Lamotrigine

(BAN, USAN, rINN)
Lamotrigine Chemical formula
Synonyms: BW-430C; Lamotrigiini; Lamotrigin; Lamotrigina; Lamotriginum; Lamotrijin. 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diyldiamine.
Cyrillic synonym: Ламотригин.

💊 Chemical information

Chemical formula: C9H7Cl2N5 = 256.1.
CAS — 84057-84-1.
ATC — N03AX09.
ATC Vet — QN03AX09.

💊 Adverse Effects and Treatment

Skin rashes may occur during therapy with lamotrigine; severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported, especially in children, and usually occur within 8 weeks of starting lamotrigine (see Effects on the Skin, below). Symptoms such as fever, malaise, flulike symptoms, drowsiness, lymphadenopathy, facial oedema and, rarely, hepatic dysfunction have been reported. Blood dyscrasias such as leucopenia, neutropenia, and thrombocytopenia have also been reported, sometimes with rashes as part of a hypersensitivity syndrome. Movement disorders such as tics, ataxia, nystagmus, and tremor have occurred; lamotrigine may worsen symptoms in patients with pre-existing Parkinson’s disease. Other adverse effects include angioedema, photosensitivity, diplopia, blurred vision, conjunctivitis, dizziness, drowsiness, insomnia, headache, tiredness, nausea and vomiting, irritability and aggression, hallucinations, agitation, and confusion. Very rarely, lupus-like reactions and increases in seizure frequency have been reported.
It has been suggested1 that multi-organ failure and disseminated intravascular coagulation, with associated rhabdomyolysis, are complications of severe convulsive seizures rather than of lamotrigine therapy. However, there has been a report2 of a patient with no history of generalised seizures who developed a syndrome of disseminated intravascular coagulation, rhabdomyolysis, renal failure, maculopapular rash, and ataxia 14 days after lamotrigine was added to her antiepileptic regimen. Two cases of disseminated intravascular coagulation were found in a cohort of 11 316 patients involved in prescription-event monitoring of lamotrigine therapy in general practice.3
1. Yuen AWC, Bihari DJ. Multiorgan failure and disseminated intravascular coagulation in severe convulsive seizures. Lancet 1992; 340: 618
2. Schaub JEM, et al. Multisystem adverse reaction to lamotrigine. Lancet 1994; 344: 481
3. Mackay FJ, et al. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997; 38: 881–6.

Effects on the blood.

Septic shock secondary to leucopenia occurred in a patient when lamotrigine was added to therapy with sodium valproate.1 There has also been a report of agranulocytosis in a child started on high-dose lamotrigine monotherapy.2 The fall in the blood count was noted several days after lamotrigine had been stopped due to skin rash. The UK CSM subsequently reported3 that 7 cases of aplastic anaemia, 12 of bone-marrow depression, and 20 of pancytopenia associated with lamotrigine had been received worldwide. Given the extensive usage of lamotrigine the CSM considered the risk of aplastic anaemia to be small and routine blood monitoring was not recommended. However, prescribers were warned to be alert for symptoms and signs suggestive of bone-marrow depression.
1. Nicholson RJ, et al. Leucopenia associated with lamotrigine. BMJ 1995; 310: 504
2. de Camargo OAK, Bode H. Agranulocytosis associated with lamotrigine. BMJ 1999; 318: 1179
3. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal): rare blood dyscrasias. Current Problems 2000; 26: 4. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON007462& RevisionSelectionMethod=LatestReleased (accessed 09/06/08)

Effects on bone.

For the effects of antiepileptics including lamotrigine on bone and on calcium and vitamin D metabolism, see under Phenytoin.

Effects on the liver.

Fatal fulminant hepatic failure has been reported1 in a patient after addition of lamotrigine to antiepileptic therapy with sodium valproate and carbamazepine. Another fatal case was reported2 in a patient who was given lamotrigine for bipolar disorder; she was also taking other drugs for pain and insomnia. Reversible eosinophilic hepatitis occurred3 as part of a hypersensitivity syndrome in a patient given lamotrigine for seizures.
1. Makin AJ, et al. Fulminant hepatic failure induced by lamotrigine. BMJ 1995; 311: 292
2. Overstreet K, et al. Fatal progressive hepatic necrosis associated with lamotrigine treatment: a case report and literature review. Dig Dis Sci 2002; 47: 1921–5
3. Fix OK, et al. Eosinophilic hepatitis caused by lamotrigine. Clin Gastroenterol Hepatol 2006; 4: xxvi.

Effects on the lungs.

Interstitial pneumonitis with pulmonary infiltrates occurred when lamotrigine was added to antiepileptic therapy in a 57-year-old woman; the condition resolved when lamotrigine was stopped.1
1. Saravanan N, et al. Interstitial pneumonitis during lamotrigine therapy. Br J Clin Pharmacol 2005; 60: 666–7.

Effects on mental function.

Acute psychosis was reported1 in 6 out of about 1400 patients when lamotrigine was added to antiepileptic therapy and/or when the dose of lamotrigine was increased. Symptoms resolved when lamotrigine was stopped, and recurred in 1 case of rechallenge. For a review of the effects of antiepileptic therapy including lamotrigine on cognition, and on mood (including the risk of suicidal ideation).
1. Brandt C, et al. Development of psychosis in patients with epilepsy treated with lamotrigine: report of six cases and review of the literature. Epilepsy Behav 2007; 11: 133–9.

