2. Practical uses of newer antiepileptic drugs.pptx

Practical uses of newer antiepileptic drugs

1. Practical uses of newer antiepileptic drugs

2. Flow of the presentation Aim of treatment with AEDs Ideal properties of AED Newer AEDs Brief information on all new AEDs Interaction of newer AEDs with oral contraceptives Clobazam mouth dissolving tablets Use in epilepsy Use in anxiety Dosage Advantages of mouth dissolving formulation conclusion

3. Aims of treatment with antiepileptic drugs Complete freedom of seizures. Avoidance of negative effects on cognitive function, emotional, physical, or general wellbeing. Postgrad Med J 2004 80: 581-587

4. Ideal Properties for an AED Broad spectrum activity against all seizure types High Efficacy Good tolerability No risk of allergic or idiosyncratic reactions (including teratogenicity) Low interaction potential Favorable pharmacokinetics ( linear kinetics, half life compatible with once or twice daily dosage) No tolerance to antiepileptic effects No withdrawal seizures No need for intensive laboratory monitoring Availability of convenient formulations (pediatric and parenteral ) Low cost

5. “Older” AEDs Phenobarbital 1912 Phenytoin 1938 Primidone 1952 Ethosuximide 1960 Carbamazepine 1974 Valproate 1978

6. Despite a broad range of AEDs currently available, about 30 % of patients with epilepsy are uncontrolled with available treatment and a further 25 % suffer from manifestation of drug toxicity. An introduction to Antiepileptic drug. Epilepsia 2005; 46 ( Suppl 4): 31-37

7. Newer AEDs Equally effective as older AEDs Better tolerated than older AEDs Most have fewer interactions with other medications than older AEDs Expensive compared to older drugs

8. Newer Antiepileptic drugs Felbamate 1993 Gabapentin 1993 Lamotrigine 1994 Topiramate 1996 Tiagabine 1998 Levetiracetam 1999 Oxcarbazepine 2000 Zonisamide 2000 Pregabalin 2005 Lacosamide 2008 Eslicarbazepine 2009 Vigabatrin 2009 Rufinamide 2010 Clobazam 2011 Retigabine 2011 So called “New AEDs”, these drugs were developed in last 20 years (1993-till date). Some of them were used for a much longer time in other countries for example Zonisamide in Japan and Clobazam . Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

9. Felbamate Mechanism of action Main indications Advantages Disadvantages Blockade of sodium channels, potentiation of GABAA mediated inhibition and antagonism of NMDA mediated response Severe and/or refractory epilepsies (Lennox- Gastaut syndrome) Broad spectrum Unknown mechanism Risk of severe adverse effects ( aplastic anemia, hepatic failure) CNS and GI effects Drug interactions Requires close monitoring for adverse effects Felbamate is a reserve drug for patients with LGS or refractory partial seizures with or without secondary generalization where other treatments have failed. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

10. Gabapentin Mechanism of action Main indications Advantages Disadvantages Structurally related to gamma- aminobutyric acid (GABA) but it precise mechanism of action in humans is unknown Adjunctive treatment of refractory partial seizures with/without secondary generalization Well tolerated No idiosyncratic reactions No drug interactions Rapid titration Effective against some comorbidities (neuropathic pain) Variable absorption Weight gain Three times daily dosing Limited spectrum of activity Modest efficacy Gabapentin offers the unique advantages of a wide margin of safety with good tolerability in the absence of any significant drug interactions but with modest efficacy. The efficacy may be enhanced by higher doses up to and in some cases exceeding 3600mg/day. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

11. Lamotrigine Mechanism of action Main indications Advantages Disadvantages Blockade of sodium channels and, to a lesser extent, calcium channels Adjunctive therapy and monotherapy of partial and generalized seizures Good CNS profile Twice daily dosing Broad spectrum Predictable kinetics Additive reaction with valproate Efficacy against some comorbidities (e.g., bipolar depression) Slow titration Interaction with carbamazepine and other enzyme inducers/inhibitors Dose-related rash May aggravate severe myoclonic epilepsy Lamotrigine is a broad-spectrum agent with minimal sedation or drug interactions. Main drawback is a slow titration schedule requiring 8 to 12 weeks to reach therapeutic maintenance doses which becomes even longer when used in conjunction with valproate . Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

