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Lamotrigine …
- Updated 09.12.2021
- Released 12.16.1998
- Expires For CME 09.12.2024
Lamotrigine
Introduction
Historical note and terminology
The era of antiepileptic drugs started with the introduction of bromides in 1857. It was followed by the discovery of the anticonvulsant effect of barbiturates in 1912 and the introduction of hydantoins in 1916. Carbamazepine was introduced into clinical practice as an antiepileptic drug in 1963. Carbamazepine as well as lamotrigine blocks the repetitive firing of neurons by blocking sodium channels. Unrelated to any previous antiepileptic drug, lamotrigine reduces presynaptic excitatory amino acid release. Like most other antiepileptic drugs, the discovery of lamotrigine was serendipitous. Its discovery was based on the suggestion that the antiepileptic effect of phenytoin and phenobarbital is due to the disturbances of folate metabolism caused by these drugs (33). This led to an investigation of several folate antagonists in animal models, including phenyltriazines with strong antiepileptic action, even though the antifolate action was mild. Lamotrigine was developed from this category of compounds for treatment of partial seizures in 1995. It is approved worldwide.
Pharmacology
The chemical name of lamotrigine is 3,5-diamino-6-(2,3-Dichlorophenyl)-1,2,4-triazine.
Pharmacodynamics. Lamotrigine acts mainly by inhibiting excitatory amino acid (glutamate) release through the blockade of sodium channels and, thus, stabilizing neuronal membranes. It has a neuroprotective effect after cerebral ischemic insult.
The anticonvulsant activity of lamotrigine in animal studies resembles that of phenytoin and carbamazepine, suggesting activity against partial and generalized seizures.
PET studies have shown that lamotrigine treatment reduces glucose metabolism in the thalamus, basal ganglia, and multiple regions of the cerebral cortex in newly diagnosed patients with idiopathic generalized epilepsy who were receiving the drug for the first time.
Use of lamotrigine for refractory epilepsy in patients with severe motor and intellectual disabilities has been shown to not only reduce seizure frequency, but also to improve quality of life (01).
Pharmacokinetics. Lamotrigine is completely absorbed following oral administration, and the bioavailability is approximately 98%. In general, the pharmacokinetics of lamotrigine are linear over the dose range of 30 to 240 mg. Maximum plasma concentrations of lamotrigine in healthy volunteers and patients with epilepsy (0.96 to 3.16 mg/L) are achieved within 1 to 3 hours after the dose is given. Steady-state elimination half-life of lamotrigine in healthy young adults is approximately 25 to 30 hours. In patients also receiving enzyme-inducing drugs such as carbamazepine or phenytoin, the half-life is around 15 hours, whereas in the presence of valproic acid it is prolonged to 60 hours. In elderly patients and patients with Gilbert syndrome, the half-life of lamotrigine is lengthened but is still within the normal range. Elimination is mainly by hepatic metabolism and is reduced in the elderly. The pharmacokinetic characteristics of lamotrigine are still under investigation in children, and the elimination of the drug appears to be faster in these patients.
For clinical application, lamotrigine maintenance dose could be optimized using population pharmacokinetic models employing covariates such as concomitant antiepileptic drugs, body weight, and genetic polymorphisms (24). However, these models should be assessed for their predictability in the target population before utilizing such models in clinical settings.
Pharmacogenetics. Polymorphisms in the P-glycoprotein-encoding gene ABCB1 have an impact on lamotrigine drug disposition. A study has shown that polymorphism 1236C-2677G-3435C carriers had higher lamotrigine concentrations than 1236T-2677G-3435T carriers followed by 1236T-2677T-3435C carriers (20).
Therapeutic drug monitoring. A highly sensitive, specific and fully validated liquid chromatography/mass spectrometry method has been developed for quantitative estimation of lamotrigine in human plasma (17). This assay has been used for a human pharmacokinetics study of oral bioequivalence. Lamotrigine serum concentration correlate significantly with diplopia, but not with other side effects or with clinical efficacy (15).
The lamotrigine population pharmacokinetic model, which takes into consideration the concomitant drug and the weight of the patient, is a reliable method for individualizing the dosing regimen in young patients during therapeutic drug monitoring (07). For example, estimated oral clearance (CL/F) of lamotrigine for a patient weighing less than or equal to 25 kg who is concomitantly treated with carbamazepine is 3.28 l/h.
