Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 150
Lamotrigine
Torbjörn Tomson
Linda J. Stephen
Martin J. Brodie
Introduction
Lamotrigine, a phenyltriazine derivative, has been available globally as an antiepileptic drug (AED) for more than 15 years. The drug was initially synthesized as one of a sequence of folic acid antagonists following the suggestion that antifolate drugs may have antiepileptic properties. Although this theory was subsequently discredited, lamotrigine was discovered to have multiple mechanisms of action that may account for its broad spectrum of activity.62 Following regulatory studies during the 1980s and 1990s, lamotrigine became available as an adjunctive agent for the treatment of partial and primary and secondary generalized seizures in adults. More recently, it has been used in children, in patients with the Lennox-Gastaut syndrome (LGS), and as monotherapy in newly diagnosed epilepsy.121
Chemical structure, formulations, and methods for determination in body fluids
Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-tria-zine) (Fig. 1) is synthesized by reacting thionyl chloride with 2,3-dichlorobenzoic acid to make an acid chloride derivative, which is converted to the corresponding ketonitrile in the presence of cuprous cyanide.34 When the ketonitrile is condensed with aminoguanidine under strongly acidic conditions, the resulting amidinohydrazone compound is cyclized in basic conditions to produce lamotrigine. The drug is poorly soluble in water and ethanol, and has a molecular weight of 256.09 and a pKa of 5.5.
Lamotrigine is available as Lamictal (GlaxoSmithKline) in 25-, 50-, 100-, and 200-mg tablets, and as dispersible chewable tablets in 2-, 5-, 25-, and 100-mg doses.66 No difference has been shown in bioequivalency between the two formulations. A number of generic preparations are available. The drug can be measured in serum or plasma by high-performance liquid chromatography27,39 and by immunofluorometric assay.102
Pharmacology
Seizure Models
The anticonvulsant activity of lamotrigine has been demonstrated in models of different seizure types. Positive results have been obtained with maximal electroshock (MES) and pentylenetetrazole-induced tonic seizures, which are thought to be models of partial and generalized tonic–clonic seizures.82,120 The drug abolished hind limb extension in the MES model at an oral mean effective dose (ED50) of 2.6 mg/kg in the mouse and 1.9 mg/kg in the rat.81 The ED50 was smaller and the therapeutic index and duration of action greater than those of phenyt-oin, carbamazepine, sodium valproate and diazepam. Similar ED50 values were obtained in maximal seizure tests with pic-rotoxin and bicuculline but, like phenytoin and in contrast to ethosuximide and valproate, lamotrigine had no effect on leptazol threshold64 or on clonus latency after leptazol,81 suggesting lack of efficacy against absence seizures. The drug was ineffective in the genetic absence epilepsy rat from Strasbourg, although it did not aggravate spike-and-wave discharges, unlike some other antiepileptic drugs.33 Lamotrigine yielded positive results in the lethargic mouse model of absence epilepsy.57 As with valproate and ethosuximide, lamotrigine inhibited visually evoked afterdischarges in the rat, which may also be interpreted to suggest efficacy against absence seizures.65 Lamo-trigine delayed the development of electrical kindling and modified seizures, but failed to prevent subclinical afterdischarges during the kindling process in the rat.89
Mechanisms of Action
Lamotrigine acts by use- and voltage-dependent blockade of neuronal voltage-activated sodium (Na+) channels124 in a similar way to carbamazepine and phenytoin.67
Waldmeier et al. found that lamotrigine attenuated veratrine-induced glutamate, γ-aminobutyric acid (GABA), and dopamine release in rat brain slices, but much less potently inhibited electrical stimulation–induced GABA and dopamine release.118 The drug also inhibited electrical stimulation–induced release of serotonin, acetylcholine and, to a lesser extent, noradrenaline. Leach et al. reported that lamotrigine inhibited veratrine-induced glutamate and aspartate release, but less potently inhibited GABA and acetylcholine release.68
Lamotrigine also has effects on other ion channels.117,119 In rodents, the drug modulated transient potassium outward currents in CA1 pyramidal cells,52 and inhibited cortical and striatal voltage-activated calcium currents.111 Some studies have suggested that lamotrigine may have selective neuroprotective effects. Hippocampal neuronal loss and optic nerve axonopathy were reduced by the drug in rats.31 Lamotrigine was also neuroprotective in gerbil107 and pig29 models of global ischaemia.
