Pharmacology related to newer third generation antiepileptics.

1. NEW ANTI-EPILEPTICS
MOSTAFA SABER IBRAHIM
LECTURER OF NEUROLOGY
ASWAN UNIVERSITY

3. AGENDA
• BRIVARACETAM
• ESLICARBAZEPINE ACETATE
• LACOSAMIDE
• PERAMPANEL
• RUFINAMIDE
• STIRIPENTOL
• VIGABATRIN
• ZONISAMIDE
• EZOGABINE (RETIGABINE)
• CANNABIDIOL

4. BRIVARACETAM
Date of FDA approval: Feb, 2016.
Brand Name: Briviact
Licensed Indications for Epilepsy:
• Adjunctive treatment of partial-onset (focal) seizures, with or
without secondary generalization, in adults 16 years of age and
older with epilepsy (UK and FDA).
Mechanism of Action
• It binds to synaptic vesicle protein SV2A (the same target as levetiracetam but with
approximately 20-fold higher affinity and greater selectivity), which is involved in
synaptic vesicle exocytosis.
• Brivaracetam is a partial antagonist of sodium channels.

5. Pharmacokinetics
• Oral bioavailability: ~100%
• Food co-ingestion: slow the rate of absorption
• Pharmacokinetics: linear
• Protein binding: 17%
Metabolism
• Brivaracetam undergoes extensive (>90%) hepatic metabolism through the
cytochrome P450.
• The major metabolites are not pharmacologically active
Elimination
• The elimination half- life is 7– 8 hours.
• Renal excretion: approximately 95% of brivaracetam, including its
metabolites, is excreted in urine within 3 days.

6. Drug Interaction Profile
 Effects on brivaracetam: Carbamazepine, phenobarbital, and phenytoin can
increase the clearance of brivaracetam and decrease brivaracetam plasma
levels
 Effects by brivaracetam: Brivaracetam can increase the conversion of
carbamazepine to carbamazepine- 10 and increase plasma levels of phenytoin.
Common Adverse Effects
Somnolence, dizziness, fatigue, and nausea/vomiting.
Irritability was reported only in 3.2% of patients receiving brivaracetam.
One small open-label study suggested that behavioral adverse effects from
levetiracetam may improve after switching to brivaracetam.

7. Dosing and Use
Usual Dosage Range: 50– 200 mg/ day in divided doses
Starting Total Daily Dose: 1–2 mg/kg/d.
Usual Maximal Effective Dose: 1–5 mg/kg/d.
Available Formulations
• Tablets: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg
• Oral solution: 10 mg/mL
• Injection: 50 mg/5 mL single-dose vial
Pregnancy and breastfeeding
• Risk category C (potential teratogen)
• It is unknown whether brivaracetam is secreted in human
breast milk.

8. ESLICARBAZEPINE ACETATE
Date of FDA approval: Aug, 2015
Brand Names: Aptiom, Exalief, Stedesa, Zebinix
Generic Available: Eslizepine
Licensed Indications for Epilepsy
• Adjunctive treatment of focal (partial)-onset seizures with or without secondary
generalization in patients with epilepsy aged 16 years and older (UK).
• Adjunctive treatment of focal (partial)-onset seizures with or without secondary
generalization in patients with epilepsy aged 18 years and older (FDA).
Non-licensed Use for Non-epilepsy Conditions
• Bipolar disorder
• Cranial neuralgia
• Headache
• Neuropathic pain
• Trigeminal neuralgia

9. Mechanism of Action
• Acts as a blocker of voltage- sensitive sodium channels.
• An effect on glutamate release may also occur.
Pharmacokinetics
• Oral bioavailability: >90%
• Food co-ingestion: No effect
• Pharmacokinetics: linear
• Protein binding: 30%
Metabolism
• Eslicarbazepine acetate is rapidly metabolized (hydrolysis) in the liver to its
pharmacologically active metabolite, eslicarbazepine.
Elimination
92% of an administered dose is excreted as eslicarbazepine metabolites in
urine.

