PROCEEDINGS PHARMACOLOGIC TREATMENT CONSIDERATIONS * Dennis J. Dlugos, MD ABSTRACT

PHARMACOLOGIC TREATMENT CONSIDERATIONS * Dennis J. Dlugos, MD ABSTRACT A number of traditional and newer antiepileptic drugs (AEDs) are used for the initial treatment of new-onset epilepsy. The decision-making process for selecting the first AED is complex and involves considerations of seizure type, seizure frequency, AED side effects, and patient comorbidities. This review addresses 4 questions about the initial choice of AED monotherapy in patients with newly diagnosed epilepsy: How should US Food and Drug Administration indications influence prescribing practices? What is the target dose for the initial AED? Is therapeutic drug monitoring needed for all patients? Assuming accurate seizure classification, should the first AED be chosen on the basis of patient comorbidities? (Adv Stud Med. 2005;5(1B):S77-S82) ANTIEPILEPTIC DRUGS AND US FOOD AND DRUG ADMINISTRATION INDICATIONS In contrast to the early 1990s, there are now at least 11 possible choices for initial antiepileptic drug (AED) monotherapy in patients with newly diagnosed epilepsy (Table 1). Some AEDs have specific roles, such as phenobarbital for neonatal seizures or ethosuximide for absence epilepsy. Traditionally, carbamazepine and *Based on a presentation given by Dr Dlugos at a roundtable discussion. Assistant Professor of Neurology, University of Pennsylvania, Division of Neurology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania. Address correspondence to: Dennis J. Dlugos, MD, Children s Hospital of Philadelphia, 6th floor - Wood Bldg, 34th St and Civic Center Blvd, Philadelphia, PA 19014. E-mail: dlugos@email.chop.edu. phenytoin have been considered first-line choices for focal epilepsy with or without secondary generalization, whereas valproic acid has been viewed as the firstline choice for idiopathic or symptomatic generalized tonic-clonic seizures. Newer AEDs may offer similar efficacy with better tolerability, but official US Food and Drug Administration (FDA) indications for newonset epilepsy lag behind clinical use. Table 2 lists official indications for new-onset epilepsy as of December 2004. Only felbamate not an appropriate first-line AED due to risks of hepatic toxicity and aplastic anemia and oxcarbazepine carry FDA indications for initial monotherapy. Evidence exists to support the use of newer AEDs, such as gabapentin, lamotrigine, and topiramate in newly diagnosed epilepsy, although official FDA indications have not been obtained. 1-6 An application for the use of topiramate as initial monotherapy in newly diagnosed epilepsy is currently under review by the FDA. Finally, although there is no specific evidence to support the use of zonisamide or levetiracetam as initial monotherapy, both agents are used in clinical practice. Given the disconnect between FDA indications and clinical use, what is the value of an FDA indication, and should it affect clinical prescribing practices? An FDA indication does provide a level of assurance that efficacy and tolerability have been assessed in a systematic fashion. However, an indication can be obtained before large numbers of patients have been exposed; thus, rare adverse effects may not be evident until larger-scale clinical use (eg, felbamate). Once a drug is approved for use, FDA indications do not govern standard of care, and licensed physicians may prescribe the approved drug for any condition deemed appropriate (off-label use). For pediatric practice, this flexibility is crucial, because the majority of medications available have no specific labeling for children, especially infants. 7-9 Standard of care is not determined by the FDA but is governed by all avail- Advanced Studies in Medicine S77

able evidence, expert opinion, and usual local practice. Of course, physicians who prescribe an AED for an offlabel use must be familiar with existing evidence for efficacy and tolerability. SEIZURE CLASSIFICATION AND CHOICE OF INITIAL AED Diagnosis of a specific epilepsy syndrome is often difficult with new-onset seizures. Hopefully, the seizures can at least be classified as focal with or without secondary generalization, generalized convulsive, or generalized nonconvulsive. This broad seizure classification is necessary to select the optimal initial AED. For focal epilepsy with or without secondary generalization, evidence exists to support the use of phenobarbital, carbamazepine, phenytoin, valproate, gabapentin, oxcarbazepine, lamotrigine, and topiramate. The traditional AED of choice for focal epilepsy is carbamazepine because of improved tolerability over phenobarbital and phenytoin. Newer AEDs may offer improved tolerability over carbamazepine. For generalized convulsive epilepsy, valproate is the traditional AED of choice, although valproate does not carry a specific FDA indication for use in primary generalized tonic clonic seizures (GTCs). Newer broad-spectrum agents, such as lamotrigine and topiramate, have evidence of efficacy in generalized convulsive seizures. 