12. Levetiracetam Mechanism of action Main indications Advantages Disadvantages Binds to synaptic vesicle 2A (SV2A) protein First line and adjunctive therapy in partial onset seizures; adjunctive and first line treatment of generalized tonic clonic seizures and myoclonic seizures associated with generalized seizures Well tolerated Twice daily dosing Rapid titration No drug interactions Behavioural disturbance in about 10-15% may be problematic Levetiracetam offers the advantage of a favourable pharmacokinetic profile and high safety margin with the capability of rapid dosage titration. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

13. Oxcarbazepine Mechanism of action Main indications Advantages Disadvantages Voltage gated sodium and calcium channels (N and P type) blockade Adjunctive treatment and monotherapy of partial seizures and primary or secondary generalized Seizures Well tolerated (including CNS profile) Ease of titration Less allergenic than carbamazepine Efficacy against some comorbidities (acute mania) Limited spectrum Interacts with oral contraceptives Rash, hyponatremia Teratogenic potential Oxcarbazepine offers similar efficacy to carbamazepine but with fewer drug interactions and overall fewer adverse effects, with the exception of hyponatremia . Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

14. Tiagabine Mechanism of action Main indications Advantages Disadvantages Blocking reuptake of GABA into neurons and glial Cells Adjunctive treatment of refractory partial seizures with/without secondary generalization Known mechanism Lacks idiosyncratic reactions Not an enzyme inducer Low allergenic potential Limited spectrum Slow titration Three times daily dosing Inducible metabolism Dizziness Modest efficacy with poor tolerability Tiagabine offers a novel mechanism of action with modest efficacy in partial-onset seizures but tolerability may limit its use in many patients.s Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

15. Topiramate Mechanism of action Main indications Advantages Disadvantages Multiple mechanisms including sodium and calcium channel blockade, GABA potentiation , glutamate receptor antagonism and inhibition of carbonic anhydrase Adjunctive treatment of partial and generalized seizures Twice daily dosing Low allergenic potential High efficacy No idiosyncratic reactions Efficacy against some comorbidities (binge eating disorder) Slow titration CNS adverse effects Interacts with oral contraceptives Renal stones Teratogenic potential Efficacy against absence seizures not established Topiramate offers the advantage of a broad spectrum agent with minimal drug interactions, the absence of serious adverse effects, and the potential for weight loss but with the slight risk of kidney stones and a slow titration schedule (8-12 weeks). Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

16. Vigabatrin Mechanism of action Main indications Advantages Disadvantages Irreversible inhibitor of GABA transaminase Adjunctive treatment of partial seizures with/ without secondary generalization refractory to all other drugs; infantile spasms (West syndrome) Ease of titration No important drug interactions Good efficacy in infantile spasms Visual field defects Limited spectrum Weight gain Vigabatrin is a useful AED for a specific indication (infantile spasm). It can also be used in adults for refractory partial seizures when all other drugs become ineffective. Serious adverse event like peripheral visual loss limits its usage. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

17. Zonisamide Mechanism of action Main indications Advantages Disadvantages Multiple mechanisms including sodium and calcium channel (T type) blockade, GABA potentiation , inhibition of carbonic anhydrase Adjunctive treatment of refractory partial and generalized seizures Twice daily dosing Slow titration CNS adverse effects and allergic reactions Zonisamide is efficacious as adjunctive therapy for many seizure types, particularly myoclonus , with the advantage of once-daily dosing. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

18. Pregabalin Mechanism of action Main indications Advantages Disadvantages Modulates neurotransmitter release by binding to the alpha-2-delta subunit of voltage gated calcium Channel Adjunctive treatment of partial- onset seizures with or without secondary Generalization Efficacy against some comorbidities (diabetic neuropathic pain, post-herpetic neuralgia, fibromyalgia) Modest efficacy; caution in renal dysfunction Pregabalin is an appropriate option in patients with drug resistant partial epilepsy. It has moderate efficacy with mild to moderate adverse effects. It may not be an appropriate choice for overweight patients and those with renal dysfunction. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