10. Drug Interaction profile
Effects on eslicarbazepine:
• Carbamazepine, phenytoin, and topiramate can increase the clearance of
eslicarbazepine and decrease eslicarbazepine plasma levels
Effects by eslicarbazepine:
• Eslicarbazepine can increase plasma levels of phenytoin.
• Eslicarbazepine can decrease plasma levels of lamotrigine, topiramate, and
valproic acid.
Common Adverse Effects
• Dizziness, headache, somnolence, tremor, Diplopia and blurred vision
• Vertigo, rash, fatigue, gait disturbance and hyponatremia.
Life- threatening Adverse Effects
• Increases PR interval, therefore patients with known second- or third- degree
atrioventricular block may be at risk of myocardial infarction or heart failure.
• Increased risk of suicidal ideation and behavior.

11. Dosing and Use
Usual Dosage Range
• Adults: 800– 1200 mg/ day
Available Formulations
• Tablets: 400 mg, 800 mg
• Suspension: 60 mg/ mL
Pregnancy and breastfeeding
Eslicarbazepine acetate enhances the metabolism of oral contraceptives so as
to decrease plasma levels of hormonal contraceptives and to reduce their
effectiveness, leading to breakthrough bleeding and contraceptive failure.
Eslicarbazepine acetate has yet to be classified by the FDA; if it was to be
classified it would probably be in risk category C.
It is not known whether eslicarbazepine is excreted in breast milk.

12. LACOSAMIDE
Date of FDA approval: 2014
Brand Names: Vimpat
Generics Available: Andovimpamid and Lacovimp
Licensed Indications for Epilepsy
• Adjunctive or monotherapy treatment of partial (focal)-onset seizures with or
without secondary generalization in patients with epilepsy aged 16 years and older
(UK).
• Adjunctive or monotherapy treatment of partial (focal)-onset seizures with or
without secondary generalization in patients with epilepsy aged 17 years and older
(FDA).
Non-licensed Use for Epilepsy
• Monotherapy in newly diagnosed epilepsy in adults
• Status epilepticus (iv formulation)
Non-licensed Use for Non-epilepsy Conditions
• Neuropathic pain. • Restless legs syndrome

13. Mechanism of Action
• Slow inactivation of voltage- gated sodium channels.
Pharmacokinetics
• Oral bioavailability: 100%
• Food co-ingestion: no effect
• Pharmacokinetics: linear
• Protein binding: <15%
Metabolism
Metabolized in the liver, by demethylation, to O- desmethyl lacosamide (30%)
The metabolites of lacosamide are not pharmacologically active.
Elimination
• The plasma half- life is 13 hours.
• 40% of an administered dose is excreted unchanged in urine.

14. Drug Interaction Profile
Effects on lacosamide:
 Carbamazepine, phenobarbital, and phenytoin can increase the clearance of
lacosamide and decrease lacosamide plasma levels.
Effects by lacosamide:
 Lacosamide can decrease plasma levels of 10-hydroxycarbazepine.
Common Adverse Effects
• Dizziness, headache, balance disorder, abnormal coordination, memory
impairment, somnolence, tremor, nystagmus and vertigo.
• Diplopia, blurred vision
• Nausea, vomiting, constipation, flatulence
• Pruritus
• Depression
Life- threatening Adverse Effects
• Increases PR interval, therefore, patients with known second- or third- degree
atrioventricular block may be at risk of severe symptomatic bradycardia or syncope.

15. Usual Dosage Range
• Adults: 200– 400 mg/ day
Available Formulations
• Tablets: 50 mg, 100 mg, 150 mg, 200 mg
• Oral Solution: 10 mg/ mL
•Injection: 10 mg/ml solution for infusion (20
mL/vial)
Pregnancy and breastfeeding
Lacosamide does not enhance the metabolism of
oral contraceptives.
Risk category C (Potential teratogen).
It is not known whether lacosamide is excreted
in breast milk.

