Update on Newer AEDs What is their role?

Master Class Nov 2012 Young Epilepsy

K.B. Das

Learning objectives

 To understand the role of newer AEDs in managing epilepsy

 Discuss some newer drugs

Assumptions

 Newer drugs are more efficacious

 They have novel modes of action

 Their side effects are less

 Drug interactions are less

 They are more cost effective

Drug-resistant Epilepsy (ILAE 2010)

 ‘Failure of adequate trials of two tolerated, appropriate chosen and used AED schedules (where as monotherapy or in combination) to achieve seizure freedom’

Previously : intractable, refractory, difficult epilepsy Cumulative probability of being seizure-free by time from start of treatment and number of antiepileptic drug regimens

Lucky 7 !

Brodie ,Neurology 2012 ,78:1548

Zonisamide 2005

 Japan 1989, US 2000

 Broad spectrum Indications

 Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adult patients (>18 yrs)

 Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy

Mechanism

 The mechanism of action of zonisamide is not fully elucidated

 It appears to act on voltage-sensitive sodium and calcium channels

 Zonisamide also has a modulatory effect on GABA-mediated neuronal inhibition Dosing

 1-2 - 5-8 mg/kg/day ; build up 2 weekly

 Adults:100mg/day – 200 mg/day – 300- 500mg/day

 Can be given OD for focal sz

 Steady state 13 days

 Half life 105 hrs

 Zonegran

Effectiveness

Placebo Zonisamide

Sz reduction 16% 51%  Very common (>1 in 10) Side Effects  Somnolence , dizziness ,loss of appetite

 Agitation, irritability, confusion, depression, ataxia,memory impairment, diplopia and decreased blood bicarbonate levels.

 Common (1/10 - 1/100)

 Weight decreased

 Ecchymosis ,Rash ,Hypersensitivity (including cases of Stevens-Johnson syndrome )

 Abdominal pain

 Anxiety, Insomnia

 Psychotic disorder

 Nephrolithiasis

 Nausea, Constipation ,Diarrhoea ,Dyspepsia

 Pruritis ,Alopecia

 Fatigue

 Influenza-like illness

 Pyrexia

 Peripheral oedema Caution  Unexplained Rash

 Serious rashes can occur including cases of Stevens- Johnson syndrome.

 Sulphonamide reactions

 Serious immune based adverse reactions include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal.

 Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported.

 Pancreatitis

 Rhabdomyolysis

 Heat stroke

 Kidney stones

 Renal stones have occurred in patients treated with zonisamide.

 It should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalcuria.

 Metabolic acidosis

 Hyperchloraemic, non-anion gap, metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase.

 The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients.

 If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing it as osteopenia may develop.

 Should be used with caution in patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate. Rufinamide 2007 (Orphan )

 Used to treat patients aged 4 years or older who have Lennox-Gastaut syndrome

 Tablets (100 mg, 200 mg or 400 mg)

 Oral suspension (40 mg/ml)

 Adults with focal sz 20 % reduction ( in those not on Carbamazepine)

 Inovelon Mechanism

 Rufinamide modulates the activity of sodium channels, prolonging their inactive state Dosing

 Use in children four years of age or older and less than 30 kg

 Patients <30 kg not receiving valproate:

 Treatment should be initiated at a daily dose of 200 mg

 Increase by 200 mg/day increments, as frequently as every two days, up to a maximum recommended dose of 1000 mg/day

 Patients <30 kg also receiving valproate:

 As valproate significantly decreases clearance of rufinamide, a lower maximum dose of Rufinamide is recommended for patients <30 kg being co-administered valproate.

 Treatment should be initiated at a daily dose of 200 mgs

 The dose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day.

 Use in adults, adolescents and children four years of age or older of 30 kg or over

 Treatment should be initiated at a daily dose of 400 mg

 The dose may be increased by 400 mg/day increments, as frequently as every two days, up to max 1-8-3.2gm/day.

Side effects

>1 in 10 patients

 somnolence

 headache

 vomiting

 dizziness

 nausea

 fatigue Caution

 Status epilepticus

 Status epilepticus cases have been observed during clinical development studies, under rufinamide whereas no such cases have been observed under placebo.

 These events led to rufinamide discontinuation in 20 % of the cases.

 Central Nervous System reactions

 Dizziness, somnolence, ataxia and gait disturbances can occur, which could increase the occurrence of accidental falls.