19. Lacosamide Mechanism of action Main indications Advantages Disadvantages Acts by enhancing slow inactivation of sodium channels Adjunctive treatment of partial- onset seizures with or without secondary Generalization Novel mechanism IV formulation Caution in patients with heart disease Lacosamide has a novel mechanism of action and has been found to be efficacious for adults with uncontrolled partial seizures. The intravenous formulation expands options for patients who require an AED and who are unable to receive oral medication. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

20. Rufinamide Mechanism of action Main indications Advantages Disadvantages Modulation of sodium channels, specifically, prolongation of time spent in the inactive state of the Channel Adjunctive treatment of atonic seizures in LGS Role in LGS To be avoided in patients with familial short QT Interval syndrome and others using drugs which shortens QT interval. Rufinamide is a limited-spectrum seizure drug, having a narrow therapeutic role in treating patients with LGS. However, for patients with atonic seizures and falls, rufinamide is an appropriate option. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

21. Eslicarbamazepine Mechanism of action Main indications Advantages Disadvantages Voltage gated sodium channels blockade Partial-onset seizures as monotherapy or adjunctive therapy. Useful as both monotherapy and adjunctive therapy Limited monotherapy experience Favourable efficacy and safety profiles of eslicarbazepine 800 and 1200 mg makes eslicarbazepine as a valuable addition in armamentarium of AEDs for partial onset seizures Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

22. Ezogabine ( Retigabine ) Mechanism of action Main indications Advantages Disadvantages Enhancement of potassium currents mediated by a particular family of ion channels known as KCNQ Adjunctive treatment of partial- onset seizures with or Without secondary Generalization Unique mechanism Neuropsychiatric Symptoms Potential for abuse and dependence QT prolongation Retigabine may be helpful for patients with partial epilepsy when other medications have failed. Serious adverse effects and multiple drug interactions may limit its use. Epilepsia 2004;45(Suppl. 6):28–34. Journal of the association of physicians of India 2013;61:19-29.

23. Antiepileptic drugs and hormonal contraception Drugs that reduce the effectiveness of hormonal contraception Carbamazepine Felbamate Phenobarbital Phenytoin Primidone Oxcarbazepine Topiramate Drugs that do not reduce the effectiveness of hormonal contraception Ethosuximide Gabapentin Lamotrigine Levetiracetam Tiagabine Valproate Vigabatrin Zonisamide Benzodiazepines Postgrad Med J 2004 80: 581-587

24. To conclude… New AEDs have expanded our therapeutic options for treating difficult to treat epilepsies. Some of them have also emerged as first line treatment options in new onset seizures, both generalized from onset and partial at onset with or without secondary generalization. Compared to traditional AEDs, as a group, they are neither more efficacious nor have lesser adverse effect profile. However, in a given clinical situation, they may be very useful when others have failed or they may have some unique advantages due their pharmacokinetic and pharmacodynamic profiles. Journal of the association of physicians of India 2013;61:19-29.

25. Cloba mt Clobazam mouth dissolving formulation

26. CLOBA MT Mouth dissolving formulation of clobazam Clobazam : 1,5-benzodiazepine with marked anxiolytic and anticonvulsant properties Acts as partial agonist on the GABA receptor complex When clobazam binds to the GABA A receptor, it causes an influx of chloride, leading to membrane hyperpolarization and an increase in inhibitory postsynaptic potentials Unlike 1,4-benzodiazepines, it is selective for the ω -2 subunit Clobazam has less affinity than 1,4 benzodiazepines for the ω -1 receptor and ω -5 subunit of the GABA receptor, which are known to be associated with sedation and cognitive changes Pediatr Neurol 2014 Jul;51(1):60-6.