Clinical pharmacokinetics
Lamotrigine is rapidly absorbed after oral administration. The peak plasma concentration is achieved in 1 to 3 hours, and increases linearly with dosage (Table 1).28 Bioavailability is almost 100%. The weight-normalized volume of distribution after intravenous administration and the weight-normalized apparent volume of distribution after oral administration vary between 0.9 to 1.5 L/kg.28 Protein binding is approximately 55%.43 Salivary concentrations appear to be similar to free plasma concentrations.114
FIGURE 1. Structure of lamotrigine
Table 1 Pharmacokinetic properties of lamotrigine
Parameter Mean ± SD
Cmax (mg/L) 1.6 ± 1.3 (120 mg dose)
tmax (hours) 2.8 ± 1.3
F (%) 98 ± 5
Plasma protein binding (%) 55
Fe (%) 70
Vd/F (L/kg) 1.2 ± 0.1
CL/F (L/h) 2.5 ± 0.6
T1/2β (h) 24 ± 6
Cmax, peak plasma concentration; tmax, time to cmax; F, absolute bioavailability; Fe, fractional urinary excretion; Vd/F, apparent volume of distribution; CL/F, apparent oral clearance; T1/2β, plasma elimination half life.
Lamotrigine undergoes linear pharmacokinetics, with an elimination half-life varying between 24 and 35 hours.28
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The drug is metabolized primarily by hepatic glucuronidation catalyzed by a number of different isoforms of UDP-glucuronosyltransferase converting lamotrigine to N-2- and N-5-glucuronides (80% and 10%, respectively) and other minor N-oxide metabolites.28 The metabolites are almost entirely excreted in the urine, with 94% of radiolabeled lamotrigine being recovered in this way and 2% being found in the faeces.35 There is conflicting evidence as to whether the drug induces its own metabolism.58 As would be expected, the drug passes freely into breast milk.90
Lamotrigine’s clearance is reduced in patients with unconjugated hyperbilirubinemia (Gilbert syndrome96) and in severe hepatic cirrhosis,74 but not in end-stage renal failure.42 There is little difference in lamotrigine pharmacokinetics in the elderly compared with younger adults.58 In children, oral clearance and volume of distribution are greater, but half life is similar to corresponding values in adults.25 Limited data available for different races suggests that clearance may be lower in Asians.34
Concentration–Effect Relationships
A variety of reports have been published regarding the relationship between lamotrigine dose and circulating plasma concentration. Of six large scale clinical trials, only two demonstrated a significant relationship between plasma concentration and efficacy.70,104 Loiseau et al. found lamotrigine concentrations ranged from 0.3 to 4.9 mg/L on 150 to 300 mg/day.70 Schapel et al. documented concentrations ranging from 0.66 to 4.65 mg/L in patients taking 150 or 300 mg daily.104 Of the four studies that found no clinically statistical relationship,60,80,99,110 Jawad et al. reported that 75 to 400 mg lamotrigine produced trough plasma concentrations of between 1.5 and 2.5 mg/L.60 Using 200 to 400 mg lamotrigine daily, Smith et al. achieved mean plasma levels of 2.2 to 2.4 mg/L.110 Messenheimer et al. achieved mean steady-state concentrations of 1.6 mg/L on 200 mg/day and 2.9 mg/L on 400 mg/day.80 Concentrations of 3.8 mg/L on 200 mg and 2.06 mg/L on 100 mg were reported by Reunanen et al. when la-motrigine was used as monotherapy.99
Kilpatrick et al.63 found widely varying lamotrigine doses in patients who were seizure-free (median dose 200 mg, range 25–850 mg; median concentration 3.8 mg/L, range 1.4–8.7 mg/L) and in those reporting side effects (median dose 300 mg, range 100–900 mg; median concentration 4.0 mg/L, range 0.4–18.5 mg/L). These results are partly at odds with those from Hirsch et al.,55 who reported a significant relationship between increasing lamotrigine concentrations and toxicity. With concentrations of less than 0.5 mg/L, 7% of patients reported side-effects; with 5 to 10 mg/L, 14%; with 15 to 20 mg/L, 34%; and with greater than 20 mg/L, 59%. Increasing efficacy occurred with concentrations up to and exceeding 20 mg/L. A target range of 1.5 to 10 mg/L was recommended. Another study retrospectively examined the relationship between plasma lamo-trigine concentrations and dosage and concluded that a therapeutic range of 3 to 14 mg/L was realistic, although hardly precise.85
Chong and Dupuis argued that, although the majority of studies did not demonstrate a clear relationship between lamotrigine concentration and pharmacologic response, many of these were methodologically flawed.26 They concluded that clinical end-points rather than plasma concentrations remain the most important guide for lamotrigine therapy. Certain special populations exist, however, in which obtaining a circulating concentration may be useful. These include patients in whom poor drug adherence is suspected and those with renal or hepatic failure.55 Because lamotrigine concentrations are decreased markedly during pregnancy,93,94 and dose adjustments are frequently needed under these circumstances to control seizures,115 therapeutic drug monitoring has benefit in pregnant women with poor seizure control or symptoms of drug toxicity. The ethinylestradiol component of oral contraceptives can reduce circulating lamotrigine concentration by up to 50%.98,101 Women taking the combined oral contraceptive pill could, therefore, also be candidates for lamotrigine measurement.
