1. MANAGING SUBTHERAPEUTIC AED LEVELS Edwin Kuffner, MD, FACEP Rocky Mountain Poison and Drug Center Denver, Colorado

2. Edwin Kuffner, MD, FACEP Case Presentation 35-year old, otherwise healthy, male presents to ED after having a seizure35-year old, otherwise healthy, male presents to ED after having a seizure PMH: seizures since childhood, last 2 years priorPMH: seizures since childhood, last 2 years prior Meds: phenytoin (non-compliant x 2 weeks)Meds: phenytoin (non-compliant x 2 weeks) Normal vital signs, normal mental status and normal physical examNormal vital signs, normal mental status and normal physical exam Serum phenytoin level: undetectableSerum phenytoin level: undetectable

3. Edwin Kuffner, MD, FACEP Question What is the most effective phenytoin or fosphenytoin dosing strategy for preventing short term seizure recurrence in a patient with a pre-existing seizure disorder who presents to the ED within 24 hours of having had a seizure without status epilepticus and who is determined to have a “subtherapeutic” serum phenytoin level?What is the most effective phenytoin or fosphenytoin dosing strategy for preventing short term seizure recurrence in a patient with a pre-existing seizure disorder who presents to the ED within 24 hours of having had a seizure without status epilepticus and who is determined to have a “subtherapeutic” serum phenytoin level?

4. Edwin Kuffner, MD, FACEP What common dosing strategy would you use? 1.Load the patient with IV phenytoin or fosphenytoin and start/restart daily oral maintenance doses 2.Load the patient with oral phenytoin and start/restart daily oral maintenance doses 3.Start/restart daily oral maintenance doses without administering a loading dose

5. Edwin Kuffner, MD, FACEP Dosing Strategy Emergency physicians should understand that the most important measure of a particular antiepileptic drug dosing strategy should be efficacy in preventing seizure recurrence when viewed in conjunction with adverse events and cost.Emergency physicians should understand that the most important measure of a particular antiepileptic drug dosing strategy should be efficacy in preventing seizure recurrence when viewed in conjunction with adverse events and cost.

6. Edwin Kuffner, MD, FACEP Questions Surrounding This Issue What is the relationship between a “therapeutic” serum phenytoin level and the prevention of seizures?What is the relationship between a “therapeutic” serum phenytoin level and the prevention of seizures? What are the pharmacokinetic concerns as they relate to achieving a phenytoin level > 10 mg/L?What are the pharmacokinetic concerns as they relate to achieving a phenytoin level > 10 mg/L? What adverse events are associated with PO, IV and IM dosing of phenytoin and fosphenytoin?What adverse events are associated with PO, IV and IM dosing of phenytoin and fosphenytoin? What are the pharmacoeconomic concerns as they relate to phenytoin and fosphenytoin?What are the pharmacoeconomic concerns as they relate to phenytoin and fosphenytoin? What is the risk of seizure recurrence in a patient that is discharged from the ED?What is the risk of seizure recurrence in a patient that is discharged from the ED?

7. Edwin Kuffner, MD, FACEP What is the relationship between a “therapeutic” serum phenytoin level and the prevention of seizures? Many patients remain seizure free at levels 20 mg/L for seizure control. 1Many patients remain seizure free at levels 20 mg/L for seizure control. 1 At levels > 20 mg/L patients are more likely to have adverse events but many patients will experience adverse events at “therapeutic levels”. 2At levels > 20 mg/L patients are more likely to have adverse events but many patients will experience adverse events at “therapeutic levels”. 2 1 Carter: Arch Neurol Psych 1958 and Leppick: Adv Neurol 1983 2 Ambrosetto: Epilepsia 1977 and Product information

8. Edwin Kuffner, MD, FACEP Clinical Efficacy Achieving a serum phenytoin level between 10-20 mg/L may be a measure of pharmacokinetic efficacyAchieving a serum phenytoin level between 10-20 mg/L may be a measure of pharmacokinetic efficacy A more relevant measure of clinical efficacy should be prevention of seizure recurrence with an acceptable adverse effects profile.A more relevant measure of clinical efficacy should be prevention of seizure recurrence with an acceptable adverse effects profile.

9. Edwin Kuffner, MD, FACEP What are the pharmacokinetic concerns related to achieving a phenytoin level > 10 mg/L? A level > 10 mg/L can be achieved: –Immediately following an IV load 1 –Within 3-10 hours in some cases and within 24 hours in most cases following an oral load 2 –Within 3-7 days following daily maintenance dosing without a loading dose 3 –Within 1-2 hours in most cases and within 24 hours in almost all cases following an IM load 4 1 Carducci, Kugler, Leppick, Salem 1 Carducci, Kugler, Leppick, Salem 2 Osborn, Rantakorn, Record, Wilder 2 Osborn, Rantakorn, Record, Wilder 3 Buchanan Gugler Svensmark 3 Buchanan Gugler Svensmark 4 Boucher, Browne, Kugler, Uthman, Wilder 4 Boucher, Browne, Kugler, Uthman, Wilder

10. Edwin Kuffner, MD, FACEP Maintenance Strategy Regardless of the initial dosing strategy patients require daily maintenance doses to maintain the serum level > 10 mg/L. Less than 20% of adult patients taking 300 mg/day will achieve a serum level > 10 mg/L. 1Regardless of the initial dosing strategy patients require daily maintenance doses to maintain the serum level > 10 mg/L. Less than 20% of adult patients taking 300 mg/day will achieve a serum level > 10 mg/L. 1 1 Buchanan, Gugler

