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PhenytoinVS
levetiracetamfor seizure prophylaxis
in secondary seizure
Kristy WuMedicine Rotation
Western University of Health SciencesCollege of Pharmacy, PSIII
Preceptor: Doreen Pon, PharmD
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Objectives
Introduce patient case
Brief review of secondary CNS lymphoma andsecondary seizure
Brief review of phenytoin and levetiracetam Discuss the clinical trials of phenytoin and
levetiracetam comparisons in seizure prophylaxis
Advantages of levetiracetam over phenytoin
Evaluation of the patient case
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Patient CaseRH is a 69 year-old male with aggressive diffuse large B-cell non-
Hodgkinlymphoma who is being admitted for autologous stem cell
transplantationwith conditioning chemotherapy of BEAM (carmustine, etoposide,cytarabine, melphalan)
HPI: Diagnosed in 10/2009 Bone marrow biopsy showed involvement with lymphoma on
10/14/2009 The cytogenetics were normal
Had 3 cycles of R-CHOP with 3rd cycle given on 11/30/2009 Developed new onset seizure on 12/15/2009 MRI of the brain: mass in the right occipital lobe Treated with phenytoin and dexamethasone Received 2 cycles of high-dose methotrexate with cytarabine in
12/2009 and had complete remission
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Patient Case
Brain MRI of 12/2009:
3 x 2.2 x 2.2 cm mass in the right
occipital lobe extending toward the corpuscallosum without midline shift or evidenceof herniation
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Patient Case
PMH Type 2 DM
Hypertension
Hypercholesterolemia
Sleep apnea Benign prostatic hypertrophy.
FH
There is no cancer history in the family
Father heart problem; paternal uncle heartproblem; maternal grandfather heart attackyears ago
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Patient Case
Medications
Phenytoin PO 500mg/400mg at bedtimealternating every other day
trazodone, buspirone, fluconazole, nystatin,acyclovir, ursodiol, famotidine, metformin,Flomax
Allergies: NKDA
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Clinical Question
Can levetiracetam (Keppra) beused as 1st line option for seizureprophylaxis in secondary seizure?
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Secondary CNS lymphoma ~ 10-30% of systemic lymphoma have secondary CNS
involvement.
Almost all CNS lymphoma are non-Hodgkin B-cell tumors
Typically develops in the subcortical and subependymal whitematter and the corpus striatum, and may extend to corpuscallosum
Spinal cord is frequently affected
Clinical presentation is nonspecific, may involve focal neurologicimpairment, headache, confusion and seizures.
Zee CS, Neuroradiology: A Study Guide. 1996:158-60.Gerstner ER, et al. Blood. Sep 2008;112(5):1658-61.
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Secondary Seizure
Symptomatic epilepsy Secondary to known structural or metabolic
diseases adversely affecting the brain Disorders included: drug-induced, alcohol related,
stroke, trauma, brain infection, neurosurgery,neoplasm, metabolic disorders, degenerative CNSconditions
Seizure due to CNS metastases: should receiveanticonvulsive treatment with phenytoin
Fauci, AS, et al. Harrisons principles of internal medicine, 17th edition. Chap 270, Sec 4, Oncologic Emergencies.World Health Organization. http://www.who.int/mediacentre/factsheets/fs999/en/index.html
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Phenytoin FDA indications: management of generalized tonic-clonic and
complex partial seizures; prevention of seizures following head
trauma/neurosurgery
Mechanism of Actions: Neuronal sodium channel blocker
PK profile:
Absorption depends on the formulation Highly protein bound: > 90% Half-life: 12-36 hours (average 24 hours) Elimination: dose-dependent; metabolized to inactive
metabolite and excreted in the urine
Monitoring parameters: Therapeutic plasma level: 10-20 mcg/mL >20 mcg/mL: Far lateral nystagmus >30 mcg/mL: 45 lateral gaze nystagmus and ataxia >40 mcg/mL: Decreased mentation >100 mcg/mL: Death
Katzung, BG, et al. Basic & Clinical Pharmacology, 11 th Edition. Chapter 24, Antiseizure Drugs.
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Levetiracetam FDA indications: Adjunctive therapy in the treatment of partial
onset, myoclonic, and/or primary generalized tonic-clonic seizures
Mechanism of Action: binds selectively to the synaptic vesicularprotein SV2A
function of this protein is not understood
modifies the synaptic release of glutamate and GABA.
PK profile:
Oral absorption: rapid and unaffected by food
Protein bound: < 10%
Half-life: 6-8 hours Elimination: 2/3 excreted unchanged in the urine
Monitoring parameters:
- Renal adjustment is required
Katzung, BG, et al. Basic & Clinical Pharmacology, 11 th Edition. Chapter 24, Antiseizure Drugs.