27. Conventional BZDs vs clobazam : comparison Parameters Clobazam Conventional BZDs Chemical designation 1,5 BZD 1,4 BZD Mechanism of action Partial agonist at the GABA A receptor Full agonists at the GABA A receptor Pharmacological action Anticonvulsant, mild sedative, mild anxiolytic Anticonvulsant, sedative-hypnotic, anxiolytic , muscle relaxant Sedative effect Mild Strong CNS Drugs 2012;26:983–91. Acta Neurol Scand 2008:118:69–86.

28. Conventional BZDs vs clobazam : comparison (cont…) Parameters Clobazam Conventional BZDs Clinical uses First-line adjunctive treatment for treatment-resistant partial and generalized seizures, intermittent therapy in febrile seizure and non-convulsive status epilepticus Benzodiazepines used in epilepsy: clonazepam , diazepam, lorazepam and midazolam Clonazepam : Second-line adjunctive treatment for partial and generalized (particularly absence and myoclonic ) seizures, early status epilepticus and LGS; second-line treatment of status epilepticus Diazepam: First-line treatment for early status epilepticus ; second-line therapy for established status epilepticus ; treatment of non-convulsive status epilepticus ; intermittent prophylactic therapy for febrile seizures; and at-home treatment of ARS Lorazepam : First-line treatment for early status epilepticus and out-of-hospital status epilepticus Midazolam : Second-line therapy for early status epilepticus CNS Drugs 2012;26:983–91. Acta Neurol Scand 2008:118:69–86.

29. CLOBA MT: uses Drug-resistant seizures (drug of choice) Adjunctive therapy for partial and generalized seizures and status epilepticus , febrile seizures , reflex seizures , and hyperekplexia Short-term management (2-4 weeks) of severe anxiety (for adults, and elderly ) Pediatr Neurol 2014 Jul;51(1):60-6.

30. CLOBA MT: uses in pediatric epilepsy Adjunctive therapy in patients with epilepsy who are not adequately stabilized with their current anticonvulsant therapy Adjunctive therapy for the treatment of seizures associated with LGS in patients aged ≥2 yrs Intermittent therapy in febrile seizures

31. Clobazam : refractory childhood epilepsy n=250 First-line AEDs tried on these patients included phenobarbitone , phenytoin , carbamazepine or sodium valproate in maximum physiological doses Out of these patients, 88 patients were refractory to treatment with first-line AEDs, were started on clobazam , as an add-on therapy Clobazam was effective against all seizure types Therapeutic response : complete with 100% seizure control was seen in 53 (60.2%) patients, good in 22 (25%) patients, uncontrolled in 4(4.5%) patients and the status was not known in 9(10%) patients Time period required for seizure control: immediate-3 month Indian J Pediatr 2010; 77 (3):263-6. Clobazam was effective broad-spectrum antiepileptic with mild side effects in Indian children.

32. Clobazam : refractory focal epilepsy Add-on clobazam given to monotherapy failure patients n=100 Mean dosage: 23.6 mg/day seizure-free patients 42%; patients with >75% seizure reduction 36% Duration of efficacy: >1 yr Survival curve plot of 72 patients over the 18-month follow- up period, showing the percentage of patients with retention of clobazam as a fraction of time Mean use of clobazam : 18.6 months Clobazam seems to be safe and effective in the treatment of focal epilepsy in childhood and should be considered in patients with refractory seizures Arq Neuropsiquiatr 2006;64(3-B):705-10.

33. Clobazam : intractable epilepsy Response rates for >50% seizure reduction were 59%, 39%, and 30% of patients at 6, 12, and >12 months’ therapy, respectively 49% experienced an event indicating a change in response with a mean survival time of 15.51 months Seizure reduction within the first 6 months was positively correlated with seizure reduction at 12 months (r = 0.456, P < .001) and >12 months (r = 0.417, P < .001) Kaplan-Meier survival plot for maintained response to clobazam Retrospectively reviewed medical charts of children treated with clobazam Journal of Child Neurology 2013;28(1):34-9. Clobazam has efficacy against a wide spectrum of seizure types and epilepsy etiologies

34. Clobazam : LGS Mean percentage decreases in weekly rate of seizures from baseline to maintenance period n=238 Double-Blind, Placebo-Controlled, Efficacy and Safety Study of ClObazam in PatieNTs with Lennox- GAstaut SyNdrome or CONTAIN trial 0.5 mg/kg/d Neurology 2011;77:1473-81.