Effects on the nervous system.

Of 93 patients with idiopathic generalised epilepsy who were treated with lamotrigine, 5 adults experienced de novo or exacerbated myoclonic jerks.1 In each case, symptoms resolved when the dose of lamotrigine was reduced by 25 to 50% or stopped altogether. In another report, a 17-year-old girl with idiopathic Rolandic epilepsy experienced a sudden increase in seizure frequency when lamotrigine was added to therapy with sodium valproate; other adverse effects included emotional lability, headaches, and drowsiness.2 Again symptoms resolved when lamotrigine was stopped.2 Overdose of lamotrigine has been known to cause seizures (see below).
1. Crespel A, et al. Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology 2005; 65: 762–4
2. Cerminara C, et al. Lamotrigine-induced seizure aggravation and negative myoclonus in idiopathic rolandic epilepsy. Neurology 2004; 63: 373–5.

Effects on the skin.

Rashes account for withdrawal from therapy in about 2% of those given lamotrigine,1,2 and serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis occur in about 1 in 1000 adult patients.3,4 The majority of rashes resolve once lamotrigine has been stopped; however, some patients have developed permanent scarring and there have been rare reports of fatalities. The main risk factors appear to be use with valproate, exceeding the recommended initial dose of lamotrigine or the recommended rate of dose escalation, and a history of antiepileptic-induced rash. The risk appears to be greater in children1,4-6 and has been estimated to be between 1 in 300 and 1 in 50. These skin reactions usually occur within 8 weeks of starting therapy with lamotrigine, but onset as early as the first day and as late as 2 years has been noted.7 After continuing reports of serious skin reactions in children, UK recommended dosage regimens for children have been revised to further reduce the risk of such reactions.8 For the relative incidence of rash with different antiepileptics see under Phenytoin.
1. Mackay FJ, et al. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997; 38: 881–6
2. Messenheimer J, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Safety 1998; 18: 281–96
3. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal) and serious skin reactions. Current Problems 1996; 22: 12. Also available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2015622&RevisionSelectionMethod= LatestReleased (accessed 09/06/08
4. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal): increased risk of serious skin reactions in children. Current Problems 1997; 23: 8. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023230&RevisionSelectionMethod= LatestReleased (accessed 09/06/08
5. Mitchell P. Paediatric lamotrigine use hit by rash reports. Lancet 1997; 349: 1080
6. Hirsch LJ, et al. Predictors of lamotrigine-associated rash. Epilepsia 2006; 47: 318–22
7. Adverse Drug Reactions Advisory Committee (ADRAC). Lamotrigine and severe skin reactions. Aust Adverse Drug React Bull 1997; 16: 3. Also available at: http://www.tga.health.gov.au/ adr/aadrb/aadr9702.htm (accessed 09/06/08
8. Committee on Safety of Medicines/Medicines Control Agency. Lamotrigine (Lamictal): revised doses for children. Current Problems 2000; 26: 3. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON007462& RevisionSelectionMethod=LatestReleased (accessed 09/06/08)

Overdosage.

An evaluation1 of 493 cases of lamotrigine-only overdoses reported to the American Association of Poison Control Centers over a 2-year period found that 52.1% of patients had no toxic effects. The most commonly reported adverse effects were drowsiness, nausea, vomiting, and ataxia. Serious effects such as seizures, coma, and respiratory depression were reported in 0.6 to 1.2% of cases; no deaths were reported. No serious toxicity was seen in a patient who deliberately took an overdose of 1.35 g of lamotrigine and was subsequently treated with gastric lavage and activated charcoal.2 Symptoms at presentation one hour after ingestion had included nystagmus and muscle hypertonicity. ECG monitoring had revealed widening of the QRS interval. Low-grade fever, erythema, and periorbital oedema suggestive of a hypersensitivity syndrome developed in another patient who inadvertently received lamotrigine 2.7 g daily for 4 days.3 The patient recovered after corticosteroid treatment and stopping lamotrigine. Generalised tonic-clonic seizures, tremor, muscle weakness, ataxia, and hypertonia were reported4 in a 2-year-old child after ingestion of 800 mg of lamotrigine. Symptoms resolved within 24 hours after treatment with gastric lavage and activated charcoal, midazolam, and fluids. Plasma-lamotrigine concentrations were in the high adult therapeutic range (3.8 micrograms/mL) with a slow elimination rate. Generalised seizures also occurred5 after an unknown quantity of lamotrigine was ingested by a 19-month-old child who had no history of seizures; other presenting symptoms included tachycardia and vomiting. The serum-lamotrigine concentration measured 1 hour post ingestion was 20.3 mg/L. Symptoms resolved within 24 hours after treatment with trimethobenzamide and activated charcoal. For a further review of the features and management of poisoning with some antiepileptics, including lamotrigine, see under Phenytoin.
1. Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother 2004; 38: 1811–15
2. Buckley NA, et al. Self-poisoning with lamotrigine. Lancet 1993; 342: 1552–3
3. Mylonakis E, et al. Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome. Ann Pharmacother 1999; 33: 557–9
4. Briassoulis G, et al. Lamotrigine childhood overdose. Pediatr Neurol 1998; 19: 239–42
5. Thundiyil JG, et al. Lamotrigine-induced seizures in a child: case report and literature review. Clin Toxicol 2007; 45: 169–72.

