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

MANAGING SUBTHERAPEUTIC AED LEVELS

Edwin Kuffner, MD, FACEPRocky Mountain Poison and Drug Center

Denver, Colorado

Edwin Kuffner, MD, FACEP

Case PresentationCase Presentation

• 35-year old, otherwise healthy, male presents to 35-year old, otherwise healthy, male presents to ED after having a seizureED 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 vital signs, normal mental status and

normal physical examnormal physical exam• Serum phenytoin level: undetectableSerum phenytoin level: undetectable


QuestionQuestion

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


What common dosing strategy would you use?What common dosing strategy would you use?

1.1. Load the patient with IV phenytoin or Load the patient with IV phenytoin or fosphenytoin and start/restart daily oral fosphenytoin and start/restart daily oral maintenance dosesmaintenance doses

2.2. Load the patient with oral phenytoin and Load the patient with oral phenytoin and start/restart daily oral maintenance dosesstart/restart daily oral maintenance doses

3.3. Start/restart daily oral maintenance doses Start/restart daily oral maintenance doses without administering a loading dosewithout administering a loading dose


Dosing StrategyDosing Strategy

• Emergency physicians should understand Emergency physicians should understand that the most important measure of a that the most important measure of a particular antiepileptic drug dosing strategy particular antiepileptic drug dosing strategy should be efficacy in preventing seizure should be efficacy in preventing seizure recurrence when viewed in conjunction recurrence when viewed in conjunction with adverse events and cost.with adverse events and cost.


Questions Surrounding This IssueQuestions Surrounding This Issue

• What is the relationship between a “therapeutic” serum What is the relationship between a “therapeutic” serum phenytoin level and the prevention of seizures?phenytoin level and the prevention of seizures?

• What are the pharmacokinetic concerns as they relate to What are the pharmacokinetic concerns as they relate to achieving a phenytoin level achieving a phenytoin level >> 10 mg/L? 10 mg/L?

• What adverse events are associated with PO, IV and IM What adverse events are associated with PO, IV and IM dosing of phenytoin and fosphenytoin?dosing of phenytoin and fosphenytoin?

• What are the pharmacoeconomic concerns as they relate What are the pharmacoeconomic concerns as they relate to phenytoin and fosphenytoin?to phenytoin and fosphenytoin?

• What is the risk of seizure recurrence in a patient that is What is the risk of seizure recurrence in a patient that is discharged from the ED?discharged from the ED?


What is the relationship between a “therapeutic” What is the relationship between a “therapeutic” serum phenytoin level and the prevention of seizures?serum phenytoin level and the prevention of seizures?

• Many patients remain seizure free at levels Many patients remain seizure free at levels < 10 mg/L and some patients require levels < 10 mg/L and some patients require levels > 20 mg/L for seizure control.> 20 mg/L for seizure control.11

• At levels > 20 mg/L patients are more likely At levels > 20 mg/L patients are more likely to have adverse events but many patients to have adverse events but many patients will experience adverse events at will experience adverse events at “therapeutic levels”.“therapeutic levels”.22

1 Carter: Arch Neurol Psych 1958 and Leppick: Adv Neurol 19832 Ambrosetto: Epilepsia 1977 and Product information


Clinical EfficacyClinical Efficacy

• Achieving a serum phenytoin level between Achieving a serum phenytoin level between 10-20 mg/L may be a measure of 10-20 mg/L may be a measure of pharmacokinetic efficacypharmacokinetic efficacy

• A more relevant measure of clinical A more relevant measure of clinical efficacy should be prevention of seizure efficacy should be prevention of seizure recurrence with an acceptable adverse recurrence with an acceptable adverse effects profile.effects profile.


What are the pharmacokinetic concerns related to What are the pharmacokinetic concerns related to achieving a phenytoin level achieving a phenytoin level >> 10 mg/L? 10 mg/L?

A level A level >> 10 mg/L can be achieved: 10 mg/L can be achieved:– Immediately following an IV loadImmediately following an IV load11

– Within 3-10 hours in some cases and within 24 hours in most Within 3-10 hours in some cases and within 24 hours in most cases following an oral loadcases following an oral load22

– Within 3-7 days following daily maintenance dosing without a Within 3-7 days following daily maintenance dosing without a loading doseloading dose33

– Within 1-2 hours in most cases and within 24 hours in almost all Within 1-2 hours in most cases and within 24 hours in almost all cases following an IM loadcases following an IM load44

1 Carducci, Kugler, Leppick, Salem1 Carducci, Kugler, Leppick, Salem 2 Osborn, Rantakorn, Record, Wilder2 Osborn, Rantakorn, Record, Wilder 3 Buchanan Gugler Svensmark 3 Buchanan Gugler Svensmark 4 Boucher, Browne, Kugler, Uthman, Wilder4 Boucher, Browne, Kugler, Uthman, Wilder


Maintenance StrategyMaintenance Strategy

• Regardless of the initial dosing strategy patients Regardless of the initial dosing strategy patients require daily maintenance doses to maintain the require daily maintenance doses to maintain the serum level serum level >> 10 mg/L. 10 mg/L.