Formulations. Lamotrigine is available in a once-daily extended-release version, which may minimize serum concentration fluctuation and may improve patient compliance as compared to the immediate-release version of the compound although there is no difference in adverse event profiles of the 2 preparations (37).
Clinical trials
Lamotrigine as an add-on therapy suppresses seizures in patients with intractable partial epilepsy. Improvement is observed in at least 55% to 65% of trial participants. Some key clinical trials are shown in Table 1.
Table 1. Key Clinical Trials of Lamotrigine in Epilepsy
Study | Results |
A multicenter, parallel-design study comparing the efficacy of lamotrigine versus placebo in patients with simple or complex partial seizures unresponsive to a combination of standard anticonvulsants (23). | Thirty-four percent of patients had a 50% or greater reduction in seizure frequency with lamotrigine. |
An open, long-term study in patients with poorly controlled epilepsy examined the efficacy of adjunctive therapy with lamotrigine (09). | Lamotrigine was effective in significantly reducing seizure frequency over a 1-year period, but the number of patients in the study was small. |
Lamotrigine/Carbamazepine Monotherapy Trial Group patients with newly diagnosed epilepsy received increasing doses of lamotrigine or carbamazepine (05). | The proportion of patients remaining seizure-free was similar with lamotrigine and with carbamazepine. |
Patients with Lennox-Gastaut syndrome participated in a multicenter study; they were randomized to receive lamotrigine and concomitant valproic acid or placebo in addition to their usual anticonvulsant therapy (26). | The addition of lamotrigine to standard anticonvulsant therapy reduced the frequency of generalized seizures by 50% or more. |
A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children (13). | Found to be safe and effective for the adjunctive treatment of partial seizures in children. |
A randomized, double-blind study compared gabapentin and lamotrigine as monotherapy in newly diagnosed epilepsy (04). | Both therapies were similarly effective and well tolerated. |
A randomized, double-blind, placebo-controlled trial of adjunctive lamotrigine in patients with a diagnosis of epilepsy with primary generalized tonic-clonic seizures (03). | Adjunctive lamotrigine was effective in the treatment of primary generalized tonic-clonic seizures and had a favorable tolerability profile. |
Patients aged 65 years or older who had experienced at least 2 unprovoked partial or generalized tonic-clonic seizures were randomized to receive lamotrigine or sustained release carbamazepine according to a 40- week, multicenter, double-blind, parallel-group design trial. | Lamotrigine and carbamazepine showed comparable effectiveness, with a trend for higher seizure-free rates for the latter and better tolerability for the former (34). Some of the differences may be due to different dosage schedules and use of a sustained release preparation of carbamazepine. |
A systematic review of clinical trials of lamotrigine as add-on treatment for drug-resistant focal seizures showed that it was well-tolerated and appears to be effective in reducing seizure frequency, but the trials were of relatively short duration and provided no evidence for long-term efficacy (28).
Indications
Lamotrigine is indicated as adjunctive therapy for the treatment of partial seizures in adults with epilepsy as well as in the generalized seizures of Lennox-Gastaut syndrome in pediatric (2 years) and adult patients. Lamotrigine is indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with a single enzyme-inducing antiepileptic agent. In 2004, the FDA approved lamotrigine tablets for use as monotherapy for treatment of partial seizures in patients 16 years and older when converting from the older antiepileptic drug, valproate. In 2011, the FDA approved lamotrigine extended-release tablets for conversion to monotherapy in patients 13 years and older with partial seizures taking 1 antiepileptic drug. Lamotrigine is also approved for maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.