35. Clobazam : LGS long-term (5 years) extension trial n=267 Median decrease in drop seizures: 85% at yr 1, 87% at ur 2, 92% at yr 3, 97% at yr 4, 91% for patients who reached yr 5 Total seizures reduction: 79% at both yrs 1 and 2, 82% at yr 3, 75% at yr 4, and 85% at yr 5 Responder rates: stable for duration of the trial Epilepsia 2014;55(4):558–67.

36. Clobazam : efficacy trials Journal of Child Neurology 2013;28(2):219-29.

37. Clobazam Vs other therapies in LGS 5 RCTs included Indirect comparisons between clobazam and other approved adjunctive LGS therapies ( felbamate , lamotrigine , topiramate , rufinamide Acta Neurol Scand 2013;128:91–9. High-dosage clobazam (1.0 mg/kg/ day): strongest treatment effect vs placebo (effect size 0.80) Medium-dosage clobazam (0.5 mg/kg/day): moderate effects (effect sizes >0.50) Low effect sizes for: rufinamide . Felbamate , lamotrigine , topiramate

38. Clobazam Vs other therapies in LGS (cont…) Acta Neurol Scand 2013;128:91–9. % decrease in total seizures frequency Indirect comparisons of numbers of total seizures demonstrated superiority of both clobazam dosages over all comparators.

39. Clobazam Vs other therapies in LGS (cont…) Acta Neurol Scand 2013;128:91–9. % decrease in frequency of drop attacks or tonic- atonic seizures Indirect comparisons of numbers of tonic- atonic seizures (‘drop attacks’) demonstrated superiority of both clobazam dosages over all comparators.

40. Clobazam Vs other therapies in LGS (cont…) Odds of achieving at least 50% decrease in the frequency of drop attacks: ~2 times greater for high-dosage clobazam vs with lamotrigine , topiramate , or rufinamide , with statistically significant results vs lamotrigine Odds of a parent or caregiver indicating ‘at least minimal improvement’: greater for clobazam compared with other therapies Acta Neurol Scand 2013;128:91–9. Conclusion: High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments

41. Clobazam Vs other therapies in LGS (cont…) AEDs (dark gray columns) compared with placebo (light gray columns) Percentage of patients with >50% reduction in drop seizures with AEDs approved for LGS Ther Adv Neurol Disord 2014;7(3) 169-76.

42. Clobazam : in febrile seizures Prospective, randomized controlled trial on neurologically normal children aged from 6 months to 5 years with a history of simple febrile seizures & normal EEG without any evidence of acute CNS infection Oral clobazam (n=37) or diazepam (n=35); advised to use the medications during the first 48 h of the onset of fever Follow-up: 12 months 243 episodes of fever occurred during the period, including 116 episodes in clobazam group, 127 episodes in diazepam group. Recurrence of seizures: 2 (1.7%) subjects in clobazam group, 4 (3.1%) cases in diazepam group. (P value=0.474) Indian J Pediatr 2011;78:38–40. Intermittent clobazam therapy seems advantageous to diazepam due to similar efficacy but significantly lower adverse effects such as drowsiness and sedation.

43. Clobazam : in febrile seizures Prospective, randomized, double-blind placebo-controlled trial Inclusion criteria: neurologically normal children between 6 months and 3 years of age with a history of febrile seizures and no evidence of acute CNS infection or EEG abnormality Clobazam group= 19 children, placebo group= 20 children Temperature reduction measures with paracetamol and tepid sponging were advised to all children. In addition, dispensed medication was administered. Total of 110 episodes of fever during study period Mean number of febrile episodes: clobazam group=3.1, placebo group=2.56 Seizure recurrence: 6 (12.5%) of 48 episodes in placebo group, 1 (1.7%) of 60 episodes in clobazam group [statistically significant (p = 0.01)] Indian J Pediatr 2005; 72(1):31-3. Intermittent clobazam therapy is an effective measure in the prevention of recurrence of febrile seizures.

