Phenytoin VS levetiracetam for seizure prophylaxis in secondary seizure Kristy Wu Medicine Rotation...

Phenytoin Phenytoin VS VS

levetiracetam levetiracetam for seizure prophylaxis for seizure prophylaxis

in secondary seizurein secondary seizure

Kristy WuKristy WuMedicine RotationMedicine Rotation

Western University of Health SciencesWestern University of Health SciencesCollege of Pharmacy, PSIIICollege of Pharmacy, PSIII

Preceptor: Doreen Pon, PharmDPreceptor: Doreen Pon, PharmD

ObjectivesObjectives

• Introduce patient case • Brief review of secondary CNS lymphoma and

secondary 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

Patient CasePatient 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

Patient CasePatient Case

• Brain MRI of 12/2009:3 x 2.2 x 2.2 cm mass in the right occipital lobe extending toward the corpus callosum without midline shift or evidence of herniation

Patient CasePatient 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 – heart

problem; maternal grandfather – heart attack years ago

Patient CasePatient Case

• Medications– Phenytoin PO 500mg/400mg at bedtime

alternating every other day– trazodone, buspirone, fluconazole, nystatin,

acyclovir, ursodiol, famotidine, metformin, Flomax

• Allergies: NKDA

Clinical QuestionClinical Question

• Can levetiracetam (Keppra®) be used as 1st line option for seizure prophylaxis in secondary seizure?

Secondary CNS lymphomaSecondary 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 white

matter and the corpus striatum, and may extend to corpus callosum

• Spinal cord is frequently affected • Clinical presentation is nonspecific, may involve focal neurologic

impairment, headache, confusion and seizures.

Zee CS, Neuroradiology: A Study Guide. 1996:158-60.Gerstner ER, et al. Blood. Sep 2008;112(5):1658-61.

Secondary SeizureSecondary 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 CNS conditions

• Seizure due to CNS metastases: should receive anticonvulsive treatment with phenytoin

Fauci, AS, et al. Harrison’s principles of internal medicine, 17 th edition. Chap 270, Sec 4, Oncologic Emergencies.

World Health Organization. http://www.who.int/mediacentre/factsheets/fs999/en/index.html

PhenytoinPhenytoin• 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.

LevetiracetamLevetiracetam• 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 vesicular protein 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.

AbbreviationsAbbreviations and Terminologies and Terminologies

• GCS = Glasgow coma score: trauma scoring; scored between 3-15; 3 being the worst and 15 the best

• GOS = Glasgow outcome score: score for the long-term follow-up after severe brain injuries; scored between 1-5; 5 being 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

Levetiracetam versus phenytoin for Levetiracetam versus phenytoin for seizure prophylaxis seizure prophylaxis

in severe traumatic brain injuryin 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 received levetiracetam 500mg IV Q12H for the 1st 7 days after traumatic injury

– Historical cohort from severe TBI database: 41 patients with TBI from 07/2005-06/2006 received phenytoin for 7 days after trauma.

• Inclusion Diagnostic criteria: – GCS score of 3-8– Hospital standard protocol: not defined in the study– Only patients who received an EEG examination were included in

the analysis.

Jones, K.E., et al. Neurosurg. Focus. Volume 25(4):E3, 2008

ResultsResults

• Patient baseline characteristics: No significant differences

• Patients with EEG examinations: 15/32 in the levetiracetam cohort vs. 12/41 in the phenytoin cohort

• 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

ResultsResults

Jones, K.E., et al. Neurosurg. Focus. Volume 25(4):E3, 2008

Prospective, Randomized, single-Blinded Comparative Trial of Prospective, Randomized, single-Blinded Comparative Trial of Intravenous Levetiracetam Versus Phenytoin for Seizure Intravenous Levetiracetam Versus Phenytoin for Seizure

ProphylaxisProphylaxis

• Design: prospective, single-center, randomized, single-blinded comparative 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 hemorrhage admitted

to the hospital < 24 hours prior to randomization– GCS score 3-8 or GCS motor score < 5 with abnormal

admission CT scan showing intracranial pathology– Hemodynamically stable with sBP ≥90mmHg; at least 1

reactive pupil– ≥ 17 years of age

Szaflarski JP, et al. Neurocrit Care. 2010 Apr;12(2):165-72.