💊 Precautions

Lamotrigine should be given with caution to patients with hepatic or renal impairment. All patients should be warned to see their doctor immediately if rashes or symptoms associated with hypersensitivity develop. To minimise the risk of developing serious skin reactions, dosage recommendations should not be exceeded. Particular care is needed in patients also receiving valproate—see Interactions, below. Withdrawal of lamotrigine should be considered if rash, fever, flu-like symptoms, drowsiness, or worsening of seizure control occurs. Care is required when withdrawing lamotrigine therapy—see also under Uses and Administration, below. Abrupt withdrawal should be avoided unless serious skin reactions have occurred. Lamotrigine should not be restarted in patients with previous hypersensitivity.

Breast feeding.

The American Academy of Pediatrics1 considers that the use of lamotrigine by mothers during breast feeding may be of concern, since there is the potential for therapeutic serum concentrations to occur in the infant. A report in 4 breast-fed infants whose mothers were taking lamotrigine found that although serum concentrations of the drug 10 days after birth were about 30% of maternal concentrations in 3 infants, no short-term adverse effects were seen; the drug was undetectable in the fourth.2 A study3 in 6 mothers taking lamotrigine found that the relative dose in their breast-fed infants was 7.6% (mean absolute dose: 450 micrograms/kg daily) and infant plasma concentrations were 18% of maternal concentrations; no adverse effects were reported. The authors also noted that no adverse effects were reported in 12 previous cases. For further comment on antiepileptic therapy and breast feeding.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 09/06/08
2. Liporace J, et al. Concerns regarding lamotrigine and breastfeeding. Epilepsy Behav 2004; 5: 102–5
3. Page-Sharp M, et al. Transfer of lamotrigine into breast milk. Ann Pharmacother 2006; 40: 1470–1.

Driving.

For a comment on antiepileptic drugs and driving.

Hepatic impairment.

The pharmacokinetics of lamotrigine were not significantly altered in patients with moderate cirrhosis;1 however, those with severe cirrhosis showed significantly lower oral clearance and longer elimination half-lives than those in healthy subjects. The recommended licensed doses in patients with hepatic impairment are given under Uses and Administration, below.
1. Marcellin P, et al. Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol 2001; 51: 410–14.

Intellectual impairment.

Aggressive behaviour has been reported in intellectually impaired patients given lamotrigine.1 Of 19 such patients given lamotrigine, aggressive behaviour developed in 9; the drug was stopped in 5, and stopped but reintroduced in a further 2, together with psychiatric management. One patient responded to a reduction in lamotrigine dosage.
1. Beran RG, Gibson RJ. Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine. Epilepsia 1998; 39: 280–2.

Pregnancy.

For comments on the management of epilepsy during pregnancy. For reference to alteration of lamotrigine pharmacokinetics in pregnancy, see under Pharmacokinetics, below. There is a theoretical risk of teratogenicity with lamotrigine because, like valproate, it is a folate antagonist. In 2002 the manufacturer of lamotrigine, GlaxoSmithKline, reported1 that it had follow-up information on 395 outcomes of pregnancies exposed to lamotrigine between September 1992 and September 2001 from the International Lamotrigine Pregnancy Registry. Major birth defects were found in 13 infants but no distinctive pattern of abnormalities suggestive of a common cause could be identified. Of the 168 who had been exposed to lamotrigine monotherapy during the first trimester, birth defects were reported in 3 (1.8%). The frequency of major birth defects in pregnancies exposed to polytherapy containing lamotrigine with valproate was 10% compared with 4.3% in lamotrigine polytherapy without valproate. Although it was considered that the sample sizes were too small to rule out a small increase in the frequency of major birth defects, it was noted that the frequency of malformations after lamotrigine monotherapy did not differ from that reported in the literature for women with epilepsy receiving antiepileptic monotherapy. Updated results from 785 pregnancies up to March 2004 included 414 first-trimester exposures to lamotrigine monotherapy, of which 12 were associated with a major abnormality.2 As of March 2006, the registry had recorded 802 first-trimester exposures to lamotrigine monotherapy with major abnormalities occurring in 22; there was no evidence to suggest a dose-response relationship with daily doses of up to 400 mg.3 In August 2006, the manufacturer4 reported that data from the North American Antiepileptic Drug Pregnancy Registry suggested an association between lamotrigine and an increased risk of oral clefts. Of 564 first-trimester exposures to lamotrigine monotherapy, 5 cases of oral clefts were reported giving an incidence rate of 8.9 per 1000 compared with 0.37 per 1000 in the reference population. Again, however, no increase in the overall risk of major malformations was found. Analysis of data from other pregnancy registries found 4 additional cases of oral clefts in about 2200 first-trimester exposures to lamotrigine monotherapy.
1. Tennis P, Eldridge RR. International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia 2002; 43: 1161–7
2. Cunnington M, Tennis P. International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005; 64: 955–60
3. Cunnington M, et al. International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Effect of dose on the frequency of major birth defects following fetal exposure to lamotrigine monotherapy in an international observational study. Epilepsia 2007; 48: 1207–10
4. GlaxoSmithKline, Canada. Association of Lamictal® (lamotrigine) with an increased risk of non-syndromic oral clefts (issued 1st August, 2006). Available at: http://www.hc-sc.gc.ca/dhp-mps/ alt_formats/hpfb-dgpsa/pdf/medeff/lamictal_2_hpc-cps-eng.pdf (accessed 01/09/08)

Renal impairment.

