Antiepileptic Drugs (AED): New Drugs & New Uses. Disclosures of Interest 2/25/2015. Objectives

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1 Antiepileptic Drugs (AED): New Drugs & New Uses Rex S. Lott, Pharm.D., BCPP Professor, ISU College of Pharmacy Mental Health Clinical Pharmacist Boise VA Medical Center Clinical Associate Professor University of Washington School of Medicine Department of Psychiatry & Behavioral Sciences Disclosures of Interest Perampanel (Fycompa ) Advisory Board, Eisai Pharmaceuticals, Honorarium Objectives Pharmacists, Nurses & Prescribers Discuss clobazam, eslicarbazepine, ezogabine, and perampanel their pharmacodynamics, relevant pharmacokinetics, dosing, adverse effects and indications for the treatment of epilepsy Describe optimal dosing and use of AED for neuropathic pain and migraine Formulate patient education regarding clobazam, eslicarbazepine, ezogabine, and perampanel Technicians List the brand and generic names of 4 new antiepileptic drugs Describe the relationship of these new antiepileptic drugs with older, similar agents Describe the potential advantages of unique new antiepileptic drugs over previously available agents A 24 y.o. married female has migraine attacks 4 times monthly. Which AED would be the best choice for migraine prophylaxis? She takes no other medications. 1. Divalproex 2. Ezogabine 3. Perampanel 4. Topiramate A patient with moderately severe neuropathic pain is experiencing incomplete relief on generic gabapentin 400 mg BID. The patient complains of no side effects except mild drowsiness. The next best step is? 1. Add a tricyclic antidepressant 2. Increase dose and frequency of gabapentin 3. Switch to duloxetine 4. Add tramadol Eslicarbazepine (Aptiom ) is a new antiepileptic drug that is the active metabolite of: 1. Carbamazepine 2. Ezogabine 3. Oxcarbazepine 4. Topiramate 1

2 AED: What s New? Clobazam (Onfi ) (CLB) Eslicarbazepine (Aptiom ) (ESL) Ezogabine (Potiga ) (EZG) Perampanel (Fycompa ) (PMP) New / different Mechanisms of Action (MOA) EZG & PMP Improved tolerability ESL Niche Indication CLB Clobazam (CLB) Primary FDA-labeled indication: Adjunctive treatment of seizures in Lennox-Gastaut Syndrome (LGS) in patients over 2 years old 1,5-benzodiazepine Possibly better-tolerated than other benzos Less sedation Less interference with performance / cognition **Tolerance/tachyphylaxis LESS concern than with long-term use of other benzodiazepines. Kinetics & Active Metabolite similar to diazepam Conry et al. Epilepsia. 2014;556:558 Sankar CNS Drugs. 2012;26:229 Lennox-Gastaut Syndrome Onset: Early childhood. Associated brain damage (encephalopathy) Mental Retardation common Mixed Generalized Seizures: **Atonic/akinetic (helmets) Atypical absence Myoclonic GTCS Status epilepticus commonly occurs Abnormal interictal EEG Poor response to AEDs Medication toxicity from over-zealous treatment Over-sedation may worsen seizure frequency Preferred AEDs Felbamate Rufinamide Valproic Acid Benzodiazepines (Clobazam) Lamotrigine??Topiramate????Vigabatrin?? Atonic Seizures Drop Attachks Total Seizures Conry et al. Epilepsia. 2009;50:1158 Conry J, et al. Epilepsia. 2014;55:558 2

3 CLB: Dosing & Interactions Dosing based on body weight 30 kg or less Start at 5 mg/day Up to 20 mg/day Over 30 kg Start at 10 mg/day Up to 40 mg/day BID dosing recommended for doses over 5 mg/day CYP 2C19 substrate (fluconazole, omeprazole inhibit) Mild CYP 3A4 inducer (MAY reduce effectiveness of oral contraceptives. CLB Patient Education Sedation, Dizzy Drowsy Possible changes in mood BID dosing above 5 mg/day Caution if used with alcohol 50% increase in CLB exposure Additive CNS depressant effects Risk of rapid discontinuation or running out Eslicarbazepine (ESL) Active metabolite of oxcarbazepine (Trileptal ) Gimmick or significant improvement?? Administered as acetate ester of ESL Significance? Oxcarbazepine Kinetics ESL Kinetics Nunes et al. Epilepsia. 2013;54:108 Nunes et al. Epilepsia. 2013;54:108 3