16. PERAMPANEL
Date of FDA approval: 2012
Brand Names: Fycompa
Generics Available: Perampanel
Licensed Indications for Epilepsy
• Adjunctive treatment of partial- onset seizures with or without secondary
generalization in patients aged 12 years and older (UK and FDA).
• Adjunctive treatment of primary generalized tonic–clonic seizures in
adults and adolescents from 12 years of age with idiopathic generalized
epilepsy (UK and FDA).
• Treatment of Partial-Onset Seizures in Pediatric Patients as Young as 4
Years Old (FDA, 2018)
Non- licensed Use for Epilepsy
• Lafora disease, Lance–Adams syndrome, Lennox–Gastaut syndrome,
Status epilepticus and Unverricht–Lundborg disease.

17. Mechanism of Action
Perampanel is a non- competitive antagonist of the AMPA- type glutamate
receptor, thereby inhibiting AMPA- induced increases in intracellular calcium
and reducing neuronal excitability.
Pharmacokinetics
• Oral bioavailability: 100%
• Food co-ingestion: decreases the rate of absorption by 2 hours.
• Pharmacokinetics: linear
• Protein binding: 95%
Metabolism
Perampanel undergoes substantial metabolism (98%) in the liver primarily by
oxidation followed by glucuronidation.
Elimination
The plasma half-life is about 105 hours after single and in the presence of
enzyme-inducing co-medication, half-life value fall to 25 hours.
Perampanel is eliminated mostly in the feces and to a lesser extent in the urine.

18. Drug Interaction Profile
Effects on perampanel:
 Carbamazepine, oxcarbazepine, phenytoin, and topiramate can increase the
clearance of perampanel and decrease perampanel plasma levels
Effects by perampanel:
 Perampanel can decrease plasma levels of carbamazepine, clobazam,
lamotrigine, midazolam, and valproic acid.
 Perampanel can increase plasma levels of oxcarbazepine.
Common Adverse Effects
• Somnolence, dizziness
• Ataxia, dysarthria, balance disorder, irritability
• Aggression, anger, anxiety, confusional state
• Diplopia, blurred vision
• Vertigo, nausea, gait disturbance, fatigue
Life- threatening Adverse Effects
Depression and suicidal ideations and acts.

19. Dosing and Use
Usual Dosage Range
• Partial- onset seizures: 4– 12 mg/ day
• Primary generalized tonic–clonic seizures: up to 8 mg/ day
Available Formulations
• Tablets: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg
Pregnancy and breast feeding
Risk category C (Potential teratogen).
It is not known whether perampanel is excreted in breast milk.

20. RUFINAMIDE
Date of FDA approval: 2008
Brand Names: Banzel and Inovelon
Generics Available: No
Licensed Indications for Epilepsy
• Adjunctive treatment of seizures in Lennox– Gastaut syndrome in
patients 4 years and older (UK and FDA).
Non- licensed Use for Epilepsy
• Epileptic spasms
• Myoclonic- astatic epilepsy
• Partial (focal) seizures
• Status epilepticus
Mechanism of Action
• Acts as a blocker of voltage- sensitive sodium channels.
• Prevents sodium channels from returning to an activated state.

21. Pharmacokinetics
• Oral bioavailability: not determined; however, it is dose- dependent in that as
dose increases the bioavailability decreases
• Food co-ingestion: increases the absorption.
• Pharmacokinetics: linear up to 1600 mg/ day; non- linear >1600 mg/ day due to
reduced oral bioavailability
• Protein binding: 35%
Metabolism
• Rufinamide is metabolized in the liver to inactive metabolite.
Elimination
About 66% of the dose is excreted as the acid metabolite, with 2% of the dose
excreted as rufinamide.