Clinical efficacy
The clinical effects of lamotrigine have been investigated in a wide range of seizure and epilepsy types in children and adults, in previously untreated patients, as well as in those with refractory epilepsy.
Partial Seizures and Localization-Related Syndromes
A series of randomized, double-blind, placebo-controlled studies have assessed the effectiveness of lamotrigine as add-on therapy in patients with refractory partial epilepsy. Three studies in adults77,80,104 and one in children36 met the Class I criteria in the American Academy of Neurology assessment of new AEDs.46 In the largest, 191 patients taking enzyme-inducing AEDs were randomized to placebo, or lamotrigine 300 mg/day or 500 mg/day.75 The responder rate (that proportion of patients with at least 50% seizure reduction from baseline) was 18% on placebo, 20% on lamotrigine 300 mg/day, and 34% on lamotrigine 500 mg/day. In a second study, 88 adult patients taking enzyme-inducing drugs were randomized in a cross-over design to placebo or lamotrigine 400 mg/day.80 The
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responder rate with lamotrigine was 20% compared with 0% with placebo. The third study included only 41 patients on enzyme-inducers and or valproic acid randomized in a cross-over design to placebo or lamotrigine 300 mg/day (150 mg/day if on valproic acid).104 The responder rate on lamotrigine was 22%, and 0% on placebo.
In a meta-analysis, Ramaratnam et al.97 included eight additional randomized trials—two cross-over and six parallel studies.10,14,60,70,99,103,106,110 A total of 1,243 patients (1,044 adults and 199 children) were included in this analysis of la-motrigine add-on for drug-resistant partial epilepsy. The overall odds ratio versus placebo for 50% or greater reduction in seizure frequency was 2.71 (95% confidence interval [CI] 1.87–3.91), demonstrating the efficacy of lamotrigine in this patient population. The odds ratio for treatment withdrawal in the same meta-analysis was 1.12 (95%; CI,0.78–1.61), indicating that patients were not more likely to discontinue lamotrigine than placebo.97 One of these studies evaluated lamotrigine as add-on treatment in children with refractory partial epilepsy.36 In this double-blind parallel group study, 199 children aged 2 to 16 years were randomized to placebo or lamotrigine (2.7–12.9 mg/kg/day). The responder rate was 45% with lamotri-gine and 25% with placebo, whereas the discontinuation rates were similar in the two groups, 5% and 6%, respectively.
One randomized double-blind study assessed lamotrigine as monotherapy in adults and adolescents with refractory partial epilepsy.50 Overall, 156 patients with different baseline medications were randomized to receive lamotrigine 500 mg/day or a low dose of valproic acid (1,000 mg/day). Baseline medication was gradually withdrawn, aiming at monotherapy with lamo-trigine or valproic acid. More patients on lamotrigine (56%) compared to valproic acid (20%) were successfully maintained on monotherapy. Although this regulatory trial demonstrated the effect of lamotrigine as monotherapy in refractory partial epilepsy, it is difficult to translate the results into clinical practice.
Lamotrigine has also been assessed as monotherapy in new-onset partial epilepsy in adults. Three randomized double-blind parallel group studies met American Academy of Neurology Class I criteria.45 The first study18 randomized adult patients with partial seizures (n = 146) or primary generalized tonic–clonic seizures (n = 122) to lamotrigine (initial target dose 150 mg/day) or carbamazepine (initial target dose 600 mg/day). Of patients with partial seizures, 22% on lamotrigine and 31% on carbamazepine remained seizure-free during the last 40 weeks of treatment, compared to 35% and 37%, respectively, during the last 24 weeks. Retention was presented for partial and generalized seizure patients together. More lamotrigine (65%) than carbamazepine (51%) recipients completed the study. This difference was due to fewer withdrawals because of adverse events on lamotrigine.
