A comparison between newer and older anti-seizure medications with a review of major studies comparing these drugs

1. Old vs New Antiseizure drugs:
What has changed?
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist,
Manipal Hospital, Bengaluru

2. The ideal ASD: the elusive goal
Parameter The ideal AED would …
Efficacy Be effective in controlling seizures completely, resulting in sustained seizure freedom
Safety and
tolerability
Not cause adverse side effects or at least display a highly favourable safety and tolerability
profile
Spectrum
of activity
Have a broad spectrum of activity (especially for generalised epilepsies and childhood
epilepsies, and if the epilepsy syndrome is unclear)
Pharmacokinetic
profile
Have rapid absorption, rapid penetration into the CNS, good bioavailability, rapid achievement
of steady-state concentrations, linear kinetics, minimal or no protein binding, a terminal
elimination half-life that allows once- (or twice-) daily dosing, and absence of drug–drug
interactions; have no active metabolites and minimise the risk of complications

3. 1st generation ASD: introduced before 1985.
2nd generation ASDs: introduced between 1985 and 2015.
3rd generation ASDs: introduced after 2015.
1900-1950 1951-1985 1986-2000 2001-2015 2015-2022
Phenobarbitone Carbamazepine Felbamate Eslicarbazepine Brivaracetam
Phenytoin Clobazam Fosphenytoin Lacosamide Cannabidiol
Clonazepam Gabapentin Perampanel Cenobamate
Diazepam Lamotrigine Pregabalin Everolimus
Ethosuximide Levetiracetam Rufinamide Fenfluramine
Midazolam Lorazepam Stiripentol
Primidone Oxcarbazepine
Valproic acid Tiagabine
Topiramate
Vigabatrin
Zonisamide
Emilio Perucca. Acta Epileptologica 2021. 3: 22.

4. GABAergic:
Prolongs Cl- channel opening: Phenobarbitone
Opens Cl- channel more often: Clobazam
Inhibits GABA transaminase: Vigabatrin
Blocks synaptic GABA reuptake: Tiagabine
Ca channel blockers:
High voltage activated channel:
Gabapentin, Pregabalin
Low voltage activated channel:
Ethosuximide
Zonisamide:
Blocks Na channels.
Blocks T type Ca channel.
Potentiates GABA
Fast inactivation of VGSC:
PHT, OXC, CBZ.
Slow inactivation of VGSC:
LCS, Eslicarbazepine.
Others: LTG, VPA, TPM,
FBM, ZSN, Rufinamide.

5. Conventional AEDs
Newer AEDs
Monotherapy
Polytherapy
Comparative RCTs
Drops outs due to drug
interactions, adverse effects
CBZ, PHT, VPA
ESM (only in absences)
Polytherapy in DREs
Rational polytherapy
RCTs of monotherapy
(TIG failed)
Serious adverse effects
(FBM, VGB)
RCTs of add-on trials in DRE
LTG, TPM, OXC,
LEV, GBP, ZSN,
LCM
Specific indications
VGB in West syn
STR/TPM in SMEI
PER in PME
LTG/TPM/RFM in LGS

6. Advantages of newer ASMs
• Novel mechanisms of action.
• Less of enzyme induction, drug interactions.
• Better pharmacokinetic profile.
• Better tolerability.
• Less risk of hypersensitivity.
• Safety in pregnancy (however, many newer ASMs lack data).