22. Drug Interaction Profile
Effects on rufinamide:
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and vigabatrin
can increase the clearance of rufinamide and decrease rufinamide plasma levels.
• Valproic acid can decrease the clearance of rufinamide and increase rufinamide
plasma levels
Effects by rufinamide:
• Rufinamide can decrease plasma levels of carbamazepine and lamotrigine
• Rufinamide can increase plasma levels of phenobarbital and phenytoin
Common Adverse Effects
• Dizziness, diplopia, somnolence, nausea, vomiting and fatigue.
Life-threatening Adverse Effects
• Hypersensitivity syndrome (fever, rash, lymphadenopathy, liver function test
abnormalities, and hematuria).
• Decreases QT interval.

23. Dosing and Use
Usual Dosage Range
• Weight range <30 kg: up to a maximum dose of 1000 mg/ day
• Weight range 30– 50 kg: up to a maximum dose of 1800 mg/ day
• Weight range 50.1– 70 kg: up to a maximum dose of 2400 mg/ day
• Weight range >70 kg: up to a maximum dose of 3200 mg/ day
Available Formulations
• Tablets: 100 mg, 200 mg, 400 mg.
• Oral suspension: 40 mg/ml.
Pregnancy and breast feeding
Risk Category C (Potential teratogen).
It is not known whether rufinamide is excreted in breast milk.

24. STIRIPENTOL
Date of FDA approval: 2018
Brand Name: Diacomit
Generics Available: No
Licensed Indications for Epilepsy
• Adjunctive treatment of seizures in children with severe myoclonic epilepsy in
infancy (Dravet syndrome).
Non- licensed Use for Epilepsy
• Adjunctive treatment with carbamazepine in children with refractory partial
(focal) seizures.
Mechanism of Action
• Inhibition of synaptic uptake of GABA and inhibition of GABA transaminase.
• Enhances GABA A receptor- mediated transmission.
• Inhibition of CYP enzymes and increasing concurrent AED blood levels.

25. Pharmacokinetics
• Oral bioavailability: not determined
• Food co-ingestion: food co- ingestion is essential because stiripentol degrades
rapidly in the acidic environment of an empty stomach
• Pharmacokinetics: non- linear (due to saturable metabolism) so that clearance
decreases with increasing dose
• Protein binding: 99%
Metabolism
• Stiripentol is metabolized in the liver to pharmacologically inactive
metabolites.
• Plasma half- life and clearance are dose- dependent, with clearance values
decreasing with increasing dose
Elimination
•Renal excretion: about 73% of an administered dose is excreted in urine as
metabolites.

26. Drug Interaction Profile
Effects on stiripentol:
• Carbamazepine, phenobarbital, phenytoin, and primidone can increase the
clearance of stiripentol and decrease stiripentol plasma levels
• Clobazam can decrease the clearance of stiripentol and increase stiripentol plasma
levels
Effects by stiripentol:
• Stiripentol can increase plasma levels of carbamazepine, ethosuximide,
phenobarbital, phenytoin, primidone, valproic acid and clobazam.
Common Adverse Effects
• Anorexia, loss of appetite, nausea, vomiting
• Drowsiness, ataxia, hypotonia and dystonia, hyperkinesias
• Insomnia, aggressiveness, irritability, behavior disorders, hyperexcitability.
• Cutaneous photosensitivity, rash, and urticaria.

27. Dosing and Use
Usual Dosage Range
• Initially 50 mg/ kg/ day (in combination with clobazam and
valproic acid) but up to a maximum of 4 g
Available Formulations
• Capsules: 250 mg, 500 mg
• Sachets: 250 mg, 500 mg
Pregnancy
• In view of the indication for stiripentol, its administration
during pregnancy and in women of childbearing potential
would not be expected.

