ARTICLES Monotherapy in adults and elderly persons

ARTICLES Monotherapy in adults and elderly persons Edward Faught, MD Address correspondence and reprint requests to Dr. Edward Faught, Department of Neurology, University of Alabama at Birmingham Epilepsy Center, Civitan International Research Center 312, 1719 6th Avenue South,Birmingham, AL 35294 faught@uab.edu ABSTRACT Treatment of epilepsy with a single drug has many advantages. Potential benefits of monotherapy vs polytherapy include fewer adverse events and better tolerability, avoidance of drug drug interactions, reduced treatment costs, and improved compliance. Initial treatment should always be monotherapy. Avoidance of pharmacokinetic interactions is a major advantage. Some patients who have achieved seizure control with polytherapy may be candidates for conversion to monotherapy because there is no conclusive evidence that polytherapy provides better seizure control in the majority of patients. Recently published treatment guidelines that take into account the efficacy and tolerability profiles of new and old antiepileptic drugs (AEDs) provide recommendations for drug selection in adults. Elderly patients with epilepsy face unique treatment challenges, which include age-related reductions in liver or kidney function that may alter drug pharmacokinetics. Older persons are more sensitive to CNS side effects; some drugs may exacerbate preexisting problems such as tremor, ataxia, and cognitive difficulty. Many common conditions in the elderly are treated with drugs that are subject to interactions with AEDs. Complex dosing schedules and high drug costs are often barriers to proper care. For all these reasons, monotherapy is especially attractive for the elderly. NEUROLOGY 2007;69(Suppl 3):S3 S9 RATIONALE FOR MONOTHERAPY Adults with epilepsy need complete seizure control with tolerable drug side effects in order to work, drive, and lead a normal social life. Monotherapy is often the best way to achieve these goals. Treatment of epilepsy with a single AED has become the preferred management strategy for most patients over the past three decades. 1 During the 1980s, opinions favoring polytherapy gradually gave way to monotherapy. 2 4 This stems from clinical experience showing that monotherapy offers fewer adverse effects (AEs), lower toxicity, and reduced risk for teratogenicity. Monotherapy also avoids the complex dosing regimens, poorer compliance, and increased treatment costs associated with polytherapy. 1,5,6 Moreover, several studies have shown that polytherapy offers no clear advantage in terms of seizure control and reduced side effects. An early example was a 1983 study of institutionalized, intellectually disabled persons converted from polytherapy to monotherapy, which revealed that 78% remained seizure-free with monotherapy and that many of the patients became more alert. 7 Polytherapeutic treatment plans should be reassessed from time to time to determine if a trial of monotherapy should be undertaken. However, perhaps the single best reason to choose monotherapy is avoidance of pharmacokinetic and pharmacodynamic drug interactions. 1 PHARMACOKINETIC INTERACTIONS BE- TWEEN ANTIEPTILEPTIC DRUGS Careful consideration should be given to the potential interactions resulting from coadministration of AEDs. 8 Most clinically relevant drug interactions among AEDs are pharmacokinetic. These involve interference by one drug with the disposition (metabolism, elimination, absorption) of another, thereby altering the concentration of that drug. 8 In general, the new AEDs have better pharmaco- From the Department of Neurology, University of Alabama School of Medicine, Birmingham, Alabama. This supplement was supported by an educational grant from Novartis Pharmaceuticals Corporation. Disclosure: Dr. Faught has receired honoraria in excess of $10.000 from the sponsor during the course of this study. Neurology supplements are not peer-reviewed. Information contained in Neurology supplements represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology. Copyright 2007 by AAN Enterprises, Inc. S3

