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Learning Objectives for Pharmacists • List treatment pearls for common Important Tips in the issues related to the management of epilepsy in the hospital setting Managgppyement of Epilepsy • Describe alternative treatment options Deepika Pereira, Pharm.D, BCPS for epilepsy due to medication Neuro/Spine Critical Care Pharmacist Northwestern Memorial Hospital shortage issues in the hospital setting

No conflicts of interest to disclose

Learning Objectives for Epilepsy: Background Pharmacy Technicians • Recognize the impact of drug • Affects ~3 million people in the US each year shortages on the management of • 10% of Americans will experience a seizure sometime in their lives epilepsy in the hospital setting • 3% will receive a diagnosis of epilepsy by age • List the available dosage forms of the 80 anti-epileptic medications discussed • Encompasses different seizure types and during this presentation syndromes • Usually difficult to ascertain cause • Idiopathic (unknown cause) vs symptomatic (secondary to an identifiable condition)

Epilepsy: Definitions Management of Epilepsy

• Seizures: disordered, synchronous • Medication management and rhythmic firing of neurons – First unprovoked seizure thought to arise from the cerebral – Chronic epilepsy syndromes cortex – Status epilepticus • Epilepsy: disorder of brain function • Surgery characterized by the periodic and unpredictable occurrence of seizures

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Medication management Timing challenges • Status epilepticus (SE) is defined as 5 minutes or • Timing of medication administration more of (i) continuous clinical and/or electrographic seizure activity or (ii) recurrent • Evidence based literature includes seizure activity without recovery between mostly expert opinion seizures • • “Animal data suggest that permanent neuronal Extensive drug-drugg, interactions, short injury and pharmacoresistance may occur before term and long term adverse effects, the traditional definition of 30 min of continuous therapeutic drug monitoring seizure activity have passed” • Control of SE should be achieved within 60 • Pharmacoresistance mintutes of onset • Drug shortages • Refractory SE is defined as those patients who have failed first 2 anti-epileptic drugs (AEDs) • Education of healthcare providers administered – Consider use of continuous infusions

Tips on timing Evidence-based support

• No established intravenous access – Alternate routes of benzodiazepines • Rectal diazepam • Intramuscular (IM) midazolam • IM: 2 ml in the de lto id an d thigh muscl es, and up to 5 ml in the gluteus maximus – Fosphenytoin is not caustic • Hemodynamically unstable patients – Use of fosphenytoin – Maximum rate: 150 mg/min

Evidence-based support Evidence-based support

• SE guidelines include recommendations made from the results of an international survey and expert opinion • International League Against Epilepsy updated review concluded that existing randomized controlled trials researching adult generalized tonic-clonic epilepsy are methodologically flawed and not adequate to answer important clinical questions

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Drug Metabolism Half‐life Therapeutic ADE Dosage forms Comments (hours) drug Medication profiles monitoring Pentobarbital Hydroxylated 15‐50 5‐20 mcg/ml Respiratory IV: 50 mg/ml Can mimic Drug Metabolism Half‐life Therapeutic ADE Dosage forms Comments and then depression brain death glucuronidated Cardiac depression Must be (hours) drug Paralytic ileus mechanically monitoring ventilated