Results from a pharmacokinetic study1 indicated that impaired renal function was likely to have little effect on plasma concentrations of lamotrigine. The drug is mainly cleared by metabolism and although the glucuronide metabolite accumulates it is inactive. Nevertheless, there is limited clinical experience with lamotrigine in such patients and caution was recommended.
1. Wootton R, et al. Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers. Br J Clin Pharmacol 1997; 43: 23–7.

💊 Interactions

There are complex interactions between antiepileptics and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy. The metabolism of lamotrigine is enhanced by the enzyme inducers carbamazepine, phenytoin, phenobarbital, and primidone, and inhibited by valproate (see below).

Analgesics.

Paracetamol affects the metabolic disposition of lamotrigine but the clinical significance of this interaction remains to be determined.1 Paracetamol reduced the area under the plasma concentration-time curve for lamotrigine, reduced lamotrigine’s half-life, and increased the percentage of lamotrigine recovered in the urine.
1. Depot M, et al. Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine. Clin Pharmacol Ther 1990; 48: 346–55.

Antibacterials.

Use with rifampicin significantly increased the clearance of lamotrigine.1 The total urinary excretion of lamotrigine and the amount excreted as glucuronide were significantly higher compared with placebo.
1. Ebert U, et al. Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol 2000; 56: 299–304.

Antidepressants.

An epileptic patient maintained on lamotrigine 200 mg daily complained1 of increasing confusion and cognitive impairment after starting sertraline 25 mg daily for posttraumatic disorder; after 6 weeks her lamotrigine blood concentrations had risen from 2.5 to 5.1 micrograms/mL during this period. The adverse effects cleared and blood concentrations of lamotrigine fell to 3.1 micrograms/mL within 3 weeks of changing the daily dosage to lamotrigine 100 mg and sertraline 50 mg. A patient, with poorly controlled epilepsy, who initially had been taking lamotrigine 450 mg and sertraline 75 mg together daily for 6 weeks without adverse effects had marked sedation, fatigue, and decreased cognition 6 weeks after the daily dosage of lamotrigine was increased to 600 mg. Her lamotrigine blood concentration was 19.3 micrograms/mL. The patient was subsequently stabilised on lamotrigine 800 mg and sertraline 50 mg daily and had less sedation and fatigue and clearer cognition; blood concentrations of lamotrigine fell to 9.8 micrograms/mL.
1. Kaufman KR, Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure 1998; 7: 163–5.

Antiepileptics.

Valproate can inhibit the metabolism of lamotrigine resulting in increased concentrations of lamotrigine. This effect can be beneficial in the control of certain seizures, although careful monitoring is required as toxicity may occur. Disabling tremor occurred in 3 patients taking such a combination which resolved when the dose of lamotrigine or valproate was reduced.1 Other reports of toxicity, resolving on reduction of the lamotrigine dose, were marked by sedation, ataxia, and fatigue,2or delirium.3 Symptoms of neurotoxicity were reported in 3 patients on lamotrigine therapy who were given valproate, intravenously then orally, for absence status epilepticus. Serum concentrations of lamotrigine in these patients were raised about threeto sevenfold.4 Reversible encephalopathy has been reported5when sodium valproate was substituted for phenytoin in a patient also taking lamotrigine, although her clinical condition had been satisfactory on this new regimen for several months. Symptoms improved when the doses of both valproate and lamotrigine were reduced. Pharmacokinetic studies6,7 in healthy adults have attempted to elucidate the mechanism of the interaction between lamotrigine and valproate. The clearance of lamotrigine was found to be reduced, and exposure and elimination half-life increased when valproate was also given. Renal elimination was not affected and the investigators6 suggested that there was hepatic competition for glucuronidation between valproate and lamotrigine. However, there was no substantial alteration in the linear kinetics of lamotrigine in the presence of therapeutic plasma concentrations of valproate.7 Similar observations were made when lamotrigine was added to existing antiepileptic regimens in children,8 although the clinical relevance of the influence of age on the pharmacokinetics remains to be determined. Both young age and use with valproate are risk factors for lamotrigine-induced dermatological toxicity—see Effects on the Skin, above. For details of dosage reductions required for lamotrigine used with valproate, see Uses and Administration, below. Other antiepileptics also affect plasma concentrations of lamotrigine. In contrast to valproate, carbamazepine, phenytoin, or phenobarbital all markedly induced the elimination of lamotrigine.9 Others have confirmed a reduction in plasma-lamotrigine concentrations when given with phenytoin and other enzymeinducing antiepileptics,10 but analysis of results from another study11 suggested that the increase in lamotrigine clearance by phenytoin and carbamazepine was of minimal clinical significance. Oxcarbazepine has also been reported12 to decrease serum-lamotrigine concentrations (although to a lesser extent than carbamazepine). However, a study13 in healthy subjects found that oxcarbazepine did not affect the pharmacokinetics of lamotrigine, although adverse effects occurred more frequently when they were used together. Mesuximide was found12,14 to have a marked inducing effect on the metabolism of lamotrigine. In one study,14 plasma-lamotrigine concentrations were significantly reduced when given together. For reports of an interaction between lamotrigine and carbamazepine. For the effect of lamotrigine on clonazepam concentrations.
1. Reutens DC, et al. Disabling tremor after lamotrigine with sodium valproate. Lancet 1993; 342: 185–6
2. Pisani F, et al. Interaction of lamotrigine with sodium valproate. Lancet 1993; 341: 1224
3. Mueller TH, Beeber AR. Delirium from valproic acid with lamotrigine. Am J Psychiatry 2004; 161: 1128–9
4. Burneo JG, et al. Neurotoxicity following addition of intravenous valproate to lamotrigine therapy. Neurology 2003; 60: 1991–2
5. Hennessy MJ, Wiles CM. Lamotrigine encephalopathy. Lancet 1996; 347: 974–5
6. Yuen AWC, et al. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–13
7. Anderson GD, et al. Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996; 60: 145–56
8. Vauzelle-Kervroëdan F, et al. Influence of concurrent antiepileptic medication on the pharmacokinetics of lamotrigine as add-on therapy in epileptic children. Br J Clin Pharmacol 1996; 41: 325–30
9. May TW, et al. Serum concentrations of lamotrigine in epileptic patients: the influence of dose and comedication. Ther Drug Monit 1996; 18: 523–31
10. Battino D, et al. Lamotrigine plasma concentrations in children and adults: influence of age and associated therapy. Ther Drug Monit 1997; 19: 620–7
11. Grasela TH, et al. Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy. J Clin Pharmacol 1999; 39: 373–84
12. May TW, et al. Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. Ther Drug Monit 1999; 21: 175–81
13. Theis JGW, et al. Lack of pharmacokinetic interaction between oxcarbazepine and lamotrigine. Neuropsychopharmacology 2005; 30: 2269–74
14. Besag FM, et al. Methsuximide lowers lamotrigine blood levels: a pharmacokinetic antiepileptic drug interaction. Epilepsia 2000; 41: 624–7.