Table 1 Antiepileptic drug interactions involving the cytochrome P450 system 8 Cytochrome P450 isoenzyme associated with AED metabolism AED Metabolism CYP1A2 CYP2A6 CYP2B CYP2C8 CYP2C9 CYP2C19 CYP2E1 CYP3A4 First-generation AEDs Carbamazepine Cytochrome P450 NA NA? Inhibitor? NA Clobazam Cytochrome P450 Clonazepam Cytochrome P450 Diazepam Cytochrome P450? Ethosuximide Cytochrome P450? Phenobarbital Cytochrome P450?? Phenytoin Cytochrome P450 NA NA Primidone Cytochrome P450?? Valproate Cytochrome P450, glucuronidation (UGT), -oxidation Second-generation AEDs NA Inhibitor NA? Inhibitor? Felbamate Cytochrome P450 NA Inhibitor Gabapentin Not metabolized Lamotrigine Glucuronidation (UGT) Levetiracetam Nonhepatic hydrolysis NA NA NA NA NA NA Oxcarbazepine Glucuronidation of MHD (UGT) and limited Cytochrome P450 metabolism of MHD Inhibitor Tiagabine Cytochrome P450 Topiramate Cytochrome P450, glucuronidation (UGT) NA NA NA NA NA Inhibitor NA NA Vigabatrin Not metabolized NA NA NA NA NA NA NA NA Zonisamide Primarily Cytochrome P450 NA NA NA NA NA NA not affected; no data available; MHD 10,11-dihydro-10-hydroxy-5H-dinenzo b,f azepine-5-carboxamide (the primary pharmacologically active metabolite of ocarbazepine); AED antiepileptic drug; UGT uridine diphosphate glucuronosyl transferase. Reprinted with permission. 8 kinetic profiles and are involved in fewer drug interactions. The most important pathway for drug metabolism among AEDs is the hepatic cytochrome (CYP) P450 enzyme system. 8 Enzyme-inducing drugs such as carbamazepine, phenobarbital, and phenytoin readily enhance the metabolism of other AEDs, thus reducing the therapeutic efficacy of many coadministered drugs (table 1). 8 For example, coadministration of these enzyme-inducing AEDs increases the metabolic rate, reduces the half-life, and therefore lowers the serum concentrations of valproate, lamotrigine, topiramate, zonisamide, and oxcarbazepine. 8 Oxcarbazepine and topiramate inhibit the secondary metabolic enzyme for phenytoin, CYP2C19. At higher serum phenytoin levels, addition of one of these drugs may result in symptoms of phenytoin toxicity. 9 Conversely, discontinuation of one of these enzyme-inducing drugs may cause an increase in serum levels of other AEDs. Selection of drugs with few or no enzyme-inducing or inhibiting effects avoids these complexities and, other factors being equal, is preferable. CANDIDATES FOR MONOTHERAPY There are three situations in which the question of monotherapy may arise: (a) patients embarking on initial treatment of epilepsy; (b) patients with incomplete seizure control on polytherapy; and (c) patients seizure-free on polytherapy. Monotherapy should always be chosen for initial therapy of seizures. FDA-approved agents for initial monotherapy of most seizure types include the older-generation drugs, such as phenytoin, S4 Neurology 69(Suppl 3) December 11, 2007

Table 2 Summary of AAN/AES evidence-based guidelines level A or B recommendation for use Drug Newly diagnosed monotherapy partial/mixed seizures Newly diagnosed absence seizures Gabapentin Yes* No Lamotrigine Yes* Yes* Topiramate Yes No Tiagabine No No Oxcarbazepine Yes No Levetiracetam No No Zonisamide No No *Not US FDA-approved for this indication. Reprinted with permission. 11 carbamazepine, and valproate, and the newer agents topiramate and oxcarbazepine. Lamotrigine is approved as a transition to monotherapy; many patients will have been started initially on phenytoin or a benzodiazepine, so this restriction is often moot. However, several randomized controlled trials have supported the use of lamotrigine as initial monotherapy and some single randomized controlled trials support the use of gabapentin and levetiracetam as initial monotherapy. Patients who continue to have seizures on polytherapy may achieve better control by increasing the dose of the single agent in the regimen that appears to have been the most helpful and gradually discontinuing the other drugs. Often an adequate dosage of a single drug is both more effective and better tolerated than inadequate dosages of two or three drugs. Several studies suggest that reducing the number of AEDs may actually provide better seizure control. 