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7/27/2015 Jim Thigpen, PharmD, BCPS Associate Professor of Pharmacy Practice ETSU Bill Gatton College of Pharmacy Jim Thigpen, PharmD, BCPS Associate Professor of Pharmacy Practice ETSU Bill Gatton College of Pharmacy I, Jim Thigpen, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. 1 7/27/2015 I, Jim Thigpen, DO NOT anticipate discussing the unapproved/investigative use of a commercial product/device during this activity or presentation. Describe the more common adverse drug reactions (ADRs) caused by standard anti‐ epileptic drugs (AEDs) Recognize the dangerous ADRs seen with AEDs Compare the different behavioral effects reported with the AEDs Predict those patients at highest risk of behavioral effects from AEDs Improve seizure control Minimize side effects of the drugs Risk vs. benefit 2 7/27/2015 Carbamazepine Clobazam Esilcarbazepine Ethosuximide Ethotoin Gabapentin Felbamate Lacosamide Lamotrigine Levetiracetam Methsuximide Carbamazepine Clobazam Esilcarbazepine Ethosuximide Ethotoin Gabapentin Felbamate Lacosamide Lamotrigine Levetiracetam Methsuximide Carbamazepine Ethosuximide Phenobarbital Phenytoin/Fosphenyto in Primidone Valproic Acid Oxcarbazepine Perampanel Phenobarbital Phenytoin/Fosphenytoi n Primidone Rufinamide Tiagabine Valproic Acid Vigabatrin Zonisamide Oxcarbazepine Perampanel Phenobarbital Phenytoin/Fosphenytoi n Primidone Rufinamide Tiagabine Valproic Acid Vigabatrin Zonisamide 3 7/27/2015 Carbamazepine Ethosuximide Phenobarbital Phenytoin/Fosphenyto in Primidone Valproic Acid Clobazam Esilcarbazepine Ethotoin Gabapentin Felbamate Lacosamide Lamotrigine Levetiracetam Methsuximide Oxcarbazepine Perampanel Rufinamide Tiagabine Vigabatrin Zonisamide Condition AED Alopecia VPA, CBZ,OXC, LTG Hyponatremia Condition AED CBZ, OXC Gum hypertrophy PHT Pancreatitis VPA Hirsutism PHT, VPA Hepatic failure FBM, VPA Acne VPA, PHT SLE‐like syndrome CBZ, PHT, PRM Oligohydrosis TPM, ZNS Aplastic anemia FBM, CBZ, PHT Amenorrhea PHT, PB, CBZ Vision loss VGB Osteopenia PHT, PB, TPM, CBZ Glaucoma TPM, CBZ Weight gain VPA, GBP,PGB, VGB Drowsiness PB,CBZ,GBP,VGB Weight loss TPM,ZNS,FBM Insomnia LTG, FBM Folate deficiency VPA,CBZ,PRM Cognitive impairment PB,PRM,TPM,PHT, ZNS Kidney stones TPM,ZNS,ACZ Psychosis VGB,TGB,ZNS,LEV Dose‐related (Type A) Generic and predictable Explainable Early in therapy or with a dose adjustment Rarely require stopping the drug Most ADRs seen in clinical trials Patient‐specific Guerrini R, et al. Drug Safety 2012;35(7):519‐533. 4 7/27/2015 Dose‐related (Type A) Idiosyncratic (Type B) Generic and predictable Unpredictable Explainable Most likely in susceptible patients Early in therapy or with a Pathogenesis is dose adjustment Rarely require stopping the drug Most ADRs seen in clinical trials Patient‐specific unrelated to known mechanism of drug Results from abnormal immunological reaction May be more than one mechanism Guerrini R, et al. Drug Safety 2012;35(7):519‐533. Dose‐related (Type A) Idiosyncratic (Type B) Generic and predictable Unpredictable Explainable