Single Technology Appraisal Cannabidiol with clobazam for ...
AEDs from the past to present...Rescue therapy for aura or SPS Disadvantage Less effecve Sedave...
Transcript of AEDs from the past to present...Rescue therapy for aura or SPS Disadvantage Less effecve Sedave...
7/31/09
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Dr. Yotin Chinvarun M.D. Ph.D.
Comprehensive Epilepsy and Sleep disorder Program PMK hospital
Conventional AEDs New AEDs
New AEDs
Pregabalin
NEW
OLD
Pregabalin
1st genera*on AEDs
• Phenytoin • Carbamazepine • Valproate • Phenobarbital • Clobazam
2nd genera*on AEDs
• Felbamate 1993 • Lamotrigine 1994 • Topiramate 1996 • Tiagabine 1997 • Levi*racetam 1999 • Oxcarbamazepine 2000 • Zonisamide 2000 • Pregabalin 2004
AEDs
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Brivaracetam
Eslicarbazepine Fluorofelbamate
Ganaxolone Huperzine
JZP‐4
Lacosamide Licarzepine
Losigamone NS1209
• Re*gabine • Rufinamide
• RWJ 333‐369 (Carisbamate) • Seletracetam
• Safinamide
• SPD421 • S*ripentol • Talampanel • Valrocemide
New AEDs
3rd genera*on AEDs Introduced in the treatment of epilepsy in 1938
Advantage Par*al onset seizure
2 GTCS
Parenteral form and single dose daily
Disadvantage Adverse reac*ons, dose‐related; ataxia, nystagmus, slurred
speech, and dizziness. High‐dose phenytoin can cause peripheral neuropathy, cerebellar atrophy, chronic side effect cogni*ve impairment, gum hypertrophy, course faces, acnes etc
Significant drug interac*on
Phenytoin
Advantage Idiopathic generalized epilepsy Myoclonic epilepsy Par*al seizure Parenteral form
Disadvantage Teratogenicity Side effect; weight gain, tremor, transient hair loss, Endocrine and metabolic dysfunc*ons
Valproate
Advantages Par*al onset seizure
2 GTCS
Disadvantages Common side effect; dizziness, ataxia, Severe drug erup*ons are rare
Significant drug interac*on
Carbamazepine
• Had been used since 1912 Advantages
Par*al onset seizure 2 GTCS Effec*ve in refractory seizure Parenteral form and single dose daily
Disadvantages Seda*on and hypnosis Cogni*ve impairment Significant drug interac*on
Phenobarbital
Advantage Added on par*al seizure
Rescue therapy for aura or SPS
Disadvantage Less effec*ve Seda*ve side effect
Clobazam
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Advantage Highly effec*ve in severe resistance epilepsy Par*al‐onset seizures with or without secondarily generalized seizures (adult‐monotherapy)
Par*al and generalized seizures associated with Lennox‐Gastaut syndrome (children‐adjunc*ve therapy)
Disadvantage Serious side effect: Aplas*c anemia, hepa*c failure Significant drug interac*on Not available
Felbamate
• Advantages
Easy to use, well tolerated, No interac*ons, no enzyme induc*on
When to use it
Par*al seizures
Early add‐on
Useful in the elderly
• Disadvantages
Variable absorp*on
Wide dosage range tds dosing, satura*on effect
Moderate efficacy
Unknown teratogenicity
Gabapentine
• Advantages
Broad spectrum of efficacy, favourable pharmacokine*cs, Favourable cogni*ve profile, fewer interac*ons
Par*al seizure, Idiopathic generalized epilepsy alterna*ve or adjunct to valproate, Symptoma*c generalized epilepsy, Lennox Gastaut Syndrome
• Disadvantages
Rash, especially with valproate (some*me severe)
Slow *tra*on
Interac*on with carbamazepine
Lamotrigine
• Advantages Known mode of ac*on, Favourable pharmacokine*cs, Easy to use, Few
interac*ons, No enzyme induc*on Added on Par*al seizures
Currently rarely used
Infan*le spasms
• Disadvantages
Seda*on
Psychiatric effects
Seizure worsening in some
Irriversibel visual field constric*on
Unknown teratogenicity
Vigabatrin
n Advantages • Broad spectrum of efficacy, Favourable pharmacokine*cs, Few interac*ons, No enzyme induc*on
• Par*al seizures mono/ added on therapy • Symptoma*c generalized epilepsy
n Disadvantages • Weight loss, hypoesthesia • Cogni*ve impairment • Glaucoma, ? cataract • Very slow *tra*on, rapidly *tra*on caused language difficulty
• Unknown teratogenicity
Topiramate
• Advantages
Known mode of ac*on, toxicity mild, No enzyme induc*on
Added on par*al onset seizure
• Disadvantages
CNS side effect, Dizziness
Inducible metabolism Short half life; tds dosing
Unknown teratogenicity Not available
Tiagabine
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n Advantage • No drug interac*on • Well tolerate and highly effec*ve • Par*al seizure, alterna*ve for idiopathic generalized epilepsy
• Parenteral form
n Disadvantage • Side effects: somnolence, asthenia, infec*on, dizziness, headache, depression, UTI
Levetiracetam
n Advantage • Close structure similarly to Carbamazepine but beher tolerated, Fewer drug interac*on