Antipsychotics.

An apparent interaction between lamotrigine and aripiprazole, resulting in Stevens-Johnson syndrome, has been reported1 in 2 patients with schizophrenia after the introduction of lamotrigine; both patients recovered with supportive treatment.
1. Shen Y-C, et al. Concomitant use of lamotrigine and aripiprazole increases risk of Stevens-Johnson syndrome? Int Clin Psychopharmacol 2007; 22: 247–8.

Antivirals.

A study1 in healthy subjects found that ritonavirboosted lopinavir decreased the steady-state minimum plasma concentration of lamotrigine by about 55%; doubling the dose of lamotrigine achieved concentrations similar to those with lamotrigine alone.
1. van der Lee MJ, et al. Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects. Clin Pharmacol Ther 2006; 80: 159–68.

Sex hormones.

Studies in patients taking lamotrigine have indicated that combined oral contraceptives1,2 may halve plasma concentrations of the antiepileptic. Other studies3,4 have also found a significant increase in lamotrigine-plasma concentrations within one week of stopping contraceptive therapy; however, wide interpatient variability was noted in one study.3 Significant adjustments in maintenance doses of lamotrigine may be needed if combined contraceptives are started or stopped (see below), and patients should be warned not to make changes in their contraceptive therapy without consulting their physician.5 However, in a study,6 progestogen-only contraceptives did not appear to affect lamotrigine concentrations. Licensed drug information recommends that, when starting treatment with combined oral contraceptives, the dose of lamotrigine may need to be increased by as much as twofold in those women not taking drugs known to induce cytochrome P450-mediated metabolism of lamotrigine; conversely, the dose of lamotrigine may need to be halved when stopping contraceptive therapy in women not taking enzyme inducers. Dosage adjustment may not be necessary when starting or stopping combined oral contraceptive therapy in women taking lamotrigine with known enzyme inducers. Adjustments may also be needed if other hormonal preparations are taken with lamotrigine. Some reduction in plasma concentrations of levonorgestrel, and to a lesser extent ethinylestradiol, may also occur with lamotrigine, and there have been reports of breakthrough bleeding and unexpected pregnancies.5
1. Sabers A, et al. Oral contraceptives reduce lamotrigine plasma levels. Neurology 2003; 61: 570–1
2. Sidhu J, et al. The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol 2006; 61: 191–9.
3. Contin M, et al. Variation in lamotrigine plasma concentrations with hormonal contraceptive monthly cycles in patients with epilepsy. Epilepsia 2006; 47: 1573–5
4. Christensen J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial Epilepsia 2007; 48: 484–9
5. GlaxoSmithKline, Canada. Important new safety information concerning the antiepileptic, Lamictal (lamotrigine) (issued September 2004). Available at: http://www.hc-sc.gc.ca/dhp-mps/ alt_formats/hpfb-dgpsa/pdf/medeff/lamictal_hpc-cps-eng.pdf (accessed 01/09/08
6. Reimers A, et al. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia 2005; 46: 1414–17.

💊 Pharmacokinetics

Lamotrigine is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of 98%. Peak plasma concentrations occur about 2.5 hours after oral doses. It is widely distributed in the body and is reported to be about 55% bound to plasma proteins. It is extensively metabolised in the liver and excreted almost entirely in urine, principally as an inactive glucuronide conjugate. It slightly induces its own metabolism and the mean elimination half-life is reported to be 24 to 35 hours. Clearance is reported to be higher in children aged up to 12 years than in adults, with the highest values occurring in those under 5 years of age. Lamotrigine is distributed into breast milk. The pharmacokinetics of lamotrigine are affected by other antiepileptics (see Interactions, above).
1. Rambeck B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet 1993; 25: 433–43
2. Elwes RDC, Binnie CD. Clinical pharmacokinetics of newer antiepileptic drugs: lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clin Pharmacokinet 1996; 30: 403–15
3. Reimers A, et al. Lamotrigine in children and adolescents: the impact of age on its serum concentrations and on the extent of drug interactions. Eur J Clin Pharmacol 2007; 63: 687–92
4. Punyawudho B, et al. Population pharmacokinetics of lamotrigine in elderly patients. J Clin Pharmacol 2008; 48: 455–63.