Less than 20% of adult patients taking 300 mg/day Less than 20% of adult patients taking 300 mg/day will achieve a serum level will achieve a serum level >> 10 mg/L. 10 mg/L.11

1 Buchanan, Gugler


What adverse events are associated with PO, IV What adverse events are associated with PO, IV and IM phenytoin and fosphenytoin?and IM phenytoin and fosphenytoin?

• Irrespective of dosing ataxia, nystagmus and Irrespective of dosing ataxia, nystagmus and somnolence are common.somnolence are common.

• Following IV dosing:Following IV dosing:• Adverse local effects:Adverse local effects:

– phlebitis, purple glove syndrome, tissue necrosisphlebitis, purple glove syndrome, tissue necrosis11

• Adverse systemic effects: Adverse systemic effects: – impaired myocardial contractility, dysrhythmias, impaired myocardial contractility, dysrhythmias,

hypotension, cardiac arresthypotension, cardiac arrest22

1 Comer, Marchetti, O’Brien, Kilarski1 Comer, Marchetti, O’Brien, Kilarski2 Earnst, Russell, York2 Earnst, Russell, York


Adverse EffectsAdverse Effects

• Both local and systemic adverse effects are reported much Both local and systemic adverse effects are reported much less commonly with fosphenytoin than with IV phenytoin. less commonly with fosphenytoin than with IV phenytoin.

Boucher. Pharmacotherapy 1996Jameson Pharmacotherapy 1994;14:47-52Henken. Epilepsia 1996;37(suppl 5):157


What are the pharmacoeconomic concerns as they What are the pharmacoeconomic concerns as they relate to phenytoin and fosphenytoin?relate to phenytoin and fosphenytoin?

In 10/2001 it costs approximately: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


What is the risk of seizure recurrence in a What is the risk of seizure recurrence in a patient that is discharged from the ED?patient that is discharged from the ED?

• Data on the risk of seizure recurrence is Data on the risk of seizure recurrence is commonly reported in years, not days or commonly reported in years, not days or weeks.weeks.

• It is difficult to compare studies because:It is difficult to compare studies because:– the background incidence of short term seizure the background incidence of short term seizure

recurrence is unknown.recurrence is unknown.– most studies included patients with many most studies included patients with many

different etiologies for their seizures. different etiologies for their seizures.


Seizure Response with PhenytoinSeizure Response with Phenytoin

• IV phenytoin mostly 15-18 mg/kg to 139 patients on IV phenytoin mostly 15-18 mg/kg to 139 patients on 159 occasions for “repetitive seizures”159 occasions for “repetitive seizures”

• 20% had a recurrence 20% had a recurrence – 6% with “antiepileptic drug withdrawal, 11% with 6% with “antiepileptic drug withdrawal, 11% with

“epilepsy cause undetermined” and 18% with “epilepsy cause undetermined” and 18% with “miscellaneous conditions”“miscellaneous conditions”

• If there was anoxic or metabolic disturbances more If there was anoxic or metabolic disturbances more than 60% had a recurrencethan 60% had a recurrence

Cranford. Neurology 1978;28:874-880


Oral Phenytoin LoadingOral Phenytoin Loading

• Oral phenytoin 18 mg/kg to 44 patients with Oral phenytoin 18 mg/kg to 44 patients with “one or more recent seizures” who were “one or more recent seizures” who were awakeawake

• No patient had a recurrence during the 8 No patient had a recurrence during the 8 hour observation periodhour observation period

Osborn. Ann Emerg Med 1987; 16:407-412


• Based upon 2 studies the rate of short Based upon 2 studies the rate of short term seizure recurrence in the population term seizure recurrence in the population of interest varies from 0-20%.of interest varies from 0-20%.11

Seizure RecurrenceSeizure Recurrence

Osborn. Ann Emerg Med 1987; 16:407-412Cranford. Neurology 1978;28:874-880


Dosing StrategyDosing Strategy

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


Common Dosing StrategiesCommon Dosing Strategies

1.1. Load the patient with IV phenytoin or Load the patient with IV phenytoin or fosphenytoin and start/restart daily oral fosphenytoin and start/restart daily oral maintenance dosesmaintenance doses

2.2. Load the patient with oral phenytoin and Load the patient with oral phenytoin and start/restart daily oral maintenance dosesstart/restart daily oral maintenance doses

3.3. Start/restart daily oral maintenance doses Start/restart daily oral maintenance doses without administering a loading dosewithout administering a loading dose


What the Literature Can Tell UsWhat the Literature Can Tell Us

• A serum phenytoin level A serum phenytoin level >> 10 mg/L can be 10 mg/L can be achieved by all of the common contemporary achieved by all of the common contemporary dosing strategies and by IM fosphenytoin dosing strategies and by IM fosphenytoin administration.administration.

• Fewer adverse effects are associated with Fewer adverse effects are associated with administration of fosphenytoin than parenteral administration of fosphenytoin than parenteral phenytoin preparations.phenytoin preparations.

• Fosphenytoin remains considerably more Fosphenytoin remains considerably more expensive than parenteral phenytoin.expensive than parenteral phenytoin.


What the Literature Cannot What the Literature Cannot YetYet Tell Us Tell Us

• Whether there is a difference in Whether there is a difference in the short term rate of seizure the short term rate of seizure recurrence between the different recurrence between the different common dosing strategies.common dosing strategies.


ConclusionConclusion

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

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

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