28. VIGABATRIN
Date of FDA approval: 2009
Brand Names: Sabril; Sabrilan; Sabrilex
Generics Available: No
Licensed Indications for Epilepsy
• Adjunctive treatment of partial (focal) seizures with and without secondary
generalization not satisfactorily controlled with other AEDs (UK)
• Monotherapy in the treatment of infantile spasms (West syndrome) (UK)
• Adjunctive therapy for adult patients with refractory complex partial seizures who have
inadequately responded to several alternative treatments (FDA)
• Monotherapy for pediatric patients 1 month to 2 years of age with infantile spasms
(FDA)

29. Precautions
• May exaggerate typical and atypical absence and myoclonic seizures.
• In the USA, vigabatrin can be obtained only through the manufacturer and only
with proper documentation that the patient fulfills the licensed indication criteria;
accordingly, children older than 2 years will not receive vigabatrin
Mechanism of Action
• As an analog of GABA, it was specifically developed to increase brain GABA
• Inactivation of GABA transaminase, which is the enzyme responsible for the
breakdown of GABA.
Pharmacokinetics
• Oral bioavailability: 60– 80%
• Food co-ingestion: no effect
• Pharmacokinetics: linear
• Protein binding: 0%

30. Metabolism
• Vigabatrin is not metabolized
Elimination
•100% of an administered dose is excreted unchanged in urine.
Drug Interaction Profile
Effects on vigabatrin:
• Felbamate increases the excretion of vigabatrin and decreases vigabatrin
plasma levels.
Effects by vigabatrin:
• Vigabatrin can decrease plasma levels of carbamazepine, phenytoin, and
rufinamide.

31. Common Adverse Effects
• Visual field defects (males have a twofold greater risk than females), diplopia, nystagmus
• Sedation, dizziness, headache, ataxia
• Cognitive and behavioral disturbances (e.g., agitation, especially in children).
• Psychosis, mania, depression
• Nausea, abdominal pain and Fatigue.
• Vigabatrin commonly causes MRI abnormalities seen most prominently in the basal
ganglia and the upper brainstem; these abnormalities tend to be reversible, even without
discontinuation of the drug.
Life-threatening Adverse Effects
• May cause an increase in seizure frequency, including status epilepticus, patients with
myoclonic or absence seizures may be particularly at risk of status epilepticus.
• Rare encephalopathic symptoms such as marked sedation, stupor, and confusion.
Rare and not Life- threatening Adverse Effects
• Angioedema, Urticaria, Hallucinations and Rash.
• Retinal atrophy, optic neuritis

32. Dosing and Use
Usual Dosage Range
• Adult and children: 1000– 3000 mg/ day
• Infants (monotherapy for infantile spasms): 150– 200 mg/ kg/ day
Available Formulations
• Tablets: 500 mg
• Sachet: 500 mg (sugar- free powder)
Pregnancy and breast feeding
Risk category C (potential teratogen).
Breast milk: 4– 20% of maternal plasma levels.

33. ZONISAMIDE
Date of FDA approval: 2000
Brand Names: Excegran, Zonegran; Zonicare; Zonimid.
Generics Available: Zonivan
Licensed Indications for Epilepsy
• Monotherapy for partial (focal) and secondary generalized seizures in adults
with newly diagnosed epilepsy (UK).
• Adjunctive therapy for partial (focal) and secondary generalized seizures in
adolescents, and children aged 6 years and above (UK).
• Adjunctive therapy for partial (focal) and secondary generalized seizures in
adults (FDA).
Non- licensed Use for Epilepsy
• Absence seizures and Infantile spasms (West syndrome)
• Juvenile myoclonic epilepsy
• Lennox– Gastaut syndrome and Myoclonic astatic epilepsy (Doose syndrome)
• Progressive myoclonus epilepsy (Unverricht– Lundborg and Lafora disease)

34. Mechanism of Action
• Partial blockade of sodium channels.
• Blockade of T- type calcium channels.
• Inhibition of glutamate release.
•Carbonic anhydrase inhibition, but potency is much lower than that of acetazolamide
Pharmacokinetics
• Oral bioavailability: >90%
• Food co-ingestion: delays the rate of absorption.
• Pharmacokinetics: linear
• Protein binding: ~40%
Metabolism
• Zonisamide undergoes acetylation in the liver to pharmacologically inactive metabolite.
Elimination
About 65% of an administered dose is excreted as metabolites in urine and 35% is excreted
as unchanged zonisamide in urine.

