Safety review of adult clinical trial experience with lamotrigine.

To date approximately 4000 adults > 12 years of age have been treated with lamotrigine in Glaxo Wellcome sponsored clinical trials. Review of the data from these trials shows lamotrigine to be effective and well tolerated in both add-on and monotherapy treatment. Safety of lamotrigine was comparable to that of other anticonvulsants in add-on controlled clinical trials. In addition, fewer than half the number of patients in monotherapy studies who were taking lamotrigine discontinued treatment because of adverse events compared to those taking carbamazepine and phenytoin. Most of the reported adverse events seen in lamotrigine treated patients in all studies were judged by the investigator to be mild or moderate in severity; few of the adverse events resulted in the withdrawal of patients from studies. Analysis of vital signs and clinical laboratory data have revealed no undesirable effect of lamotrigine on major systems of the body. The most concerning adverse event has been rash. In clinical trials, this has most often been limited to a simple morbilliform rash which is not associated with evidence of systemic involvement. The incidence of Stevens-Johnson syndrome (SJS) in clinical trials is approximately 1 in 1000. Rash associated with lamotrigine has typically occurred within the first 8 weeks of treatment. Data from clinical trials clearly point to exceeding currently recommended dosage guidelines of lamotrigine and co-administration of valproic acid (valproate sodium) as risk factors for rash. Early in 1997, Glaxo Wellcome strengthened existing warnings in the product label regarding the risk of rash and reinforced the importance of adherence to administration guidelines in an effort to reduce the incidence of rash.

Clinical experience with lamotrigine monotherapy in adults with newly diagnosed epilepsy: a review of published randomised clinical trials.

OBJECTIVES: This paper aimed to provide an overview from published randomised clinical trials of the efficacy and tolerability of lamotrigine monotherapy compared with carbamazepine and phenytoin when initiated in adult patients with newly diagnosed epilepsy. DESIGN: The review included two double-blind, randomised trials of lamotrigine monotherapy compared with carbamazepine and phenytoin, respectively, and one open randomised trial comparing lamotrigine with carbamazepine. The results of the three trials were pooled for comparison of tolerability. SETTING: Multicentre in Europe. PATIENTS: Adult patients (>12 years of age) with newly diagnosed partial seizures (with or without secondary generalisation) and primary generalised tonic-clonic seizures (n = 443 patients on lamotrigine, n = 246 on carbamazepine, n = 95 on phenytoin). RESULTS: Comparable efficacy was demonstrated between lamotrigine and both carbamazepine or phenytoin. The time to withdrawal survival analysis supported a significant difference in favour of lamotrigine [hazard ratio 1.57 (95% CI 1.07 to 2.31)] in the double-blind trial. Overall, twice the proportion of patients withdrew from carbamazepine or phenytoin because of adverse events (19.1 and 18.9%, respectively) compared with lamotrigine (9.5%). Lamotrigine was particularly well tolerated with regard to adverse effects affecting the central nervous system. Rash was the most common adverse event necessitating discontinuation of each drug, the rates being very similar across treatment groups (6.1% on lamotrigine, 8.9% on carbamazepine, 5.3% on phenytoin). The rate of rash resulting in withdrawal of lamotrigine was clearly related to the dose escalation employed in the different trials during the first month of therapy. CONCLUSIONS: Lamotrigine is an effective monotherapy treatment for adult patients with newly diagnosed epilepsy, and is better tolerated than either carbamazepine or phenytoin monotherapy. The incidence of rash requiring withdrawal of lamotrigine is related to dose escalation (2.2% of patients withdrawing when the recommended escalation was followed).

Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. Lamictal Lennox-Gastaut Study Group.

