Refractory Partial Onset Epilepsy: Evaluation of retigabine Therapy

Ajay Shukla PharmD Candidate 2013

Ernest Mario School of Pharmacy Rutgers, The State University of New

Jersey

Objectives

• To explain the etiology, pathophysiology, and treatments for partial onset seizures.

• To discuss the medication profile of retigabine including indication, mechanism of action, pharmacokinetics, adverse effects, and monitory parameters.

• To review the two pivotal trials used for FDA approval of retigabine and determine its place in current clinical practice.

Outline

• Partial Onset Seizures – Epidemilogy – Etiology – Pathophysiology – Treatment

• Ezogabine [a.k.a. retigabine (Potiga®)] – Pharmacology – Administration – Pharmacokinetics – Misc

• RESTORE1 • RESTORE2 • Clinical Recommendation

Introduction: Epilepsy

Definition: at least two unprovoked seizures separated by 24 hours

A result of abnormal electrical activity in the brain

Bimodal Distribution

Newborn-young children

Elderly ≥65 years old

Etiology

• Idiopathic – Unprovoked seizure without a readily identifiable cause

with some suspected genetic component

• Cryptogenic – Seizure without a readily identifiable cause for partial-

onset seizure

• Other Causes – Neuronal injury – Sleep changes – Stress – Hormonal changes – Drug induced

Pathophysiology

• Partial Seizures

– Simple

– Complex

– Secondary Generalized

• Complex Seizures

– Absense

– Myoclonic

– Clonic

– Tonic

– Tonic-Clonic

– Atonic

– Infantile Spasm

http://epilepsy.med.nyu.edu/diagnosis-treatment/eeg/overview-electroencephalograpy http://nursingplanet.com/Quiz/eeg_quiz.html

General Treatment Approach

• Start with monotherapy

• Use combination therapy with different mechanisms of action if the primary therapy has not achieved sufficient seizure control

• Monitor seizure frequency with a seizure diary and adverse effects of therapy

Treatment Guidelines

First Line Agents Alternative Therapies

ILAE Guidelines2

(2006)

Partial Seizures

Adults

Elderly

Carbamazepine

Phenytoin

Valproic Acid

Lamotrigine

Gabapentin

Gabapentin

Lamotrigine

Oxcarbazepine

Phenobarbital

Topiramate

Vigabatrin

Carbamazepine

AAN Guidelines3,4

(2004)

Partial Seizures

Carbamazepine

Valproic Acid

Phenobarbital

Lamotrigine

Gabapentin

Oxcarbazepine

Topiramate.

NICE Guidelines5

(2012)

Partial Seizures

Carbamazepine

Lamotrigine

Levetiracetam

Oxcarbazepine

Valproic Acid

Treatment Guidelines

First Line Agents Alternative Therapies

AAN Guidelines3,4

(2004)

Refractory Partial

Seizures (adjunctive)

Gabapentin

Lamotrigine

Topiramate

Tiagabine

Oxcabazepine

Levetiracetam

Zonisamide

NICE Guidelines5

(2012)

Refractory Partial

Seizures (adjunctive)

Carbamazepine

Clobazam

Gabapentin

Lamotrigine

Levetiracetam

Topiramate

Valproic Acid

Oxcabazepine

Eslicarbazepine

Lacosamide

Phenobarbital

Phenytoin

Pregabalin

Tiagabine

Vigabatrin

Zonisamide

Ezogabine (Potiga®) [a.k.a Retigabine]

• Manufacturer – Valean Pharmaceuticals

• How Supplied – 50-mg Tablets: purple, round, film-coated

• (NDC 0173-0810-59) [#90]

– 200-mg Tablets: yellow, oblong, film-coated tablets • (NDC 0173-0812-59) [#90]

– 300-mg Tablets: green, oblong, film-coated tablets • (NDC 0173-0813-59). [#90]

– 400-mg Tablets: purple, oblong, film-coated tablets • (NDC 0173-0814-59) [#90]

Overview

• Indication:

– Adjunct treatment for partial onset seizures

• Mechanism of Action:

– Stabilizing the open KCNQ (Kv7.2-7.5) voltage-gated potassium channels thus enhancing M-current and suppressing neuronal excitability

Dosing & Administration

• Adult – Initial = 100mg TID (increase weekly ≤150mg/day) – Maintenance = 200-400mg TID (Max: 1200mg/day)

• Geriatric – Initial = 50mg TID (increase weekly ≤150mg/day) [Max:

750mg/day]

• Renal Impairment – CrCl <50 or ESRD on HD: initial = 50mg TID [Max:

600mg/day]

• Hepatic Impairment – Moderate Impairment : 50mg TID [Max: 750mg/day] – Severe Impairment : 50mg TID [Max: 600mg/day]

Pharmacokinetics

• Absorption – Bioavailability: 60% (PO)

• Distribution – Protein Binding: 80% (ezogabine); 45% (NAMR)

• Metabolism – Glucuronidation – Acetylation active metabolite

• Excretion – Urine and feces – T½: 7-11hrs; 9.1-14.3 (elderly patients)

– Time to peak: 0.5-2hrs (1.25-2.75hrs when administered with high-fat meals)

Adverse Effects & Safety

• Dizziness and somnolence

– (during titration)

• Confusion

• QT prolongation

• Suicidal ideation

• Urinary retention

• Nausea

• Tremor

• Pregnancy Category C

• Schedule: CV

Monitoring Parameters

• Seizures

• Electrolytes

• Bilirubin

• AST/ALT

• SCr

• QT interval

• Urinary retention

• Mental status

RESTORE 1

• Objective – To evaluate the efficacy and safety of retigabine

1200mg/day as adjunctive treatment for refractory partial-onset epilepsy

• Design – Multinational, multicenter, randomized, double-blind,

parallel-group, placebo-controlled, ITT trial

• Treatment Regimen: • 8 week baseline assessment and screening

• 18 week double-blind treatment period

RESTORE 1

Inclusion Criteria

• Age = 18-75yrs

• Refractory partial-onset with or without secondary generalization

• ≥4 seizures/28 days over the 8 week assessment period where there was no more than 21days without a seizure

Exclusion Criteria

• CrCl < 50ml/min

• QTc > 430ms (men)

• QTc >450ms (women)

• Treatment with – Retigabine in a previous study

– Felbamate or vigabatrin in the previous 6 months

• History of – Pseudoseizures, generalized

seizures, clustering, status epilepticus

RESTORE 1

Intervention

• Randomized 1:1 to either retigabine 400mg TID (~q8hr) or placebo

• Start at retigabine 100mg TID and increase weekly 150mg/day (50mg TID)

Outcome Measures

• Percent change in 28day total partial-seizure frequency from baseline to 18-week double blind period [FDA]

• Responder rate [EMA]

Enrollment

Placebo

• 152 randomized

• 152 ITT

• 137 entered maintenance

• 127 completed treatment

Retigabine 1200mg/day

• 154 randomized

• 153 ITT

• 119 entered maintenance

• 97 completed treatment

French JA, et al. Neurol 2011;76:1555-63

French JA, et al. Neurol 2011;76:1555-63

French JA, et al. Neurol 2011;76:1555-63

RESTORE 1

• Conclusion • Retigabine 1200mg/day demonstrated a significant

reduction in median seizure frequency in patients with refractory partial onset epilepsy.

• While efficacious, high dose retigabine was also met with higher rates of adverse effects.