Fosphenytoin rapidly Conversion Free phenytoin Arrhythmias IV: 50 mg PE/ml Preferred use in Phenobarbital 50% 80‐100 10‐40 mcg/ml Sedation Oral: 20 mg/5ml solution Sequential converted via half‐life: 15 level: 1‐2 hemodynamically hydroxylated, Hypotension 15 mg, 16.2 mg, 32.4 loading if hydrolysis to minutes Total phenytoin unstable patients or 25% Respiratory mg, 60 mg, 64.8 mg, hypotensive phenytoin level: 10‐20 those with glucuronidated depression 97.2 mg and 100 mg inadequate IV access 25% excreted tablets Lacosamide 40% unchanged 13 None PR Oral: 50 mg, 100 mg, 150 Reduce dose in unchanged IV: 65 mg/ml and 130 30% O‐ prolongation mg, 200 mg tablets and severe liver cirrhosis mg/ml desmthyl‐LCM 10 mg/ml solution 50% supplemental Phenytoin 70% 20‐60 Free phenytoin Arrhythmias Oral: 50 mg chew tabs, Saturable (CYP2C19) IV: 10 mg/ml dose after dialysis hydroxylated, level: 1‐2 Hypotension 30 mg and 100 mg ER pharmacokinet then Total phenytoin Purple glove capsules, 125 mg/ml ics Levetiracetam 66% excreted 7Well Oral (IR): 250 mg, 500 Renal dose glucuronidated level: 10‐20 syndrome solution Unpredictable unchanged tolerated mg, 750 mg, 1000 mg adjustment IV: 50 mg/ml levels in 24% hydrolyzed and 100 mg/ml solution Supplemental dose uremia Oral (ER): 500 mg and adjustments after Valproate 50% 9‐16 Total valproate Hyperammonemia Oral: 125 mg sprinkle Preferred in 750 mg dialysis glucuronidated levels: Hepatotoxicity capsules, 250 mg and anoxic brain IV: 100 mg/ml sodium 50% multiple 50‐150 mcg/ml Thrombocytopenia 500 mg ER tablets, injury Lorazepam Glucuronidation 14‐18 None Hypotension Oral: 0.5 mg, 1mg, 2 mg Contains propylene other pathways 125mg, 250 mg and 500 Many 75% of Respiratory tablets and 2 mg/ml glycol including beta‐ mg DR tablets formulations metabolite depression solution oxidation 250 mg IR capsules excreted in IV: 2 mg/ml and 4 250 mg/5 ml solution urine mg/ml IV: 100 mg/ml

Pharmacoresistance Pharmacoresistance

• Failure of adequate trials of two • Alternative treatment options: tolerated, appropriately chosen and – Combination medication therapy administered antiepileptic drugs – Newer agents: eslicarbazepine and (whether as monotherapy or in perampanel combination) to achieve seizure freedom – Ketogenic diet • Likelihood of successful treatment – Rapid cooling with other drugs of different class – Herbal: ginger, ginseng, ginkgo biloba, diminishes kava kava, marijuana, melatonin, St. John’s wort, valerian

Drug shortages Current Shortages

• Defined as a supply issue that affects Drug Name Shortage date Reason how the pharmacy prepares or Divalproex sodium June 8, 2015 Product discontinued, manufacturer delay, on tablets allocation dispenses a drug product or Levetiracetam July 22, 2015 Manufacturer delay, increased demand influences patient care when injection Lorazepam July 16, 2015 Product discontinued, increased demand prescribers must use an alternative injection Valproate sodium August 11, Manufacturer delay when prescribers must use an injection 2015 alternative agent

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Alternative treatment options Resolved Shortages • Evidence based literature

Drug Name Date resolved Diazepam injection October 4, 2013 Fosphenytoin injection April 2, 2015 Ketamine injection October 23, 2014 Midazolam injection August 6, 2015 Phenobarbital injection and tablets October 19, 2011 and May 8, 2014 Phenytoin injection and oral January 23, 2015 and Octiber 4, 2011 Propofol injection January 19, 2014 Topiramate capsules August 10, 2011 Topiramate sprinkle capsules April 23, 2014

Alternative treatment options Alternative treatment options

• Use different agents within the same • Use different dosage forms class – Oral loading: phenytoin – Benzodiazepines • Maximum absorption= 400 mg – Barbiturates – Switch from oral solutions to tablets or – Phenytoin versus fosphenytoin capsules • dose based on drug delivery of formulation

Alternative treatment options Summary • Use agents with similar mechanism of action • Management of epilepsy is complex and Drug Name Sodium channel Calcium channel GABA challenging Benzodiazepines ++ • No established guideline or literature to Carbamazepine ++ + support the use of one AED over another Lacosamide ++ *Lamotrigine ++ + • guidelines exist for the treatment of status Levetiracetam + epilepticus Oxcarbazepine ++ + • Pharmacists and technicians can make Phenobarbital ++ an impact in assisting healthcare Phenytoin ++ providers with alternatives in the setting *Topiramate+++ of drug shortages. *Valproate+++ *Broad spectrum

