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 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 ESLICARBAZEPINE A 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 PERAMPANEL AMPA 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 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. QUESTIONS? emedicine.Medscape.com.