Spotlight Case May 2007

1. Spotlight Case May 2007 Antiseizure Medication Disorder

2. Source and Credits • This presentation is based on the May 2007 AHRQ WebM&M Spotlight Case • See the full article at http://webmm.ahrq.gov • CME credit is available through the Web site • Commentary by: Brian K. Alldredge, PharmD, UCSF School of Pharmacy • Editor, AHRQ WebM&M: Robert Wachter, MD • Spotlight Editor: Tracy Minichiello, MD • Managing Editor: Erin Hartman, MS

3. Objectives At the conclusion of this educational activity, participants should be able to: • Appreciate the challenges of safe use of antiepileptic medications • Identify phenytoin toxicity • Understand the pharmacodynamics and pharmacokinetics of phenytoin • List clinical scenarios when phenytoin levels may be unreliable

4. Case: Antiseizure Medication Disorder A 76-year-old man was admitted for evaluation of increasing lethargy, confusion, and decreased appetite. The patient had a past medical history of seizure disorder with a recent admission for uncontrolled seizures, anemia, and hip arthroplasty. His medications included phenytoin 300 mg once a day, phenobarbital 30 mg three times a day, residronate 35 mg once a week, and iron supplements.

5. Case: Antiseizure Medication Disorder On physical exam, his vital signs were unremarkable and he had no fever. By report, neurological exam revealed only confusion and diminished deep tendon reflexes. Laboratory data was significant for a slightly elevated white blood cell count (WBC) and abnormal urinalysis, with 6-10 WBCs. A phenobarbital level was 30 (therapeutic 10-40 mcg/mL) and phenytoin level was 19 (therapeutic 10-20 mcg/mL).

6. Case: Antiseizure Medication Disorder The rest of his electrolytes, renal function, and liver function tests (AST, ALT, bilirubin and alkaline phosphatase) were normal. CT scan of the head was unremarkable. The providers thought the patient’s mental status change was likely due to urinary tract infection and effects of phenobarbital. The patient was treated with antibiotics and his phenobarbital was held.

7. Epilepsy and Treatment • Epilepsy affects approximately 2 million people in the United States • Antiseizure medications are the primary mode of epilepsy treatment • Medications successfully control seizures in approximately two-thirds of patients

8. Antiseizure Medications • More than 15 antiseizure medications are commonly used in the US • Choice of agent dictated by • Epilepsy syndrome • Drug-drug or drug-disease state interactions • Unique medication-related adverse effects

9. Traditional Antiseizure Medications • “Enzyme-inducing” • Phenytoin, Carbamazepine, Phenobarbital • “Enzyme-inhibiting” • Valproate

10. Oxcarbazepine, Lamotrigine, Topiramate, Levetiracetam Mostly approved for 2nd line therapy, but often used as initial therapy Equally effective in suppressing seizures Many fewer drug interactions than the older drugs Newer Antiseizure Medications

11. Clinical Activity of Antiseizure Drugs for Various Types of Epileptic Seizures* *“Standard” antiseizure drugs shown in black; newer antiseizure drugs shown in red.

12. Challenges in Safe Use of Antiseizure Medications • 7th most common ADR in study of 1 million hospitalized patients • Lack of standardization in dosing and monitoring of these agents Bond CA, Raehl CL. Pharmacotherapy. 2006;26:601-608.

13. Challenges in Safe Use of Antiseizure Medications • Significant interpatient variability in dosages needed to reach therapeutic goals, minimal tolerable adverse effects • Therapeutic index low • Complex pharmacokinetics and drug interactions (particularly phenytoin, phenobarbital, carbamazepine)

14. Initiation of Antiepileptics • Traditional agents • Begun at low doses and gradually titrated upward based on clinical response • Newer agents • Doses increased to a serum concentration or daily dose that is effective for most patients • Poor correlation between levels and clinical activity

15. Initiation of Antiepileptics • For rapid protection from seizures • Loading doses of select medications can be used (eg, oral or intravenous phenytoin, intravenous valproate, or intravenous phenobarbital) • For status epilepticus, near immediate effect with IV benzodiazepines • For bridge therapy, scheduled oral doses of clonazepam until an effective oral maintenance dose can be attained

16. Errors in Dosing Antiseizure Drugs • Initiating therapy at too high a dose or escalating dosage too quickly • Not considering drug interactions when devising initial dosing scheme • Adjusting doses based solely on blood level results • Withholding dose escalations in patients with partial response and good medication tolerability due to fear of exceeding the “usual” or “maximal” dose • Escalating antiseizure medication doses too slowly in patients with uncontrolled seizures

17. Case (cont.) Despite these interventions, the patient continued to be confused. A neurology consult was obtained. Review of the laboratory data revealed a serum albumin of 2.4 g/dL. This led to the calculation of a corrected phenytoin level: it was 33 (therapeutic 10-20 mcg/mL). Phenytoin was held and the patient's mental status returned to baseline in 72 hours.

