Epilepsy in the Elderly: The Use of Tiagabine

Summary: The incidence of epilepsy increases sharply in patients older than 60 years. There is a clear need for clinical trials designed specifically for this age group, as elderly patients differ from younger patients with epilepsy with respect to seizure etiology, coexisting diseases, concomitant drug therapy, and drug disposition. The new antiepileptic drugs (AEDs) are often associated with fewer side effects than are the traditional AEDs and may be particularly useful in the elderly. The pharmacokinetics of tiagabine (TGB) are not significantly modified in elderly patients, although elimination is more rapid in the presence of enzyme-inducing AEDs. Efficacy and tolerability data on TGB in elderly patients is currently limited, and a formal trial of TGB monotherapy in this age group is needed.     

International Experience with Tiagabine Add-On Therapy

Summary: Tiagabine (TGB) hydrochloride is a novel antiepileptic drug (AED) that is a potent and specific inhibitor of γ-aminobutyric acid (GABA) uptake into glial and neuronal elements. In accordance with medical and regulatory standards, the clinical development program for TGB as an AED has assessed the value of TGB in add-on treatment, focusing mainly on partial seizures, including secondarily generalized seizures. Five add-on, placebo-controlled trials and six non-comparative, open-label, long-term multicenter trials have been or are being conducted in Australia, Europe, and the U.S.A. The results of these trials, involving 2,261 patients, indicate that TGB has efficacy as add-on therapy in patients with epilepsy difficult to control with existing AEDs. Efficacy of TGB is also sustained with long-term treatment. A clear dose-response has been demonstrated, and the minimal effective dose level is 30 mg. TGB is also tolerated, and with long-term therapy no new or more severe types of adverse events develop. These studies have included a wide age range of patients, including adolescents and the elderly.     

Characteristics of patients initiated on the new antiepileptic drugs: a PADS study

Whereas randomized controlled trials remain a standard for evaluating and comparing efficacy and safety of the new antiepileptic drugs (AEDs), postmarketing drug research offers a useful means of comparing efficacy and safety of new AEDs. However, differences in baseline characteristics of patients in different drug groups create the potential for bias in drug comparison studies. In this study, baseline demographic characteristics of 1,386 patients initiating lamotrigine (LTG), tiagabine (TGB), or topiramate (TPM) were compared to identify patient characteristics that may influence AED use in epilepsy patients. Data were collected at 14 epilepsy centers and included medications, seizure types and syndromes, and prior adverse events. There were 402 patients in the LTG group, 725 TPM, and 259 TGB. The groups differed both in their number of concurrent AEDs (p<0.001) and in their number of prior AEDs (p<0.01). There was no difference in proportion with partial versus generalized epilepsy syndromes. The groups differed in the proportions of patients with complex partial seizures (p=0.049), primary generalized tonic-clonic seizures (p=0.01), and myoclonic seizures (p=0.03). Baseline behavioral adverse event rate was lowest in patients initiating TPM (p<0.01); LTG patients had the lowest rate of prior AED-related rash (p=0.02). There was no relationship between AED assignment and patient age, age of epilepsy onset, epilepsy duration, institutionalization status, gender, or psychiatric history. Numerous epidemiological differences were identified among patients placed on the new AEDs, including current and prior AED profiles, seizure types, and prior adverse event history. Accounting for these differences is of crucial importance because they may bias conclusions of nonrandomized post-marketing trials comparing the drugs.     

Tiagabine: The Safety Landscape

Summary: Tiagabine (TGB) hydrochloride is a potential new antiepileptic drug (AED) undergoing clinical development. Experience in humans amounts to 1,810 patient-years of exposure. TGB was found to be tolerated in an integrated safety analysis of five double-blind, add-on therapy trials involving approximately 1,000 patients with epilepsy with difficult-to-control seizures with existing AEDs. Discontinuation resulting from adverse events were infrequent, occurring in 15% of patients receiving TGB compared to 5% receiving placebo. The most frequently reported adverse event was dizziness, which was usually transient and did not require medical intervention. Adverse events that were statistically significantly more common with TGB than placebo were dizziness, asthenia, nervousness, tremor, diarrhea, and depression (not major depression). Adverse events were usually mild to moderate in severity and transient, and most were associated with dose titration. The incidence, type, and severity of adverse events in long-term studies were comparable with those in short-term studies. Serious adverse events were uncommon and no idiosyncratic events were reported.     

