This document discusses a study evaluating the use of the medication retigabine for refractory partial onset epilepsy. It begins with an introduction on epilepsy and outlines objectives to discuss partial seizures, retigabine's mechanism and profile, and two clinical trials. It reviews the RESTORE 1 and RESTORE 2 trials which found retigabine reduced seizure frequency but was associated with higher adverse effects. The document concludes retigabine shows promise but more data is needed before adding it to the formulary due to other available treatment options having similar efficacy and cost.
Partial Onset Seizures and Retigabine Powerpoint (Printable)
1. 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
2. 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.
4. 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
5. 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
8. 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
17. 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
18. 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
19. 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]
24. 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
25. 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
26. 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
27. 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]
28. 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
32. 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
34. 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
35. References
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