Steiner et al.112 randomized 90 patients with partial and 91 with primary generalized tonic–clonic seizures to lamotri-gine (modal dose 150 mg/day) or phenytoin (modal dose 300 mg/day). Of those with partial seizures only randomized to lamotrigine, 16% remained on treatment and were seizure-free during the last 40 weeks of the study, compared with 22% on carbamazepine. Corresponding figures for the last 24 weeks were 41% and 48%, respectively. These differences were not statistically significant, nor was there a significant difference between the drugs in time to discontinuation from the trial.
In a third study, 150 elderly (65 years and older) patients with newly diagnosed epilepsy were randomized in a 2:1 ratio to lamotrigine (median dose 100 mg/day) or carbamazepine (median dose 400 mg/day).17 Although a proportion was classified as having idiopathic generalized epilepsy, the vast majority of patients had partial seizures. Significantly more patients continued on treatment with lamotrigine than on carbamazepine, 71% versus 42%. This was largely explained by a higher dropout rate due to adverse events on carbamazepine (42%) compared with lamotrigine (18%).
Lamotrigine has been assessed in an additional comparative study of new-onset partial epilepsy in older people.100 In this double-blind, parallel group study, 593 patients aged 60 years or older were randomized to gabapentin (target dose 1,500 mg/day), lamotrigine (target dose 150 mg/day), or carbamazepine (standard tablets, target dose 600 mg/day). Although epilepsy was of new onset, 43% of the patients were already taking AEDs, which were tapered to zero during titration of the study medication. The primary outcome measure was retention in the trial for 12 months. Early termination, largely due to adverse events, was significantly more common with carbamazepine (65%) than with lamotrigine (44%) or gabapentin (51%). Seizure-free rates at 12 months were similar across treatment groups.
Lamotrigine has also been compared with gabapentin in adults with newly diagnosed partial or primary generalized tonic–clonic seizures.16 In this double-blind, parallel group study, 309 patients were randomized to gabapentin (flexible dosage from 1,200 to 3,600 mg/day) or lamotrigine (100 to 300 mg/day). There was no difference in the primary end-point, time to exit, or in the proportion of patients completing the 24-week maintenance phase—72% on gabapentin and 67% on lamotrigine. Of those completing, 76% taking gabapentin or lamotrigine remained seizure free during the last 12 weeks of the trial.
Two additional open randomized studies compared the efficacy of lamotrigine and carbamazepine in newly diagnosed partial epilepsy88 or partial and/or generalized tonic–clonic seizures,99 both supporting the view that the two drugs are equally effective, although lamotrigine may be better tolerated. It should, however, be noted that the controlled-release formulation of carbamazepine has not been used in any of the comparative trials, and that the statistical power to detect differences in efficacy has been low.
The only sizeable data from randomized trials on children with newly diagnosed partial epilepsy come from the open comparison with carbamazepine.88 This study included 233 patients aged 2 to 12 years, of whom 158 were randomized to lamotrigine (2–15 mg/kg/day) and 75 to carbamazepine (5–40 mg/kg/day). Of those with data for at least 18 weeks, 66% on lamotrigine were seizure-free for the last 16 weeks, which was not statistically different from the 75% on carbamazepine.
Generalized Tonic–Clonic Seizures
Two of the Class I studies of lamotrigine in newly diagnosed epilepsy included subgroups of adult patients with primary generalized tonic–clonic seizures.18,112 In the study by Brodie et al.,18 37% of the 60 patients randomized to lamotrigine remained seizure free during the last 40 weeks, compared with 35% among the 62 assigned to carbamazepine. The corresponding numbers for the last 24 weeks were 47% for both treatment groups. In the study by Steiner et al.,112 42 patients with primary generalized tonic–clonic seizures were randomized to lamotrigine and 49 to carbamazepine. Of those taking lamotrigine, 30% were seizure-free and remaining on treatment during the last 40 weeks, compared with 32% on phenytoin. Corresponding figures for the last 24 weeks were 44% and 34%, respectively, which did not significantly differ.
Lamotrigine has also recently been assessed as add–on treatment in patients with refractory primary generalized tonic-clonic seizures.13 In this double-blind, parallel group study, 121 patients aged 2 to 55 years (23 were 2–12 years of age) were randomized to adjunctive treatment with lamotrigine or placebo. The median percent reduction in frequency of generalized tonic–clonic seizures from baseline (primary efficacy endpoint)
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was 67% with lamotrigine and 33% with placebo. The study included 33 patients who had myoclonic in addition to tonic–clonic seizures. Although not designed to assess effects on seizure types other than tonic–clonic, there was no evidence of deterioration in other seizure types with lamotrigine.