7. Patient oriented
choice of AED
Disease oriented
choice of AED
Patient factors
Drug
Epilepsy
Physiological variables: age,
gender, weight
Comorbidities
Concomitant drugs
Psychosocial variables
Seizure type: focal, generalised
Epilepsy Syndrome: LGS, JME
EEG and other clinical
features.
Pharmacokinetics
Pharmacodynamics
EBM: RCTs, meta-analysis,
guidelines.
Expert opinion
Pharmacogenomics.
Clinical experience

8. Condition Choose Avoid
Obesity+/- diabetes TPM, ZSN VPA, PGB, GBP, PER
Migraine TPM, VPA, ZSN, PGB, GBP -
Skin rash LEV, GBP, PGB, TPM, VPA, PER, LCM LTG, OXC, CBZ, PHT, PB
Neuropathic pain PGB, GBP, CBZ, OXC, PHT -
Depression/Behav/Psychosis LTG, CBZ, OXC, VPA, PGB LEV, PB, PRM, TPM, ZSN, PER
Cognitive dysfunction LTG, LEV, OXC PB, TPM, ZSN
Concomitant drugs GBP, LEV, PGB, VPA Enzyme inducers
Restless legs syndrome GBP, PGB, CZP. -
Renal stone - TPM, ZSN
Glaucoma - TPM
Hematological disorder - CBZ, VPA
Choice of AEDs related to comorbidities
Lee BI, et al. Clinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy.
Epilepsy Res 2019;156:106165

9. Condition Choose Avoid
Hyponatremia - OXC, ESL, CBZ
Hepatic disease New AEDs (mainly renal excretion) VPA
Renal disease Old AEDs (mainly hepatic metabolism) -
Osteoporosis LTG, LEV Enzyme inducers, TPM, VPA, ZSN
Gait disturbances - CBZ, PHT, PER
Tremor TPM, PER VPA
Parkinson disease ZSN VPA
Cardiac arrhythmia - Sodium channel blockers
Cancer VPA, LEV, PER Enzyme inducers
Heat stroke - TPM, ZSN
Atherosclerosis - Enzyme inducers
Choice of AEDs related to comorbidities
Lee BI, et al. Clinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy.
Epilepsy Res 2019;156:106165

10. • 716 Patients were randomly assigned to VPA, LTG or TPM.
• Time to treatment failure: VPA was significantly better than TPM (HR 1·57 [95% CI 1·19–
2·08]), but there was no significant difference between VPA and LTG (1·25 [0·94–1·68]). For
patients with IGE, VPA was significantly better than both LTG (1·55 [1·07–2·24] and TPM
(1·89 [1·32–2·70]).
• Time to 12-month remission: VPA was significantly better than LTG overall (0·76 [0·62–0·94]),
and for the subgroup with IGE 0·68 (0·53–0·89). But no significant difference between VPA and
TPM in either the analysis overall or for the subgroup with IGE.
Lancet 2007; 369: 1016–26

12. Lancet 2007; 369: 1000–15
• 1721 patients were randomly assigned to receive CBZ, GBP, LTG, OXC or TPM.
• Time to treatment failure: LTG was significantly better than CBZ (HR 0·78 [95% CI 0·63–
0·97]), GBP (0·65 [0·52–0·80]), and TPM (0·64 [0·52–0·79]), and had a non-significant
advantage compared with OXC (1·15 [0·86–1·54]).
• Time to 12-month remission: CBZ was significantly better than GBP (0·75 [0·63–0·90]), and
had a non-significant advantage over LTG (0·91 [0·77–1·09]), TPM (0·86 [0·72–1·03]), and
OXC (0·92 [0·73–1·18]).
• Conclusion: LTG is better than CBZ for time to treatment failure outcomes.

15. Lancet 2021; 397: 1363–74
• 990 children and adults were randomly assigned to receive LTG, LEV or ZSN.
• The non-inferiority limit was a hazard ratio (HR) of 1·329. A HR > 1 indicated that an event was more
likely on LTG.
• LEV did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission
versus LTG (HR 1·18; 97·5% CI 0·95–1·47) but ZSN did meet the criteria for non-inferiority versus LTG
(1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with LTG than both
LEV (HR 1·32 [97·5% CI 1·05 to 1·66]) and ZSN (HR 1·37 [1·08–1·73]).
• Adverse reactions were reported by 108 (33%) participants who started LTG, 144 (44%) participants
who started LEV and 146 (45%) who started ZSN.
• LTG was superior in the cost-utility analysis.

