Lamotrigine: A Review of its Pharmacological Properties and Clinical Efficacy in Epilepsy

Abstract

Synopsis Lamotrigine is an antiepileptic drug which is believed to suppress seizures by inhibiting the release of excitatory neurotransmitters. Efficacy has been demonstrated for lamotrigine as add-on therapy to existing regimens in patients with resistant partial seizures. Total seizure frequency was reduced by 17 to 59% compared with placebo, and 13 to 67% of patients experienced reductions of ⩾50% in seizure frequency. Secondarily generalised tonic-clonic seizures respond well to lamotrigine, and there is preliminary evidence of improvement in patients with primary generalised seizures, Lennox-Gastaut syndrome and in children with multiple seizure types. Seizure control has been maintained in patients who have continued to receive lamotrigine as monotherapy after discontinuation of other medications. Results of one trial suggest similar efficacy for lamotrigine monotherapy as for carbamazepine, but confirmation of its use in this setting awaits more extensive controlled comparisons with established agents. Adverse events associated with lamotrigine as add-on therapy are typical of antiepileptic drugs, namely dizziness, ataxia and other CNS-related symptoms. Rash, which has occurred in 10% of patients in placebo-controlled trials, may be severe and its appearance has led to discontinuation of therapy in 1% of patients. Lamotrigine appears well tolerated in the longer term, but this facet of its profile requires further monitoring. Influences of valproic acid and enzyme-inducing antiepileptics on lamotrigine elimination necessitate dosage modification of lamotrigine. Conversely, lamotrigine has little apparent influence on the pharmacokinetics of other agents, although it may increase plasma concentrations of the active metabolite of carbamazepine during concomitant administration. Thus, lamotrigine permits improved seizure control in some patients with refractory partial seizures, and may prove to be especially effective in secondarily generalised tonic-clonic seizures. As is usual at this stage in a drug’s development, several aspects of the profile of lamotrigine are incompletely defined, notably its efficacy in other seizure types, in children, as monotherapy, and its longer term tolerability. Nonetheless, lamotrigine presently offers a worthwhile alternative for the physician confronted with the challenge of treating patients with intractable partial seizures with or without secondarily generalised seizures, and shows potential for broader applications in other areas of epilepsy management. Pharmacodynamic Properties Lamotrigine probably exerts its anticonvulsant effects by blocking voltage-dependent sodium channels, thus stabilising the presynaptic membrane and preventing the release of excitatory neurotransmitters, predominantly glutamate. Its lack of activity at the N-methyl- d-aspartate (NMDA) receptor negates the possibility of phencyclidine-like central nervous system (CNS) effects occurring with its use. The profile of anticonvulsant activity of lamotrigine in animal studies resembles that of phenytoin and carbamazepine. Lamotrigine suppressed seizures induced in rodents by maximal electroshock and pentetrazol (pentylenetetrazol), suggesting activity against partial and generalised tonic-clonic seizures. The drug also decreased electrically evoked after-discharge duration in various animals, a further indication of activity in simple and complex partial seizures. Activity was demonstrated in the photically evoked after-discharge test, which is considered a model of the absence seizure, and some patients with this seizure type have responded to lamotrigine (see Clinical Efficacy). Single oral doses of lamotrigine 240mg have suppressed interictal epileptiform discharges recorded by electroencephalographic tracings in epileptic patients, but to a lesser extent than diazepam 20mg, and doses of lamotrigine 120 to 240mg reduced the photosensitivity range in patients with a photoconvulsive response. Effects on psychomotor function have been minimal in healthy volunteers administered single doses of lamotrigine 120 to 300mg, and were fewer than occurred with diazepam 10mg, phenytoin 1000mg or carbamazepine 400 and 600mg. Pharmacokinetic Properties Linear pharmacokinetics are demonstrable for lamotrigine over the dose range 50 to 400mg, with some recent reports indicating linearity up to 700mg in epileptic patients receiving concomitant enzyme-inducing antiepileptic drugs. Maximum plasma lamotrigine concentrations determined in kinetic studies in healthy subjects and patients with epilepsy were generally achieved within 1 to 3 hours of oral administration of doses in this range. Bioavailability of lamotrigine is calculated as approximately 98%, and apparent volume of distribution as 0.9 to 1.3 L/kg. Plasma protein binding is about 55%. Lamotrigine undergoes biotransformation by glucuronidation to a 2- N-glucuronide derivative, which accounts