4 ESL Tolerability ESL Group (N = 7) 24 Treatment Emergent Adverse Events in 86% (6) of patients Dizziness in 43% Headache in 29% Oxcarbazepine Group (N = 7) 84 Events in 100% (7) of patients Headache in 100% Dizziness in 86% Nunes et al. Epilepsia. 2013;54:108 ESL Patient Education Once daily dosing best at bedtime Possible changes in mood Possible dizziness, headache, tired/sleepy Usually early & temporary Possible GI upset take with food AED Mechanisms Inactivation of Sodium Channels Phenytoin, Carbamazepine, Oxcarbazepine, Eslicarbazepine, Lamotrigine, Topiramate, Valproate, Zonisamide Inhibition of Calcium Channels Ethosuximide, Valproate, Lamotrigine, Gabapentin, Pregabalin Enhance or modify GABA Gabapentin(?), Pregabalin(?), Vigabatrin, Valproate, Phenobarbital, Benzodiazepines Ezogabine (EZG) Potassium channel opener = Unique MOA Stabilizing K+ channels in open state acts as a brake on neuronal excitability Stabilizes resting neuron potential May also have effects on GABA systems EZG: Pharmacokinetics & Dosing Short half-life (~ 6 10 hrs) TID dosing Well-absorbed with/without food No CYP450 metabolism Directly glucuronidated and N-acetylated Some renal excretion of active drug Dose adjustments for moderate/severe renal impairment Initial dose: 100 mg TID Weekly increases by no more than 150 mg/day Target Doses: 600 mg/day 1200 mg/day 4

5 EZG: Adverse Effects Black Box: Retinal pigmentary abnormalities with possible loss of visual acuity 33% after 4 years Baseline and Q 6 months visual evaluation Blue discoloration of Skin, Mucous Membranes, Sclera Neuropsychiatric Adverse Effects (Schedule V): Confusion, Psychosis, Hallucinations ~50% required hospitalization QT Prolongation: 7.7 msec (significance????) Healthy volunteers not seen in clinical trials Risk of urinary retention Deeks. CNS Drugs. 2011;25:887 EZG: Patient Education Important to take 3 times daily? Adherence / Compliance Sleepy, tired, dizziness Possible changes in mood or behavior Possible changes in vision Possible changes in skin color Potential difficulty with urination Perampanel (PMP) Non-competitive AMPA glutamate receptor antagonist = unique MOA Glutamate = principal excitatory neurotransmitter Different glutamate receptors (NMDA, AMPA, Kainate) NMDA blockade not sufficient to suppress seizures AMPA receptors important to seizure generation and spread PMP Adjunct for focal (partial) onset seizures Research into use for generalized onset seizures Doses 2 12 mg QD (~ 8 as a target) Weekly titration Long half-life (~ 100 hours) CYP3A4 substrate significant effects of inducers and inhibitors on PMP plasma concentrations. Carbamazepine decreases half-life to ~ 25 hours Plosker. CNS Drugs. 2012;26:1085 5

6 PMP: Adverse Events Common: Dizzy, Sleepy, Fatigue, Headache Black Box Warning: Neuropsychiatric adverse effects in 12-20% Hostility & Aggression Homicidality?? Schedule III controlled substance 12 mg/day dosage MAY reduce effectiveness of oral contraceptives PMP: Patient Education Sedation, dizziness, fatigue, headache Changes in mood or behavior Once daily dosing Patient Education on AEDs Website for The Epilepsy Foundation and the Epilepsy Therapy Project Basic and more advanced information AEDs: Other Indications Neuropathic Pain Migraine Bipolar Disorder Neuropathic Pain & AEDs Diabetic Neuropathy (Pregabalin) Post-Herpetic Neuropathy (Pregabalin, Gabapentin) Fibromyalgia (?) (Pregabalin) MS / Spinal Cord Injury Cancers, stroke, trauma AEDs for Neuropathic Pain Pregabalin / Gabapentin: Possible firstline agents for most neuropathic pain Carbamazepine: Possible second-line agent Combinations of AEDs and: Tricyclic antidepressants (amitriptyline) Duloxetine Opiods or Tramadol Venlafaxine 6

