8. The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy--an open-label, prospective, randomised controlled multicenter study. Rosenow F , Schade-Brittinger C , Burchardi N , et al. Randomised, open-label, controlled, parallel group, multicenter trial evaluated superiority of the LEV arm over the LTG arm. Primary endpoint: rate of seizure-free patients in the 1 st 6 wks. Also, efficacy, tolerability and quality of life were evaluated. N=409 patients (≥12 yrs) with newly diagnosed focal or generalised epilepsy Titrated dose:- LEV: 2000 mg/d (by day 22); LTG: 200 mg/d (by day 71) Results: Proportions of seizure-free patients at 6 wks after randomisation LEV 67.5% LTG 64.0% Adverse events LEV: 74.5% LTG: 70.6% Study discontinuation due to AE LEV: 17/204 LTG: 8/201 Conclusion: no significant differences with regard to efficacy and tolerability of LEV and LTG in newly diagnosed focal and generalised epilepsy despite more rapid titration in the LEV arm.

30. TPM vs. LEV [ Bootsma HPR, et al. Seizure 2008; 17: 19-26] Summary Objective: To assess long-term performance of topiramate (TPM) vs. levetiracetam (LEV) on the basis of results from long-term open label observational studies Method: We analyzed all patients referred to a tertiary epilepsy centre treated with either TPM (period: spring 1993 to mid-2002) or LEV (period: early 2001 to end-2003) using a medical information system

31. TPM vs. LEV [ Bootsma HPR, et al. Seizure 2008; 17: 19-26] Summary (Cont’d.) Results: 301 patients were included for LEV and 429 patients for TPM. Retention rate after 1 year was 65.6% for LEV-treated patients and 51.7% for TPM-treated patients ( p = 0.0015). Similarly, retention rates for LEV were higher at the 24-month mark: 45.8% of LEV-treated patients and 38.3% of TPM-treated patients were still continuing treatment ( p = 0.0046). Adverse events led to drug discontinuation in 21.9% of TPM-treated patients compared to 6.0% of LEV-treated patients ( p < 0.001). The number of patients discontinuing treatment because of lack of efficacy was similar for both groups. Seizure freedom rates varied between 11.6 and 20.0% for TPM and between 11.1 and 14.3% for LEV per 6-months interval. Several important AED specific adverse events leading to drug discontinuation were identified, including neurocognitive side effects from TPM and mood disorders from LEV.

32. Table. Patient demographics and characteristics TPM vs. LEV

33. Figure. Comparison between the Kaplan-Meier survival curves of TPM and LEV (*RR: retention rate). TPM vs. LEV

34. Figure. Reason for discontinuation; comparison between TPM and LEV. TPM vs. LEV

35. Figure. (A) Seizure freedom rates per 6-month interval; comparison between TPM and LEV. (B) Seizure remission for at least 1 year; comparison between TPM and LEV. TPM vs. LEV

36. Table. Most frequently reported side effects a TPM vs. LEV

37. Table. Reported side effects in patients who discontinued drug treatment a TPM vs. LEV

38. Table. Seizure reduction in patients who discontinued drug treatment; follow-up period 24 months TPM vs. LEV

39. TPM vs. LEV [ Bootsma HPR, et al. Seizure 2008; 17: 19-26] Summary (Cont’d.) Conclusion: The retention rate for LEV is significantly higher than for TPM. LEV had a more favourable side effect profile than TPM with comparable efficacy. Patients on TPM discontinued treatment mainly because of neurocognitive side effects. In the treatment with LEV, the effects on mood must not be underestimated.

40. Efficacy of LEV in Partial & Generalized Tonic-Clonic Seizures Brodie MJ, et al. Neurology 2007;68:402-408. Major finding: LEV and CBZ CR produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. * double-blind, randomized, parallel-group, positive-controlled, non-inferiority monotherapy trial

41. Efficacy of LEV in Partial & Generalized Tonic-Clonic Seizures Brodie et. al.: Study design

42. Efficacy of LEV in Partial & Generalized Tonic-Clonic Seizures Seizure freedom at 6 and 12 months

43. Efficacy of LEV in Partial & Generalized Tonic-Clonic Seizures Non-inferiority of the treatments

44. Efficacy of LEV in Newly Diagnosed Epilepsy Pohlmann -Eden et.al.,* found levetiracetam to be equivalent to sodium valproate ER and carbamazepine CR in newly diagnosed epilepsy * open-label, randomized, parallel-group, community-based study. ER: extended release; CR: controlled release.

45. Efficacy of LEV in Newly Diagnosed Epilepsy Pohlmann -Eden et. al.: Study design

46. Efficacy of LEV in Newly Diagnosed Epilepsy Seizure freedom at 6 and 12 months

47. Efficacy of LEV in Newly Diagnosed Epilepsy Pohlmann -Eden B et.al. study: Implications Typically, sustained release preparations are preferred. However, levetiracetam is equivalent to extended-release sodium valproate and controlled-release carbamazepine. The study included patients with any type of epilepsy; results testify the broad spectrum of activity of levetiracetam .

48. Efficacy of LEV in Newly Diagnosed Epilepsy Levetiracetam confers superior protection w.r.t to time to first seizure as compared to standard treatments.* *KOMET: Multicentre , unblinded , randomized, 52-week, controlled superiority trial with a two-parallel group design.