Idiopathic Generalized Epilepsy Syndromes
One double-blind study assessed the short-term effects of la-motrigine in children with newly diagnosed typical absence seizures.44 It enrolled 45 patients into an open-label dose escalation phase of lamotrigine. Responders (n = 28) entered a 4-week double-blind, placebo-controlled comparison in which they were randomized either to continue lamotrigine or be weaned onto placebo. The proportion of patients remaining seizure free during the double-blind treatment phase was greater for lamotrigine (62%) compared to placebo (21%). There are no randomized trials of lamotrigine in juvenile myoclonic epilepsy (JME). Some case series and open uncontrolled studies indicate that the drug may be effective and that some patients can be switched successfully from valproic acid to lamotrigine.20,48,84 There are, however, also reports of exacerbations in myoclonic seizures with lamotrigine.30
Lennox-Gastaut Syndrome
Adjunctive lamotrigine has been shown to significantly reduce the frequency of major seizures in a double-blind, placebo-controlled study of children with LGS.87 In this parallel group study, 169 patients were randomized to treatment with lamo-trigine or placebo. The median frequency of all major seizures changed from 16.4 during baseline to 9.9 per week during lamotrigine treatment, and from 13.5 to 14.2 in the placebo group. Among patients receiving lamotrigine, 33% demonstrated at least a 50% reduction on seizures compared to 16% in the placebo group. Lamotrigine was assessed as add-on in 20 children with LGS and 10 with other therapy-resistant generalized epilepsy syndromes.38 The 17 responding during open-phase treatment with lamotrigine went into a randomized, double-blind, placebo-controlled, cross-over study, 60% of whom demonstrated at least 50% reduction in seizure frequency.
Indications Other Than Epilepsy
Lamotrigine has been investigated as a mood stabilizer in bipolar disorders. Lamotrigine 50 mg/day or 200 mg/day was significantly more effective than placebo in improving depressive symptoms in a short-term, randomized, double-blind, controlled study of bipolar depression.21 Lamotrigine, 50 to 400 mg/day, was also more effective than placebo in a 26-week, randomized, controlled study in the prophylaxis of rapid-cycling bipolar disorders.22 A small cross-over study compared lamotrigine, gabapentin, and placebo in rapid-cycling bipolar patients resistant to other mood stabilizers.47 Lamotrigine, but not gabapentin, was superior to placebo in this study. A larger randomized, double-blind, parallel group study compared lamotrigine (100–400 mg/day), lithium, and placebo in the long-term treatment of patients with bipolar I disorder with recent manic or hypomanic episodes.15 In this study, lamotri-gine was particularly effective in the prevention of depressive episodes.
At a dose of 400 mg/day, lamotrigine was superior to placebo as add-on treatment in patients with refractory trigeminal neuralgia,126 but randomized monotherapy studies are lacking. The effects of lamotrigine have also been studied in other pain syndromes. Although a randomized, placebo-controlled, double-blind study failed to show an effect of la-motrigine, 200 mg/day, in a mixed population of neuropathic pain syndromes77 the same dosage was superior to placebo in the treatment of post-stroke pain in another randomized controlled trial.116 Lamotrigine, 300 mg/day, also significantly reduced pain scores in a placebo-controlled, double-blind study of neuropathic pain in HIV patients.109 The only double-blind, placebo-controlled study in the prophylaxis of migraine failed to demonstrate efficacy with 200 mg lamotrigine daily.113
Adverse effects
Dose-Related, Nonidiosyncratic Adverse Effects
The most common dose-related adverse effects affect the central nervous system. Headache, asthenia, nausea, sleepiness/somnolence/drowsiness, and dizziness are the most frequently reported symptoms in monotherapy trials of lamotrigine.18,99,112 However, drowsiness was less common in patients on lamotrigine monotherapy (100–300 mg daily) than among those on carbamazepine (300–1,400 mg daily, non–controlled release tablets)18,99 or on phenytoin (300–600 mg daily).112 Fewer patients on lamotrigine (15%) than on carbamazepine (27%) withdrew because of adverse effects in the randomized comparative monotherapy study.112 A similar difference was reported in an open study comparing fixed dosages of lamotrigine (100 or 200 mg/day) and carbamazepine (600 mg/day). The withdrawal rate due to adverse events was 4.3% to 4.5% with lamotrigine, and 10.3% for patients on carbamazepine,99 whereas there was no difference between lamotrigine and phenytoin in discontinuation because of adverse events in a double-blind randomized trial.112 A double-blind comparison between lamotrigine and carbamazepine in 150 elderly patients with new-onset epilepsy also reported a lower dropout rate due to adverse events with lamotrigine compared with carbamazepine, 18% versus 42%.17
In another comparative study of new-onset epilepsy in senior citizens, 12.1% taking lamotrigine terminated the study due to adverse events compared with 21.6% on gabapentin and 31% on carbamazepine.17 It should be noted that standard carbamazepine tablets rather than controlled-release formulations were used in all these comparative trials. Nevertheless, the results indicate that lamotrigine is comparatively well tolerated in these patient populations. A systematic Cochrane review of lamotrigine as add-on for drug-resistant partial epilepsy included three parallel and eight cross-over, randomized, add-on trials.97 In this meta-analysis, ataxia, dizziness, diplopia, and nausea were more likely to occur with lamotrigine compared to placebo, whereas odds ratios for fatigue and somnolence included unity.