BACKGROUND: The Lennox-Gastaut syndrome, a severe form of epilepsy that usually begins in early childhood, is difficult to treat. Dose-related drug toxicity is common. METHODS: We conducted a double-blind, placebo-controlled trial of the antiepileptic drug lamotrigine in patients with the Lennox-Gastaut syndrome. Eligible patients had more than one type of predominantly generalized seizure, including tonic-clonic, atonic, tonic, and major myoclonic, and had seizures on average at least every other day. After a 4-week base-line period in which all participants received placebo, we randomly assigned 169 patients (age range, 3 to 25 years) to 16 weeks of lamotrigine (n= 79) or placebo (n=90) in addition to their other antiepileptic drugs. RESULTS: The median frequency of all major seizures changed from base-line levels of 16.4 and 13.5 per week in the lamotrigine and placebo groups, respectively, to 9.9 and 14.2 per week after 16 weeks of treatment (P=0.002). Thirty-three percent of the patients in the lamotrigine group and 16 percent of those in the placebo group had a reduction of at least 50 percent in the frequency of seizures (P= 0.01). There were no significant differences between groups in the incidence of adverse events, except for colds or viral illnesses, which was more common in the lamotrigine group (P=0.05). CONCLUSIONS: Lamotrigine was an effective and well-tolerated treatment for seizures associated with the Lennox-Gastaut syndrome.

Long-term safety and efficacy of lamotrigine (Lamictal) in paediatric patients with epilepsy.

This study was initiated to evaluate the long-term safety, tolerability and effect on seizure control of lamotrigine (Lamictal) in paediatric patients with epilepsy. A total of 155 children (aged 2-19 years) with treatment-resistant epilepsy received add-on therapy or monotherapy lamotrigine for up to four years. Patients had already experienced benefit from lamotrigine treatment in an open one-year study before entering this open continuation study of up to three additional years of treatment. Overall, including both these studies, patients were treated with lamotrigine for 53-221 weeks, representing 417.9 patient-years of experience. The physician's global assessment of seizure control compared to the three-month period before lamotrigine treatment, indicated that seizure control was generally maintained during long-term lamotrigine treatment for up to four years. For 19 patients, the investigator recorded a subjective improvement in behaviour, alertness, seizure severity, quality of life and mobility with lamotrigine treatment, sometimes independent of seizure control. In total, 34 patients received lamotrigine monotherapy; 22 of these were maintained on lamotrigine monotherapy for at least one year. Lamotrigine was well tolerated. The majority of adverse experiences were classified by the physician as being mild in intensity and only six patients (4%) withdrew from the study due to adverse experiences.

Pituitary corticotrope tumor (AtT20) cells as a model system for the study of early inhibition by glucocorticoids.

The utility of the established ACTH secreting mouse pituitary tumor cell line AtT20 for investigating early glucocorticoid inhibition was examined. Three different strains of the cell line D1, D16v, and D16:16, respectively, were analyzed. In initial studies CRF and phorbol esters were used as secretagogues to examine the properties of hormone secretion. In a perifusion system (cells in suspension) D1 cells failed to respond to the secretagogues, whereas both D16v and D16:16 cells were responsive. However, hormone release declined upon repeated exposure to secretagogue in both D16v and D16:16 cells and similar data were obtained when cells adhering to cover slips were perifused. In static incubation D16:16 cells gave more consistent results especially with respect to inhibition by glucocorticoids and were used in all subsequent studies. Synthetic glucocorticoids acting through the type II receptor inhibited CRF-induced ACTH release within 45 min; at 120 min, stimulated release was strongly (80-90%) suppressed. In contrast, no consistent inhibition by corticosterone could be found. In the presence of glycyrrhetinic acid, an inhibitor of 11 beta-hydroxysteroid dehydrogenase, a high concentration of corticosterone (10 microM) did produce a slight inhibition of ACTH release. Dexamethasone also inhibited ACTH release induced by the calcium channel activator compound (+)202-791. The accumulation of cAMP in response to CRF was not altered by dexamethasone. The inhibitory effect of synthetic glucocorticoids on ACTH release was prevented by blockers of messenger RNA (actinomycin D, dichlorobenzimidazole ribofuranoside) or protein (puromycin) biosynthesis, indicating the induction of new proteins. Immunoblotting for lipocortin I (annexin I) and chromogranin A revealed no induction by dexamethasone of any of these proteins in D16:16 cells. Messenger RNA encoding lipocortin I was not detectable and was not induced by treatment with dexamethasone in D16:16 cells. These data show that the AtT20 D16:16 strain is a useful model for early glucocorticoid action, which is mediated by type II receptors and involves the induction of new protein(s). Notably, induction of lipocortin I messenger RNA or protein could not be detected at a time when the inhibitory effect of glucocorticoids on stimulated hormone secretion was maximal.