• Retigabine 1200mg/day allowed for an increase in seizure free days amounting to 31.6 days per year

RESTORE 2

• Objective – To evaluate the efficacy and safety of retigabine as

adjunctive treatment for refractory partial-onset epilepsy

• Design – Multinational, multicenter, randomized, double-blind,

parallel-group, placebo-controlled, ITT trial

• Treatment Regimen – 8 week baseline assessment and screening – 16 week double-blind treatment period – 4 week transition phase (open-label extension) or

discontinue therapy

RESTORE 2

Inclusion Criteria

• Age = 18-75yrs

• Refractory partial-onset with or without secondary generalization

• ≥4 seizures/28 days over the 8 week assessment period where there was no more than 21days without a seizure

Exclusion Criteria

• CrCl < 50ml/min

• QTc > 430ms (men)

• QTc >450ms (women)

• Treatment with – Felbamate or vigabatrin in the

previous 6 months

• History of – Pseudoseizures, generalized

seizures, clustering, status epilepticus

RESTORE 2

Intervention

• Randomized 1:1:1 to either retigabine 200mg TID (q8hr), retigabine 300mg TID (q8hr) or placebo

• Start at retigabine 100mg TID and increase weekly 150mg/day (50mg TID)

Outcome Measures

• Percent change in 28day total partial-seizure frequency from baseline to 18-week double blind period [FDA]

• Responder rate [EMA]

Enrollment

Placebo

179 randomized

179 ITT FDA

164 ITT EMA

153 completed treatment

140 OLE

Retigabine 900mg

• 181 randomized

• 181 ITT FDA

• 158 ITT EMA

• 135 completed treatment

• 127 OLE

Retigabine 600mg

179 randomized

178 ITT FDA

149 ITT EMA

121 completed treatment

109 OLE

Brodie MJ, et al. Neurol 2010;75:1817-24

Brodie MJ, et al. Neurol 2010;75:1817-24

Brodie MJ, et al. Neurol 2010;75:1817-24

RESTORE 2

• Conclusion

– Addition of either retigabine 600mg/day and 900mg/day demonstrated a significant reduction in median seizure frequency in patients with refractory partial onset epilepsy.

– Adding retigabine shows promise in controlling seizure frequency

Cost Comparison

Drug Price

Retigabine (Potiga®) 50mg 200mg/300mg/400mg

$356.40 $712.80

Felbamate (Felbatol®) 400mg 600mg

$345.10 $395.95

Levetiracetam (Keppra®) 250mg 500mg 750mg 1000mg

$23.99 $29.99 $34.99 $210.99

Tiagabine (Gabitril®) 2mg 4mg 12mg 16mg

$192.01 $185.48 $207.85 $300.26

http://kinray.com and http://epocrates.com

Conclusion & Recommendation

• Don’t add to formulary, more data is needed to assess efficacy

• Based on other drugs available for this category with similar pricing there is no need to add this one to formulary despite its novel mechanism of action

References

1. Rogers SJ, Cavazos JE. Epilepsy. In: Dipiro JT, Talvert RL, Yee GC, et al, editors. Pharmacotherapy: A Pathophysiologic Approach. New York: McGrawHill; 2011. [accessed 2012 Jun 10]. Available from: http://accesspharmacy.com

2. Glauser T, Ben-Menachem E, Burgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47:1094-1120.

3. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy: Report of the therapeutics and technology assessment subcommittee and quality standards subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurol 2004;62:1252-60.

4. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Theodore WH, et al. Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy: Report of the therapeutics and technology assessment subcommittee and quality standards subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurol 2004;62:1261-73.

5. National Institute for Health and Clinical Experience. The epilepsies: The diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE Clinical Guideline 137. 2012 Jan [accessed 2012 Jun 10]. Available from: http://guidance.nice.org.uk/CG137

6. Potiga® (ezogabine) [package insert]. Research Triangle Park, NC: GlaxoSmithKline;2011 7. Retigabine. Lexicomp online [update daily; cited 2012 Jun 10]. Available from: http://online.lexi.com 8. Kinray Wholesaler [accessed 2012 Jun 10]. Available from: http://kinray.com/ 9. French JA, Abou-Khalil BW, Leroy RF, Yacubian EMT, Shin P, Hall S, et al. Randomized, double-blind, placebo-controlled trial of

ezogabine (retigabine) in partial epilepsy. Neurol 2011;76:1555-63 10. Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S, Shin P, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory

partial epilepsy. Neurol 2010;75:1817-24

Questions?