Newer Anticonvulsants: Targets and Toxicity Laura Tormoehlen, MD Neurology 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
LACOSAMIDE Another 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
RUFINAMIDE Yet Another Sodium Channel Blocker, for Lennox-Gastaut
ESLICARBAZEPINE
Trade Names: Aptiom Dosage Forms: Oral Eslicarbazepine 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
ESLICARBAZEPINE A Once-A-Day Oxcarbazepine
PERAMPANEL
Trade Names: Fycompa Dosage Forms: Oral Perampanel 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
PERAMPANEL AMPA antagonist, limited use due to SI/HI
CLOBAZAM
Trade Names: Onfi Dosage Forms: Oral Clobazam 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
Trade names: Sabril Dosage Forms: Oral Mechanism of Action: Vigabatrin 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.
Case reports Vigabatrin : Toxicity 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
VIGABATRIN Novel 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.
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