18. Lancet 2021; 397: 1375-86
• 520 adults and children were randomised to receive LEV or VPA.
• LEV did not meet the criteria for non-inferiority in the ITT analysis of time to 12-
month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP
analysis showed that the 12-month remission was superior with VPA than with LEV.
• Adverse reactions were reported by 96 (37%) participants on VPA and 107 (42%)
participants on LEV.
• LEV was dominated by VPA in the cost-utility analysis.

21. Summary of SANAD I and II trials.
• LTG should be considered as one
of the treatment of first choice in
focal epilepsy.
• It is clinically better than CBZ.
• It is more efficacious, better
tolerated and more cost-effective
than LEV and ZSN.
• VPA is superior to LTG, LEV and
TPM in the treatment of
generalised epilepsy.
• VPA is better tolerated than TPM
and more efficacious than LTG.
• LEV was neither clinically
effective nor cost- effective when
compared to VPA.

22. Newest ASDs

23. Brivaracetam
• Indication: focal seizures in patients aged 1 month and older.
• Mechanism: SV2A modulator with higher specificity than LEV.
• Adverse effects: Somnolence, fatigue, dizziness, behavioural issues,
hypersensitivity can occur. Less behavioural adverse effects than LEV.
• Drug interactions: Yes (reduced by Rifampicin, enzyme inducing ASDs;
increased by CBD; increased CBZ).
• Oral bioavailability is 100%
• Indications and safety is expected to be like LEV.

24. • 37 patients with GGE, JME was the most common seizure type (43.2%).
• The primary indications for starting BRV were lack of efficacy (51.4%) and adverse
events (27%) of other AEDs.
• Retention rate at 6 months was 81.1%; 83.8% of patients were responders, and 62.2%
achieved seizure freedom.

25. Brivaracetam in GGE
• Patients with previous response to
VPA and LEV showed good
response to BRV.
• Outcome was not good in those who
had failed multiple AEDs.
• LEV related psychiatric adverse
effects resolved in 79.8% of patients.
• Dose range of 100-200 mg/day.
• BRV monotherapy in 32% patients.
• Better tolerability than LEV.

26. Perampanel
• Indication: Monotherapy in focal seizures +/- generalisation in patients
aged 4 years of age or older. Adjunctive therapy in primary GTCS.
• Mechanism: non-competitive antagonist of AMPA glutamate receptor
on post synaptic neurons.
• Adverse effects: Somnolence, fatigue, dizziness, behavioural issues.
• Drug interactions: Yes. Levels are reduced by enzyme inducers. PER
can reduced effectiveness of OCPs.
• Oral bioavailability is 100%, with half life of 105 hours.
• Dose: start at 2 mg once daily. Increase by 2 mg every 2-4 weeks upto 8-
10 mg/d. When used with enzyme inducing ASDs, start with 4 mg/d,
increase by 2 mg every week.

27. Neurology® 2015;85:950–957
• This study provided Class 1 evidence.
• This was a multicenter, randomized, double-blind, placebo-
controlled, parallel-group study.
• Patients 12 years or older with drug resistant primary GTC
seizures and IGE.
• Patients in the PER group received an initial daily dose of 2 mg,
before uptitration in weekly 2-mg increments to the targeted daily
dose of 8 mg or the highest tolerated dose (whichever was lower).
• Study duration was 4 weeks titration + 17 weeks maintenance.

28. Results
• PER did not aggravate absence seizures or myoclonus in IGE patients.
• Response rates for absence seizure freedom were 22.2% for PER vs 12.1% for
placebo.
• Response rates were 16.7% vs 13.0%, respectively, for myoclonic seizure
freedom.
• In an open-label extension of the same study of up to 2.5 years (136 weeks),
the median percent reduction in PGTC seizure frequency was 91.3% among 68
patients taking PER , and responder rate was 75%.
• The clinical benefits and tolerability over the longer term were similar.