 Hypersensitivity reactions

 Fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, liver function tests abnormalities, and haematuria.

 QT shortening

 Rufinamide produced a decrease in QTc interval proportional to concentration. Interactions

 No clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate

 No effect on OCP

Stiripentol 2007 (Orphan)

 It is available as capsules and sachets (250 and 500 mg)

 Start 10mg/kg/day in 2-3 doses

 The normal dose is 50 mg per kg/day, divided into two or three doses

 Add on therapy for Dravet ( with Valproate + Clobazam)

 Also tried in drug resistant epilepsy

 Diacomit

Stiripentol in SMEI Side effects Seen >1 in 10 patients:

 loss of appetite

 weight loss

 insomnia

 drowsiness

 hypotonia

 dystonia

 behaviour

 Monitor FBC,LFT/6 monthly, growth

 Need to monitor drug levels, adjust dose

Pregablin

 The active substance, pregabalin, is a gamma- aminobutyric acid analogue ((S)-3- (aminomethyl)-5-methylhexanoic acid).

 Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system

Indications

 Is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation

 In the treatment of peripheral and central neuropathic pain in adults

 Generalised Anxiety Disorder in adults

Dosing

 Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses.

 Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week.

 The maximum dose of 600 mg per day may be achieved after an additional week.

 Lyrica Side effects

 Dizziness

 Somnolence

 Weight gain (Diabetic)

 Hypersensitivity

 Blurred vision

 Renal failure

 CCF Benefits

 No interactions with other drugs

 No interactions with OCP Lacosamide 2008

 Adjunctive treatment of focal seizures >16yrs

 Selectively enhance slow inactivation of Na channels ( others act on fast inactivation)

 Start 50 mg /day , increase to 100 mg bd , max 200 mg bd

 IV formulation available

 Vimpat

Indications

 It is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adult and adolescent (16-18 years) patients with epilepsy.

 Solution for infusion: Is an alternative for patients when oral administration is temporarily not feasible.

Dosing

 The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.

 Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day)

Efficacy

Placebo Lacosamide Lacosamide Lacosamide 200mg 400mg 600mg 50% reduction 23% 34% 40% 40% + in the number of seizures Side effects

 Very common(1/10) :dizziness ,headache , diplopia, nausea

 Common(1/100): depression, conduction defects, CNS, GIT

 Not sedative

Caution  Dizziness

 Treatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls.

 Cardiac Rhythm and Conduction

 Prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide should be used with caution in patients with known conduction problems or severe cardiac disease such as a history of myocardial infarction or heart failure.

 Second degree or higher AV block has been reported in post- marketing experience.

 In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however both have been reported in open-label epilepsy trials and in post-marketing experience

Interactions

 No interaction with CMZ, Valproate concentrations

 Enzyme inducers reduce Lacosamide levels

 No significant interaction with OCP

Eslicarbazepine Acetate 2009

 Eslicarbazepine acetate is a third generation of a family of antiepileptic drugs (AEDs), which includes carbamazepine (first generation) and oxcarbazepine (second generation)  Eslicarbazepine is thought to work by blocking ‘voltage-gated sodium channels’  Less hyponatraemia (1%), rash(1.1%) and CNS side effects  It is used to treat adults with partial-onset seizures with or without secondary generalisation  (Children- trial on)  Tab 200 mg, 400 mg, 600 mg and 800 mg  Start at 400 mg once a day, before increasing it to 800 mg once a day after one or two weeks.  Zebinix Efficacy

Placebo Eslicarbazepine Eslicarbazepine Eslicarbazepine 400mg 800mg 1200mg

50% Sz 19% 21% 34% 36% reduction Carbamazepine & Oxcarbazepine

 CMZ reduces Eslicarbazepine levels by 32%

 CMZ levels unchanged

 Increased diplopia, ataxia, dizziness

 Concomitant use with Oxcarbazepine is not recommended because this may cause overexposure to the active metabolites Side effects

 The most common side effects (>in 10) are dizziness and somnolence

 It must not be used in people with second or third degree atrioventricular block Retigabine 2011

 It is indicated as adjunctive treatment of partial onset seizures with or without secondary generalisation in adults >18 years

Mechanism

 In vitro studies indicate that retigabine acts primarily through opening neuronal potassium channels (KCNQ2 [Kv7.2] and KCNQ3 [Kv7.3]).