7 AEDs for Neuropathic Pain: Dosing Gabapentin: Initial 300 mg daily (HS) Day 2: 300 mg Q 12 hours Day 3: 300 mg Q 8 hours Titrate up to 1800 mg/day (600 mg Q 8 hours) Gralise : sustained-release Gabapentin Once daily HS bioavailability with high-fat meal Gradual titration to 1800 mg/day over 2 weeks AEDs for Neuropathic Pain: Dosing (cont.) Pregabalin (Lyrica ) Initial: mg/day divided Q 8 hours Labeled Maximum Doses: 300 mg/day for most neuropathic pain syndromes 450 mg/day for fibromyalgia Carbamazepine Gradual titration up to 1200 mg/day AEDs for Migraine Preventive vs. Abortive Therapy Indicated: 2 or more attacks per month causing at least 3 days of disability per month Frequent headaches Use of abortive medication more than twice weekly Patient preference FDA-Indicated: Divalproex (Depakote ) Topiramate (Topamax ) AEDs for Migraine: Dosing Divalproex: Initial: Divalproex DR: 250 mg BID X 1 week Divalproex ER: 500 mg QD X 1 week Titration to response Maximum Recommended: mg/day Topiramate Initial: 25 mg HS Increase weekly by 25 mg/day BID dosing Maximum Recommended: 100 mg/day AEDs for Migraine: Side Effect Profiles Divalproex: Initial sedation Gastrointestinal Tremor Weight gain Endocrine (females) Teratogenic risk RARE hepatotoxicity Topiramate: Dizziness Confusion, psychomotor slowing Gastrointestinal Weight loss Teratogenic risk Metabolic acidosis Reduced sweating Visual disturbances A 24 y.o. married female has migraine attacks 4 times monthly. Which AED would be the best choice for migraine prophylaxis? She takes no other medications. 1. Divalproex 2. Ezogabine 3. Perampanel 4. Topiramate 7

8 A patient with moderately severe neuropathic pain is experiencing incomplete relief on generic gabapentin 400 mg BID. The patient complains of no side effects except mild drowsiness. The next best step is? 1. Add a tricyclic antidepressant 2. Increase dose and frequency of gabapentin 3. Switch to duloxetine 4. Add tramadol Eslicarbazepine (Aptiom ) is a new antiepileptic drug that is the active metabolite of: 1. Carbamazepine 2. Ezogabine 3. Oxcarbazepine 4. Topiramate Which of the following newer antiepileptic drugs should be dosed 3 times daily and is associated with visual changes and pigmentation changes in the skin and mucous membranes? ASSESSMENT QUESTIONS FOR PHARMACISTS, NURSES AND PRESCRIBERS A. Clobazam B. Ezogabine C. Perampanel D. Eslicarbazepine Which of the following represents an antiepileptic drug and its optimal target dose for neuropathic pain (assuming no dose-limiting side effects)? A. Pregabalin 50 mg Q 8 hours B. Topiramate 100 mg Q 12 hours C. Carbamazepine 100 mg Q 12 hours D. Gabapentin (generic) 600 mg Q 8 hours For which of the following newer antiepileptic drugs should potentially significant behavioral changes be included in patient education (beyond the class warning regarding suicidality)? A. Clobazam B. Ezogabine C. Perampanel D. Both a & b E. Both b & c 8

9 Which pair of brand and generic names is correct? ASSESSMENT QUESTIONS FOR TECHNICIANS A. Clobazam Potiga B. Elicarbazepine Aptiom C. Ezogabine Fycompa D. Perampanel Onfi Clobazam is most similar to which older antiepileptic drug? A. Phenytoin B. Carbamazepine C. Oxcarbazepine D. Clonazepam Ezogabine and perampanel possess unique mechanisms of antiepileptic activity. A. True B. False References 1. Sankar R. GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs. 2012;26: Conry JA, et al. Clobazam in the treatment of Lennox-Gastaut Syndrome. Epilepsia. 2009;50: Dickinson RG, et al. First dose and steady-state pharmacokinetics of oxcarbazepine and its 10-hydroxy metabolite. Eur J Clin Pharmacol. 1989;37:69 4. Schutz H, et al. The metabolism of 14C-oxcarbazepine in man. Xenobiotica. 1986;16: Nunes T, et al. Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia. 2013;54: Deeks E. Retigabine (Ezogabine) in partial onset seizures in adults with epilepsy. CNS Drugs. 2011;25: Plosker GL. Perampanel as adjunctive therapy in patients with partial onset seizures. CNS Drugs. 2012;26:1085 References (cont.) 8. Talian K. Neurologic Disorders, in Psychiatric Pharmacotherapy Review Course. College of Psychiatric and Neurologic Pharmacists, Lincoln, NE; 2014; pp Conry JA, et al. Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years. Epilepsia. 2014;55: Gabapentin Package Insert 11. Gralise Package Insert 12. Divalproex Package Insert 13. Carbamazepine Package Insert 14. Topiramate Package Insert 9