newer anticonvulsants: targets and toxicity...antiepileptic drugs for improved tolerability and...

Newer Anticonvulsants: Targets and Toxicity

Laura Tormoehlen, MDNeurology and EM-Toxicology

Disclosures• No financial disclosures

DEFINITIONS

Objectives/Outline• Mechanism of Action• Specific Indications• Toxicity• Adverse Effects

LACOSAMIDE

Lacosamide• Trade Names: Vimpat• Dosage Forms: Oral, Intravenous• Mechanism of Action: Functionalized Amino Acid, decreases

hyperexcitability via:– Enhancing slow inactivation of voltage-gated sodium channels– CRMP-2 binding

• Indication:– Partial seizure, monotherapy– Partial seizure, adjunct

Lacosamide : Targets

Beyreuther BK, et al. Lacosamide: A Review of Preclinical Properties. CNS Drug Reviews 2001: 13(1): 21-42

Lacosamide : Toxicity• Cardiac Arrest

– 1 Fatal (Malissin 2013, PMID 23534387)

• Ingestion of 7 grams of lacosamide• Co-ingestion with lamotrigine, phenobarbital, and carbamazepine, plus• Initial rhythm asystole, resuscitated, followed by shock and multi-organ failure

– 1 Survival (Chua-Tuan 2015, PMID 25951877)

• Ingestion of 4.5 grams of lacosamide• Co-ingestion of cyclobenzaprine and levetiracetam• Initial rhythm pulseless ventricular tachycardia

• Coma and Seizures (Bauer 2008, PMID 20171144)

– Ingestion of 12 grams of lacosamide– Co-ingestion with gabapentin (56g), topiramate (2g), zonisamide (2.8g)– Also had PR prolongation (265 ms) and hypotension (60/30 mmHg)

Lacosamide : Adverse Effects• Common: Nausea/Vomiting, Somnolence, Memory

Impairment, Dizziness/Vertigo, Headache, Diplopia, Ataxia, Tremor

• Worse with other VGSC blocking agents• Serious

• CV – Atrial fibrillation/flutter, PR interval prolongation, all degrees of AV block, bradycardia, syncope

• Immune – Drug hypersensitivity• Psych – Suicidal thoughts/behavior, Depression, Hallucinations

LACOSAMIDEAnother Parenteral Sodium Channel Blocker

RUFINAMIDE

Rufinamide• Trade Names: Banzel• Dosage Forms: Oral• Mechanism of Action: Triazole Derivative

– Prolongs inactive state of sodium channels

• Indication:– Lennox-Gastaut syndrome, seizure, adjunct– Off Label: Partial seizure, adjunct

Rufinamide : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

Rufinamide : Toxicity• An adult received 7200 mg during a clinical

trial without any adverse effects

Rufinamide : Adverse Effects• Common: Nausea/Vomiting, Somnolence, Dizziness,

Headache, Diplopia/Blurred Vision, Ataxia/Gait Disturbance, Shortened QT Interval

• Serious:– Neurologic – Status Epilepticus– Psychiatric – Suicidal behavior– Hematologic – Leukopenia– Immune – Drug hypersensitivity syndrome/DRESS, Stevens-Johnson

syndrome

RUFINAMIDEYet Another Sodium Channel Blocker, for Lennox-Gastaut

ESLICARBAZEPINE

Eslicarbazepine• Trade Names: Aptiom• Dosage Forms: Oral• Mechanism of Action: Structurally related to

carbamazepine and oxcarbazepine– Inhibition of voltage-gated sodium channels

• Indication:– Partial seizure, monotherapy– Partial seizure, adjuct

Johannessen-Landmark C and Johannessen SI. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy. Perspect Med Chem 2008; 2: 21-39

Eslicarbazepine : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

Eslicarbazepine : Toxicity• Oxcarbazepine

Eslicarbazepine : Adverse Effects• Common: Nausea/Vomiting, Somnolence, Dizziness,

Headache, Diplopia/Blurred Vision, Ataxia, Tremor• Serious:

– Psychiatric – Suicidal thoughts– Ophthalmologic – Visual impairment– Metabolic – Hyponatremia– Hematologic – Eosinophilia– Hepatic – Increased transaminases, Increased bilirubin– Immune – Anaphylaxis, Drug hypersensitivity syndrome/DRESS,

Stevens-Johnson syndrome– Other – Angioedema

ESLICARBAZEPINEA Once-A-Day Oxcarbazepine

PERAMPANEL

Perampanel• Trade Names: Fycompa• Dosage Forms: Oral• Mechanism of Action: Noncompetetive antagonism

of AMPA receptors• Indication:

– Partial seizure, adjunct– Tonic-clonic seizure, adjunct– Orphan drug status for Lennox-Gastaut