29. • Retrospective study of 81 patients with RSE and super-refractory SE.
• The median period from onset of SE to PER initiation was 100 hrs.
• Patients had already failed a median of 3 AEDs (range of 1-7).
• Initial dose was 2-36 mg (median== 4 mg).
• Maintenance dose of 4-16 mg (median 12 mg).

30. Results
• Cessation of SE was attributed to PER in 27 patients (33.3%, responder
group), with a median response time of 40 h (range = 1 to 69 h).
• The number of AEDs and the dosages of topiramate use at the time of
first PER administration were significantly different between the
responder and non-responder groups.
• Patients with NCSE had higher responder rates.
• Post traumatic SE responded poorly and post anoxic SE responded very
well.
• No cardio respiratory or liver adverse effects were noted in doses upto
36 mg/d.

31. Lacosamide

32. Treatment with lacosamide met the predefined
non-inferiority criteria when compared with
carbamazepine-CR.
Therefore, LCM might be useful as first-line
monotherapy for adults with newly diagnosed
epilepsy.
Lancet Neurol. 2017 Jan;16(1):43-54.

33. Proportion of patients who completed 6 months
of treatment and were free from seizures
Patients with a clear diagnosis of focal epilepsy Patients aged ≥65 years.
Both the groups had similar results
Lancet Neurol. 2017 Jan;16(1):43-54.

34. This prospective real-world study suggest
that lacosamide added to one
concomitant AED, was effective at
improving seizure control and was well
tolerated in patients treated in routine
clinical practice
Epilepsia. 2015 Dec;56(12):1921-30.

35. Lacosamide in combination with other ASDs
Epilepsia. 2015 Dec;56(12):1921-30.

36. Cenobamate
• Indication: focal seizures in adults.
• Mechanism: Blockade of persistent sodium currents and increased GABA
inhibition.
• High level of seizure freedom in refractory epilepsy trials (21% vs 1% in
placebo).
• Oral bioavailability of 90%, half life of 50-60 hrs.
• Adverse effects: Dizziness, fatigue, somnolence, ataxia, dysarthria, visual
disturbances, GI disturbances, hypersensitivity.
• Drug interactions: significant.
• Dose: 200- 400 mg once a day. Start at 12.5 mg/d for 2 weeks, then 25 mg for 2
weeks, 50 mg for 2 weeks, therafter increase by 50 mg every 2 weeks.
• Start low, go slow because of risk of DRESS.

37. Cannabidiol
• Indication: Seizures in Dravets, Lennox Gastaut syndrome, TSC in patients age 1
year or older.
• Mechanism: GPR55 antagonism, desensitization of TRPV1 channels, enhanced
adenosine mediated signalling, and GABAergic effects. It lacks unwarranted
psychoactive effects.
• Oral bioavailability: About 6% in the fasting state. About 25% when taken with a
high-fat meal.
• Adverse effects: Somnolence, anorexia, diarrhea, fatigue, sleep disorders, behavioral
disturbances, hypersensitivity, elevated liver enzymes, pneumonia.
• Drug interactions: significant. Has strong synergistic action with Clobazam as it is a
powerful inhibitor of CYP2C19.
• Dose: start at 2.5 mg/kg BD, increase to 5 mg/kg BD. Max of 10 mg/kg BD.

38. Fenfluramine
• Indication: Seizures in Dravets, possibly Lennox Gastaut syndrome also, in
patients 2 years of age or older.
• Mechanism: Several, including indirect stimulation of 5-HT2C and 5-HT1D
receptors as well as interactions with σ1- receptors. Amphetamine derivative.
• Oral bioavailability: 80%
• Adverse effects: Anorexia, decreased weight, diarrhea, constipation,
somnolence, fatigue, coordination disturbances, behavioral disturbances.
Cardiac valvulopathy, Pulm HTN not yet reported in epilepsy patients.
• Drug interactions: significant. May trigger serotonin syndrome.
• Dose: start at 0.1 mg/kg BD, increase weekly. Not to exceed 26 mg/d. If used
with Stiripentol and Clobazam, increase dose more slowly, and not to exceed
17 mg/d.