Hepatic impairment.

See under Precautions, above.

Pregnancy.

Decreased plasma-lamotrigine concentrations have occurred during pregnancy, with deterioration of seizure control and a need for dosage adjustment in some patients. References
1. Pennell PB, et al. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004; 62: 292–5
2. de Haan G-J, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004; 63: 571–3
3. Petrenaite V, et al. Individual changes in lamotrigine plasma concentrations during pregnancy. Epilepsy Res 2005; 65: 185–8.

Renal impairment.

See under Precautions, above.

Therapeutic drug monitoring.

A literature review1 concluded that a clear relationship between lamotrigine concentrations and toxicity or antiepileptic efficacy has not been demonstrated. Routine therapeutic drug monitoring was therefore not recommended and clinical end-points rather than plasma concentrations remained the best guide for dosage adjustment of lamotrigine.
1. Chong E, Dupuis LL. Therapeutic drug monitoring of lamotrigine. Ann Pharmacother 2002; 36: 917–20.

💊 Uses and Administration

Lamotrigine, a phenyltriazine compound, is an antiepileptic used mainly for monotherapy or adjunctive treatment of partial seizures and primary and secondarily generalised tonic-clonic seizures. It may be used for seizures associated with the Lennox-Gastaut syndrome and for the maintenance treatment of bipolar disorder. The doses given below for the use of lamotrigine in epilepsy are those licensed in the UK; similar doses are given in the USA although the use of lamotrigine is more limited than in the UK.
The initial oral dose for use as monotherapy is 25 mg once daily for 2 weeks followed by 50 mg once daily for 2 weeks; thereafter the dose is increased by a maximum of 50 to 100 mg every 1 to 2 weeks to usual maintenance doses of 100 to 200 mg daily, given as a single dose or in 2 divided doses. Some patients have required up to 500 mg daily
The initial oral dose of lamotrigine for use as an adjunct to therapy with enzyme-inducing antiepileptics (but not with valproate) is 50 mg once daily for 2 weeks followed by 50 mg twice daily for 2 weeks; thereafter the dose is increased by a maximum of 100 mg every 1 to 2 weeks to usual maintenance doses of 200 to 400 mg daily given in 2 divided doses. Some patients have required up to 700 mg daily
In those taking valproate the initial oral dose of lamotrigine is 25 mg every other day for 2 weeks followed by 25 mg once daily for 2 weeks; thereafter the dose is increased by a maximum of 25 to 50 mg every 1 to 2 weeks to usual maintenance doses of 100 to 200 mg daily given as a single dose or in 2 divided doses
In those taking oxcarbazepine but no enzyme-inducing or -inhibiting antiepileptics the dosage regimen of adjunctive lamotrigine is as for monotherapy
If the potential for interaction with adjunctive antiepileptics is unknown, treatment with lamotrigine should be started with lower doses such as those used with valproate. For comment on the need to modify maintenance doses when starting or stopping oral contraceptives see Sex Hormones, under Interactions, above. For doses in children, see below. In the management of bipolar disorder, the target dose of lamotrigine is 200 mg daily as monotherapy; for patients taking valproate the target dose is 100 mg daily and in those taking enzyme-inducing drugs (but not with valproate) the target dose is 400 mg daily. Lamotrigine should be started at a reduced dose and increased gradually to the target dose in a regimen similar to that used in the treatment of epilepsy (see above). Doses should be reduced in patients with hepatic impairment regardless of indication (see below). As with other antiepileptics, withdrawal of lamotrigine therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients. Licensed drug information recommends that regardless of indication the withdrawal of lamotrigine should be tapered over at least 2 weeks.

Administration in children.

Lamotrigine is used as an adjunct in the treatment of partial seizures and primary and secondarily generalised tonic-clonic seizures in children aged 2 years and over; it is used as monotherapy in those over 12 years of age. Lamotrigine may also be used for seizures associated with the Lennox-Gastaut syndrome. The doses given below are those licensed in the UK; similar doses are given in the USA although the use of lamotrigine is more limited than in the UK.
In those taking enzyme-inducing antiepileptics (but not with valproate) the initial oral dose of lamotrigine is 600 micrograms/kg daily in 2 divided doses for 2 weeks followed by 1.2 mg/kg daily for 2 weeks; thereafter the dose is increased by a maximum of 1.2 mg/kg every 1 to 2 weeks to usual maintenance doses of 5 to 15 mg/kg daily given in 2 divided doses
In those taking valproate the initial oral dose of lamotrigine is 150 micrograms/kg once daily for 2 weeks followed by 300 micrograms/kg once daily for 2 weeks; thereafter the dose is increased by a maximum of 300 micrograms/kg every 1 to 2 weeks to usual maintenance doses of 1 to 5 mg/kg daily, given as a single dose or in 2 divided doses
In those taking oxcarbazepine but no enzyme-inducing or -inhibiting antiepileptics the initial oral dose of lamotrigine, given as a single dose or in 2 divided doses, is 300 micrograms/kg daily for 2 weeks, followed by 600 micrograms/kg daily for 2 weeks; thereafter the dose is increased by a maximum of 600 micrograms/kg every 1 to 2 weeks to usual maintenance doses of 1 to 10 mg/kg daily, to a maximum of 200 mg daily.
If the calculated daily dose of lamotrigine lies between 1 and 2 mg, then 2 mg may be given on alternate days for the first 2 weeks of therapy. Lamotrigine should not be given if the calculated daily dose is less than 1 mg. Children over 12 years of age may be given the adult dosage regimen for monotherapy and adjunctive therapy (see above).

