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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.
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I, Jim Thigpen, DO NOT anticipate discussing the unapproved/investigative use of a commercial product/device during this activity or presentation.
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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
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Improve seizure control
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Minimize side effects of the drugs
 Risk vs. benefit
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Carbamazepine
Clobazam
Esilcarbazepine
Ethosuximide
Ethotoin
Gabapentin
Felbamate
Lacosamide
Lamotrigine
Levetiracetam
Methsuximide
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Carbamazepine
Clobazam
Esilcarbazepine
Ethosuximide
Ethotoin
Gabapentin
Felbamate
Lacosamide
Lamotrigine
Levetiracetam
Methsuximide
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Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin/Fosphenyto
in
Primidone
Valproic Acid
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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
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Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin/Fosphenyto
in
Primidone
Valproic Acid
Clobazam
Esilcarbazepine
Ethotoin
Gabapentin
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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
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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.
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Dose‐related (Type A)
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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.
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Dose‐related (Type A)
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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.
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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.
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Associated drugs
 Co‐administration of two (or more) AEDs
 Additive or sometimes supra‐additive ADRs
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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.
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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.
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CNS – Cognitive Effects
 Diminished attention, executive function, intelligence, language skills, memory and processing speed
▪ Phenobarbital
▪ Lower IQ scores
▪ Topiramate
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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 (+/‐)
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“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.
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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.
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Poorer seizure control
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Mental retardation
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Previous behavioral problems/psychiatric history
 ADHD
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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
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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.
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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)
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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.
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Other diseases associated with epilepsy
 Metabolic disorders, rheumatoid arthritis, SLE, multiple carboxylase deficiency, mitochondrial dysfunction, and others predispose to VPA toxicity
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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.
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Previous history of allergic drug reactions
 Cross‐sensitivity occurs in about 50%
▪ Especially when using lamotrigine or oxcarbazepine
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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.
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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
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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.
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Weight gain
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Hypohidrosis
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Kidney stones
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Hyponatremia
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Concentric visual field defect
 Valproate, Vigabatrin, Pregabalin
 Topiramate
 Topiramate, Zonisamide
 Carbamazepine, oxcarbazepine
 Vigabatrin (30‐ 50% incidence)
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All AEDs cause ADRs, most often CNS‐related
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Early ADRs (dose related), Late (idiosyncratic)
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Go low, go slow for best tolerability
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Idiosyncratic effects require discontinuation
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CNS effects include cognitive and psychiatric effects
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