Effectiveness of lamotrigine in clinical practice: results of a retrospective population-based study.

OBJECTIVE: Evaluation of the effectiveness of lamotrigine in a population-based cohort of epilepsy patients. METHODS: Medical charts of 360 patients treated in 37 centres in The Netherlands were reviewed. Effectiveness of lamotrigine therapy was assessed during the first year of use, with patients serving as their own controls. Effectiveness was measured by reduction in seizure frequency and retention time. RESULTS: Effectiveness could only be assessed in 165 patients; assessment in remaining patients was not possible due to various reasons, such as insufficient medical chart information. Lamotrigine was effective in 40% of patients who had been prescribed lamotrigine because of insufficient seizure control (n=112), and 14% of these 112 patients became seizure free. Duration of epilepsy, baseline seizure frequency, valproate use, drug load and number of antiepileptic drugs (AED) used were related to effectiveness of lamotrigine. In this group, 36% continued lamotrigine (LTG) throughout the first year without experiencing a >50% seizure reduction. Lamotrigine was effective in 63% of patients who received the drug because of poor tolerability of other antiepileptic drugs (n=53). DISCUSSION: Lamotrigine is an effective drug in clinical practice. Use of retention time measures only may not correctly reflect the efficacy of antiepileptic drugs.

Cost-effectiveness of add-on lamotrigine therapy in clinical practice.

OBJECTIVE: This retrospective study addresses the cost-effectiveness of add-on therapy with lamotrigine in clinical practice. METHODS: Two years' observational data of 165 patients were used. Seizure frequency, adverse effects and direct medical costs were recorded for the year before and the year after the start of lamotrigine add-on therapy. Therapy effectiveness was measured by: (1) reduction in seizure frequency and (2) retention time. The incremental cost-effectiveness ratio expressed the direct medical cost per patient treated effectively with lamotrigine. RESULTS: The cost of medication was 492 (95% CI: 399-583) higher after the start of lamotrigine therapy. The extra cost of lamotrigine therapy (622) was partly offset by a reduction of the cost of co-medication (-130; 95% CI: -210 to -50). Overall, the total medical cost was 453 higher in the first year of lamotrigine therapy than in the year before the start of lamotrigine. Lamotrigine was effective in 47% of all the patients, making the resultant incremental cost-effectiveness ratio 954 per year. DISCUSSION: Add-on therapy of lamotrigine for patients with uncontrolled epilepsy offers improved health outcomes. Lamotrigine therapy is associated with increased cost (453) and an annual incremental cost-effectiveness ratio of 954. These data, together with utility data published in the literature, support the notion that lamotrigine should be considered as an add-on therapy in for patients with refractory epilepsy.

Selection criteria for the clinical use of the newer antiepileptic drugs.

In recent years, several new antiepileptic drugs (AEDs) have been licensed: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. These drugs have proven efficacy as add-on therapy in patients with difficult-to-treat partial epilepsy, as 20-50% of patients treated in add-on trials experienced a seizure reduction of >or=50%. Relatively few trials have been conducted to evaluate these drugs as monotherapy for patients with newly diagnosed epilepsy. In the monotherapy trials that have been conducted, the newer drugs were often as efficacious as conventional drugs, and their tolerability was often better. However, the methodology of these trials can be criticised. Because of the relative lack of robust data for the newer agents, the conventional drugs have thus far maintained their status as first-line monotherapy. However, when first-line monotherapy fails, an alternative drug has to be chosen from the available conventional and newer drugs. This article aims to give detailed background information on the newer AEDs in order to enable physicians to make a rational choice from the available drugs for individual patients. Data are provided for the different newer AEDs on mechanisms of action; efficacy in refractory partial epilepsy, newly diagnosed epilepsy in adults and generalised seizure types; adverse effects; pharmacokinetics; and use in special patient categories.

Clinical pharmacokinetics and pharmacodynamics of anticancer agents in pediatric patients (review).