Off-label uses
(1) A systematic review of the literature and clinical trials provides sound evidence to support the off-label use of lamotrigine for psychiatric disorders such as acute bipolar depression, treatment-resistant schizophrenia, and treatment-resistant obsessive-compulsive disorder (27). | |
(2) Lamotrigine may be beneficial in the treatment of neuralgia after nerve section following the failure of previous pharmacological or surgical attempts. | |
(3) Painful phenomena in multiple sclerosis including paroxysmal burning paresthesias and painful tonic spasms. | |
(4) Juvenile neuronal ceroid lipofuscinosis. | |
(5) Startle-induced seizures. | |
(6) Posttraumatic stress disorder. | |
(7) Prophylaxis of migraine with an aura. | |
(8) An interventional crossover study that compared lamotrigine with carbamazepine showed that it is safe and effective for treatment of trigeminal neuralgia (35). | |
(9) Preclinical studies show neuroprotective activity of lamotrigine after cerebral ischemia in animal models. | |
(10) Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. | |
(11) The Cochrane Database of Systematic Reviews has concluded that lamotrigine does not have a significant place in the management of acute and chronic pain (43). A further review found no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of about 200 to 400 mg daily (44). | |
(12) SUNCT syndrome. | |
(13) For treatment of aggression and agitation in patients with a traumatic brain injury. | |
(14) Amyotrophic lateral sclerosis. | |
(15) Treatment of depersonalization disorder. | |
(16) Findings of a randomized, double-blind, placebo-controlled trial of lamotrigine for prescription corticosteroid effects on the human hippocampus show that its action as a glutamate release inhibitor may attenuate some of the effects on the human memory associated with corticosteroids (06). | |
(17) A systematic review and meta-analysis of randomized controlled trials has shown that lamotrigine is less effective than valproic acid or ethosuximide for treatment of absence seizures in children and adolescents, but may be tried as initial therapy because of its relative safety as compared to other 2 drugs (08). | |
(18) An exploratory, retrospective study showed response to lamotrigine in some patients with myoclonic astatic epilepsy (Doose syndrome), which is a difficult to treat idiopathic generalized epilepsy of early childhood (12). | |
(19) Lamotrigine is usually contraindicated in Dravet syndrome as it aggravates seizures, but a favorable response to this drug by reduction of seizure duration and frequency has been reported in 2 adults and 1 child (11). Withdrawal of lamotrigine resulted in an increased frequency and duration of seizures, but reintroduction of the drug improved seizure control. | |
(20) Continuous lamotrigine administration for 6 months in a mouse model of Alzheimer disease led to improvement in executive function and attenuation in the expression of proinflammatory cytokines, suggesting the therapeutic potential of lamotrigine in early stages of Alzheimer disease (41). | |
(21) A randomized, double-blind, placebo-controlled, 2-period crossover study on patients with nondystrophic myotonia showed that lamotrigine reduced myotonia and its use as first-line therapy for this condition is suggested (02). |
Contraindications
Lamotrigine is contraindicated in patients who have a demonstrated hypersensitivity to the drug or its ingredients.
Goals and duration of treatment
The aim of therapy is to control seizures. Therapy is continued for as long as seizure control is required. Lamotrigine administered as monotherapy or adjunctive therapy during long-term extension of open-label continuation studies is associated with a low incidence of adverse events in adult patients with epilepsy.
Conversion from lamotrigine immediate release to extended release formulation can help improve seizure control in some individuals with drug-resistant epilepsy (31).
Dosing
The starting dosage of lamotrigine in adults and children older than 12 years is 50 mg per day (25 mg twice daily) for the first 2 weeks. Maintenance dosages are typically 200 to 400 mg per day. With concomitant valproic acid, the starting dosage of lamotrigine should be reduced to 25 mg every other day in the first 2 weeks and increased to 25 mg/day in weeks 3 and 4. The maintenance dosage is 100 to 200 mg per day. Children older than 2 years should be started on lamotrigine 0.6 mg/kg per day in 2 doses for the first 2 weeks, increasing to 1.2 mg/kg in weeks 3 and 4. The maintenance dose is 5 to 15 mg/kg per day. With concomitant valproic acid, the recommended dosage is 0.15 mg/kg per day in 2 divided doses during the first 2 weeks, increasing to 0.3 mg/kg in 2 divided doses in weeks 3 and 4. Maintenance dose is 1 to 5 mg/kg per day.
A new, divisible lamotrigine formulation is bioequivalent to rate and extent of absorption to both the plain lamotrigine product and to the dispersible/chewable formulation.
Special considerations
Pediatric. Safety and efficacy of lamotrigine in children below 16 years of age has not been established other than in those with Lennox-Gastaut syndrome.
Geriatric. No specific statements can be made as to the efficacy and safety of lamotrigine in the elderly, but there was no evidence of increased adverse effects in elderly patients in the clinical trial population.
