Shands Jacksonville Department of Pharmacy

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1 Shands Jacksonville Department of Pharmacy Medication Use Evaluation: IV Levetiracetam Evaluation Time Period: 05/27/ /24/2013 Important Aspect of Care: Care of Patients, Medication Use, Prescribing & Monitoring Basis of Choice: Levetiracetam intravenous (IV) injection is indicated for the adjunctive treatment in adults (> 16 years of age) with the following seizure types when oral administration of Keppra is temporarily not feasible: partial onset seizures, myoclonic seizures in patients with juvenile myoclonic epilepsy, and primary generalized tonic- clonic seizures. Approved doses range from 1,000 mg/day to 3,000 mg/day, given as two divided doses. Caution should be used in dosing patients with moderate to severe renal impairment and in patients undergoing hemodialysis. Levetiracetam is pregnancy category C based on animal studies and should be used during pregnancy only if the potential benefits outweigh the risks. 1 According to the latest guidelines published by the Brain Trauma Foundation and the American Academy of Neurology, posttraumatic seizure (PTS) prophylaxis is recommended only during the first 7 days after a severe traumatic brain injury (TBI). 2-4 Currently, there is not enough evidence to support PTS prophylaxis for longer than 7 days after TBI. Phenytoin has the most data regarding prophylaxis of PTS, although it is not FDA approved for that indication. Phenytoin has been approved by the FDA for the management of generalized tonic- clonic and complex partial seizures, as well prevention and treatment of seizures occurring during or after neurosurgery. 5 Levetiracetam has several advantages over phenytoin for its use in seizure prophylaxis. It is well tolerated, does not require monitoring levels, has minimal drug interactions, and has been recently approved for IV administration in the acute setting. 6 Animal studies have indicated that levetiracetam may have neuroprotective effects following brain injuries. 6 A small, retrospective cohort study found that while levetiracetam was as effective as phenytoin in preventing PTS, it was also associated with an increase in seizure tendency. 7 Another study indicated that levetiracetam had similar efficacy to phenytoin for early PTS prophylaxis after TBI and may be more tolerable. 8 There is no consensus on what a potentially appropriate dosage would be for PTS prophylaxis following TBI or neurosurgery, however the doses studied have been 500 mg BID x 7 days and 1,000 mg BID x 7 days. 7-8 Data regarding the use of levetiracetam in refractory status epilepticus is limited. 9-10

2 IV levetiracetam was selected for a medication use evaluation (MUE) because it is a high cost and high risk medication. Its nonformulary use has been increasing. In January 2011, the Shands Jacksonville Pharmacy and Therapeutics Committee approved the use of levetiracetam for the following criteria: (1) initial treatment of partial onset seizures, myoclonic seizures in patients with juvenile myoclonic epilepsy, and primary generalized tonic- clonic seizures (2) seizure prophylaxis following TBI (3) seizure prophylaxis prior to neurosurgery (4) refractory complex partial status epilepticus. Method of Collecting Data: Inpatient orders for IV levetiracetam were retrospectively assessed using Epic. The following information was recorded: basic patient information, prescribing service, indication for use, medication dosage, home use of levetiracetam, and patient ability to tolerate oral intake. Renal function was also assessed. Results: A total of 44 patients and orders were analyzed. Indications: The most common reason for receiving an IV levetiracetam order was for adjunctive epilepsy (25/44) o 14/25 of the orders did not specify the type of seizure o 7/25 of the orders were for generalized tonic- clonic seizure o 1/25 of the orders were for complex partial seizure o 1/25 of the orders were for myoclonic seizure o 1/25 of the orders were for febrile seizure o 1/25 of the order were for alcohol withdrawal seizure Seizure prophylaxis in post- traumatic brain injury (14/44) Treatment of status epilepticus (5/44) Figure 1A represents a breakdown of the indications, and Figure 1B shows the breakdown of indications of seizure types

Figure 1A: Indications 32% 11% 57% Adjunctive epilepsy TBI Status Epilepticus Figure 1B: Seizure Types 4% 4% 4% 28% 56% Not speci8ied Generalized tonic- clonic Myoclonic Ordering Services: The most

3 Figure 1A: Indications 32% 11% 57% Adjunctive epilepsy TBI Status Epilepticus Figure 1B: Seizure Types 4% 4% 4% 28% 56% Not speci8ied Generalized tonic- clonic Myoclonic Ordering Services: The most common order service for IV levetiracetam orders was neurology (16/44) o 13/16 of the orders were for epilepsy o 3/16 of the orders were for TBI Emergency medicine (9/44) o 7/9 of the orders were for epilepsy o 2/9 of the orders were for TBI Trauma surgery (9/44) o 2/9 of the orders were for epilepsy o 7/9 of the orders were for TBI Internal medicine (5/44) o 4/5 of the orders were for epilepsy o 1/5 of the orders were for TBI Hospitalists (2/44) o 2/2 of the orders were for epilepsy General surgery (2/44) o 1/2 of the orders were for epilepsy o 1/2 of the orders were for TBI Cardiothoracic surgery (1/44) o 1/1 of the orders were for epilepsy Figure 2 gives a breakdown of the services