10,11 Oxcarbazepine is best considered as a narrow-spectrum agent against focal epilepsy at this point, and there is no evidence to support the use of zonisamide or levetiracetam as initial therapy in primary GTCs. For generalized nonconvulsive seizures, most typically seen in childhood absence epilepsy, evidence exists to support the use of ethosuximide, valproate, or lamotrigine, although lamotrigine does not have a specific FDA indication for absence seizures. 4,12 INITIAL TARGET DOSE Once seizure classification has been made and the first AED has been chosen, the initial target dose must be determined. A traditional method of establishing Table 1. Initial Antiepileptic Drug Choices Traditional Newer Newest Phenobarbital Gabapentin Oxcarbazepine Phenytoin Lamotrigine Zonisamide Ethosuximide Topiramate Levetiracetam Carbamazepine Valproate Table 2. FDA-Approved Indications for New AEDs Initial Monotherapy Indication Adjunctive Therapy Indication Child-friendly Dosing Form Felbamate Partial seizures: Partial seizures: 14 yrs and up Oral suspension 14 yrs and up Partial and generalized seizures in LGS: 2 yrs and up Gabapentin No Partial seizures: 3 yrs and up Oral solution Lamotrigine No Partial seizures: 2 yrs and up Chewable tablets Generalized seizures in LGS 2 yrs and up Levetiracetam No Partial seizures: 16 yrs and up Oral solution Oxcarbazepine Partial seizures: 4 yrs and up Partial seizures: 4 yrs and up Oral suspension Tiagabine No Partial seizures: 12 yrs and up No Topiramate No (pending as of Partial seizures: 2 yrs and up Sprinkle caps December 2004) Primary GTCs: 2 yrs and up Generalized seizures in LGS: 2 yrs and up Zonisamide No Partial seizures: 16 yrs and up No FDA = US Food and Drug Administration; AEDs = antiepileptic drugs; LGS = Lennox-Gastaut syndrome; GTC = generalized tonic-clonic seizures. S78 Vol. 5 (1B) January 2005

target dose is to titrate to a low-to-moderate dose based on age and weight, then titrate upward if breakthrough seizures occur and the patient is not experiencing side effects. If efficacy remains suboptimal, then titration should continue until symptoms of clinical toxicity occur. If seizures persist at the maximum tolerated dose, the AED has failed and a different AED should be selected. However, a new school of thought is emerging based on recent observational data indicating that moderate dosing is usually adequate, and titration to high doses is usually not necessary or effective. 13 In a hospital-based cohort study from Scotland, approximately 80% of 470 drug-naive patients were treated with either carbamazepine, valproate, or lamotrigine. Overall, 47% of the patients ultimately became seizure free. Among those treated with carbamazepine, 85% who became seizure free did so with doses between 400 mg and 600 mg daily. There was only a small increase in efficacy when the carbamazepine dose was raised to 800 mg to 1600 mg. Similar results were seen with the other agents. For valproate, 75% of patients who became seizure free took doses between 200 mg and 1000 mg a day. With lamotrigine, 80% of patients who were seizure free received doses between 125 mg and 200 mg, and only a small increase in lamotrigine efficacy was noted by titrating doses to 600 mg. When evaluating this study, it is important to consider the limitations of an observational study. The primary role of an observational study is to generate hypotheses for future, hypothesis-driven studies. Nonetheless, a strength of this observational study is that it does reflect typical clinical practice. Which titration strategy is best: dosing to maximum tolerability or to a moderate dose? The answer remains unclear, but one reasonable strategy is to decide based on the dose response as the AED is titrated. If there are signs of a dose response during titration and no significant adverse effects are reported, it seems appropriate to continue titrating upward rather than to switch to another AED. Detailed questioning may be required to determine whether subtle adverse effects are present. In contrast, if there is no evidence of a dose response during titration or side effects occur, changing to another AED in monotherapy is appropriate. The goal of AED therapy is no seizures and no side effects. If this is achieved on a low-to-moderate dose or any dose, then that AED dose should be maintained. Much better data is needed on this topic for other AEDs, including lamotrigine, oxcarbazepine, and topiramate, as well as data specific to pediatric patients for all AEDs. THERAPEUTIC DRUG MONITORING The appropriate role of therapeutic drug monitoring (TDM) in patients with new-onset epilepsy is controversial and is complicated by some widespread misconceptions. The first misconception is that traditional AEDs must be titrated to achieve a serum level within the therapeutic range. Although therapeutic ranges