Phenytoin Versus Levetiracetam for Seizure Prophylaxis

8/2/2019 Phenytoin Versus Levetiracetam for Seizure Prophylaxis

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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



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Results



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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.



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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).



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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



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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



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Results



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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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Phenytoin Versus Levetiracetam for Seizure Prophylaxis