for approximately 75 to 90% of the amount recoverable in the urine after a single oral dose, and to a 5- N-glucuronide. Under steady-state conditions, 43 to 87% of an oral dose of lamotrigine was retrievable within 24 hours, 95% as the glucuronide metabolite and the remainder as parent drug. Total clearance is about 0.03 L/h/kg in healthy persons. The steady-state elimination half-life (t½) of lamotrigine in healthy young adults is approximately 25 to 30 hours. This value is halved in epileptic patients also receiving enzyme-inducing drugs such as carbamazepine and phenytoin, and doubled in the presence of valproic acid. Despite findings that the t½ of lamotrigine was lengthened in patients with Gilbert’s syndrome (asymptomatic unconjugated hyperbilirubinaemia), and in the elderly, t½ values nonetheless remained within the normal range. The pharmacokinetic profile of lamotrigine in children has not been well described, but elimination of the drug appears faster in these patients than in adults. Any relationship between plasma lamotrigine concentrations and therapeutic effect appears tenuous; therefore, dosage should be modified according to clinical response rather than to a defined therapeutic range. Clinical Efficacy Lamotrigine as add-on therapy suppresses seizures in patients with intractable partial epilepsy, with some improvement observed in at least 55 to 65% of trial participants. Data amassed from crossover placebo-controlled studies indicate that lamotrigine (75 to 400mg daily for 8 to 18 weeks) produced reductions in total seizure frequency of 17 to 59%, and decreases in seizure frequency of ⩾50%, in 13 to 67% of patients, relative to placebo. Efficacy persisted during treatment for 24 weeks with lamotrigine 500 mg/day, which was superior to 300 mg/day and placebo. Patients with secondarily generalised tonic-clonic seizures have responded at least as well as those with partial seizures. Preliminary evidence suggests potential for the combination of lamotrigine and vigabatrin. Although detailed longer term data are scarce, response to lamotrigine has been maintained for periods of up to 33 months in a few patients in noncomparative trials. In some patients, the addition of lamotrigine to the therapeutic regimen has facilitated withdrawal of all other antiepileptic medications, with several patients continuing on lamotrigine monotherapy for up to 4 years. An interim report found lamotrigine 100 and 200 mg/day monotherapy to be of comparable efficacy to carbamazepine 600 mg/day. Some evidence of improved quality of life and seizure severity during lamotrigine therapy is of interest, and further such investigations are awaited. Encouraging preliminary results have been obtained with lamotrigine as add-on therapy in children with multiple seizure types participating in small noncomparative trials, and in some patients with Lennox-Gastaut syndrome. Anecdotal evidence of efficacy exists for lamotrigine in patients with primary generalised seizures. Tolerability Most adverse events recorded during lamotrigine administration as add-on therapy are CNS-related, notably dizziness, diplopia, somnolence and ataxia. Rash, which may be severe and has led to discontinuation of lamotrigine in 1% of patients, has occurred in 2.3% of patients in non-comparative trials, and in 10% of lamotrigine recipients versus 5% of placebo groups in controlled comparisons. Rash leading to treatment withdrawal was less frequent with lamotrigine (1%) than carbamazepine (6%) in a comparative trial. Lamotrigine has been well tolerated in the longer term, although present evidence is limited, as are data regarding its tolerability profile in children. Drug Interactions Concomitant administration of lamotrigine does not appear to affect the pharmacokinetics of other antiepileptic drugs, although there is conflicting evidence regarding a possible influence on plasma concentrations of the active 10, 11-epoxide metabolite of carbamazepine. Hepatic enzyme-inducing drugs such as carbamazepine and phenytoin reduce the elimination t½ of lamotrigine by 50%; conversely, valproic acid doubles this parameter. These clinically important interactions require dosage adjustment of lamotrigine. The efficacy of oral contraceptives is not compromised by the concomitant use of lamotrigine. Dosage and Administration Dosage regimens of lamotrigine differ depending on whether patients are also receiving concomitant valproic acid, or enzyme-inducing drugs (e.g carbamazepine, phenytoin, phenobarbital, primidone). Dosage guidelines, obtained from clinical trials investigating the use of lamotrigine as add-on therapy in adults and children aged ⩾12 years with refractory partial epilepsy, can be found on page 172, as can guidelines for younger children. Preliminary evidence suggests that lamotrigine should be slowly initiated using dosage escalation to avoid the development of rash, and should be withdrawn slowly to prevent rebound seizures. © 1993, Adis International Limited. All rights reserved.