Pharmacological and clinical aspects of antiepileptic drug use in the elderly

In this article, epidemiological and clinical aspects related to the use of antiepileptic drugs (AEDs) in the elderly are highlighted. Studies have shown that people with epilepsy receiving AED treatment show important deficits in physical and social functioning compared with age-matched people without epilepsy. To what extent these deficits can be ascribed to epilepsy per se or to the consequences of AED treatment remains to be clarified. The importance of characterizing the effects of AEDs in an elderly population is highlighted by epidemiological surveys indicating that the prevalence of AED use is increased in elderly people, particularly in those living in nursing homes. Both the pharmacokinetics and the pharmacodynamics of AEDs may be altered in old age, which may contribute to the observation that AEDs are among the drug classes most commonly implicated as causing adverse drug reactions in an aged population. Age alone is one of several contributors to alterations in AED response in the elderly; other factors include physical frailty, co-morbidities, dietary influences, and drug interactions. Individualization of dosage, avoidance of unnecessary polypharmacy, and careful observation of clinical response are essential for an effective and safe utilization of AEDs in an elderly population.     

Women with Epilepsy: Must Contraception and Pregnan Add to the Burden of Epilepsy?

Summary: In addition to seizure control, women with epilepsy face particular complications associated with menstruation, fertility, contraception, pregnancy, and breastfeeding. With traditional long-term antiepileptic drug (AED) therapy there is a risk of menstrual irregularities, contraceptive failure, and adverse pregnancy outcome. Many women intentionally discontinue AED therapy during pregnancy because of concerns about the risk of fetal malformation and effects on fetal growth and development. However, trauma resulting from seizures is the leading cause of maternal and fetal death in women with epilepsy. In addition, mothers are concerned about the presence of AEDs in breast milk and therefore tend to choose bottle feeding. Clearly, a balance must be achieved between seizure control for the mother and exposure of the fetus or infant to AEDs. Tiagabine (TGB) is a new AED which acts by inhibiting uptake of the neurotransmitter γ-aminobutyric acid into glial cells. Animal studies show that TGB has no toxic effects either on reproductive function or on the developing fetus, although there is still insufficient evidence to permit conclusions from human studies. TGB does not induce hepatic metabolism, and a study in healthy volunteers indicates no interaction with oral contraceptives. It is hoped that the availability of new AEDs such as TGB, with the promise of a better safety profile and a lower propensity for drug interactions, will alleviate the burden for women with epilepsy.     

Population Analysis of the Pharmacokinetics of Tiagabine in Patients with Epilepsy

Summary: Purpose: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy.
Methods: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach.
Results: The patients'average (±SD) weight and age were 73.8 ± 20.7 kg and 32.1 ± 12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates.
Conclusions: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.     

Occurrence of psychosis in patients with epilepsy randomized to tiagabine or placebo treatment

PURPOSE: Patients with drug-resistant epilepsy have a higher incidence of psychiatric problems and possibly greater intolerance to antiepileptic drugs (AEDs) than do other patients with epilepsy. Concern has been raised that gamma-aminobutyric acid (GABA)ergic drugs may be associated with treatment-emergent psychosis. Tiagabine (TGB; Gabitril), a new AED that blocks synaptic GABA uptake, was developed in trials of drug-resistant patients with epilepsy. We conducted ad hoc analyses of adverse events, drug intolerance, and treatment response to evaluate the association between TGB treatment and psychosis and whether psychiatric history might be predictive of tolerance or effectiveness of this GABAergic drug. METHODS: Data were analyzed from two multicenter, randomized, double-blind, placebo-controlled trials of add-on TGB therapy (32 or 56 mg daily) in 554 adolescents and adults with complex partial seizures (CPSs). After an 8- or 12-week baseline phase, double-blind treatment consisted of a 4-week titration period (with TGB dose gradually increased to 32 or 56 mg daily) and an 8- or 12-week fixed-dose period. Adverse events commonly associated with psychosis were evaluated. Treatment intolerance and effectiveness (> or =50% reduction in CPS rate) were compared among patients with and without psychiatric histories. RESULTS: Psychotic symptoms (hallucinations) were observed in three (0.8%) of 356 TGB-treated patients and none of 198 placebo-treated patients (p = 0.556, NS). Statistical analysis showed no interaction between psychiatric history and drug intolerance or treatment outcome. CONCLUSIONS: TGB administration appears to carry no significant increased risk of treatment-emergent psychosis. Psychiatric history was not predictive of the tolerance or effectiveness of the drug.     