Cross-sectional and short-term studies indicate that there are no major adverse effects of lamotrigine on endocrine function, body weight, or bone mineralization.12,59,91
Idiosyncratic Reactions
Skin rash has been the most concerning adverse effect of la-motrigine leading to withdrawal in 6.1% of adult patients in the early monotherapy trials,78 which, however, should be compared to withdrawal rates due to rash of 8.9% for carbamazepine and 5.3% for phenytoin in the same trials. In a review of all clinical trials including 3,348 adult patients
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and 1,096 children (<16 years of age) exposed to lamotrigine, the incidence of rash was 10.7% among adults and 12.6% in children.79 Rashes were generally mild, often morbilliform in appearance, with onset usually within the first 2 to 3 weeks. However, serious skin reactions, such as anticonvulsant hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), can occur.6,53 Rash has been the single most frequently reported serious adverse event in both add-on and monotherapy trials of lamotrigine.79 In the randomized trials, 3.5% of adults and 4.7% of children discontinued lamotrigine because of rash. Possible SJS or hospitalization for rash occurred in 0.3% of adults and 1.0% of children.53
The risk of SJS and TEN in relation to exposure to AEDs has recently been assessed using the German Registry for Serious Cutaneous Reactions.83 Fifteen cases of SJS or TEN among lamotrigine users were reported during the period 1998 to 2001, all but one occurring within the first 63 days of starting treatment. The incidence per 10,000 person-years of use, based on sales data of defined daily doses in Germany, was 1.8 for lamotrigine compared to 0.5 for carbamazepine, 1.3 for phenobarbital, 1.2 for phenytoin, and 0.1 for valproic acid.83 However, when an attempt was made to estimate the risk of SJS/TEN in new users of AEDs, the assumed incidence was 3.8 per 10,000 for lamotrigine, 1.5 for carbamazepine, 8.2 for phenobarbital, 6.9 for phenytoin, and 0.5 for valproic acid.83
The risk of severe rash appears to be higher in the pediatric population than among adults.79 Comedication with valproic acid, high starting doses, and rapid dose-escalations have been identified as additional risk factors.6,53,78 The highest incidence (19.5%) of all types of rash occurred when lamotrigine was combined with valproic acid in the absence of other AEDs, whereas the lowest incidence (6.7%) occurred in combination with enzyme-inducers. Severe rash associated with hospitalization was also more common when lamotrigine was combined with valproic acid.78 Previous allergy to another antiepileptic drug, particularly carbamazepine, has been found to predict the risk of rash with lamotrigine.9
Other serious idiosyncratic adverse effects of lamotrigine are rare but have included a few cases of multiorgan failure with disseminated intravascular coagulation.24,72,73,105
At least 12 cases of serious liver toxicity induced by la-motrigine have been reported, five of which resulted in death.73 A British prescription-event monitoring study of 11,316 patients, however, confirmed that such serious adverse events are rare. Only two cases of disseminated intravascular coagulation, four cases of neutropenia, and three cases of thrombocytopenia were identified.71
A potential association between the use of lamotrigine and the occurrence of sudden unexplained death in epilepsy (SUDEP) was discussed during the clinical development of the drug. However, the SUDEP rate in epilepsy patients exposed to lamotrigine in clinical trials was not found to be higher than expected in patients with severe epilepsy.69 A postmarketing surveillance study reported similar SUDEP rates for those exposed to lamotrigine and gabapentin.123
Additional Safety Issues
Among the newer-generation drugs, lamotrigine has by far the most extensive documentation with respect to use in pregnancy and teratogenic outcome. The manufacturer, GlaxoSmithKline, set up an international lamotrigine pregnancy registry in 1992. The outcome of prospective pregnancies with first-trimester exposure to lamotrigine was recently summarized.32 There were 12 outcomes with major malformations among 414 pregnancies with lamotrigine monotherapy, yielding a malformation rate of 2.9% (95% CI, 1.6%–5.1%). Among 88 first-trimester exposures to lamotrigine in combination with valproic acid, 11 outcomes were noted with major birth defects (12.5%; 95%; CI,6.7%–21.7%), an apparently higher rate than in association with lamotrigine in other combinations (n = 182, 2.7%, 95%; CI,1.0%–6.6%).