Perampanel : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

Perampanel : Toxicity– Case report: 34 year-old with tuberous

sclerosis (Hoppner 2013, PMID 24001596)

• Ingestion of 204 mg, initially estimated to be 264 mg

• Dysarthria and fatigue, followed by stupor, then misperception and disorientation

• Impaired consciousness lasted 2 days• EEG without epileptiform discharges

Perampanel : Adverse Effects• Common: Somnolence, Dizziness, Headache,

Ataxia/Abnormal Gait/Falls, Dysarthria, Irritability, Mood Disorder

• Serious: – Psychiatric – Aggressive behavior, Homicidal

thoughts, Suicidal thoughts– Dermatologic – Drug hypersensitivity syndrome

PERAMPANELAMPA antagonist, limited use due to SI/HI

CLOBAZAM

Clobazam• Trade Names: Onfi• Dosage Forms: Oral• Mechanism of Action: Benzodiazepine

– Binds to benzodiazepine site of GABA(A) and potentiate neurotransmission

• Indication:– Lennox-Gastaut, seizure, adjunct– Off Label: SGE, Partial seizure, adjunct– Not labeled for EtOH withdrawal or anxiety

Clobazam : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

Clobazam : Toxicity• It’s a Benzodiazepine

Clobazam : Adverse Effects• Common: Somnolence/Sedation, Ataxia,

Dysarthria, Cough, Fever, Dependence, Constipation, Drooling, Insomnia

• Serious:– Dermatologic – Stevens-Johnson Syndrome, Toxic

Epidermal Necrolysis– Psychiatric – Suicidal Behavior/Ideation,

Aggressive Behavior

CLOBAZAM“Less Sedating” Benzodiazepine

VIGABATRIN

Vigabatrin• Trade names: Sabril• Dosage Forms: Oral• Mechanism of Action:

– Irreversibly inhibits GABA Transaminase– May also stimulate GABA release

• Indication:– Partial seizure, adjunct– Infantile spasms– Restricted distribution, black box warning for vision loss

Vigabatrin : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

Vigabatrin : Toxicity• Case reports

– Adult ingested 8-12 grams• Psychosis

– 25 year-old woman ingested 60 grams• Severe delirium

Davie MB, Cook MJ, Ng C. Vigabatrin Overdose. Med J Aust 1996; 165: 403.

Vigabatrin : Adverse Effects• Common: Somnolence, Dizziness/Vertigo,

Headache, Agitation• Serious:

– Ophthalmologic: Permanent vision loss– Neurologic: Coma, Seizures– Psychologic: Psychosis– Respiratory: Respiratory depression– Cardiovascular: Hypotension, Bradycardia

VIGABATRINNovel agent, VERY limited use due to visual impairment

EZOGABINE/RETIGABINE

Ezogabine• Trade names: Potiga (US), Trobalt (Europe)• Dosage Forms: Oral• Mechanism of Action: Opens voltage-gated potassium

channels (KCNQ2/3) resulting in hyperpolarization• Indication:

– Partial seizure, in patients with inadequate response to several alternatives, adjunct

– Benign familial neonatal convulsions (loss of function of KCNQ2/3)– Black box warning for retinopathy

Ezogabine : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

Ezogabine : Toxicity– Moderate: agitation, aggressive behavior,

irritability (doses greater than 2500 mg)– Severe:

• Cardiac dysrhythmias (asystole or ventricular tachycardia) within 3 hours of single 900-mg dose in 2 volunteers.

• QT prolongation known, TdP possible but not yet reported

Product Information: Potiga ® oral tablets, ezogabine oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2015

Ezogabine : Adverse Effects• Common: Fatigue, Memory Impairment, Vertigo,

Diplopia/Blurred Vision, Tremor, Incoordination/Abnormal gait, Aphasia/Dysarthria

• Serious:– Neurologic – Dizziness, Somnolence, Confusion– Ophthalmologic – Retinal disorder, Pigment change– Psychiatric – Hallucinations/Psychosis, Suicidal thoughts– Cardiovascular – Prolonged QT interval– Renal – Urinary retention– Dermatologic – Skin pigmentation (blue, grey, brown)

Zaugg BE, et al. Ezogabine maculopathy. Retinal Cases & Brief Reports 2016; 0: 1-6.

EZOGABINE“Niche drug,” limited use due to retinal/skin pigment changes and urinary retention

GANAXOLONE

Johannessen-Landmark C and Johannessen SI. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy. Perspect Med Chem 2008; 2: 21-39

Ganaxolone : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

SIRIPENTOL

Stiripentol : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

BRIVARACETAM

Brivaracetam : Targets

Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14): 1925-39.

QUESTIONS?

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