Practical strategies for switching to newer antiepileptic drugs

Traditional antiepileptic drugs (AEDs) are associated with drug interactions and side effects that limit their safety and tolerability. Side effects of traditional AEDs are especially problematic for children and adolescents, women of childbearing age, and the elderly. Many patients with epilepsy may benefit from switching from a traditional AED to a newer agent because the newer agents are generally better tolerated and are less likely to cause drug interactions. Clinical studies have demonstrated improved therapeutic efficiency with better tolerability in patients switching from a traditional AED to lamotrigine, oxcarbazepine, or topiramate monotherapy or combination therapy.     

Tiagabine in the Management of Epilepsy

Summary: Tiagabine (TGB) is a new antiepileptic drug (AED) that uniquely reduces the uptake of the inhibitory neurotransmitter -γ-aminobutyric acid into presynaptic neuronal and glial cells. It is metabolized in the liver with an elimination half-life of approximately 7 to 9 h. Although TGB does not induce or inhibit hepatic metabolic processes, it does provide a target for other enzyme-inducing AEDs. TGB has proved effective as add-on treatment for partial seizures, with or without becoming secondarily generalized, as demonstrated in five placebo-controlled trials and six long-term open studies. Preliminary results with TGB in children with refractory epilepsy and as monotherapy are promising. Few patients withdrew from these trials because of adverse events. The most common side effects with TGB involved the central nervous system, i.e., dizziness, asthenia, somnolence, nervousness, headache, and tremor. Most adverse events occurred during dosage titration, were often transient, and were usually of mild to moderate severity. The recommended maintenance dose for TGB, when combined with enzyme-inducing drugs as add-on therapy, is 30 to 50 mg/day. Trials are under way in patients with primarily generalized seizures and in newly diagnosed epilepsy. TGB is a well-tolerated and effective novel AED that will find an enduring place in the management of epilepsy.     

Pharmacotherapy of epilepsy: new armamentarium, new issues.

Since 1990 there have been over ten antiepileptic drugs (AEDs) approved for the therapy of epilepsy. These agents have a new spectrum of efficacy and novel adverse effects, some totally unexpected. They also represent an enormous escalation of costs. Few have been subjected to head-to-head comparisons in monotherapy against established AEDs. The aim of therapy is to eliminate rather than to reduce seizure manifestations. Many traditional agents have been phased out due to poor tolerability. New epilepsy syndromes and genetic contributions to epilepsy have been refined. Special considerations apply to various classes of sufferers such as the elderly, women of childbearing age, and sufferers with concomitant disorders, treated with medications capable of drug interactions. There is a recognition of the value of slow introduction, a preference for monotherapy, recognition of the effects of AEDs on hormones and reproductive function and effects on the fetus exposed to AEDs in utero, comprising physical malformations and effects on cognitive development. A balance between efficacy and safety is pivotal, as every preference about the initial pharmacotherapy of epilepsy and subsequent polytherapy has its protagonists. With improvement in diagnostic techniques and new therapeutic modalities it is likely that in the future, pharmacogenomics and an understanding of pharmacoresistance may influence drug selection for individual patients with epilepsy.     

New strategies for the identification of drugs to prevent the development or progression of epilepsy

During the last decade, several new antiepileptic drugs (AEDs) have been introduced in Europe, the United States, or other parts of the world. Although the antiepileptic efficacy of these drugs is not superior to that of older AEDs, some of the new drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential with other drugs. However, the new AEDs have only a modest impact on patients with refractory epilepsies, so that about one third of patients with epilepsy continue to have seizures with current pharmacotherapies. Thus, there is a continuing need for new medical therapies in epilepsy. During the Workshop on "New Horizons in the Development of Antiepileptic Drugs" (November 28-29, 2001, Philadelphia, PA), one topic dealt with the critical re-evaluation of previous preclinical strategies for the discovery and the development of new AEDs. The discussion of this session, which was chaired by the authors, is summarized in this article. Main issues of the discussion were whether epilepsy is a progressive disease and whether refractory epilepsy is preventable, the use of acute versus chronic animal models in the discovery and development of new AEDs, models for drug-resistant epilepsy, mechanisms of drug resistance, alterations in adverse effect potential of AEDs by epilepsy, and advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy. Overall, it was felt that the current preclinical strategies for the discovery and development of new AEDs have to be redefined in order to identify agents that are clearly superior to current medications.     