The UK Epilepsy and Pregnancy Register86 reported a rate of major congenital malformations of 3.2% (95%; CI,2.1%–4.9%) among 647 prospective pregnancies with lamotri-gine monotherapy, similar to the 2.2% (95%; CI,1.4%–3.4%, n = 900) with carbamazepine, whereas the malformation rate associated with valproic acid monotherapy in the same study was 6.2% (95%; CI,4.6%–8.2%, n = 715). A positive dose-response relationship was noted with lamotrigine, as with valproic acid and carbamazepine, with a malformation rate of 5.4% (95%; CI,3.3–8.7%) for daily lamotrigine doses exceeding 200 mg. The malformation rate for pregnancies exposed to lamotrigine in combination with valproic acid was 9.6% (95%; CI,5.7–15.7%, n = 141).
In the North American pregnancy registry, 15 of 564 infants born to women taking lamotrigine in the first trimester had major malformations, 2.7% (95% CI 1.5%–4.3%), the relative risk (RR) compared with background rate was 1.7 (95% CI 1.0–2.7). Five of those exposed to lamotrigine had oral clefts, considerably higher than expected from the background rate, RR 32.8 (95% CI 10.6–101.3).56
Seizure Aggravation
Although lamotrigine is effective in the treatment of idiopathic generalized epilepsies (IGEs), reports of seizure aggravation also exist. Lamotrigine has been shown to worsen seizures in severe myoclonic epilepsy.54 It has also been associated with exacerbation, de novo myoclonus, and myo-clonic status in patients with IGEs including JME, juvenile absence epilepsy, and IGE with isolated generalized tonic–clonic seizures.11,23,30
Drug interactions
Pharmacokinetic Interactions
Enzyme-inducing AEDs, such as phenobarbital, primidone, phenytoin, and carbamazepine enhance lamotrigine clearance and lead to reduced steady-state concentrations and shortened half-life, sometimes resulting in the need for dose adjustments.2,5
Oxcarbazepine, methsuximide, and possibly topiramate can also induce the metabolism of lamotrigine.8,76,122 Among non-AEDs, rifampicin reduces lamotrigine concentrations.37 Likewise, oral contraceptives induce lamotrigine metabolism, reducing steady-state concentrations by 40% to 65%.101,108 This effect appears to be associated with the ethinylestradiol component, whereas progesterone-only contraceptives do not seem to affect lamotrigine plasma concentrations.98 The de-induction of lamotrigine metabolism is fairly rapid. As a consequence, lamotrigine plasma concentrations become twofold higher during the pill-free week with use of sequential oral contraceptives.108
Table 2 Lamotrigine dosing and titration schedules
As add-on therapy Concomitant antiepileptic drugs
Adults Valproate Others
Weeks 1 and 2 12.5 mg dailya 50 mg daily
Weeks 3 and 4 25 mg daily 50 mg twice daily
Maintenance 50–100 mgb twice daily 100–200 mgb twice daily
Children Valproate Others
Weeks 1 and 2 0.15 mg/kg 0.6 mg/kg
Weeks 3 and 4 0.3 mg/kg 1.2 mg/kg
Increments 0.3 mg/kg 1.2 mg/kg
Maintenance 1–5 mg/kgb 5–15 mg/kgb
As monotherapy Adults Children
Weeks 1 and 2 25 mg daily 0.5 mg/kg
Weeks 3 and 4 25 mg twice daily 1 mg/kg
Maintenance 50–100 mgb twice daily 2–8 mg/kgb
a25 mg every other day is more common in the United States.
bHigher doses can be tried if seizures persist and the patient’s tolerance is good.