35. Drug Interaction Profile
Effects on zonisamide:
• Carbamazepine, phenobarbital, phenytoin, and primidone can increase the
clearance of zonisamide and decrease zonisamide plasma levels
Effects by zonisamide:
• Zonisamide can decrease the clearance of carbamazepine-epoxide and increase
carbamazepine- epoxide plasma levels.
Common Adverse Effects
• Drowsiness, fatigue and ataxia
• Psychomotor slowing and impairments in verbal learning (may be transient)
• Behavioral adverse effects (e.g., aggression, agitation and dysphoria)
• Psychiatric adverse effects (i.e., hallucinations, paranoia, and psychosis)
• Anorexia, nausea, abdominal pain, vomiting, and weight loss
• Metabolic acidosis.
• Hypohydrosis (especially in children, may lead to hyperthermia)
• Allergic rash (risk lower than for antibiotic sulfonamides)

36. Life-threatening Adverse Effects
• Very rarely, Stevens-Johnson syndrome, toxic epidermic necrolysis, hepatic
necrosis
• Rare blood dyscrasias (aplastic anemia, agranulocytosis)
Rare and not Life- threatening Adverse Effects
• Nephrolithiasis (1–2%)
• Paresthesias, mostly tingling in the fingers and toes
• Mild elevation of serum creatinine and BUN values
• Weight loss is common

37. Dosing and Use
Usual Dosage Range
• Adults: 100– 600 mg/ day (lower doses may be sufficient in monotherapy, while
higher doses may be necessary with enzyme- inducing AEDs).
• Children: 8 mg/ kg/ day (monotherapy); 12 mg/ kg/ day (with enzyme-inducing
AEDs)
Available Formulations
• Capsules (hard): 25 mg, 50 mg, 100 mg
Pregnancy and breast feeding
• Risk category C (potential teratogen).
• Breast milk: 90% of maternal plasma levels
• Breastfed infants: zonisamide plasma levels are 100% of maternal plasma levels.

38. EZOGABINE (RETIGABINE)
Ezogabine (known as retigabine outside the
United States) was a promising new AED with
a novel mechanism of action as a potassium
channel opener.
However, long-term use was associated with
bluish pigmentation in the skin, nails, and
retina and possibility of vision loss.
Its use declined to the point that its maker
withdrew it from the market in 2017, which is
why it will not be discussed further here.

39. CANNABIDIOL
Date of FDA approval: 2018
Brand Names: Epidiolex
Generic names: No
Licensed Indications for Epilepsy
Cannabidiol is indicated for the treatment of seizures associated with Lennox-
Gastaut syndrome or Dravet syndrome in patients 2 years of age and older based on
blinded controlled trials (FDA).
Mechanism of Action
Its exact mechanisms of action are not known, but it may enhance GABA activity
through modulation of the GABA-A receptor.

40. Pharmacokinetics
• Oral bioavailability: 6%
• Food co-ingestion: Its bioavailability is increased with a high-fat meal.
• Protein binding: (>94%)
Metabolism
• Cannabidiol is metabolized in the liver and converted to an active then an inactive
metabolite.
Elimination
It undergoes extensive first pass metabolism by the liver before the remainder and its
metabolites are mostly excreted in urine.
Drug Interaction Profile
It interacts with several AEDs, most notably with clobazam, increasing the
concentration of its active metabolite.
Its clearance is increased by enzyme inducers and decreased by enzyme inhibitors.

41. Common Adverse Effects
• Sedation, fatigue, decreased appetite, and diarrhea.
• It may produce an increase in liver enzymes, particularly when used in conjunction
with valproate or with valproate and clobazam.
Liver enzymes and total bilirubin levels should be obtained before and after treatment.
Dosing and Use
The recommended starting dose is 5 mg/kg/d in 2 divided doses for 1 week, then 10
mg/kg/d in 2 divided doses.
Available Formulations
Cannabidiol is available only as an oral solution.
Pregnancy and breast feeding
FDA pregnancy risk category: Not assigned due to no adequate data.
Excreted into human milk: Unknown

42. THANK YOU