• Par*al onset seizure • 2 GTCS
n Disadvantage • Hyponatremia in 2.5% More commonly in older pa*ents
• 25% cross –sensi*vity with carbamazepine
Oxcarbazepine
Advantage Good bioavailability Par*al seizure 2 GTCS Alterna*ve valproate for myoclonic seizure
Disadvantage Significant drug interac*on, increased by approximately 30‐40%, when given concomitantly with enzyme‐inducing AEDs
Seda*on, fa*gue, dizziness, ataxia, confusion, cogni*ve impairment, including word finding difficulty, weight loss/anorexia, Depression & psychosis has also been reported, renal stone
Zonisamide n FDA approved in early 2009
n Advantage ‒ Add‐on therapy for the treatment of par*al‐onset seizures in adult >
17 yrs with epilepsy. ‒ Demonstrated efficacy and safety when combined with a broad
range of exis*ng AEDs ‒ Oral and IV form
n Mechanism; selec*vely enhances slow inac*va*on of sodium channels and interacts with the neuroplas*city‐relevant target ‐collapsin response mediator protein‐2 (CRMP‐2)
n Disadvantage ‒ * Dizzines ‒ * Nausea ‒ * Diplopi ‒ * Blurring Vision, * Vomi*ng, * Fa*gue, * Ataxia
Lacosamide
• Novel, voltage‐gated sodium channel blocker
• Advantage – Par*al‐onset seizures with or without secondary generaliza*on in combina*on with other an*‐epilep*c drugs
– Responder rate (> or = 50% decrease in seizure frequency) for eslicarbazepine acetate 800 mg and 1200 mg that ranged between 32 percent and 43 percent
– Safety profile was favorable – Incidence of CNS side effects was low.
Eslicarbazepine
• Seizure type
• Epilepsy syndrome
• Pharmacokine*c profile
• Interac*ons/other medical condi*ons
• Efficacy
• Expected adverse effects
• Cost
Choosing AEDs
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• Broad‐Spectrum Agents
• Valproate • Felbamate • Lamotrigine • Topiramate • Zonisamide • Leve*racetam • Rufinamide*
Narrow-Spectrum Agents
Partial onset seizures Phenytoin Carbamazepine Oxcarbazepine Gabapentin Pregabalin Tiagabine Lacosamide*
Absence Ethosuximide
Choosing AEDs
(Broad Spectrum AEDs)
PHT, PB CBZ, OXC
GBP, VGB, PGB
VPA, LTG, TPM, ZNS, LEV, (FBM)
Drug Partial Secondary generalized
I° Tonic-clonic
Absence
Myoclonic
phenytoin + + + - -
carbamazepin
e
+' + + - -
valproate acid + + + + +
phenobarbital + + + 0 ?+
primidone + + + 0 ?+
ethosuximide 0 0 0 + 0
Traditional AEDs
felbamate + + ?+ ?+ ?+
Gabapentin/
Pregabalin
+ + ?+ 0 ?‑
lamotrigine + + + + +/- *
topiramate + + + ? ?+
tiagabine + + ? ? ?
zonisamide + + ?+ ?+ ?+
levetiracetam + + + ?+ +
oxcarbazepine + + ? + - -
Drug Partial 2 GTCS I° GTCS Absence Myoclonic
2nd generation AEDs
Stein and Kanner. Drugs 2009;69:199-222
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Landmark and Johannessen. Drugs 2008;68:1925-1939
Monotherapy for Partial Seizures
Best evidence and FDA indication: Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate
Similar efficacy, likely better tolerated:
Lamotrigine, Gabapentin, Levetiracetam
Also shown to be effective:
Valproate, Phenobarbital, Felbamate, Lacosamide
Limited data but commonly used:
Zonisamide, Pregabalin
Choosing AEDs
• Monotherapy for Generalized-Onset Tonic-Clonic Seizures
• Best evidence and FDA Indica*on: • Valproate, Topiramate
• Also shown to be effec*ve:
• Zonisamide, Levetiracetam
• Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )
• Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies
•
Choosing AEDs
• Absence seizures
• Best evidence: – Ethosuximide (limited spectrum, absence only) – Valproate
• Also shown to be effec*ve:
– Lamotrigine
• May be considered as second‐line:
– Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam
Choosing AEDs
• Myoclonic Seizures
• Best evidence: – Valproate – Levetiracetam (FDA indication as adjunctive tx) – Clonazepam (FDA indication)
• Possibly effec*ve: – Zonisamide, Topiramate
Choosing AEDs 2nd AEDs VS CBZ in Partial Sz and GTCS Monotherapy
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• Lennox‐Gastaut Syndrome
• Best evidence/FDA indica*on*: – Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide – * FDA approval is for adjunctive treatment for all except clonazepam
• Also effec*ve: – Valproate
• Some evidence of efficacy: – Zonisamide, Levetiracetam
Choosing AEDs
• Simplifies treatment, reduces adverse effects
• Conversion to monotherapy from polytherapy
– Eliminate seda*ve drugs first – Withdraw an*epilep*c drugs slowly over several months
AEDs Monotherapy
Simple partial carbamazepine
lamotrigine oxcarbazepine levetiracetam
Expert’s opinion: Symptomatic epilepsy Expert’s opinion: Symptomatic epilepsy
Meta-analysis of Add-on of New AEDs (Marson et al., 1997, 2001; Otoul et al., 2005)
AEDs and Evidence base