Administration in hepatic impairment.

UK licensed product information for lamotrigine recommends that doses should be reduced by about 50% in patients with moderate hepatic impairment (Child-Pugh category B), and by about 75% in severe impairment (Child-Pugh category C). US licensed product information recommends that doses should be reduced by about 25% in patients with moderate to severe hepatic impairment without ascites, and by about 50% in those with severe hepatic impairment with ascites.

Anxiety disorders.

Small studies have suggested that lamotrigine may relieve some of the symptoms of post-traumatic stress disorder.
1. Hertzberg MA, et al. A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biol Psychiatry 1999; 45: 1226–9
2. Hageman I, et al. Post-traumatic stress disorder: a review of psychobiology and pharmacotherapy. Acta Psychiatr Scand 2001; 104: 411–22.

Bipolar disorder.

In a multicentre placebo-controlled study involving 195 patients, lamotrigine 50 or 200 mg daily by mouth produced dose-related improvement in patients with bipolar disorder experiencing a major depressive episode.1 Further data from randomised controlled studies2-8 have confirmed benefit for depressive symptoms (although not for mania), and reviews9-13 have generally favoured its use, although some have queried the strength of the evidence.14 Guidelines for the treatment of bipolar disorder now recommend lamotrigine as a firstline option for bipolar depression, and it is licensed for such use in a number of countries (see also Uses and Administration, above).
1. Calabrese JR, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 1999; 60: 79–88
2. Bowden CL, et al. Lamotrigine in the treatment of bipolar depression. Eur Neuropsychopharmacol 1999; 9 (suppl 4): S113–S117
3. Calabrese JR, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 2000; 61: 841–50
4. Ichim L, et al. Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial. Ann Clin Psychiatry 2000; 12: 5–10
5. Obrocea GV, et al. Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biol Psychiatry 2002; 51: 253–60
6. Bowden CL, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60: 392–400. Correction. ibid. 2004; 61: 680
7. Calabrese JR, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003; 64: 1013–24
8. Nierenberg AA, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry 2006; 163: 210–16
9. Engle PM, Heck AM. Lamotrigine for the treatment of bipolar disorder. Ann Pharmacother 2000; 34: 258–62
10. Hurley SC. Lamotrigine update and its use in mood disorders. Ann Pharmacother 2002; 36: 860–73
11. Goldsmith DR, et al. Lamotrigine: a review of its use in bipolar disorder. Drugs 2003; 63: 2029–50
12. Muzina DJ, et al. Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder. Acta Psychiatr Scand Suppl 2005; 21–8
13. Smith LA, et al. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord 2007; 9: 394–412
14. van der Loos MLM, et al. Lamotrigine bij de behandeling van bipolaire stoornissen: een overzicht. Tijdschr Psychiatr 2007; 49: 95–103.

Epilepsy.

Lamotrigine is used in the treatment of epilepsy. It is used in partial seizures with or without secondary generalisation, and in generalised tonic-clonic seizures, although valproate is the drug of choice in the latter where these are associated with the syndrome of primary generalised epilepsy. It is also recommended in absence seizures, although the evidence base is not particularly strong, and may be used in juvenile myoclonic epilepsy and tried in tonic or atonic seizures. As monotherapy for partial seizures with or without secondary generalisation, lamotrigine was found to be better than carbamazepine (the established first-line drug) in terms of time to treatment failure and tolerability.1 In patients with newly-diagnosed partial seizures with or without secondary generalisation, lamotrigine had a similar efficacy to carbamazepine, but again was better tolerated.2 A systematic review3 of randomised, placebo-controlled studies concluded that lamotrigine is also effective in reducing the seizure frequency when added to current antiepileptic regimens in patients with refractory partial seizures. As monotherapy for primary generalised and unclassifiable seizures lamotrigine was found4 to be significantly inferior to valproate (the established first-line drug) in terms of seizure control, with almost twice the failure rate; valproate was also significantly more effective for achieving 12-month remission and prolonging the time to first seizure. Benefit was seen with adjunctive lamotrigine when compared with placebo in children5 and adults6 for treatment-resistant primary generalised seizures; it was also suggested6 that lamotrigine therapy may be appropriate when determination of the type of epilepsy in these patients is not possible. Lamotrigine appears to be an effective adjunctive treatment in children with the Lennox-Gastaut syndrome.7,8 It has also been found to be effective and well tolerated as adjunctive therapy in paediatric patients with refractory epilepsy including those with developmental impairment;9 it was particu larly effective in absence and atypical seizures in this open-label study. (Evidence for the use of lamotrigine to treat absence seizures, as for the other common alternatives ethosuximide and valproate, is, however, generally poor.10)
1. Marson AG, et al. SANAD Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15
2. Brodie MJ, et al. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995; 345: 476–9
3. Ramaratnam S, et al. Lamotrigine add-on for drug-resistant partial epilepsy. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2001 (accessed 09/06/08)
4. Marson AG, et al. SANAD Study Group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26
5. Trevathan E, et al. Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures. Abstract: Pediatrics 2006; 118: 777–8. Full version: http://www.pediatrics.org/cgi/content/full/118/2/e371 (accessed 09/06/08
6. Biton V, et al. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology 2005; 65: 1737–43
7. Donaldson JA, et al. Lamotrigine adjunctive therapy in childhood epileptic encephalopathy (the Lennox Gastaut Syndrome). Epilepsia 1997; 38: 68–73
8. Motte J, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med 1997; 337: 1807–12. Correction. ibid. 1998; 339: 851–2
9. Besag FMC, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr 1995; 127: 991–7
10. Posner EB, et al. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2005 (accessed 09/06/08).