• 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 result

liver failure– Age < 17 yo– CI treatment with LEV or PHT

• Intervention:– PHT group: loading dose of fos-PHT 20mg/kg PE IV, max of 2gm;

maintenance dose (5mg/kg/day, IV Q12H). PHT serum levels check at days 2 and 6 after randomization and dose adjustments to maintain therapeutic serum levels of 10-20 mcg/mL.

– LEV group: loading dose of 20mg/kg IV; maintenance dose (1gm, IV Q12H). Dose was adjusted to max 3gm/day if seizure occurred.

Szaflarski JP, et al. Neurocrit Care. 2010 Apr;12(2):165-72.

ResultsResults• Baseline characteristics: no differences • There were no differences in early seizure occurrence

between 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 at 7 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 PHT including 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.

• Studies have 6 months follow-up period• In Jones, et al., levetiracetam is associated

with higher seizure tendency showing on EEGs than phenytoin.

• Both levetiracetam and phenytoin do not have evidence in prevention of late epilepsy.

• Comparisons in the studies were in IV formulation for 7-day use.

• Efficacy of long-term use in PO formulation has not been compared.

Safety and feasibility of switching from phenytoin to Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control levetiracetam monotherapy for glioma-related seizure control

following craniotomy: a randomized phase II pilot studyfollowing craniotomy: a randomized phase II pilot study

• Design: randomized phase II• Subjects:

– Prior to randomization, patients were stratified into: no prior craniotomy and history of one craniotomy

– Within each stratification group, patients were randomized 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

• 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 adjusted as needed.

– LEV: started LEV 1000mg PO BID with 24 hours of surgery and PHT was tapered off as following: 100% of preoperative PHT regimen on POD0, 75% on POD1, 50% on POD2, and PHT was discontinued on POD3.

• Primary end point: proportion of patients who were seizure free 6 months after tumor resection

Lim, DA et al. J neurooncol 2009, 93:349-354

ResultsResults

• 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

ResultsResults

Lim, DA et al. J neurooncol 2009, 93:349-354

PhenytoinPhenytoin

• ADRs: blood dyscrasias, dermatologic reactions including toxic epidermal necrolysis and SJS, hepatotoxcicity, bradycardia, hypotension, cardiac arrhythmia, headache, insomnia, tremor, paresthesia; idosyncratic (gingival hyperplasia, hirsutism, coarse features)

• DDIs with patient’s current medication:– CYP4A3 substrates: BusPirone, tamsulosin,

trazodone– Fluconazole

Lexi-comp.com

LevetiracetamLevetiracetam

• ADRs: Somnolence, ataxia, headache, Less common are complaints of agitation or anxiety, emotion labile Idiosyncratic reactions are rare.

• Levetiracetam is not metabolized by CYP450 • DDIs with patient’s current medication: None

Lexi-comp.com

Advantages of Levetiracetam Advantages of Levetiracetam over Phenytoinover Phenytoin

• Non-enzyme inducing AED• No serum level monitoring • Not induce drug fever or cutaneous

hypersensitivity reactions• Less ADRs• Less DDIs• No food-drug interactions• IV:PO = 1:1

Back to Patient CaseBack to Patient Case

• Currently on Phenytoin PO 500mg/400mg at bedtime alternating 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: 14.7

mcg/ml)• No seizure activity observed• Repeat MRI: not available

ReferenceReference

• Fauci, AS, et al. Harrison’s 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 severe

traumatic brain injury. Neurosurg. Focus. Volume 25(4):E3, 2008• Katzung, BG, et al. Basic & Clinical Pharmacology, 11th Edition. Chapter 24, Antiseizure

Drugs.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 levetiracetam

monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. Journal neurooncol 2009, 93:349-354.

• Szaflarski JP, et al. Prospective, Randomized, single-Blinded Comparative Trial of Intravenous Levetiracetam Versus Phenytoin for Seizure Prophylaxis. Neurocrit care April 2010 (2):165-72

• Uptodate.com• Zee CS, Neuroradiology: A Study Guide. McGraw Hill 1996:158-60.