18. Phenytoin Toxicity • Phenytoin is one of the drugs most commonly associated with preventable clinically significant adverse events • Requires careful monitoring and dosage adjustment, particularly in the elderly Winterstein AG, et a;. Am J Health Syst Pharm. 2002;59:1742-1749.

19. Phenytoin Toxicity Symptoms • Early symptoms • Dizziness, drowsiness, lethargy, and visual disturbances • At higher levels • Ataxia and confusion • Less common • Increase in the frequency or severity of seizures

20. If Phenytoin Toxicity Suspected…Note: • Recent dosage adjustments • Changes in product appearance • Phenytoin blood level • Alterations in concomitant drug therapies, such as: • Addition of phenytoin metabolism inhibitor (e.g., cimetidine) • Removal of phenytoin metabolism inducer (e.g., rifampin)

21. Avoiding Phenytoin Toxicity • CYP2C9 and CYP2C19 enzymes responsible for phenytoin metabolism are saturable at drug concentrations near those used in clinical care • Dosage changes result in disproportionate changes in phenytoin blood levels and pharmacologic response • Limit dosage increases to no more than 30 to 50 mg per day, and increase dosages no more frequently than once every 1 or 2 weeks

22. Understanding Phenytoin Levels • 90% bound to plasma proteins, primarily albumin • Therapeutic range of 10-20 mcg/mL represents the total of both protein-bound and free drug in serum • Only unbound phenytoin has access to tissue sites responsible for efficacy and toxicity Soldin SJ. Arch Pathol Lab Med. 1999;123:822-823.

23. Understanding Phenytoin Levels • A total (bound + unbound) phenytoin concentration value – which is the result reported by most clinical laboratories when a “phenytoin level” is requested – is an indirect measure of the pharmacologically active (unbound) concentration Soldin SJ. Arch Pathol Lab Med. 1999;123:822-823.

24. Factors That Can Alter Phenytoin Protein Binding • Hypoalbuminemia • End-stage renal disease (creatinine clearance < 25 mL/min) • Presence of displacing drugs (eg, aspirin, valproic acid) Winter ME. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:321-363.

25. Determining Free Phenytoin Levels • Order an unbound phenytoin level and assess it in the context of an unbound therapeutic range of 1-2 mcg/mL • Use calculation methods to adjust the reported total phenytoin serum level to the value that would be expected if protein binding were not perturbed Winter ME. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:321-363.

26. Phenytoin Half-life • When unbound phenytoin levels are unusually high, the rate of decline in phenytoin concentrations is often slower than expected • Due to saturable metabolism, at high serum levels, phenytoin half-life is much longer than it is at lower drug levels • Varies between individuals and within an individual depending on serum concentration at any given time Soldin SJ. Arch Pathol Lab Med. 1999;123:822-823.

27. System Improvements • Replace total serum concentration monitoring with assays to measure only the unbound (“free”) concentration of phenytoin • unbound phenytoin concentrations more closely correlate with clinical status • Require that unbound phenytoin levels be reported in patients with hypoalbuminemia or end-stage renal failure Kilpatrick CJ, et al. Br J Clin Pharmacol. 1984;17:539-546.Burt M, et al. Clin Chem. 2000;46:1132-1135.

28. The Role of the Pharmacist • Pharmacist monitoring improves both economic and clinical outcomes with antiseizure drug therapy • By 2003, most states had enacted laws or amendments to permit enhanced pharmacist involvement in direct drug therapy • Pharmacist-managed drug therapy is fastest growing clinical pharmacy service in US hospitals See notes for complete references.

29. Take-Home Points • Dosing and monitoring of antiseizure drugs are challenging due to the need to individualize therapy, the low therapeutic index of these agents, and complex pharmacokinetics • Due to ease of use, newer antiseizure drugs are being used more commonly as initial therapy for epilepsy

30. Take-Home Points • Phenytoin dosing and monitoring are complex due to saturable metabolism and the potential for displacement from albumin binding sites • In patients with low serum albumin or end-stage renal disease, total (bound + unbound) phenytoin levels can be misleading and must be interpreted with caution

31. Take-Home Points • Unbound (free) phenytoin concentrations more closely correlate with clinical status of patients and are less likely to be misinterpreted than total phenytoin concentrations • Pharmacist involvement in management of antiseizure drug therapy can improve economic and patient outcomes