exist for traditional AEDs, these ranges have been established statistically for large populations. The optimal serum level for an individual patient may be difficult to define and may be above or below the usual therapeutic range. The second misconception is that serum levels are not available for the new AEDs. Serum levels do exist for all of the new AEDs, although turn-around time to determine the level is not as rapid in most centers as it is for older AEDs. The main problem with TDM for newer AEDs is that the therapeutic range is poorly defined even for broad populations, making it particularly difficult to interpret a serum level for an individual patient. The relatively slow turn-around time makes it difficult to act on a serum level obtained during a brief hospital stay or emergency department visit. A clinical trial in Italy aimed to systematically evaluate TDM in 180 patients with partial or idiopathic generalized epilepsy, excluding absence. 14 The patients were treated with carbamazepine, phenytoin, valproic acid, or primidone. Patients were randomized into one of 2 monitoring groups the first group had the AED dose adjusted to a target serum level, and the second had the AED dose adjusted based on clinical features, such as breakthrough seizures and side effects. A total of 116 patients were followed for at least 2 years. The investigators found no significant differences in time to first seizure, time to 12-month remission, or frequency of adverse events between the TDM group and the group followed on clinical grounds alone. In the monitored group, 8% of patients were outside target blood levels, with 92% being maintained well within the therapeutic range. Among patients in the clinically controlled group, 25% had breakthrough seizures or side effects within the first 6 months of treatment. Overall, 60% of the monitored group and 61% of the clinical group achieved a 12-month period of seizure freedom during the study; 38% of the monitored group and 41% of the clinical group were completely seizure free from the time drug therapy began with the first AED. Advanced Studies in Medicine S79

This study indicates that TDM may not be required for all patients, but it may be useful in certain relatively common situations concern about adherence to the drug therapy, drug interactions, or treatment-resistant epilepsy. In the Italian study, relatively few patients were treated with phenytoin, and there is no data on this topic for any of the newer AEDs. CHOOSING THE FIRST AED BASED ON COMORBIDITIES Is there enough evidence to move beyond the traditional practice of considering carbamazepine and phenytoin as first-line agents for focal epilepsy and valproic acid as the first-line agent for generalized epilepsy? An alternative strategy would be to accurately classify the patient s seizure type and choose the initial AED based on seizure frequency, seizure severity, potential AED side effects, and patient comorbidities. This type of strategy assumes that most seizures can be accurately classified at least in terms of broad categories, such as focal seizures with or without secondary generalization, generalized convulsive, or absence. This strategy also assumes that there are no clear differences in efficacy between the relatively large number of AEDs effective against focal epilepsy or between the smaller number of broad-spectrum AEDs effective against generalized epilepsy. If these assumptions are valid, then initial AED choice depends on seizure frequency, seizure severity, the side-effect profile of the AEDs under consideration, and the patient s comorbidities. Because AEDs have various titration schedules, ranging from minutes if needed for intravenous medications, such as phenobarbital, phenytoin, or valproate, to several weeks for lamotrigine, seizure frequency and seizure severity are obvious considerations. Lamotrigine is an effective, well-tolerated AED, but may not be the ideal initial choice as monotherapy for a patient who presents with frequent convulsive seizures, because it will take weeks to safely titrate lamotrigine to a therapeutic dose. There are a variety of comorbidities and other patient factors to consider, including weight, bone health, reproductive status, headache, mood disorders, polypharmacy, and the financial and insurance status of the patient. Weight may be a major consideration in some patients, given the high prevalence of obesity in the US population. Both weight gain and weight loss are side effects of some AEDs, as summarized in Table 3. 15-18 For many adults, AED-induced weight loss is potentially beneficial, although this is not true for all patients, and weight loss can be a treatment-limiting side effect in some pediatric patients with developmental disabilities. Bone health is another important consideration. Decreased bone density has been linked to use of older enzyme-inducing AEDs, such as phenobarbital, phenytoin, and carbamazepine. 