Most likely in susceptible patients Early in therapy or with a dose adjustment Rarely require stopping the drug Most ADRs seen in clinical trials Patient‐specific Pathogenesis is unrelated to known mechanism of drug Results from abnormal immunological reaction May be more than one mechanism Guerrini R, et al. Drug Safety 2012;35(7):519‐533. Starting dose and titration rate Tolerance development Early detection of toxicities Side effects may occur within the standard range ▪ Statistical estimate ▪ Inter‐individual differences ▪ Effects associated with peak levels (timing of doses) Guerrini R, et al. Drug Safety 2012;35(7):519‐533. 5 7/27/2015 Associated drugs Co‐administration of two (or more) AEDs Additive or sometimes supra‐additive ADRs Other diseases Hepatic disease ▪ Avoid those primarily metabolized in the liver ▪ Lamotrigine and tiagabine Renal disease ▪ Avoid those with predominant renal excretion ▪ Gabapentin and topiramate Guerrini R, et al. Drug Safety 2012;35(7):519‐533. Central Nervous System Gastrointestinal Guerrini R, et al. Drug Safety 2012;35(7):519‐533. CNS Somnolence, sedation, dizziness and headache are the most often reported Tolerance usually develops with slow dose titration Relation to peak level Cognitive effects Psychiatric/behavioral effects Guerrini R, et al. Drug Safety 2012;35(7):519‐533. 6 7/27/2015 CNS – Cognitive Effects Diminished attention, executive function, intelligence, language skills, memory and processing speed ▪ Phenobarbital ▪ Lower IQ scores ▪ Topiramate When AEDs are combined…..no info Ijff DM, Aldenkamp AP. Handbook of Neurology 2013 Vol 111;73:707‐719. Cramer JA, et al. Expert Rev Neurother. 2010;10(6):885‐891. Kwan P, Brodie MJ. Epilepsia 2004;45(9):1141‐1149 Drugs Effect Topiramate, Phenobarbital ‐‐‐ Area of impairment Memory, attention, language function Phenytoin, Carbamazepine Oxcarbazepine (+/‐) ‐ “mental speed” (high doses)** Valproate, Levetiracetam, Ethosuximide 0 None shown Oxcarbazepine (+/‐), Lamotrigine + Attention Vigabatrin, Gabapentin, Tiagabine, Rufinamide, Zonisamide No info Ijff DM, Aldenkamp AP. Handbook of Neurology 2013 Vol 111;73:707‐719. CNS – Psychiatric/Behavioral Effects Depression and anxiety are common with epilepsy ▪ Forced normalization Patients are often unaware of cognitive and mood changes (but the family will be) ▪ Behavioral effects (irritability and hostility) are the main concerns with levetiracetam, often seen at the start of therapy (occurring in up to 40% or more) ▪ “placebo effect” seen more often in children Cramer JA, et al. Expert Rev Neurother. 2010;10(6):885‐891. 7 7/27/2015 Poorer seizure control Mental retardation Previous behavioral problems/psychiatric history ADHD Learning disabilities Eddy CM et al. J Clin Psychopharmacol 2012;32:362‐375 Drug Aggression % Psychosis % Hyperactivity % Topiramate 1.9 – 81.8 1.3 – 18.9 2.7 – 4.4 Levetiracetam 2.3 – 27 0.3 – 1.6 2.5 – 3.8 Tiagabine 1 – 36.4 NR NR Vigabatrin 3.4 ‐ 23 0.7 – 6.7 6.1 – 25.7 Clobazam 1.3 ‐ 31.9 NR 4 ‐ 27 Perampanel < 1 ‐ 20 < 1 NR Gabapentin 9.4 ‐ 13 <1 0 ‐ 11 Primidone 3 – 18.2 1.4 4.5 