Valproic acid is a potent inhibitor of UGT1A4 and thus of lamotrigine metabolism,1,125 which can result in a 200% increase in circulating concentration.108 Maximal inhibition of lamotrigine metabolism can occur with valproate doses of 500 mg/day and above.49 The antidepressant sertraline is another inhibitor, producing a substantial increase in lamotrigine concentrations.61
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Pharmacodynamic Interactions
Patients treated with lamotrigine in combination with carbamazepine or oxcarbazepine seem to be at a higher risk of developing clinical signs of central nervous system toxicity, such as diplopia and dizziness.4,7 This is more common in patients with high serum concentrations of carbamazepine, and can be resolved by reduction in the carbamazepine dosage.7 Independent studies suggest that lamotrigine in combination with valproate may be particularly effective in preventing seizures.19,95 The pharmacokinetic interaction between the drugs is not sufficient to explain this synergistic effect, which can only be understood through a pharmacodynamic interaction.95
Role in Epilepsy treatment
Indications
Lamotrigine has a broad range of efficacy against partial-onset and primary generalized seizures and seizures associated with the LGS. The drug is licensed as adjunctive therapy for these indications in adults and in children over 2 years old and as monotherapy in adults and in children aged 12 years and over. It may also be useful in epilepsies with myoclonic seizures and typical absences.3 The combination of lamotrigine and valproic acid appears particularly effective for partial and tonic–clonic seizures.19,95 This effect has also been observed in patients with absence and myoclonic seizures.40,41,92
Dosing Recommendations
Recommended dosing schedules for lamotrigine are outlined in Table 2.51 With adjunctive therapy, the titration rate depends on comedication, and the aim of the low starting dose and slow titration schedule is to minimize the risk of rash. Lamotrigine is usually prescribed twice daily in patients taking hepatic enzyme–inducing AEDs, but a single daily dose can be taken by patients on monotherapy or treated with valproic acid. Most patients receiving monotherapy respond to doses of 100 to 300 mg/day. Higher doses of 400 to 800 mg/day may be required in refractory epilepsy or when the patient is also taking an enzyme-inducing AED. An equivalent dose in valproic acid–treated patients would be 150 to 200 mg/day.
Precautions
Lamotrigine is usually well-tolerated, with rash in 3% of patients started on the drug as monotherapy being the most serious side-effect. Evidence suggests that a low starting dose and slow titration schedule help to minimize this problem, particularly in patients also taking valproic acid. For some patients taking carbamazepine or oxcarbazepine, the addition of lamotrigine can produce headache, dizziness, ataxia, and diplopia. In severe hepatic impairment (Child-Pugh grade C), initial and maintenance doses of lamotrigine should be reduced by 75%. Caution should also be exercised when treating patients with Gilbert syndrome. Although single-dose studies in people with end-stage renal failure showed no significant alteration of plasma lamotrigine concentrations, it might be expected that toxicity could occur due to accumulation of glucuronide metabolites. It is, therefore, prudent to exercise care if using lamotrigine in this population.
Contraindications
Lamotrigine can worsen severe myoclonic epilepsy and should be avoided in patients with this condition. Increasing evidence suggests that the drug can also exacerbate some other myo-clonic syndromes.
Summary and conclusions
Lamotrigine is a broad-spectrum AED that is widely used as an adjunctive agent and as monotherapy in adults and children. Its anticonvulsant activity has been demonstrated in several seizure models. The drug has been shown to operate via a variety of cellular mechanisms, including blockade of voltage-gated Na+ channels. Lamotrigine undergoes linear pharmacokinetics and is metabolized mainly via hepatic glucuronidation. Controversy still exists over whether the drug is suited to routine therapeutic drug monitoring, although levels can be useful in pregnant women and in those starting or coming off the oral contraceptive pill. Lamotrigine is effective against most seizure types, although it may make certain types of myoclonic epilepsy worse. Adverse effects include nausea, headache, and ataxia, with rash being the most serious common problem. SJS and TEN have been reported, especially in children. Drug interactions are few, but combining lamotrigine with sodium valproate can be particularly efficacious, although at an increased risk of producing skin rash. Detrimental pharmacodynamic interactions can occur between lamotrigine and carbamazepine and oxcarbazepine. The licensing of lamotrigine in recent years for the treatment of bipolar I disorder serves to underline its therapeutic range.
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