10 This maneuver requires caution in outpatients and may be more quickly and safely accomplished in the hospital. Patients who have achieved seizure control with combination therapy are also candidates for conversion to monotherapy, but they require individual consideration. 1 The last-added drug, which presumably was the one temporally associated with complete control, may be a promising choice for monotherapy. This is especially true if either the previous drugs or the current combination of drugs are producing side effects. On the other hand, if a patient is tolerating a polytherapeutic regimen quite well and is seizure-free, continuing this regimen is not an unreasonable choice. Although conversion from polytherapy to monotherapy is a common procedure in clinical practice, patients may be reluctant to convert to a single drug for fear of losing seizure control. The choice should always be made in consultation with the patient. CHOICE OF DRUG FOR MONOTHERAPY: TREATMENT GUIDELINES Three sets of treatment guidelines have been published recently by national 6 and international organizations. All are evidence-based and were derived from literature reviews. 11 13 The guidelines go somewhat beyond FDA-approved indications but rely primarily on randomized controlled trials of each new AED. The American Academy of Neurology (AAN)/ American Epilepsy Society (AES) guidelines support the use of established older drugs for monotherapy of new-onset seizures and the use of several of the newer agents (table 2). 11 For adults with refractory partial epilepsy, the AAN and AES recommend oxcarbazepine and topiramate as monotherapy and gabapentin, lamotrigine, tiagabine, topiramate, oxcarbazepine, levetiracetam, or zonisamide as add-on therapy. 11 Topiramate is recommended for the treatment of refractory generalized tonic clonic seizures in adults. 11 Both topiramate and lamotrigine are recommended to treat drop attacks associated with the Lennox Gastaut syndrome. 11 Guidelines for the use of new AEDs published in the United Kingdom by the National Institute for Clinical Excellence (NICE) were developed from examination of the results of randomized controlled trials (RCTs) and systematic reviews comparing new AEDs with older drugs, placebo, or other new agents. 12 In general, these guidelines are more conservative than the AAN guidelines. The NICE guidelines recommend use of a new AED for the following reasons: an older drug would not be beneficial; the older drug is contraindicated because of potential interactions with other agents; there is evidence of a previous nega- Neurology 69(Suppl 3) December 11, 2007 S5

tive experience or lack of tolerability; or the patient is a woman of childbearing age. 12,14 The International League Against Epilepsy (ILAE) guidelines are based on a structured review of the literature in which quality of clinical trial evidence was used to determine the strength of the level of recommendation. 13 These guidelines focus on agent efficacy as initial monotherapy for newly diagnosed or untreated epilepsy. 13 For the treatment of adults with generalized tonic clonic seizures, no AED reached the highest level of evidence, but carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate are considered possibly efficacious as monotherapy for selected situations, based on results observed in RCTs. 13 In adults with newly diagnosed partial-onset seizures, it was considered established that carbamazepine and phenytoin are efficacious as initial monotherapy, while valproate was considered probably efficacious, and gabapentin, lamotrigine, oxcarbazepine, phenobarbital, topiramate, and vigabatrin were deemed possibly efficacious. 13 Recommendations for the treatment of elderly adults with partial-onset seizures included carbamazepine, gabapentin, and lamotrigine, all of which achieved the highest level of evidence for effectiveness. 13 CHOICE OF DRUG FOR MONOTHERAPY: SIDE EFFECTS Because there are several effective agents, the choice of a drug often depends on the assessment of side effects in each patient. All commonly used AEDs may cause CNS dysfunction, including cognitive impairment. 