11. Edwin Kuffner, MD, FACEP What adverse events are associated with PO, IV and IM phenytoin and fosphenytoin? Irrespective of dosing ataxia, nystagmus and somnolence are common.Irrespective of dosing ataxia, nystagmus and somnolence are common. Following IV dosing:Following IV dosing: Adverse local effects:Adverse local effects: –phlebitis, purple glove syndrome, tissue necrosis 1 Adverse systemic effects:Adverse systemic effects: –impaired myocardial contractility, dysrhythmias, hypotension, cardiac arrest 2 1 Comer, Marchetti, O’Brien, Kilarski 2 Earnst, Russell, York

12. Edwin Kuffner, MD, FACEP Adverse Effects Both local and systemic adverse effects are reported much less commonly with fosphenytoin than with IV phenytoin.Both local and systemic adverse effects are reported much less commonly with fosphenytoin than with IV phenytoin. Boucher. Pharmacotherapy 1996 Jameson Pharmacotherapy 1994;14:47-52 Henken. Epilepsia 1996;37(suppl 5):157

13. Edwin Kuffner, MD, FACEP What are the pharmacoeconomic concerns as they relate to phenytoin and fosphenytoin? In 10/2001 it costs approximately: $95.00 for 1000 mg of fosphenytoin $95.00 for 1000 mg of fosphenytoin $5.50 for 1000 mg of parenteral phenytoin $5.50 for 1000 mg of parenteral phenytoin $5.00 for 1000 mg of oral phenytoin $5.00 for 1000 mg of oral phenytoin

14. Edwin Kuffner, MD, FACEP What is the risk of seizure recurrence in a patient that is discharged from the ED? Data on the risk of seizure recurrence is commonly reported in years, not days or weeks.Data on the risk of seizure recurrence is commonly reported in years, not days or weeks. It is difficult to compare studies because:It is difficult to compare studies because: –the background incidence of short term seizure recurrence is unknown. –most studies included patients with many different etiologies for their seizures.

15. Edwin Kuffner, MD, FACEP Seizure Response with Phenytoin IV phenytoin mostly 15-18 mg/kg to 139 patients on 159 occasions for “repetitive seizures”IV phenytoin mostly 15-18 mg/kg to 139 patients on 159 occasions for “repetitive seizures” 20% had a recurrence20% had a recurrence –6% with “antiepileptic drug withdrawal, 11% with “epilepsy cause undetermined” and 18% with “miscellaneous conditions” If there was anoxic or metabolic disturbances more than 60% had a recurrenceIf there was anoxic or metabolic disturbances more than 60% had a recurrence Cranford. Neurology 1978;28:874-880

16. Edwin Kuffner, MD, FACEP Oral Phenytoin Loading Oral phenytoin 18 mg/kg to 44 patients with “one or more recent seizures” who were awakeOral phenytoin 18 mg/kg to 44 patients with “one or more recent seizures” who were awake No patient had a recurrence during the 8 hour observation periodNo patient had a recurrence during the 8 hour observation period Osborn. Ann Emerg Med 1987; 16:407-412

17. Edwin Kuffner, MD, FACEP Based upon 2 studies the rate of short term seizure recurrence in the population of interest varies from 0-20%. 1Based upon 2 studies the rate of short term seizure recurrence in the population of interest varies from 0-20%. 1 Seizure Recurrence Osborn. Ann Emerg Med 1987; 16:407-412 Cranford. Neurology 1978;28:874-880

18. Edwin Kuffner, MD, FACEP Dosing Strategy What is the most effective phenytoin or fosphenytoin dosing strategy for preventing short term seizure recurrence in a patient with a pre- existing seizure disorder who presents to the ED within 24 hours of having had a seizure without status epilepticus and who is determined to have a “subtherapeutic” serum phenytoin level?What is the most effective phenytoin or fosphenytoin dosing strategy for preventing short term seizure recurrence in a patient with a pre- existing seizure disorder who presents to the ED within 24 hours of having had a seizure without status epilepticus and who is determined to have a “subtherapeutic” serum phenytoin level?

19. Edwin Kuffner, MD, FACEP Common Dosing Strategies 1.Load the patient with IV phenytoin or fosphenytoin and start/restart daily oral maintenance doses 2.Load the patient with oral phenytoin and start/restart daily oral maintenance doses 3.Start/restart daily oral maintenance doses without administering a loading dose

20. Edwin Kuffner, MD, FACEP What the Literature Can Tell Us A serum phenytoin level > 10 mg/L can be achieved by all of the common contemporary dosing strategies and by IM fosphenytoin administration.A serum phenytoin level > 10 mg/L can be achieved by all of the common contemporary dosing strategies and by IM fosphenytoin administration. Fewer adverse effects are associated with administration of fosphenytoin than parenteral phenytoin preparations.Fewer adverse effects are associated with administration of fosphenytoin than parenteral phenytoin preparations. Fosphenytoin remains considerably more expensive than parenteral phenytoin.Fosphenytoin remains considerably more expensive than parenteral phenytoin.

21. Edwin Kuffner, MD, FACEP What the Literature Cannot Yet Tell Us Whether there is a difference in the short term rate of seizure recurrence between the different common dosing strategies.Whether there is a difference in the short term rate of seizure recurrence between the different common dosing strategies.

22. Edwin Kuffner, MD, FACEP Conclusion Emergency physicians who understand the pharmacokinetic, pharmacoeconomic and adverse event profiles of phenytoin and fosphenytoin as well as the limitations of the medical literature are best suited to help their patients make informed decisions regarding the different dosing strategies.Emergency physicians who understand the pharmacokinetic, pharmacoeconomic and adverse event profiles of phenytoin and fosphenytoin as well as the limitations of the medical literature are best suited to help their patients make informed decisions regarding the different dosing strategies.