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Abbreviations and Terminologies
GCS = Glasgow coma score: trauma scoring; scoredbetween 3-15; 3 being the worst and 15 the best
GOS = Glasgow outcome score: score for the long-termfollow-up after severe brain injuries; scored between 1-5; 5being the best outcome and 1 the worst.
GOSE
DRS = disability rating score; scored 1-20;
1-3 (mild), 4-6 (moderate), 7-20(severe)
LEV = levetiracetam
PHT = phenytoin
Teasdale G., Jennett B., LANCET (ii) 81-83, 1974.Center for outcome measurement in brain injury. http://www.tbims.org/combi/drs/drsprop.html
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Levetiracetam versus phenytoin forseizure prophylaxis
in severe traumatic brain injury
Design: Non-randomized, open label, historical control
Site: University of Pittsburgh Medical Center
Subjects:
Prospective cohort: 32 patients with severe traumatic brain
injury (TBI) 11/2006 12/2007 were admitted and receivedlevetiracetam 500mg IV Q12H for the 1st 7 days aftertraumatic injury
Historical cohort from severe TBI database: 41 patients withTBI from 07/2005-06/2006 received phenytoin for 7 days aftertrauma.
Inclusion Diagnostic criteria:
GCS score of 3-8
Hospital standard protocol: not defined in the study
Only patients who received an EEG examination were includedin the analysis.
Jones, K.E., et al. Neurosurg. Focus. Volume 25(4):E3, 2008
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Results
Patient baseline characteristics: No significantdifferences
Patients with EEG examinations: 15/32 in the
levetiracetam cohort vs. 12/41 in the phenytoincohort
Levetiracetam cohort: total 19 EEG examinations
4 patients had2 EEG studies Phenytoin cohort: total 19 EEG examinations
4 patients had 2 EEG studies
1 patient had 3 EEG studies
Jones, K.E., et al. Neurosurg. Focus. Volume 25(4):E3, 2008
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Results
Jones, K.E., et al. Neurosurg. Focus. Volume 25(4):E3, 2008
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Prospective, Randomized, single-Blinded Comparative Trial ofIntravenous Levetiracetam Versus Phenytoin for Seizure
Prophylaxis
Design: prospective, single-center, randomized, single-blindedcomparative trial
Site: University of Cincinnati hospital
Subjects:
Randomization occurred after admission up to 24 hours in the
NSICU at 2:1 ratio of LEV to PHT 52 patients was enrolled: 18 patients in the PHT arm and 34
patients in the LEV arm.
Inclusion diagnostic criteria:
Patients with severe TBI or subarachnoid hemorrhageadmitted to the hospital < 24 hours prior to randomization
GCS score 3-8 or GCS motor score < 5 with abnormaladmission CT scan showing intracranial pathology
Hemodynamically stable with sBP 90mmHg; at least 1reactive pupil
17 years of age
Szaflarski JP, et al. Neurocrit Care. 2010 Apr;12(2):165-72.
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Exclusion criteria:
No venous access
Spinal cord injury
History of or CT confirmation of previous brain injury Hemodynamically unstable
Suspected anoxic events; other peripheral trauma likely resultliver failure
Age < 17 yo
CI treatment with LEV or PHT
Intervention:
PHT group: loading dose of fos-PHT 20mg/kg PE IV, max of2gm; maintenance dose (5mg/kg/day, IV Q12H). PHT serum
levels check at days 2 and 6 after randomization and doseadjustments to maintain therapeutic serum levels of 10-20mcg/mL.
LEV group: loading dose of 20mg/kg IV; maintenance dose(1gm, IV Q12H). Dose was adjusted to max 3gm/day ifseizure occurred.
Szaflarski JP, et al. Neurocrit Care. 2010 Apr;12(2):165-72.
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Results Baseline characteristics: no differences
There were no differences in early seizure occurrencebetween the PHT vs. LEV groups (3/18 vs. 5/34; P = 1.0)or death (4/18 vs. 14/34; P = 0.227)
There were no differences in PHT vs. LEV groups in GCS at7 days (6 vs. 7; P = 0.58) and GOS at discharge (2 vs. 2;P = 0.33), 3 months (3 vs. 3; P = 0.61), and 6 months
(3 vs. 3; P = 0.89) LEV-treated patients experienced less worsening
neurological status (P = 0.024) and GI problems (P =0.043)
Tendency toward lower incidence of anemia in PHT group (P
= 0.076) Surviving patients treated with LEV experienced better
outcomes than surviving patients treated with PHTincluding lower DRS at 3 and 6 months (P = 0.006 and P =0.037) and higher GOSE at 6 months (P = 0.016).
Szaflarski JP, et al. Neurocrit Care. 2010 Apr;12(2):165-72.
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Studies have 6 months follow-up period
In Jones, et al., levetiracetam isassociated with higher seizure tendencyshowing on EEGs than phenytoin.