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CW is a 20 year old female who presents to the emergency department after a generalized tonic-clonic seizure and brief The guidelines for the management loss of consciousness. She is alert and oriented currently and of status epilepticus includes: able to tell you that she has never had a seizure before and she has been very stressed lately with finals. She has been pulling consecutive all nighters and consuming 2 pots of coffee each day. A. Only Class I, level A evidence based How would you treat CW? recommendations

A. Initiate phenytoin 15 mg/kg loading dose and 100 B. Only expert opinion mg PO TID C. Some expert opinion and some Class B. Do not initiate any medication at this time I, level A evidence C. Administer lorazepam 2 mg IV push and send CW home D. Evidence that cannot be interpreted D. Initiate midazolam infusion

A patient is noted to have status epilepticus Pharmacoresistance is a prevalent issue in managing epilepsy. What alternative on electroencephalogram (EEG) monitoring treatment option is recommended to but has lost IV access and the physician would like to administer medication to break overcome pharmacoresistance? the seizure now. A. Herbal supplements What medication could you provide? B. Electroconvulsive therapy A. Rectal diazepam 0.2 mg/kg C. Combining AEDs with differing B. Rectal midazolam 0.2 mg/kg mechanisms of action C. Intramuscular diazepam 0.15 mg/kg D. Warming D. Phenytoin oral loading dose 15 mg/kg

Valproate sodium injection is on short supply. A patient has been on 500 mg IV References

1. Epilepsy Foundation. Epilepsy Statistics. Available at: http://www.epilepsy.com/learn/epilepsy-statistics. infusion every 6 hours and needs to be Accessed August 20, 2015 2. Institute of Medicine Report. Epilepsy Across the Spectrum: Promoting Health and Understanding. Available converted to an oral formulation. What at: http://iom.nationalacademies.org/~/media/Files/Report%20Files/2012/Epilepsy/epilepsy_slides.pdf. Accessed August 20, 2015 dosing would be equivalent? 3. McNamara JO. Chapter 21. Pharmacotherapy of the Epilepsies. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. http://accessmedicine.mhmedical.com.ezproxy.galter.northwestern.edu/content.aspx?bookid=374&Sectionid A. Divalproex sodium 500 mg DR PO twice a =41266227. Accessed August 20, 2015. 4. Brophy GM, Bell R, Claassen J et al. Neurocritical Care Society Status Epilepticus Guideline Writing day Committee. Guidelines for the evaluation and management of status epppilepticus. Neurocrit Care. 2012 Aug;17(1):3-23 5. Krumholz A, Weibe S, Gronseth GS et al. Evidence-based guideline: Management of an unprovoked first B. Divalproex sodium 1500 mg ER PO once seizure in adults. Neurology. 2015;84:1705–1713 6. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug daily efficacyand effectiveness as initial monotherapy for epilepticseizures and syndromes. Epilepsia. 2013 54(3):551–563. 7. Kwan P, Arzimanoglou A, Berg AT et al. Definition of drug resistant epliepsy: consensus proposal by the ad C. Divalproex sodium 500 mg DR PO every 6 hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010; 51(6):1069 8. Kwan P, Schachter SC,Brodie MJ. Drug-Resistant Epilepsy. N Engl J Med 2011; 365:919-926 hours 9. Sharma AK, Rani E, Waheed A et al. Pharmacoresistant Epilepsy: A Current Update on Non-Conventional Pharmacological and Non-Pharmacological Interventions. J Epilepsy Res. 2015; 5(1); 2015 10. Fox E, Birt A, James K, Kokko H, et.al. ASHP guidelines on managing drug product shortages in hospitals D. Valproic acid oral solution 500 mg PO and health systems. Am J Health-Syst Pharm. 2009; 66:1399-406 11. American Society of Health-Systems Pharmacists. Drug Shortages: Current Drugs. Available at: every 6 hours http://www.ashp.org/drugshortages/current/. Accessed August 20, 2015

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