49. Rapid Uptitration with LEV is Both Safe and Effective Rapid uptitration of IV LEV to maintenance dose within 2 days causes fewer adverse events and reduces seizure recurrence a .* * Hufnagel et. al.: prospective, randomized, open-label study. a occurrence of at least 1 seizure between day 3 and 14 (final visit)

50. Epileptic Disord . 2008 Dec;10(4):297-305. doi : 10.1684/epd.2008.0227. Effect of levetiracetam on cognitive functions and quality of life: a one-year follow-up study. López-Góngora M , Martínez-Domeño A , García C , Escartín A . Source Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona Spain. [email protected]

51. Effect of LEV on Cognition & QoL [ Epileptic Disord . 2008 Dec;10(4):297-305 ] Abstract PURPOSE: To assess changes in cognitive functions and QoL in epilepsy patients on add-on LEV treatment over 1 yr. METHODS: 32 patients (16 women; 16 men) on add-on LEV were included. 27 completed the 1-year follow-up period. Extensive neuropsychological assessments, together with a QoL questionnaire were administered at baseline and at 1, 3, 6, and 12 months after beginning the add-on treatment. Patients received LEV starting with 500 mg/day in the first week, increasing by a further 500 mg/d/wk until a target dose of 2000 mg/d was reached by the end of the 1 st month.

52. Effect of LEV on Cognition & QoL [ Epileptic Disord . 2008 Dec;10(4):297-305 ] Abstract (Cont’d.) RESULTS: At the 1-yr follow-up, a significant improvement was observed in measurements of prospective memory, working memory, motor functions, verbal fluency, attention and quality of life . Performance for neuropsychological and quality-of-life tests was not affected by external variables such as seizure reduction or changes in previous anti-epileptic treatment. Slight changes between patients were observed, but these were not clinically significant. The limited sample size and the lack of a control group should be mentioned as limitations of the study. No control group was evaluated as in our clinical practice it was difficult to establish a comparable group of patients. Changes in the different variables were assessed by comparing baseline information with follow-up results. Despite the study limitations, we consider that the one-year treatment period provides valuable information regarding the drug's long-term effects in this setting.

53. LEV Improves Cognitive Function and Quality of Life Improved quality of life 1-year follow-up study involving 32 patients.

54. Effect of LEV on Cognition & QoL [ Epileptic Disord . 2008 Dec;10(4):297-305 ] Abstract (Cont’d.) CONCLUSIONS: Results of the present study suggest that long-term LEV treatment as add-on therapy does not interfere with cognitive function and improves quality of life .

55. Efficacy of LEV in Elderly Patients At 12-months of therapy, the efficacy of levetiracetam was rated as ‘good’ or ‘very good’ by 90.1% of physicians and 89.6% of patients. Werhann et. al.: One-year observational study involving 364 patients

56. Efficacy of LEV in Elderly Patients Levetiracetam facilitated a significant reduction in seizure frequency (p < 0.0001) 3-months: p < 0.001; 6-moths: p < 0.0001; 12-months: p < 0.0001 for all seizure types

57. Levetiracetam in Epilepsy Management: Recent Findings: Summary LEV is as effective and safe as CBZ in post-stroke seizures including that in elderly persons Has better effects on cognitive function than CBZ Is safe and effective in perioperative treatment of brain tumor-related seizures Higher long-term patient retention rates than TPM Better tolerability profile than TPM As effective as CBZ CR in producing freedom from seizure in newly diagnosed epilepsy cases Long-term add-on therapy does not interfere with cognitive function and improves quality of life

58. Levetiracetam use during pregnancy in women with epilepsy – Indian Data In this study ( n  = 99), 35 women received carbamazepine, 28 received LEV, 15 received valproate (VPA), 13 received phenytoin (PHT), three each received oxcarbazepine and lamotrigine , respectively, and two received clobazam . Although the use of VPA was associated with significantly better control of seizures compared to LEV, its use was associated with higher risk of major congenital malformations (13.3%). The incidence of gestational hypertension was lower while incidence of fetal distress was significantly higher in WWE receiving PHT during pregnancy. None of the child born to pregnant women receiving LEV had any congenital malformation . Data on efficacy and safety of levetiracetam (LEV) during pregnancy is still limited. Researchers analyzed efficacy and safety of LEV during pregnancy in North Indian women with epilepsy (WWE) LEV is a first-line AED during pregnancy. Indian J Pharmacol . 2018 Jan-Feb;50(1):39-43. doi : 10.4103/ijp.IJP_692_17.

59. Levetiracetam beyond Epilepsy – Myoclonus/Dystonia

60. Levetiracetam beyond Epilepsy – Bipolar Disorder

61. Levetiracetam beyond Epilepsy – Migraine

62. All studies found a statistically significant decrease in headache frequency per month compared to baseline or placebo when used for treatment of episodic migraine (2.96-10.9 headache/ mo decrease), and 57.9%-100% of patients had at least a 50% decrease in headache frequency from baseline. Significance was not consistently demonstrated in the prophylactic treatment of chronic migraine. The most common adverse effects noted included somnolence, dizziness and behavioural effects but generally did not require discontinuation . WHAT IS NEW AND CONCLUSION: The studies included in this review indicate that  levetiracetam  is well-tolerated and may be an alternative treatment option for episodic migraine prophylaxis . Additional clinical evidence is necessary to establish the efficacy of  levetiracetam  for the prophylactic treatment of chronic migraine.

63. Kindling-like facial nucleus hyperactivity is the cause of hemifacial spasm (HFS). Anti-kindling effect of levetiracetam (LEV) could be an important action against HFS. LEV may represent an alternative or additional treatment for HFS

64. Levetiracetam beyond Epilepsy - hemifacial spasm NEUROLOGY 62 June (1 of 2) 2004

65. Levetiracetam beyond Epilepsy - hemifacial spasm NEUROLOGY 62 June (1 of 2) 2004

66. Levetiracetam beyond Epilepsy – Pain & as monotherapy in epilepsy

67. Questions?

68. Thank You!