44. Clobazam in Anxiety Comparison with Placebo Compared with a placebo in 16 double-blind studies In 14 trials clobazam proved to be distinctly more effective than placebo, the level of significance being P<0.05. Br J Clin Pharmac 1979; 7:139S-150S.

45. Clobazam in Anxiety Comparison with Placebo… Br J Clin Pharmac 1979; 7:139S-150S.

46. Clobazam in Anxiety Comparison with Diazepam Total 22 studies comparing clobazam and diazepam. Comparisons of global efficacy (Clinical Global Impression, total scores of anxiety scales) revealed no significant difference between the two compounds in 20 studies. In the other 2 studies either clobazam or diazepam was significantly more effective than the comparator. Br J Clin Pharmac 1979; 7:139S-150S.

47. Clobazam in Anxiety Comparison with Diazepam… Br J Clin Pharmac 1979; 7:139S-150S.

48. Clobazam in Anxiety Comparison with Diazepam… Anxiolytic effects of clobazam , diazepam, and placebo were compared in a 4-wk double-blind study of 159 anxious outpatients Clobazam (30 to 80 mg/day) and diazepam (15 to 40 mg/day) Change in HAS score

49. Clobazam in Anxiety: Summary Usual duration of treatment was 2-4 weeks. 1 Clobazam was shown to be an efficacious and well tolerated anxiolytic agent in various neurotic and psychosomatic disorders. 1 Clobazam as a single dose of 20 mg has good anxiolysis without any hungover effect. 2 Br J Clin Pharmac 1979; 7:139S-150S. Indian Journal of Psychiatry 1986;28(4):51-5

50. Dosage Management of refractory epilepsy and LGS Treatment of Anxiety Adults: 20-30 mg daily in divided doses or as a single dose given at night; maximum 60 mg daily. Elderly: 10-20 mg daily; treatment requires low initial doses and gradual dose increments under careful observation. ≤30 kg Body Weight >30 kg Body Weight Starting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg Pediatric patients aged 2 years and above Cloba MT. Prescribing information. Intas Pharmaceuticals Ltd.

51. Dosage… Febrile seizures Upto 5 kg: 5 mg QD 6 kg to 10 kg: 5 mg BD 11 kg to 15 kg: 7.5 mg BD > 15 kg: 10 mg BD Give Immediately at fever onset and continue for 48 hours; stop after 48 hours irrespective of whether fever persists or not Indian J Pediatr 2005; 72(1):31-3.

52. Mouth dissolving formulation: advantages Ease of administration to patients who refuse to swallow a tablet e.g., pediatric patients. Convenience of administration and accurate dosing as compared to liquids. No need of water to swallow the dosage from, which is highly convenient feature for patients who are traveling and do not have immediate access to water. Good mouth feels properly helps to change the basic view of medication as “bitter pill”. Rapid dissolution of drug and absorption which may produce rapid onset of action. International Journal of Applied Pharmaceutics 2012;4(2):17–22.

53. CLOBA MT: salient features It is a broad spectrum antiepileptic. It is effective, well tolerated and economical. Clobazam has been found to be an effective adjunctive therapy for children with refractory seizures. Clobazam is well tolerated and efficacious in the treatment of seizures related to LGS. Clobazam was estimated to be more efficacious than other LGS treatments. Intermittent clobazam therapy is an effective measure in the prevention of recurrence of febrile seizures. It allows rapid titration to therapeutic dosage, with a predictable adverse-effect profile. Side effects observed are mild and tolerable in Indian children. Compared with the 1,4-benzodiazepine tranquillizers, there was no objective evidence of any sedative or amnestic effects or impairment of psychomotor function with clobazam . Clobazam as a single dose of 20 mg has good anxiolysis without any hungover effect.

54. Conclusion On the basis of current evidence CLOBA MT is effective and safe as Adjunctive therapy Refractory seizure Lennox- Gastaut  Syndrome Intermittent therapy Febrile seizure Short-term management (2-4 weeks) of severe anxiety (for adults, and elderly)