 This stabilises the resting membrane potential and controls the sub-threshold electrical excitability in neurons, thus preventing the initiation of epileptiform action potential bursts. The mechanism of action of retigabine (ezogabine) Dosing

 Tablets: 50 mg; 100 mg; 200 mg; 300 mg; 400 mg

 The maximum total daily starting dose is 300 mg (100 mg three times daily)

 Thereafter, the total daily dose is increased by a maximum of 150 mg every week

 Effective maintenance dose : 600 - 1,200 mg/day

 Trobalt

Side Effects

Very common Common

 Dizziness  Dysuria

 Somnolence  Urinary hesitation Fatigue  Haematuria   Chromaturia

 CNS  Weight gain  GIT

Caution

 Urinary retention

 Urinary retention, dysuria and urinary hesitation were reported in controlled clinical studies with retigabine, generally within the first 8 weeks of treatment

 QT interval

 Retigabine titrated to 1,200 mg/day produced a QT-prolonging effect

 Monitor ECG

 Psychiatric disorders

 Confusional state, psychotic disorders and hallucinations were reported in controlled clinical studies with retigabine.

 These effects generally occurred within the first 8 weeks of treatment, and frequently led to treatment withdrawal in affected patients Perampanel 2012

 Perampanel is the first highly selective, non- competitive AMPA receptor antagonist.

 It inhibits post-synaptic AMPA receptor activation by agonists, and selectively inhibits the transmission of seizures by blocking the effects of glutamate.

Dosing

• Starting Dose • Treatment should be initiated at a dose of 2 mg/day • Maintenance Dose • The dose may be increased based on clinical response and tolerability by increments of 2 mg/day to a maintenance dose of 4–8 (12 )mg/day • OD • Fixed pricing irrespective of dose • Fycompa

Caution

 Carbamazepine, Phenytoin, Oxcarbazepine & Topiramate reduce Perampanel levels

 Reduced efficacy of progesterone containing OCP

 Not recommended in moderate or severe renal failure

 Caution in mild/moderate hepatic impairment

Zonisamide Rufinamide Lacosamide Eslicarb Retigabine Perampanel 2005 2007 2008 azepine 2011 2012 2009 License >18yrs >4 yrs >16yrs Adults 18yrs >12yrs

Spec broad broad focal focal focal focal trum Mechan Na /GABA Na Na Na K AMPA

Dosing BD/OD BD BD OD TDS OD

Dosage 8mg/kg/day 400 - 1200 50-200mg bd 400- 300 - 2- 8(12) mg/ 100-300- mg bd 800mg od 1200mg tds od 500mg/day Side Sleep, dizzy, Sleep, dizzy, Dizzy Dizzy, Fatigue Dizziness, sleep effects Wt loss Headache Headache Sleepy Bladder Rash, renal Sz increase, Diplopia Rash, retention, QT stones, blood, AV block diplopia acidosis, heat AV block stroke

Others Long half life LGS No Avoid No significant Interactions No effect on Status interactions oxcarb interactions Reduces OCP OCP No effect on Reduces ECG OCP OCP IV Cost !

 Phenobarb 60mg (28) - 71 p  Rufinamide 400mg (60) £102.96  Phenytoin 100mg(28) £30.00  Stiripentol 250mg(60) - £284,  Tegretol 200mg (84) £3.83 500mg (60) - £493  Epilim 200mg(100) £7.00  Lacosamide 200mg (56)  Leveteracetam 1gm (60) £144.16 £101.10  Retigabine 400mg (84)  Pregabalin 300mg (56) £127.68 £64.60  Perampanel 12mg(28) £140  Zonisamide 100mg (56)

£ 62.72

Newer drugs are more No efficacious

They have novel modes of Some action

Their side effects are less Maybe

Drug interactions are less + / -

More cost effective No

Are they really superior to the older ones ?!

Newer AEDs

• Lack of efficacy of older drugs • Contraindications to older drugs • Interactions with other drugs (OCP) • Older drugs poorly tolerated by the child • The child is currently of childbearing potential or is likely to need treatment into her childbearing years

NICE Any questions?

Summary

 Many new drugs have novel mechanisms of action

 Side effect profile is better

 They have a role in adjunctive therapy of drug resistant epilepsy Thank you! Acknowledgments

 BNF

 NICE

 EMA

 Martin Brodie