15 In a cross-sectional survey of over 300 adults with treated epilepsy, more than 60% reported subjective complaints regarded as drug side effects. CNS-related effects (e.g., fatigue and dizziness) and cognitive complaints (e.g., memory problems, concentration difficulties) were reported most often (table 3). 16 The results of this survey illustrate that many patients experience side effects and attribute them to their AED. Although side effects may not be obvious to clinicians, the majority of patients on AED therapy are bothered by them despite good seizure control. In addition to the common dose-related CNS side effects, AEDs may have clinically relevant metabolic side effects. Long-term use of AEDs may lead to altered bone metabolism, resulting in decreased bone mineral density and increased risk for fractures. 17 Valproate, carbamazepine, gabapentin, and pregabalin may be associated with weight gain, which might be of sufficient degree to affect long-term health risks. 17 Carbamazepine, phenobarbital, and phenytoin are associated with variable increases in total serum cholesterol, triglycerides, high-density lipoproteins, and lowdensity lipoprotein, athough the clinical significance of these effects is unknown. 18 CHALLENGES IN TREATING EPILEPSY IN EL- DERLY ADULTS There are special reasons for favoring monotherapy in older patients. Epilepsy and single seizures are surprisingly common in the elderly, often caused by cerebrovascular disease or other focal pathology. 19,20 The incidence of epilepsy surges after the age of 60, with one study reporting 25% of all new cases occurring in this age group (figure). 19 The treatment of epilepsy in elderly patients presents unique challenges. 21 Injuries caused by seizures may be more severe and postictal confusion may be more prolonged. Although the impact of seizures on employment may be less for retired persons, loss of a driver s license is a serious blow to independence at any age. There are age-related changes in pharmacokinetic parameters, including protein binding, distribution, and elimination, that can lead to reduced drug clearance, increased receptor sensitivity, and therefore to increased risk for dose-related side effects. 22 Perhaps most importantly, older patients often take multiple medications, greatly increasing the chance of pharmacokinetic and pharmacodynamic drug interactions (table 4). 19 No matter which drug is chosen, it should be initiated at the lowest possible dose and titrated slowly. 19 A good rule of thumb is to start with about half the recommended dose for younger adults and to aim for an initial target dose of half to two-thirds of the optimal dose for younger adults. It is important not to make preexisting problems worse by a poor choice of drug. Phenytoin is not a good choice for those with poor balance, valproate is not a good choice for those with essential tremor, and sedative drugs are not good choices for somnolent or demented patients. 11,17 Older AEDs present the added concern of hepatic enzyme induction, which can increase the risk for drug interactions. There are only a few wellcontrolled trials of AEDs in elderly patients, although several of the new drugs have characteristics that may be favorable for this population (table 5). 19 Other drugs may be appropriate for selected patients, especially if used in conservative doses. REASONS FOR POLYTHERAPY Monotherapy results in seizure control in the majority of pa- S6 Neurology 69(Suppl 3) December 11, 2007

Table 3 Subjective reported side effects Area and type of side effect * Complaints (%) General CNS 68.2 (overall CNS complaints) Fatigue 20.3 Tiredness 18.8 General slowing 12.1 Headache 8.9 Dizziness 8.1 Motor problems 31.5 (overall motor complaints) Tremor 13.3 Ataxia 13.0 Falling 5.2 Gastrointestinal complaints 33.2 (overall gastrointestinal complaints) Weight gain 12.4 Defecation problems 8.4 Loss of appetite 5.2 Nausea 2.9 Diarrhea 2.3 Weight loss 2.0 Cognition 61.8 (overall cognitive complaints) Memory problems 21.4 Concentration difficulties 16.1 Speech problems 8.7 Language difficulties 7.8 Visual 7.5 (overall visual complaints) Double vision 7.5 Mood and behavior 22.3 (overall mood/behavior complaints) Agitation/irritability 14.8 Depression 7.5 Cosmetic 20.4 (overall cosmetic complaints) Hair loss 7.2 Gum problems 7.8 Skin complaints 5.4 Sleep problems 8.7 (overall sleep complaints) Insomnia 8.7 *One patient may be reporting several side effects. Summary of both moderate and severe complaints. Reprinted with permission. 