19 There is also a report linking valproate to decreased bone density, although the mechanism of action is unclear and this needs further study. 20 Available data, which is quite limited, suggests that lamotrigine, topiramate, and gabapentin may have a neutral effect on bone density. 21 Long-term data regarding the effect of newer AEDs on bone health is needed. Reproductive considerations include issues such as AED interactions with oral contraceptives, possible links between valproic acid and polycystic ovary syndrome, and teratogenicity. Enzyme-inducing AEDs, including phenobarbital, phenytoin, carbamazepine, and topiramate, can decrease the effectiveness of oral contraceptives, 22 necessitating the use of higher doses of estradiol. Some studies have linked valproate use to polycystic ovary syndrome, 23,24 but this is also an area needing further study. Traditional AEDs are known to carry risks of teratogenesis, especially if multiple AEDs are used. Adequate data is lacking regarding risks of birth defects with the newer AEDs, but several studies are currently under way. The AED of choice for a pregnant women with epilepsy remains the AED (used in monotherapy if at all possible) that best controls seizures at the lowest possible dose. Table 3. AEDs and Weight Change Weight Gain Weight Loss Weight Neutral Gabapentin Felbamate Lamotrigine Carbamazepine Topiramate Levetiracetam Valproate Zonisamide AEDs = antiepileptic drugs. Data from Gidal et al 15 ; DeToledo et al 16 ; Bergen et al 17 ; Jones. 18 S80 Vol. 5 (1B) January 2005

DISCUSSION Dr Montouris: Should zonisamide be used firstline for any of the epilepsies in children or adults? Dr Dlugos: Zonisamide could certainly be included as an option for focal, generalized convulsive, and absence seizures, although specific data when used as initial monotherapy is currently lacking. Theoretically, since zonisamide is a broad-spectrum AED that can be given once daily, it may have a role as initial monotherapy in some patients. Most AEDs that have efficacy as adjunctive therapy are also effective in monotherapy, although there have been some exceptions to this rule. This is an argument in favor of using zonisamide or levetiracetam as initial monotherapy, even without specific data in this population. Dr Glauser: There is a hypothesis-driven trial by Brodie et al, the authors of the observational study described earlier, that compared lamotrigine and gabapentin. 25 Patients were titrated in a blinded fashion depending on need for improved seizure control. The results were similar to the observational study that examined carbamazepine, valproate, and lamotrigine. The authors concluded that the optimal dose may be lower than what was originally thought, but it is still acceptable to push to maximally tolerated doses to control seizures if needed. Dr Dlugos: Correct. And I think that is the best strategy with any AED, but more of the AEDs need to be studied in this manner. Dr Gilliam: In general, there is a belief that observational data is biased toward increased efficacy, so that if there is an 11% response among those who have failed a first drug in an observational study, it is probably closer to 22%. Dr Montouris: So titration of monotherapy should continue only if the patient is still having seizures? Dr Crone: With monotherapy, do you wait until the patient has a breakthrough seizure before titrating the dose upward? Dr Dlugos: Initial AED titration should proceed to a low-to-moderate dose, even in the face of seizure freedom. Whether the target dose is low or moderate depends on the seizure frequency, seizure severity, and patient preferences. Most of the earlier discussion involved the question of when to abandon the initial AED and seek an alternative AED. That is a different question than what the initial maintenance dose should be in a particular patient. Dr Crone: How long is seizure freedom? Is it well defined? Dr Dlugos: Defining a meaningful period of seizure freedom depends very much on pretreatment seizure frequency. This is one of the arguments for not starting an AED after a single seizure there is no way of judging the pretreatment seizure frequency. The next seizure may not be destined to occur for 1 year, but if you start treatment too early, you do not know whether the period of seizure freedom was due to the medication or the natural history of the epilepsy. This is also why many AED clinical trials include patients with frequent seizures because data can be generated in a reasonable amount of time, whereas studying patients who seize once every 6 months takes much longer. Dr Glauser: This has to be the only specialty where therapeutic drug monitoring does not make a difference. Either we have a very unusual disease or we are not asking the right question in the trials. Why does drug monitoring not make a difference? Dr Dlugos: Epilepsy is unusual paroxysmal, unpredictable, and unprovoked by definition. With a better understanding