Ezogabine,an update

1. EZOGABINE: A NEW ANGLE ON POTASSIUM GATE DR.JITENDRA AGRAWAL FIRST YEAR RESIDENT

2. Epilepsy is among the most common neurological disorders, affecting approximately 50 million people worldwide. Partial onset seizure are the most common type of seizures in adults. SEIZURE : is a paroxysmal event due to abnormal, excessive, hyper synchronous discharges from an aggregate of central nervous system, neurons. EPILEPSY : describes a condition in which a person has recurrent seizures due to chronic underlying process. INTRODUCTION

3. 1. Partial seizures a. Simple partial seizures (with motor, sensory, autonomic, or psychic signs) b. Complex partial seizures c. Partial seizures with secondary generalization Classification of seizure

4. 2. Primarily generalized seizures Absence (petit mal) Tonic- clonic (grand mal) Tonic Atonic Myoclonic 3. Unclassified seizures Neonatal seizures Infantile spasms Classification of seizure

5. are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. SIMPLE PARTIAL SEIZURES: Clinical manifestation + consciousness is fully preserved during seizures COMPLEX PARTIAL SEIZURES focal seizure activity + impairment of conciousness PARTIAL SEIZURES WITH SECONDARY GENERALIZATION seizures that begin as partial seizures and then spread diffusely throughout the cortex Partial Seizures

6. Pharmacological therapy is initial option for the treatment of patients with newly diagnosed epilepsy. Focused area is to reduce seizure frequency with seizure freedom is ultimate goal. without side effects. Monotherapy is preferable. CURRENT STATUS OF TREATMENT

7. First-Line   Carbamazepine Phenytoin Lamotrigine Oxcarbazepine Valproic acid CURRENT STATUS OF TREATMENT Alternatives   Levetiracetam Topiramate Tiagabine Zonisamide Gabapentin Phenobarbital Primidone Felbamate

8. Epilepsy a serious and potentially life threatening condition In spite of many approved pharmacological agents, many patients are not adequately treated with currently available option. Nearly a third patients with epilepsy have either intractable or uncontrolled seizures or have significant adverse side effects secondary to medication. Why need of new drug?

9. Monotherapy is preferable to limit drug drug interactions and side effects… but Epilepsy patient need more than one AED to achieve therapeutics success. In spite of that adequate seizure control is not achieved. So the new drug should have minimal drug interactions and minimal side effect Why need of new drug?

10. Synonyms: Retigabine-(INN- international nonproprietary name) Ezogabine- (USAN- U.S. adopted name) EZOGABINE: As an adjunctive therapy to partial onset seizures.

11. Recently approved as an adjunctive treatment for partial onset seizure for patients by FDA in June 2011 EMEA in March 2011 EZOGABINE

12. Opening of neuronal voltage-gated potassium channels, which enhances inhibitory M-type potassium current. The principal mechanism by which membrane repolarisation occurs after an action potential is an outward potassium current, termed the M-current . Selectively enhance M-currents through KCNQ2/3 and KCNQ3/5 No effect on KCNQ1- present in cardiac cells KCNQ4-present in auditory system EZOGABINE- mechanism of action

13. Linear pharmacokinetic profile with dosage up to 1200mg/day Rapidly absorbed after oral administration Bioavailibility of oral EZG is about 60% Protien binding is approximately 80% Volume of distribution at steady state is about 2-3 L/kg Pharmacokinetics

14. Metabolized by: N- acetylation to the mono-acetylated metabolite, glucuronidation to form N- glucronide structure Metabolites have minimal pharmacological activity Majority of drug and metabolites excreted through kidney. Small amount excreted through feces. Plasma half life is 8 hrs for drug and metabolites. Pharmacokinetics

15. May increase the QTc interval. PHARMACODYNAMICS

16. Low potential for drug interaction No potential to inhibit major cytochrome P450 isoenzyme . It is neither substrate nor inhibitor of P-glycoprotein transporter. Drug interactions

17. No clinically significant effects of the following AEDs on Ezogabine pharmacokinetics: Carbamazepine Levetiracetam Oxcarbazepine Phenobarbitol Phenytoin Topiramate Valproate Drug interactions