Critical re-evaluation of previous preclinical strategies for the discovery and the development of new antiepileptic drugs

During the last decade, several new antiepileptic drugs (AEDs) have been introduced in Europe, the United States, or other parts of the world. Although the antiepileptic efficacy of these drugs is not superior to that of older AEDs, some of the new drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential with other drugs. However, the new AEDs have only a modest impact on patients with refractory epilepsies, so that about one third of patients with epilepsy continue to have seizures with current pharmacotherapies. Thus, there is a continuing need for new medical therapies in epilepsy. During the Workshop on "New Horizons in the Development of Antiepileptic Drugs" (November 28-29, 2001, Philadelphia, PA), one topic dealt with the critical re-evaluation of previous preclinical strategies for the discovery and the development of new AEDs. The discussion of this session, which was chaired by the authors, is summarized in this article. Main issues of the discussion were whether epilepsy is a progressive disease and whether refractory epilepsy is preventable, the use of acute versus chronic animal models in the discovery and development of new AEDs, models for drug-resistant epilepsy, mechanisms of drug resistance, alterations in adverse effect potential of AEDs by epilepsy, and advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy. Overall, it was felt that the current preclinical strategies for the discovery and development of new AEDs have to be redefined in order to identify agents that are clearly superior to current medications.     

Adults with Epilepsy: Is Monotherapy the Only Answer?

Summary: Monotherapy with antiepileptic drugs (AEDs) should be the aim in most patients with epilepsy and is achievable in most newly diagnosed cases. "Rational po-lytherapy" is a valuable new concept that can be usefully applied to a minority of patients. Assessment of new AEDs as monotherapy is a challenging problem, and appropriate clinical trial methodology is currently evolving. Although tiagabine (TGB) is established as an effective add-on agent in refractory partial epilepsy, its role in monotherapy is not yet clear. Preliminary studies suggest that TGB is effective and well tolerated as monotherapy. Ongoing large monotherapy studies should establish the comparative efficacy and tolerability of TGB vs. conventional AEDs.     

Drug absorption in the elderly: biopharmaceutical considerations for the antiepileptic drugs

The management of antiepileptic drug (AED) pharmacokinetics remains a challenge in the treatment of patients with epilepsy. Drug characteristics, such as protein binding, mechanisms of drug elimination, and the potential for pharmacokinetic/pharmacodynamic interactions, are important considerations for drug selection and may help determine overall effectiveness. In elderly patients with epilepsy, the likelihood of polytherapy, along with physiological changes associated with aging, can make pharmacokinetic issues even more significant. One aspect of pharmacokinetics that has received less attention is the process of oral drug absorption. Aging can have variable effects on the gastrointestinal system. Some of these physiological changes have the potential to impact absorption patterns of some medications, including AEDs. Altered oral protective reflexes, xerostomia, and delayed esophageal emptying in elderly patients may complicate oral administration of some medications. Altered gastric pH could modify drug absorption, and modified gastric emptying rates can influence the bioavailability of some AEDs. Finally, intestinal transit times may be slower in elderly patients compared to younger patients, possibly altering the absorption of some AEDs. These age-related physiological changes that may affect AED pharmacokinetics should be considered when treating elderly patients with epilepsy.     

Role of valproate across the ages. Treatment of epilepsy in the elderly

In June 2005, a team of experts participated in a workshop with the objective of reaching agreement on several important aspects of valproate in the treatment of elderly patients with epilepsy. Epilepsy in the elderly is relatively common and its incidence increases for each decade after age 60. The aetiology and manifestations of epilepsies in the elderly are complex because of comorbidity and other underlying risk factors. A consensus was reached that elderly patients who present with a seizure disorder should be referred rapidly to a specialist and that diagnosis should be improved by using a multidisciplinary team of cardiologists, neurologists and epilepsy experts (syncope, falls and seizure specialists). This is especially important to avoid mistreatment with antiepileptic drugs (AEDs). There was consensus that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults. For these reasons, in older persons AEDs should be started at low dosages, and titrated slowly according to clinical response. Some of the most troublesome side effects of AEDs in the elderly include sedation and cognitive side effects, as well as osteoporosis. Drug–drug interactions should be given special consideration. There was consensus that the pharmacokinetics of all AEDs are altered in the elderly, and that the most significant change common to all AEDs is a moderate reduction in renal and metabolic clearance. Predicting pharmacokinetic changes in the individual, however, can be very difficult because multiple factors contribute to a high inter-patient variability. There was agreement on the advantages and disadvantages of the use of valproate in the elderly, and consensus that valproate is a useful option in this population. There was no consensus, however, on whether valproate should be considered among the preferred first-line treatments in the elderly.     

Drug selection for the newly diagnosed patient: When is a new generation antiepileptic drug indicated?