Figure 2: Ordering Services 5% 5% 2% 11% 20% 21% 36% Neurology Emergency Medicine Trauma Surgery Internal Medicine Hospitalists General Surgery Cardiothoracic Surgery Dosage: Dosages were variable

Twenty of the patients were taking levetiracetam at home, but this could be an underestimate because 6 of the patients did not have any documentation of prior home medications.

4 Figure 2: Ordering Services 5% 5% 2% 11% 20% 21% 36% Neurology Emergency Medicine Trauma Surgery Internal Medicine Hospitalists General Surgery Cardiothoracic Surgery Dosage: Dosages were variable depending on the specific patient and indication for use. Twenty of the patients were taking levetiracetam at home, but this could be an underestimate because 6 of the patients did not have any documentation of prior home medications. Twelve patients were able to tolerate oral medications, however, 13 patients did not have documentation regarding their NPO status. Thirty- one patients were switched to oral therapy when appropriate. 2 of the orders were not dosed appropriately according to the patient s renal function and 5 patients were excluded from calculating renal function due to missing data/laboratory values. Post- traumatic brain injury: 13 patients were ordered 500 mg IV twice daily. One patient was ordered 170 mg IV once (pediatric). Adjunctive epilepsy treatment: 1 patient was given 280 mg once for a febrile seizure. 2 patients received 500 mg q12h and 3 patients received 500 mg once. 2 patients received 750 mg q12h and 1 patient received 750 mg once. 5 patients received 1,000 mg q12h, 8 patients received 1,000 mg once, and 1 patient received 1,000 mg once per day on Sunday, Monday, Wednesday, and Friday. 2 patients received 1,500 mg q12h and 1 patient received 1,500 mg once. Status Epilepticus: 1 patient received 500 mg q12h. 2 patients received 1,000 mg q12h and 2 patients received 1,500 mg q12h.

5 Compliance: Based on the P&T Committee s decision to extend the criteria for levetiracetam use, 24 orders were considered to be in compliance (54%). However, this number is inaccurate due to the lack of documentation regarding specific seizure types. The most frequent off- label use was for seizure prophylaxis in TBI. Observations/Recommendations: Lack of documentation regarding: o Seizure types o Prior home medication list o Dietary restrictions o Laboratory values (SCr) Overall there was a consistent dosage used for TBI, however dosages for other indications varied Pharmacists were actively involved in changing patients from IV to PO therapy when appropriate Recommend that nonformulary use of IV levetiracetam continue to be carefully monitored. The use of PO levetiracetam should be encouraged if applicable. Seizure types should be more clearly noted and the appropriate antiepileptic drugs should be used. References 1. Package insert: Keppra (levetiracetam) Injection. Smyrna, GA: UCB, Inc; 2009 Apr. 2. Chang BS, Lowenstein DH. Practice parameter: Antiepileptic drug prophylaxis in severe traumatic brain injury: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;60: Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. Antiseizure prophylaxis. J Neurotrauma. 2007;24 (Suppl 1):S Torbic H, Forni AA, Anger KE, et al. Use of antiepileptics for seizure prophylaxis after traumatic brain injury. Am J Health- System Pharm. 2013;70: Package insert: Dilantin (phenytoin). New York: Pfizer, Inc; 2011 Oct. 6. Wang H, Gao J, Lassiter TF, et al. Levetiracetam is Neuroprotective in Murine Models of Closed Head Injury and Subarachnoid Hemorrhage. Neurocrit Care. 2006;5(1):71-78.

6 7. Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25:E3. 8. Szaflarski JP, Sangha KS, Lindsell CJ, et al. Prospective, Randomized Single- Blinded Comparative Trial of Intravenous Levetiracetam versus Phenytoin for Seizure Prophylaxis. Neurocrit Care. 2010;12: Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry. 2008;79: Trabacca A, Profice P, Constanza MC, et al. Levetiracetam in Nonconvulsive Status Epilepticus in Childhood: A Case Report. J Child Neurol. 2007;22:

The use of Levetiracetam and Phenytoin for Seizure Prophylaxis in the Setting of Severe Traumatic Brain Injury

Pacific University CommonKnowledge School of Physician Assistant Studies Theses, Dissertations and Capstone Projects Summer 8-11-2012 The use of Levetiracetam and Phenytoin for Seizure Prophylaxis in the