Anti-Epileptic Drugs (AEDs)

Treating epilepsy has become a daunting task over the last 15 years, as the number of available anti-epileptic drugs () has skyrocketed. With so many options, it is difficult for all but the specialist to know how to select and manage therapy for the many types and stages of epilepsy. Turning to guidelines may not provide substantial assistance. Most guidelines rely on randomized controlled trials to provide evidence of benefit. Unfortunately, there are many gaps in the evidence base, which leads to similar gaps in the guidelines. For example, recent guidelines written by the International League Against Epilepsy could only advise the use of phenytoin, carbamazepine and valproate as initial treatment for adults with partial seizures. Clearly, there are circumstances under which none of these would be an optimal choice. Anti-Epileptic Drug Characteristics Second-Generation Anti-Epileptic Drugs Anti-Epileptic Drug Selection Other Issues In Anti-Epileptic Drug Use Monotherapy Vs. Polytherapy There has been a great deal of discussion in recent years relating to the question of whether monotherapy or polytherapy would be a better choice for patients who have failed their initial therapy. In fact, either option may Read more [...]

Anti-Epileptic Drug Characteristics

Phenytoin Phenytoin has been used for over 50 years. Thus, the characteristics and side-effects have been well elucidated. Its primary use is for treatment of partial epilepsy, including simple and complex partial seizures, as well as generalized tonic-clonic seizures, whether of primary or partial onset. Phenytoin can be initiated with a 'loading dose' of 13-20 mg / kg, or with a starting dose of 3-5 mg / kg / day. Phenytoin was one of the first anti-epileptic drugs that became associated with a 'therapeutic range' (10-20 mg/l in most laboratories), which represents serum concentrations most likely to produce a therapeutic effect without substantial dose-related side-effects. The phenytoin dose should be selected using therapeutic monitoring rather than a predetermined dose, such as 300 mg / day. As the serum level increases, side-effects such as lethargy, ataxia, dysarthria, fatigue, diplopia, abnormal movements, mental confusion and cognitive changes may occur. This is particularly true at concentrations above 20 mg/l. However, the therapeutic range represents an average. A number of patients may remain seizure-free at serum concentrations below the range, or may tolerate levels substantially above the range. However, Read more [...]

Second-Generation Anti-Epileptic Drugs

Drugs are listed in order of approval in the USA, from oldest to newest. Felbamate Felbamate is a broad-spectrum anti-epileptic drug. It is not considered to be a first-line drug because of its potential for serious idiosyncratic side-effects, including potentially fatal aplastic anaemia (incidence of 1 in 3000) and hepatic failure (incidence of 1 in 10000). Recent analyses indicate that aplastic anaemia and liver failure occur almost exclusively within the first year of therapy. During this period, safety monitoring consisting of liver function tests and blood counts is recommended with a frequency of up to twice monthly, despite lack of evidence that early detection of changes will prevent serious health problems, even if the drug is discontinued. Yet, felbamate may still be an important drug in the armamentarium for refractory patients, because it may control seizures when other drugs fail, and tends to be alerting rather than sedating. It has been found to be particularly effective in patients with Lennox-Gastaut syndrome. Felbamate should be started at 300-600 mg twice daily, and increased as necessary over several weeks, up to 3600 mg, or higher in some cases. Drug levels may be useful, and serum concentrations Read more [...]

Anti-Epileptic Drug Selection

Selection of anti-epileptic drugs can be very confusing. Each anti-epileptic drug has unique characteristics, including spectrum of activity, cost, pharmacokinetic and pharmacodynamic properties, likelihood for dose-related side-effects and risk of serious health risks. Therefore, to the frustration of many prescribers, there is not a 'first choice' selection in specific treatment situations such as initiation in newly diagnosed patients, first add-on, women anticipating pregnancy and so on. For each of these scenarios, there may be more optimal and less optimal choices, but the final selection will depend on many patient characteristics. Table Suggestions for initiations of anti-epileptic drugs provides pragmatic information about initiating anti-epileptic drugs. What follows is a rational sequence of issues that can be used to narrow down drug choices. Table Suggestions for initiations of anti-epileptic drugs () * Anti-epileptic drug Suggested titration Can drug be loaded? How is initial target dose usually selected? Typical initial daily target dose Carbamazepine Add 200 mg every 2-3 days No By attaining minimal serum concentration (4-6μg / ml) 400-800 mg Ethosuximide 500 mg / week No By Read more [...]

Anti-Epileptic Drug Dosing Schedules

Dosing intervals that are inappropriately long can lead to problems with both tolerability, when serum concentrations are too high, and efficacy, when they are too low. This is only a problem for certain drugs, depending on whether the drug truly has a wide therapeutic window. Carbamazepine has a narrow therapeutic window because many people experience toxicity at higher serum concentrations and breakthrough seizures if the concentration is too low. For example, serum concentrations above 11 mg/l are likely to produce dizziness, ataxia and / or diplopia, whereas serum concentrations below 8 mg/l are likely to produce breakthrough seizures. Under these circumstances, the choice of dosing strategies is relatively clearcut. Dosing intervals would have to be chosen to maintain serum concentrations within, at most, a 25% band. Carbamazepine has a serum half-life of 16 h. Consider a patient who takes 1200 mg per day. If carbamazepine was dosed at 600 mg two times a day, the serum concentration might be 11 mg/l at its maximum but would fall by almost 50% between dosing intervals. If it was dosed as 400 mg three times a day, the serum concentration would fall by 25%, which is barely acceptable. This then leads to the standard Read more [...]