16 Figure 1 Incidence of epileptic seizures by age tients but sometimes fails because of lack of efficacy, dose-related side effects, or an idiosyncratic side effect. In patients in whom two or three drugs have failed as monotherapy, a polytherapeutic regimen may be necessary (table 6). 23 Fortunately, polytherapeutic regimens are easier to administer now because of the paucity of drug interactions among many of the newer drugs. Although the concept of selecting two or more drugs with different and possibly complementary mechanisms of action is scientifically appealing, the superior- band. Reprinted with permission. 19 Neurology 69(Suppl 3) December 11, 2007 S7

Table 4 Interactions of antiepileptic drugs with medications frequently coadministered in elderly adults Comedication CBZ PHT VPA PB PMD OXC TPM TGB LTG GBP LEV VGB Warfarin??? - - - Digoxin?? - - - Neuroleptics?? -? - - - Antacids?? -?? - - Antibiotics???? - - - CBZ carbamazepine; PHT phenytoin; VPA valproate; PB phenobarbital; PMD primidone; OXC oxcarbazapine; TPM topiramate; TGB tiagabine; LTG lamotrigine; GBP gabapentin; LEV levetiracetam; VGB vigabatrin. Reprinted with permission. 19 Table 5 Profiles of some antiepileptic drugs suitable for use in elderly adults AED Advantages Disadvantages Doses/day Gabapentin No drug interactions, excellent tolerability, rapid titration Possibly less potent, dose dependent on renal function 2 3 Levetiracetam Effective, no drug interactions, good tolerability, rapid titration, effective at low doses (1,000 mg) Behavioral disturbances, somnolence, limited monotherapy experience 2 Lamotrigine Effective, very favorable cognitive profile; approved for monotherapy Slow titration, allergic reactions, some drug interactions, insomnia 2 Oxcarbazepine Effective, fewer drug interactions and AEs than carbamazepine; approved for monotherapy Hyponatremia, dizziness 2 Topiramate Effective, renal and hepatic excretion, welltolerated in low doses (100 mg); approved for monotherapy Cognitive impairment, weight loss, titration within 3 4 weeks 2 Valproate Loadable, parenteral, broad- spectrum, no enzyme induction Enzyme inhibitor, weight gain, tremor, occasional encephalopathy in elderly 1 AED antiepileptic drug. Adapted with permission. 19 Table 6 Recommended treatment strategy when first-line monotherapy fails in patients with epilepsy Reason for failure Lack of seizure control but no toxicity Lack of seizure control at the maximal dose tolerated Unacceptable dose-related adverse effects at the lowest possible maintenance dose Unacceptable idiosyncratic reactions Action Increase the dose of the first-line drug Lower the dose of first-line drug and add another drug; evaluate effectiveness of combination before withdrawing the first-line drug Rapid substitution Immediate substitution Reprinted with permission. 23 ity of this approach has never been convincingly demonstrated. SUMMARY Most of the advantages of monotherapy lower cost, simpler dosing schedules, less possibility of additive toxicities and drug interactions are readily apparent and are especially important for elderly adults. Overuse of polytherapy regimens stems primarily from the mistaken belief that efficacy is better with more drugs. For most patients, both tolerability and seizure control are superior with a sufficient dosage of a single drug rather than an insufficient dosage of several. If polytherapy is chosen, care must be taken to ensure that tolerability is not compromised and that combinations not subject to undesirable drug interactions are used. REFERENCES 1. Baulac M. Rational conversion from antiepileptic polytherapy to monotherapy. Epileptic Disord 2003;5:125 132. 2. Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epilepsy? Epilepsia 1981; 22:1 10. 3. Lesser RP, Pippenger CE, Lüders H, Dinner DS. Highdose monotherapy in treatment of intractable seizures. Neurology 1984;34:707 711. S8 Neurology 69(Suppl 3) December 11, 2007

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