The pharmacokinetics of several important anticancer agents used in pediatric oncology are reviewed. Many of the anticancer agents described showed age-dependent pharmacokinetics, the disposition in children being different compared to the adult pharmacokinetics. These age-dependent pharmacokinetics imply that it is inappropriate to extrapolate pharmacokinetic data from studies in adult patients. Interpatient pharmacokinetic variability in pediatric patients was large, and of a greater magnitude compared to the variability observed in adult patients. This variability in pharmacokinetics resulted in similar large variability in systemic exposure after administration of standardized doses (e.g. the maximum tolerated dose) of these anticancer agents. The variability of some of these agents is correlated with their clinical effects (either tumor response or toxicity). It is possible, using these anticancer agents, to monitor pediatric patients, identifying those patients at risk of severe toxicity (high systemic exposure) or those patients who may not benefit from treatment (Low systemic exposure). These pharmacodynamic relationships are described in this paper, since such correlations may contribute to further optimization of chemotherapy in pediatric patients.

The effects of guideline implementation for proton pump inhibitor prescription on two pulmonary medicine wards.

BACKGROUND: It has been demonstrated that 40% of patients admitted to pulmonary medicine wards use proton pump inhibitors (PPIs) without a registered indication. AIM: To assess whether implementation of a guideline for proton pump inhibitor (PPI) prescription on pulmonary medicine wards could lead to a decrease in use and improved appropriateness of prescription. METHODS: This prospective study comprised two periods, i.e. the situation before and after guideline implementation. In each period, 300 consecutive patients were included. We registered patient characteristics, medications and occurrence of upper gastrointestinal-related disorders. RESULTS: After implementation, fewer patients were started on PPIs [21% vs. 13%; odds ratio (OR): 0.56; 95% confidence interval (CI): 0.33-0.97] and more users discontinued their use; however, the latter was not significant (3% vs. 6%; OR for continuation: 0.56; 95% CI: 0.14-2.23). Multivariable logistic regression analysis confirmed that PPI use during hospitalization decreased after implementation (adjusted pooled OR: 0.54; 95% CI: 0.32-0.90). Implementation did not result in a change in reported reasons for PPI prescription. There was no significant difference in the occurrence of upper GI-related disorders in the first 3 months after discharge. CONCLUSIONS: Guideline implementation for PPI prescription on two pulmonary medicine wards resulted in a reduction in the number of patients starting PPIs during hospitalization, but appropriateness of prescribing PPIs was not affected. Further studies are needed to determine how appropriateness of PPI prescription on pulmonary medicine wards can be further improved.

Recruitment of a cohort of lamotrigine users through community pharmacists: differences between patients who gave informed consent and those who did not.

OBJECTIVE: Community pharmacists may function as intermediaries in the recruitment of a population-based cohort of patients using specific drugs. In this study, baseline characteristics and the retention rate of patients that gave informed consent, refused and did not answer were compared. METHODS: A total of 1819 patients using the new antiepileptic drug (AED) lamotrigine were asked to provide informed consent for a retrospective chart study via their individual pharmacist. Four possible reactions resulted from the consent question: active consent, active refusal, passive refusal and non-informed. Patient characteristics and lamotrigine retention rate of the different groups were compared. RESULTS: Pharmacists did not inform a total of 183 patients (10%). Of the remaining patients, a total of 968 (59%) gave consent; 101 (6%) actively refused and 567 (35%) did not respond. Age, burden of illness, psychotropic co-medication and continuation of lamotrigine therapy were related to active consent. Lamotrigine retention rate in patients that gave consent was higher than in other patients. CONCLUSIONS: Patient recruitment with community pharmacists as intermediaries for observational studies on the effects of (new) drugs is feasible, and allows access to a broad population of patients. The recruitment procedure, however, may lead to selection bias.

Patterns of lamotrigine use in daily clinical practice during the first 5 years after introduction in the Netherlands.