18. However lamotrigine increase 15% concentration of ezogabin Ezogabine plasma levels may be reduced by concomitant administration of phenytoin or carbamazepine . N-acetyl metabolite of ezogabine may inhibit renal clearance of digoxin Drug interactions

19. Indicated for adjunctive treatment for Partial onset seizures With or without generalization For patients 18 years of age and older. INDICATION

20. Patients can be considered drug resistant when Failed to have seizure control with 2 or more AEDs Used appropriately Tolerated by the patient. INDICATION

21. The initial dosage should be 100 mg 3 times daily (300 mg per day) for 1 week. Titrate to maintenance dosage by increasing the dosage at weekly intervals by no more than 150 mg per day. Optimize effective dosage between 200 mg 3 times daily (600 mg per day) to 400 mg 3 times daily (1,200 mg per day). DOSAGE AND ADMINISTRATION

22. When discontinuing EZOGABINE, reduce the dosage gradually over a period of at least 3 weeks. Dosing adjustments are required for geriatric patients and patients with moderate to severe renal or hepatic impairment. DOSAGE AND ADMINISTRATION

23. Most frequent Somnolence Dizziness Confusion Asthenia less frequent Speech disorder Vertigo Tremor Amnesia ADVERSE DRUG REACTION

24. Urinary retention Urinary hesitancy This is because of Inhibition of bladder contractility secondary to ezogabine’s effect on KCNQ channels in detrusor muscle of the bladder. ADVERSE DRUG REACTION

25. urologic symptoms should be carefully monitored. Closer monitoring is recommended for, benign prostatic hyperplasia [BPH] cognitively impaired patients anticholinergics PRECAUTION

26. Monitor for dizziness and somnolence QT prolongation: QT interval should be monitored in patients taking concomitant medications known to increase the QT interval or with certain heart conditions. when EZOGABINE is discontinued, it should be withdrawn gradually when possible to minimize the potential of increased seizure frequency PRECAUTION

27. STUDY 205: A multicenter, randomized, double-blind, placebo-controlled trial was performed of retigabine for partial-onset seizures. CONCLUSION : Adjunctive therapy with retigabine is well tolerated and reduces the frequency of partial-onset seizures in a dose-dependent manner. CLINICAL TRIALS

28. Study 301 : multicenter, randomized, double-blind, parallel-group trial of ezogabine (retigabine) in partial epilepsy. CONCLUSION : EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures. CLINICAL TRIALS

29. STUDY 302 : This was a multicenter, randomized, double-blind, placebo-controlled trial in adults with ≥4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs . CONCLUSIONS: In this dose-ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures CLINICAL TRIALS

30. Percent Change from Baseline in Total Partial Seizure Frequency (Double-Blind Phase) – ITT Population for Study 205 and ITT Double-Blind Population for Studies 301 and 302

31. first antiepileptic drug with a very specific effect on central nervous system potassium channels . Having minimal drug interactions Mostly renal excretion few safety concerns most side effects are those typically seen with antiepileptic agents. Conclusion

32. There are no adequate and well-controlled studies in pregnant women. conclusion

33. Harrision’s principles of internal medicine, 17th edition Ezogabine : A New Angle On Potassium Gates.Epilepsy Currents, Vol. 11, No. 3 (May/June) 2011 pp. 75–78© American Epilepsy Society. Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM. Randomized, multicenter, dose-ranging trail of retigabine for partial-onset seizures. Neurology. 2007;68:1197-204. REFERENCES

34. French J, Abou-Khalil B, Leroy R, Yacubian E, Shin P, et al. Randomized, double-blind, placebo-controlled trial of ezogabine ( retigabine ) in partial epilepsy. Neurology. 2011 May 3;76(18):1555-63. Brodie M, Lerche H, Gil-Nagel A, Elger C, Hall S, et al. Efficacy and safety of adjunctive ezogabine ( retigabine ) in refractory partial epilepsy. 2010 Nov. Neurology. 16:75:1817-24. Wikipedia and various internet sites Steve chung , kirsten M Kelly, Courtney Schussee ; Neurology research international journal, 20 june 2011. REFERENCES

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