Transcript Phenytoin versus levetiracetam for seizure

Phenytoin
VS
levetiracetam
for seizure prophylaxis
in secondary seizure
Kristy Wu
Medicine Rotation
Western University of Health Sciences
College of Pharmacy, PSIII
Preceptor: Doreen Pon, PharmD
Objectives
• 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 Case
RH is a 69 year-old male with aggressive diffuse large B-cell nonHodgkin
lymphoma who is being admitted for autologous stem cell
transplantation
with 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 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 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 Case
• Medications
– Phenytoin PO 500mg/400mg at bedtime
alternating every other day
– trazodone, buspirone, fluconazole, nystatin,
acyclovir, ursodiol, famotidine, metformin,
Flomax
• Allergies: NKDA
Clinical Question
• Can levetiracetam (Keppra®) be
used as 1st line option for seizure
prophylaxis in secondary seizure?
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 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.
Gerstner ER, et al. Blood. Sep 2008;112(5):1658-61.
Zee CS, Neuroradiology: A Study Guide. 1996:158-60.
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 CNS
conditions
• Seizure due to CNS metastases: should receive
anticonvulsive treatment with phenytoin
World Health Organization. http://www.who.int/mediacentre/factsheets/fs999/en/index.html
Fauci, AS, et al. Harrison’s principles of internal medicine, 17th edition. Chap 270, Sec 4, Oncologic Emergencies.
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, 11th Edition. Chapter 24, Antiseizure Drugs.
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 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, 11th Edition. Chapter 24, Antiseizure Drugs.
Abbreviations
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
seizure 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 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
Results
• 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
Results
Jones, K.E., et al. Neurosurg. Focus. Volume 25(4):E3, 2008
Prospective, Randomized, single-Blinded Comparative Trial of
Intravenous Levetiracetam Versus Phenytoin for Seizure
Prophylaxis
• 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:
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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.
Results
• 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
levetiracetam 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: 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
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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
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
Results
Lim, DA et al. J neurooncol 2009, 93:349-354
Phenytoin
• 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
Levetiracetam
• 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
over 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 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
Reference
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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.