39. Everolimus
• Indication: Seizures in Tuberous sclerosis complex, in patients 2 years of age
or older. It may also reduce tumor growth.
• Mechanism: mTOR inhibitor. Rapamycin derivative.
• Oral bioavailability: variable.
• Adverse effects: Stomatitis, pyrexia, pneumonia, diarrhea,
hypercholesterolemia. Hypersensitivity reactions, infections, renal failure,
myelosuppression.
• Drug interactions: Yes.
• Dose: 5 mg/m2 once a day.

40. Teratogenicity

41. Lancet Neurology 2018.
• 7355 pregnancies were exposed to one of the eight antiepileptic drugs.
• The prevalence of MCMs increased with the dose at time of conception for CBZ (p=0·0140),
LTG (p=0·0145), PB (p=0·0390), and VPA (p<0·0001).
• Prevalence of MCMs was significantly higher for all doses of CBZ, VPA and PB (>80 mg/d)
than for LTG at doses of 325 mg/day or less.
• VPA at doses of 650 mg/day or less was also associated with increased risk of MCMs
compared with LEV (OR 2·43, 95% CI 1·30–4·55; p=0·0069).
• CBZ at doses of more than 700 mg/day was associated with increased risk of MCMs
compared with LEV (OR 2·41, 95% CI 1·33–4·38; p=0·0055) and OXC (2·37, 1·17–4·80;
p=0·0169).

44. • There were pronounced changes in the use of specific AEDs over time, with a
decrease in the use of VPA and CBZ and an increase in the use of LTG and
LEV.
• The prevalence of MCMs with monotherapy exposure decreased from 6.0% in
2000–2005 to 4.4% in 2010–2013 (27% decrease).
• There was no indication of an increase over time in occurrence of GTCs during
pregnancy.

47. Improvement in pregnancy outcomes over time was related to changes in ASM prescription patterns,
including a major decline in VPA use. This reduction in teratogenic risk is one of the important
advances associated with the introduction of newer ASMs.

48. Have newer ASDs changed our practice?
Seizure type 1st choice 2nd choice 3rd choice
Absence ETS, VPA LTG LEV, ZNS, ACT, CLB, CLN
Myoclonic CLN, VPA, LEV CLB TPM, ZNS, PB, NTR
Primary GTCS VPA LTG, LEV OXC, CLB, ZNS, LCM, TPM, PB,
PER, CBZ, PHT, BRV
Primary GTCS +
myoclonus
VPA LEV CLN, LTG, ZNS, CLB, TPM, PB,
PER, PHT, LCS, BRV
Primary GTCS + absence VPA LTG, LEV TPM, ZNS, CLB
Primary GTCS +
myoclonus + absence
VPA LTG, LEV TPM, ZNS, CLB, CLN
Myoclonic + absence VPA, ETS LTG, LEV TPM, ZNS, CLB, CLN
Focal LTG, CBZ, OXC, LEV,
LCS, ESL
TPM, VPA, PER, PHT,
BRV, ZNS
CLB, PB, GBP, PGB
Unclassified, age > 21yrs LTG, CBZ, OXC, LEV,
LCS, ESL
VPA, PER, PHT, BRV,
CLB, TPM, ZNS.
PB, GBP, PGB
Unclassified, age < 21yrs VPA, LTG, LEV CLB, CBZ, PER, ESL,
OXC, LCS
PB, TPM, ZNS

49. Conclusion: So what has changed?
• More than 30 ASDs are available for clinical use.
• However, proportion of drug refractory epilepsy remains the same.
• However, safety and tolerability has improved.
• Better pharmacokinetics, minimal drug interactions.
• Ability to tailor ASDs to patient specific requirements.
• Better understanding of synergistic ASD combinations.
• Better use of monotherapy and early rational polytherapy.

50. THANK YOU