Phenytoin VS levetiracetam for seizure prophylaxis in secondary

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, Pharm. D

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 non. Hodgkin 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 3 rd 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 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 500 mg/400 mg 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 1 st 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/fs 999/en/index. html Fauci, AS, et al. Harrison’s principles of internal medicine, 17 th 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/m. L – >20 mcg/m. L: Far lateral nystagmus – >30 mcg/m. L: 45° lateral gaze nystagmus and ataxia – >40 mcg/m. L: Decreased mentation – >100 mcg/m. L: Death Katzung, BG, et al. Basic & Clinical Pharmacology, 11 th 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 SV 2 A – 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.

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/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 500 mg IV Q 12 H for the 1 st 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): E 3, 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 had 2 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): E 3, 2008

Results Jones, K. E. , et al. Neurosurg. Focus. Volume 25(4): E 3, 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 s. BP ≥ 90 mm. Hg; 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 20 mg/kg PE IV, max of 2 gm; maintenance dose (5 mg/kg/day, IV Q 12 H). PHT serum levels check at days 2 and 6 after randomization and dose adjustments to maintain therapeutic serum levels of 10 -20 mcg/m. L. – LEV group: loading dose of 20 mg/kg IV; maintenance dose (1 gm, IV Q 12 H). Dose was adjusted to max 3 gm/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 – – – 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 day 1 (POD 1); PHT dose adjusted as needed. – LEV: started LEV 1000 mg PO BID with 24 hours of surgery and PHT was tapered off as following: 100% of preoperative PHT regimen on POD 0, 75% on POD 1, 50% on POD 2, and PHT was discontinued on POD 3. • 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: – CYP 4 A 3 substrates: Bus. Pirone, 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 CYP 450 • 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 500 mg/400 mg 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 • • • Fauci, AS, et al. Harrison’s principles of internal medicine, 17 th edition (online version). Chapter 270, Section 4, Oncologic Emergencies. http: //www. accessmedicine. com. proxy. westernu. edu/content. aspx? a. ID=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): E 3, 2008 Katzung, BG, et al. Basic & Clinical Pharmacology, 11 th Edition. Chapter 24, Antiseizure Drugs. http: //www. accessmedicine. com. proxy. westernu. edu/content. aspx? a. ID=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. Mc. Graw Hill 1996: 158 -60.