OBJECTIVE: Follow-up data on the long-term effectiveness (efficacy and tolerability) of lamotrigine are limited. A useful though crude measure for effectiveness in daily clinical practice is the treatment retention rate determined from drug dispensing data. This study describes the baseline characteristics, the usage patterns and the retention rate of this antiepileptic drug (AED) in a population-based cohort of lamotrigine users in the Netherlands during the first 5 years after its registration in 1995. Data from this cohort are compared with those from the initial randomized clinical trials (RCTs) in patients with refractory epilepsy. METHODS: This retrospective cohort study used dispensing data from community pharmacies. Baseline characteristics and usage patterns were evaluated for first time users of lamotrigine in this study. Usage patterns were characterized as continued, add-on or discontinued use during the patient observation time window. Cox regression analysis was used to explore possible relationships between baseline characteristics and specific usage patterns defined. The baseline characteristics and discontinuation rates in this cohort study were compared with RCT data reported in medical literature. RESULTS: A total of 3598 lamotrigine users were identified. The mean age of the population was 39 years and 54% were female. On average, patients used two other AEDs at the start of lamotrigine therapy and approximately 6% of the patients had no history of prior AED use. The discontinuation rate was 25% after 1 year, and approximately 32% at the end of the 5-year study. Addition of another drug or discontinuation was seen in more than half of the population 3 years after the start of therapy. Concurrent use of valproic acid was associated with a better retention rate. Absence of AED history, use of antidepressants, or use of migraine abortive drugs resulted in an increased likelihood of discontinuing lamotrigine. The population from RCTs differed from the study cohort with respect to age, concurrent use of AEDs and length of follow-up. CONCLUSION: Data from RCTs cannot easily be extrapolated to daily clinical practice. In this large, observational study, lamotrigine therapy failed in a considerable number of patients, although the mean retention rate was better than previously reported by others. Population-based linkage of health care records can be used to further clarify the effectiveness of lamotrigine.

Diffusion of the new antiepileptic drug lamotrigine in Dutch clinical practice.

INTRODUCTION: Lamotrigine is one of the recently introduced antiepileptic drugs (AEDs) licensed in the Netherlands in 1995. The objective of this study was to examine the diffusion of lamotrigine into clinical practice. Three different aspects of this diffusion process were examined: incidence of use, patient characteristics and changes in prescription patterns in the first 5 years following its introduction. METHODS: A retrospective follow-up study has been conducted using drug prescription data from the database of the Dutch Drug Information Project (GIP database). Patients were included who started with lamotrigine, carbamazepine, phenytoin or valproate in the period between January 1996 and December 2000. Incidence of use was calculated for the four drugs. Multiple logistic regression analysis was used to determine differences in baseline characteristics. The Chi-square test was used to analyse changes in the usage patterns of lamotrigine. RESULTS: The study population consisted of a total of 29,718 patients who were prescribed carbamazepine, phenytoin, valproate or lamotrigine for the first time in the study period. Carbamazepine and valproate accounted for the majority of all new prescriptions; the incidence of lamotrigine use remained stable with 4.4 patients per 100,000 per year. Baseline characteristics of lamotrigine differed depending on the patient's age and gender (OR 3.7, 95% CI 3.3-4.2; OR 1.4, 95% CI 1.3-1.5) relative to the conventional AEDs. In a large majority of cases, lamotrigine was used as a second-line or third-line AED. Physicians prescribing lamotrigine were predominantly neurologists, in contrast to prescribers of conventional AEDs. The prevalence of psychotropic medication and migraine-abortive drugs was significantly lower in users of lamotrigine than in users of conventional AEDs. During follow-up, several significant trends were noticed in the prescribing of lamotrigine with regard to age groups, gender, antiepileptic history and off-label use. DISCUSSION: Lamotrigine is prescribed to a population different from that using conventional AEDs. The uptake of lamotrigine in clinical practice is slow, for reasons probably related to characteristics of the drug itself and the prescribers. During the observation period, lamotrigine diffused gradually towards more first-line use as an AED and more off-label use.

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers.

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.