Abstract. Treatment options in epilepsy have increased dramatically since the early 1990s with the introduction of nine new generation antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). This makes drug selection much more complicated and challenging. This review discusses drug selection in patients with newly diagnosed epilepsy and in particular the role of new AEDs in this population. The choice of treatment should always be based on a careful comparison of the risk-benefit ratio for the different treatment options and the outcome of such evaluation may be different in patients with new onset compared with chronic epilepsy. Efficacy, tolerability and safety are the main criteria for selection of AEDs and any first line drug for patients with newly diagnosed epilepsy must have demonstrated satisfactory efficacy as monotherapy in that patient population. So far, of the new AEDs only lamotrigine, oxcarbazepine and topiramate have documentation sufficient to be granted licence for use as monotherapy in most European countries. Because the new generation AEDs have failed to demonstrate improved effectiveness as monotherapy, old generation AEDs such as carbamazepine and valproate remain drugs of first choice for partial and generalised seizures, respectively. However, there are special situations and populations where a new AED may be a reasonable first line drug. These include vigabatrin in West syndrome associated with tuberous sclerosis, lamotrigine as alternative to valproate in idiopathic generalised seizures in women of childbearing potential and lamotrigine for the treatment of epilepsy in the elderly population. The role of the new generation AEDs is likely to become more prominent as more experience is gained.     

Epilepsy: comorbidity in the elderly

Elderly people experience the highest incidence of epilepsy and their clinical mananagement is often challenging, due to a potential increase in the likelihood of adverse treatment events. In addition, concomitant diseases are highly prevalent in this population and elderly patients are likely to be prescribed a number of medications that must be taken concurrently. As a result, the incidence of adverse drug–drug interactions and adverse drug reactions is also extremely high. Thus, the treatment of elderly patients with epilepsy requires careful consideration of any comorbid conditions and concomitant medications. Most adverse events are drug-related and are therefore preventable. It is important to consider these complications when prescribing antiepileptic drug (AED) treatment. An AED with broad-spectrum efficacy, good tolerability and a favourable drug interaction profile (e.g. valproate, gabapentin and lamotrigine) may prevent many unwanted drug interactions and side effects.     

The Effect of Age on Pharmacokinetics of Antiepileptic Drugs

Summary: Management of epilepsy in the elderly requires understanding of the unique biochemical and pharmacologic characteristics of this patient population. Accurate assessment of seizures and identification of epilepsy syndromes, thorough neurologic assessment to define etiology, and comprehensive evaluation of the patient's health and living situation are necessary for informed management decisions. Challenges to treatment include concomitant diseases, polypharmacy with accompanying drug interactions, and changes in physiology, such as changes in renal clearance and hepatic function that alter drug absorption, protein binding, metabolism, and elimination. Elderly patients with declining intellectual function, motor impairment, or altered sensory function may be especially susceptible to dose-related CNS side effects of antiepileptic drugs (AEDs). Drugs pre-scribed for concomitant illnesses such as hypertension, cardiovascular disease, infections, behavioral problems, and gastrointestinal disturbances may alter absorption, distribution, and metabolism of AEDs, with an adverse impact on efficacy and increased occurrence of adverse effects. The AEDs may induce metabolism of other drugs, resulting in decline in target response. Addition of an AED to an elderly patient's medical regimen requires careful review of all prescribed drugs. Optimal care of elderly patients with epilepsy includes use of free drug levels to monitor AED concentrations, careful dose selection, and sensitivity to the social problems that may occur in this population.     

Management of Epilepsy in the Elderly

Summary: Epilepsy in elderly patients is a growing worldwide challenge; as the population ages, the preva lence of epilepsy increases. Management of epilepsy in elderly patients requires an understanding of their unique medical and pharmacologic characteristics. Accurate as sessment of seizures, thorough neurologic assessment to define etiology, and evaluation of concomitant illnesses and living situations are necessary for comprehensive treatment planning and informed management. Expect el derly patients to present challenges to treatment that in clude concomitant diseases, obligatory polypharmacy with accompanying drug interactions, and age-related changes in renal and hepatic physiology that alter drug metabolism and elimination. Elderly patients have declin ing intellectual function, motor impairment, or altered special sensory function that make them susceptible to dose-related CNS side effects of antiepileptic drugs (AEDs). When AEDs are added to the medical regimen of an elderly patient, the physician must review all pre scribed drugs. Drugs prescribed for concomitant illnesses such as behavioral problems, cardiovascular disease, hy pertension, and infection may alter the distribution and metabolism of AEDs, with an impact on efficacy and oc currence of adverse effects. AEDs tend to induce metab olism of other drugs, leading to a decline in target re sponse. Optimal care of elderly patients with epilepsy includes use of free levels to monitor AED concentra tions, careful dose selection, and physician sensitivity to patients' social problems.