Both levetiracetam and phenytoin do nothave evidence in prevention of lateepilepsy.
Comparisons in the studies were in IV
formulation for 7-day use. Efficacy of long-term use in PO
formulation has not been compared.
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Safety and feasibility of switching from phenytoin tolevetiracetam monotherapy for glioma-related seizure control
following craniotomy: a randomized phase II pilot study
Design: randomized phase II
Subjects:
Prior to randomization, patients were stratified into: noprior craniotomy and history of one craniotomy
Within each stratification group, patients wererandomized in a 2:1 ratio to receive LEV or PHT
Inclusion diagnostic criteria:
Seizure history attributable to supratentorial glioma
PHT monotherapy for seizure prophylaxis
Planned craniotomy
Karnofosky performance scale of >70
> 18 yo
Lim, DA et al. J neurooncol 2009, 93:349-354
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Exclusion Criteria Non-glioma cancer Pregnancy or breast-feeding
Seizures unrelated to the suspected glioma Use AEDs other than PHT >1 generalized seizure per day Prior interstitial brachytherapy.
Intervention PHT: serum levels confirmed at therapeutic range
at postoperative day1 (POD1); PHT dose adjustedas needed.
LEV: started LEV 1000mg PO BID with 24 hours ofsurgery and PHT was tapered off as following:
100% of preoperative PHT regimen on POD0, 75%on POD1, 50% on POD2, and PHT was discontinuedon POD3.
Primary end point: proportion of patients who wereseizure free 6 months after tumor resection
Lim, DA et al. J neurooncol 2009, 93:349-354
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Results
29 patients enrolled: 20 in LEV vs. 9 in PHT
Baseline characteristics:
majority of patients were male
Female: 6 in LEV vs. 0 in PHT
Seizure type at presentation: Generalized: 8 in LEV vs. 3 in PHT
Simple partial: 6 in LEV vs. 1 in PHT
Complex partial: 1 in LEV vs. 4 in PHT
Lim, DA et al. J neurooncol 2009, 93:349-354
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Results
Lim, DA et al. J neurooncol 2009, 93:349-354
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Phenytoin
ADRs: blood dyscrasias, dermatologic reactionsincluding toxic epidermal necrolysis and SJS,hepatotoxcicity, bradycardia, hypotension,cardiac arrhythmia, headache, insomnia, tremor,paresthesia; idosyncratic (gingival hyperplasia,
hirsutism, coarse features)
DDIs with patients current medication: CYP4A3 substrates: BusPirone, tamsulosin,
trazodone Fluconazole
Lexi-comp.com
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Levetiracetam
ADRs: Somnolence, ataxia, headache, Lesscommon are complaints of agitation or anxiety,emotion labile Idiosyncratic reactions are rare.
Levetiracetam is not metabolized by CYP450
DDIs with patients current medication: None
Lexi-comp.com
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Advantages of Levetiracetamover Phenytoin
Non-enzyme inducing AED
No serum level monitoring
Not induce drug fever or cutaneoushypersensitivity reactions
Less ADRs
Less DDIs
No food-drug interactions
IV:PO = 1:1
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Back to Patient Case
Currently on Phenytoin PO 500mg/400mg at bedtimealternating every other day
Phenytoin serum level:
3/8: 10.2 mcg/ml (corrected with albumin: 15 mcg/ml)
3/15: 10.3 mcg/ml (corrected with albumin: 14.7mcg/ml)
No seizure activity observed
Repeat MRI: not available
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Reference
Fauci, AS, et al. Harrisons principles of internal medicine, 17th edition (online version).Chapter 270, Section 4, Oncologic Emergencies.http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=2880754.Accessed 03/22/2010
Gerstner ER, et al. CNS Hodgkin lymphoma. Blood. Sep 2008;112(5):1658-61.
Jones, K.E., et al. Levetiracetam versus phenytoin for seizure prophylaxis in severetraumatic brain injury. Neurosurg. Focus. Volume 25(4):E3, 2008
Katzung, BG, et al. Basic & Clinical Pharmacology, 11th Edition. Chapter 24, AntiseizureDrugs.http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=4512306.Accessed 03/23/2010.
Lexi-comp.com
Lim, DA et al. Safety and feasibility of switching from phenytoin to levetiracetammonotherapy for glioma-related seizure control following craniotomy: a randomizedphase II pilot study. Journal neurooncol 2009, 93:349-354.
Szaflarski JP, et al. Prospective, Randomized, single-Blinded Comparative Trial ofIntravenous Levetiracetam Versus Phenytoin for Seizure Prophylaxis. Neurocrit care April2010 (2):165-72
Uptodate.com Zee CS, Neuroradiology: A Study Guide. McGraw Hill 1996:158-60.
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