AEDs: Use Of Serum Levels

Physicians may be confused about whether measurement of serum concentrations is important for epilepsy patients, particularly for the new anti-epileptic drugs. Most experts believe that it is more important to individualize dosing, and to understand the serum concentration that is optimal on an individual basis. This may mean that some individuals have optimal control and side-effect profile at a serum concentration that is outside of the recognized therapeutic norms. Approximately 25% of patients will achieve seizure freedom below the recognized therapeutic range, and about the same number will require serum concentrations above the range to obtain the maximum seizure benefit, often with few side-effects. Many of the new anti-epileptic drugs are considered to have a wide therapeutic range. The range of serum concentrations that can be beneficial varies widely from one individual to another, yet for a particular individual it may be very important to maintain serum concentrations with minimal variability. For example, one patient on lamotrigine may have excellent seizure control within a range of 2-4 mg/l, but may experience dizziness and diplopia if the level increases to 5 mg/l. Another patient, in contrast, Read more [...]

Glatiramer Acetate (Copaxone)

The past 15 years have seen a revolution in our understanding and management of many neurologic diseases, including multiple sclerosis (MS). The US Food and Drug Administration (FDA) approved the first of the interferon (IFN) preparations, IFNβ-1b (Betaseron®) for multiple sclerosis in 1993, followed by glatiramer acetate (Glatiramer Acetate, Copaxone®) in 1995, intramuscular IFNβ-1a (Avonex®) in 1996, then mitoxatrone (Novantrone®) and subcutaneous IFNβ-1a (Rebif®) in 2000 and 2002, respectively. Treatment with Glatiramer Acetate or the interferons has become the standard of care for patients with relapsing-remitting multiple sclerosis (RRMS). FDA approval for Glatiramer Acetate was granted on the basis of two pivotal double-blind, placebo-controlled clinical trials that convincingly demonstrated the ability of Glatiramer Acetate to reduce relapse rates in multiple sclerosis and, to a lesser extent, slow the progression of neurologic disability. In addition, the clinical success of Glatiramer Acetate and the interferons has generated a wealth of basic research and clinical trials that have helped to clarify their mechanisms of action and extend their clinical applications. The purpose of this post will be to Read more [...]

Clinical Studies Of Glatiramer Acetate

Clinical Trials Of Glatiramer Acetate In Relapsing-Remitting Multiple Sclerosis Clinical Trials Of Glatiramer Acetate In Progressive Forms Of Multiple Sclerosis MRI Studies Adverse Events in Trials and Clinical Experience Adverse events in the various Glatiramer Acetate studies were numerous, but relatively mild, and this has been borne out in clinical practice. There were no hematologic abnormalities, elevated hepatic enzymes, flu-like symptoms, or significant depression. Local injection site reactions consisting of erythema with or without induration occurred in 90% of Glatiramer Acetate-treated patients, and were sometimes painful, but never resulted in skin necrosis, although subcutaneous lipoatrophy may have been more frequent than with other injectables. An immediate postinjection reaction consisting of variable combinations of flushing, sweating, chest tightness, shortness of breath, palpitations, and anxiety occurred in all of the major studies with frequencies ranging from 15.2% in the US pivotal trial to 37.8% in the European-Canadian MRI trial. The symptoms were sporadic, beginning seconds to minutes after injection, lasting up to 30 minutes, and resolving spontaneously. Most patients had only one or Read more [...]

Clinical Trials Of Glatiramer Acetate In Relapsing-Remitting Multiple Sclerosis

Phase II Pilot Study Following an open-label dose finding study in 16 patients, in which Glatiramer Acetate was shown to be safe, and the standard dose of subcutaneous 20mg / day is established, Bornstein et al. undertook a randomized, double-blind, placebo-controlled phase II trial in 50 patients with relapsing-remitting multiple sclerosis. Patients were enrolled as matched pairs, stratified by age, sex, relapse rate, and Kurtzke disability status score (DSS), and were followed at regular intervals by blinded examiners. The results were remarkable with 62 confirmed attacks in the placebo group compared to only 16 in the Glatiramer Acetate-treated group over two years, corresponding to a reduction in annualized relapse rate from 1.35 to 0.30, a highly significant result. Patients with the lowest disability scores (DSS 0-2) responded best, with 27 attacks in the placebo-treated patients, but only four among those treated with Glatiramer Acetate, suggesting that treatment should be initiated as early as possible. A beneficial effect was also found for progression of disease, with significant differences between the active drug and placebo groups in proportion of progression-free patients and time to confirmed progression. Read more [...]

Clinical Trials Of Glatiramer Acetate In Progressive Forms Of Multiple Sclerosis

Phase II Pilot Study A study of Glatiramer Acetate in 106 patients with "chronic progressive" multiple sclerosis (including both secondary progressive and primary progressive forms) was conducted in the mid-1980s. Although carefully designed and controlled, this study was marred by problems of insufficient statistical power and inter-site variation. Patients with scores of 2 to 6.5 on the Kurtzke expanded disability status scale and a progressive course in the previous two years were followed in a pretrial observation period to confirm progression, then randomized to receive either 15 mg of Glatiramer Acetate, or a placebo, administered by subcutaneous injection twice daily. The primary endpoint was time to confirmed expanded disability status scale progression, maintained for at least three months. Despite the unusual pretrial observation period, stringent progression criteria, and increased dose of Glatiramer Acetate, its effect on progression was not significant, although all outcome measures showed favorable trends. When data from the two centers were analyzed individually, there was a significant treatment effect at one center, but not the other, which was attributed to failure of placebo-treated patients at that Read more [...]