Pregnancy. Although lamotrigine is not teratogenic in pregnant rats, it reduces fetal folate concentration, which is a factor known to be associated with teratogenesis in animals as well as in humans. The rate of lamotrigine excretion into human breast milk is like that observed with other antiepileptic drugs. A review of 18 years of the International Lamotrigine Pregnancy Registry did not detect an appreciable increase in major congenital malformation frequency following first-trimester lamotrigine monotherapy exposure (10). Lamotrigine is among the safest antiepileptic medications in terms of fetal malformations and postpartum cognitive development, making it probably the first choice for treatment of an epileptic woman who wishes to become pregnant (25). However, increased risk of an isolated cleft palate or cleft lip deformity has been reported in infants exposed to lamotrigine in the first trimester of pregnancy (16). It should be used in pregnancy only if potential benefits outweigh the risks.
Lamotrigine levels in serum correlate strongly with the lamotrigine levels in amniotic fluid and umbilical cord blood, indicating the fetus is exposed to the drug administered to a woman during pregnancy (29). Lamotrigine clearance is markedly elevated during the first trimester, and an average dose increase by 250% is required to obtain therapeutic serum levels (14). Results of a study on mother baby pairs suggest that taking low to moderate doses of lamotrigine during the lactation period might be relatively safe, at least for a period of 1 month after delivery (45).
Anesthesia. There are no known interactions of lamotrigine with anesthesia.
Lamotrigine is generally a safe and effective drug, but it should be used with caution in patients on polytherapy and in those with complicated acute systemic and central nervous system conditions, such as fever, status epilepticus, or encephalitis.
Interactions
Phenytoin increases lamotrigine clearance by approximately 125%, carbamazepine increases lamotrigine clearance by approximately 30% to 50%, and valproate decreases lamotrigine clearance by approximately 60% (42). In another study of use as comedication with valproic acid, higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels (21). These interactions may necessitate adjustment of the dosage of lamotrigine. Concomitant use of lamotrigine decreases efficacy of ketogenic diet in childhood refractory epilepsy (40). No interactions have been reported with other antiepileptic drugs. The efficacy of oral contraceptives does not appear to be compromised by the addition of lamotrigine, but lamotrigine serum concentrations may fall by 50% to 60% when combined with hormonal contraceptives that contain ethinyl estradiol, which induces glucuronidizing enzyme resulting in accelerated metabolism of lamotrigine. Hormone replacement therapy with estrogens may also reduce serum lamotrigine concentrations (32). For further details of other drug interactions, see the Physicians Desk Reference.
Adverse effects
Lamotrigine was well tolerated in clinical trials. Most of the adverse events associated with lamotrigine add-on therapy in clinical trials were CNS related, notably dizziness, diplopia, somnolence, headache, ataxia, and asthenia. Patients complaining of visual disturbances have not shown any abnormalities on electroretinography or irreversible visual field impairment. Nightmares have been reported as an adverse effect of lamotrigine. Serious skin rashes requiring hospitalization and discontinuation of therapy have been reported. Cases of hepatotoxicity have been reported in patients on lamotrigine therapy. Unusual side effects of lamotrigine include eye movement abnormalities, involuntary movements, and behavioral changes. Aseptic meningitis has been reported as an adverse effect of lamotrigine treatment (19; 22; 36). Multifocal myoclonus induced by lamotrigine has been reported in a patient with temporal lobe epilepsy (38). Exacerbation or appearance of myoclonic jerks has been reported in patients with idiopathic generalized epilepsies following treatment with lamotrigine and usually resolves by dose reduction or discontinuation. Lymphadenopathy has been reported as an adverse effect of lamotrigine therapy (30). Following discontinuation of lamotrigine in treatment-resistant bipolar disorder due to adverse effects on the skin in some patients, lamotrigine was reintroduced by slow titration of dose without recurrence of skin reaction (18). Adverse events are listed in more detail in the Physicians Desk Reference.
In 2021, the U.S. Food and Drug Administration issued an alert regarding lamotrigine, warning of potential cardiac side effects (39). An FDA review of study findings showed a potential increased risk of arrhythmias in patients with clinically important structural or functional heart disorders. The risk of arrhythmias may increase further if used in combination with other medicines that block sodium channels in the heart. Healthcare professionals are advised to weigh the potential benefits of lamotrigine against the potential risk of arrhythmias for each patient.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
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K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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