of epilepsy and by asking better questions, TDM may make a difference, but based on current knowledge and treatment choices, it does not appear to make a difference for many patients. However, as soon as adherence problems, drug interactions, or treatment resistance enter the picture, TDM probably plays an important role. Dr Glauser: In the monitoring trial we discussed, the researchers did not do a systematic collection of sideeffect data. 14 At our institution, we are collecting that data with the hypothesis that drug monitoring works. Dr Gilliam: When a patient is easily controlled with a modest dose and no side effects, monitoring should not be routine. However, if you need to continue titration, I believe after 3 dosage increases, a drug level should be checked to determine if the patient is close to toxic levels. While this is not routine monitoring, it would be helpful in these special situations to have a baseline drug level as well. Dr Ramsay: A baseline level is also helpful later, when the dose is raised and there is no additional response, an additional serum level can determine whether the patient is adherent. Advanced Studies in Medicine S81

Dr Glauser: I would also want AED levels in children because their metabolism changes rapidly as they get older, which can cause decreased drug levels. Also, some agents, such as topiramate, have marked interpatient variability in terms of metabolism. In addition, children who have been on enzyme-inducing agents previously may experience different drug levels with a new agent. Dr Dlugos: There is definitely a need for better data on drug monitoring. The lack of data fuels the controversies in this area. REFERENCES 1. Chadwick DW, Anhut H, Greiner MJ, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77. Neurology. 1998;51(5):1282-1288. 2. Brodie MD, French JA. Management of epilepsy in adolescents and adults. Lancet. 2000;356(9226):323-329. 3. Nieto-Barrera M, Brozmanova M, Capovilla G, et al. A comparison of monotherapy with lamotrigine or carbamazepine in patients with newly diagnosed partial epilepsy. Epilepsy Res. 2001;46(2):145-155. 4. Frank LM, Enlow T, Holmes GL, et al. Lamictal (Lamotrigine) montherapy for typical absence seizures in children. Epilepsia. 1999;40(7):973-979. 5. Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand. 2003;107(3):165-175. 6. Arroyo S, Squires L, Wang S, et al. Topiramate: effective as monotherapy in dose-response study in newly diagnosed epilepsy. Presented at: the American Epilepsy Society 56th Annual Meeting; December 6-11, 2002; Seattle, Washington. Abstract F.07. 7. Blumer J. Off-label uses of drugs in children. Pediatrics. 1999;104(3, suppl 2):598-602. 8. Landow L. Off-label use of approved drugs. Chest. 1999;116(3):589-591. 9. American Academy of Pediatrics Committee on Drugs. Use of drugs not described in the package insert (off-label uses). Pediatrics. 2002;110(1):181-183. 10. Beran RG, Berkovic SF, Dunagan FM. Double-blind, placebo-controlled, crossover study of lamotrigine in treatmentresistant generalised epilepsy. Epilepsia. 1998; 39(12):1329-1333. 11. Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology. 1999;52(7):1330-1337. 12. Callaghan N, O Hare J, O Driscoll D, O Neill B, Daly M. Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol. 1982;24(6):830-836. 13. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42(10):1255-1260. 14. Jannuzzi G, Cian P, Fattore C, et al. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy. Epilepsia. 2000;41(2):222-230. 15. Gidal B, Maly MM, Nemire RE, Haley K. Weight gain and gabapentin therapy. Ann Pharmacother. 1995;29(10):1048-1049. 16. DeToledo JC, Toledo C, DeCerce J, Ramsay RE. Changes in body weight with chronic, high-dose gabapentin therapy. Ther Drug Monit. 1997;19(4):394-396. 17. Bergen DC, Ristanovic RK, Waicosky K, Kanner A, Hoeppner TJ. Weight loss in patients taking felbamate. Clin Neuropharmacol. 1995;18(1):23-27. 18. Jones MW. Topiramate: safety and tolerability. Can J Neurol Sci. 1998;25(3):S13-S15. 19. Pack AM. The association between antiepileptic drugs and bone disease. Epilepsy Curr. 2003;3:91-95. 20. Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology. 2001;57(3):445-449. 21. Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure. 1999;8:339-342. 22. Tauboll E, Gjerstad L, Henriksen T, Husby H. Women and epilepsy. Tidsskr Nor Laegeforen. 2003;123(12):1691-1694. 23. Rasgon N. The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence. J Clin Pharmacol. 2004;24(3):322-334. 24. Betts T, Yarrow H, Dutton N, Greenhill L, Rolfe T. A study of anticonvulsant medication on ovarian function in a group of women with epilepsy who have ever taken one anticonvulsant compared with a group of women without epilepsy. Seizure. 2003;12(6):323-329. 25. BRodie MJ, Chadwick DW, Anhut H, et al; Gabapentin Study Group 945-212. Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia. 2002;43(9):993-1000. S82 Vol. 5 (1B) January 2005