Valproate 0 ‐ 12 NR 0 ‐ 10 Rufinamide 3 – 11.6 0.6 ‐ 4 3 – 4.7 Zonisamide 2.6 ‐ 9 2.2 – 18.9 NR Thigpen J, Miller SE, Pond BB. U.S. Pharmacist 2013;HS‐15‐20. Drug Aggression % Psychosis % Hyperactivity % Topiramate 1.9 – 81.8 1.3 – 18.9 2.7 – 4.4 Levetiracetam 2.3 – 27 0.3 – 1.6 2.5 – 3.8 Tiagabine 1 – 36.4 NR NR Vigabatrin 3.4 ‐ 23 0.7 – 6.7 6.1 – 25.7 Clobazam 1.3 ‐ 31.9 NR 4 ‐ 27 Perampanel < 1 ‐ 20 < 1 NR Gabapentin 9.4 ‐ 13 <1 0 ‐ 11 Primidone 3 – 18.2 1.4 4.5 Valproate 0 ‐ 12 NR 0 ‐ 10 Rufinamide 3 – 11.6 0.6 ‐ 4 3 – 4.7 Zonisamide 2.6 ‐ 9 2.2 – 18.9 NR Thigpen J, Miller SE, Pond BB. U.S. Pharmacist 2013;HS‐15‐20. 8 7/27/2015 Gastrointestinal Nausea and vomiting are the most common Occurs in virtually every AED Tolerance usually develops Dividing doses may be helpful ▪ Higher dose given at bedtime Guerrini R, et al. Drug Safety 2012;35(7):519‐533. Genetics Siblings of patients with a h/o idiosyncratic reactions to an aromatic AED (DPH, CBZ, PB) HLA‐B*1502 allele (Han Chinese) ▪ CBZ‐induced Stevens‐Johnson syndrome (SJS) Age Children are at a greater risk than adults ▪ Greater risk of SJS with Lamotrigine vs adults ▪ Much greater risk of valproic acid toxic hepatitis (<2 y.o.) Wade JF, et al. J Emer Medicine 2019;38(2):231‐237. Au JS, Pockros PJ. Clin Liver Dis 2013;17:687‐697. Other diseases associated with epilepsy Metabolic disorders, rheumatoid arthritis, SLE, multiple carboxylase deficiency, mitochondrial dysfunction, and others predispose to VPA toxicity Associated drugs Drug interactions leading to increased levels of VPA or lamotrigine may increase risk of hypersensitivity Guerrini R, et al. Drug Safety 2012;35(7):519‐533. 9 7/27/2015 Previous history of allergic drug reactions Cross‐sensitivity occurs in about 50% ▪ Especially when using lamotrigine or oxcarbazepine Starting dose and titration rate Slow titration may allow desensitization to occur ▪ Especially important with lamotrigine (rash) Wade JF, et al. J Emer Medicine 2019;38(2):231‐237. Guerrini R, et al. Drug Safety 2012;35(7):519‐533. Skin Cutaneous manifestations are the most common idiosyncratic reactions caused by AEDs ▪ Range from benign mild rashes to potentially life‐ threatening ▪ DRESS, SJS and TEN Guerrini R, et al. Drug Safety 2012;35(7):519‐533. www.medical‐institution.com 10 7/27/2015 Skin DRESS (Dermatological Diseases, Rash with Eosinophilia and Systemic Symptoms) ▪ Fever, skin eruption, eosinophilia, atypical lymphocytosis, arthralgia, lymphadenopathy and multi‐ organ involvement Stevens‐Johnson Syndrome and Toxic Epidermal Necrolysis ▪ Greatest in the first 8 weeks of therapy Guerrini R, et al. Drug Safety 2012;35(7):519‐533. Weight gain Hypohidrosis Kidney stones Hyponatremia Concentric visual field defect Valproate, Vigabatrin, Pregabalin Topiramate Topiramate, Zonisamide Carbamazepine, oxcarbazepine Vigabatrin (30‐ 50% incidence) All AEDs cause ADRs, most often CNS‐related Early ADRs (dose related), Late (idiosyncratic) Go low, go slow for best tolerability Idiosyncratic effects require discontinuation CNS effects include cognitive and psychiatric effects 11