Migraine.

Case reports1 and open studies2,3 have suggested that lamotrigine may be of benefit in the prophylaxis of migraine aura.
1. d’Onofrio F, et al. Basilar-type migraine responsive to lamotrigine: three case reports. Neurol Sci 2007; 28: S239–S241
2. Pascual J, et al. Preventing disturbing migraine aura with lamotrigine: an open study. Headache 2004; 44: 1024–8
3. Lampl C, et al. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry 2005; 76: 1730–2.

Motor neurone disease.

Lamotrigine has been tried as a potential therapy for amyotrophic lateral sclerosis but with disappointing results.1
1. Ryberg H, et al. A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters. Acta Neurol Scand 2003; 108: 1–8.

Movement disorders.

Symptomatic improvement and a trend towards decreased chorea was reported1 with lamotrigine in a double-blind, placebo-controlled study of 64 patients with Huntington’s chorea with motor signs of less than 5 years’ duration. There was, however, no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months.
1. Kremer B, et al. Influence of lamotrigine on progress of early Huntington disease: a randomized clinical trial. Neurology 1999; 53: 1000–11.

Neuropathic pain.

There is growing evidence that lamotrigine is of use in the management of neuropathic pain.1 It was effective when used with carbamazepine or phenytoin in the treatment of refractory trigeminal neuralgia2, and has also shown promise in the treatment of pain associated with HIV-related distal sensory neuropathy3. Some benefit has been found4 in the treatment of diabetic neuropathy. Case reports5 and a placebo-controlled trial6 have also indicated that lamotrigine may be effective in central post-stroke pain. More recently, the use of lamotrigine in neuropathic pain has been reviewed.7,8Based on the same studies, one review7 concluded that lamotrigine is an effective treatment for various types of neuropathic pain and that further studies are warranted while another8 concluded that it is unlikely to be of benefit and that further studies are probably not justified.
1. McCleane GJ. Lamotrigine in the management of neuropathic pain: a review of the literature. Clin J Pain 2000; 16: 321–6
2. Zakrewska JM, et al. Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover study. Pain 1997; 73: 223–30
3. Simpson DM, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 2003; 60: 1508–14
4. Eisenberg E, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001; 57: 505–9
5. Canavero S, Bonicalzi V. Lamotrigine control of central pain. Pain 1996; 68: 179–81
6. Vestergaard K, et al. Lamotrigine for central post-stroke pain: a randomized controlled trial. Neurology 2001; 56: 184–90
7. Eisenberg E, et al. Lamotrigine for neuropathic pain. Expert Rev Neurother 2005; 5: 729–35
8. Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2007 (accessed 09/06/08).

Schizophrenia.

Lamotrigine has been tried as adjunctive therapy in treatment-resistant schizophrenic patients1 and a benefit has been reported in few studies,2-4 although patient numbers have been small. However, a systematic review5 of the use of lamotrigine in schizophrenia concluded that the evidence for its use was poor, although it was suggestive of a positive effect on symptoms.
1. Large CH, et al. The potential role of lamotrigine in schizophrenia. Psychopharmacology (Berl) 2005; 181: 415–36
2. Tiihonen J, et al. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 2003; 54: 1241–8
3. Kremer I, et al. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol Psychiatry 2004; 56: 441–6
4. Zoccali R, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res 2007; 93: 109–16
5. Premkumar TS, Pick J. Lamotrigine for schizophrenia. Available in the Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2006 (accessed 09/06/08).

💊 Preparations

Proprietary Preparations

Arg.: Dafex; Epilepax; Lagotran; Lamictal; Lamirax; Lamotril; Latrigin; Austral.: Elmendos; Lamictal; Lamidus; Lamitrin; Lamogine; Seaze; Austria: Bipolam; Gerolamic; Lamictal; Lamotriglax; Belg.: Lambipol; Lamictal; Braz.: Lamictal; Lamitor; Neural; Neurium; Canad.: Lamictal; Chile: Daksol; Lafigin; Lamictal; Lomarin; Meganox; Tradox; Trizol; Cz.: Danoptin; Epimil; Epiral; Lameton; Lamictal; Lamiger; Lamogine; Lamolep; Lamotax; Lamotri; Lamotrix; Latrigil; Plexxo; Rubimar; Triginet; Denm.: Lamictal; Fin.: Lamictal; Fr.: Lamicstart; Lamictal; Ger.: Elmendos; Lamictal; Lamo; Lamotriax; Lamotrig; Gr.: Lamictal; Lamotrix; Hong Kong: Lamictal; Hung.: Epitrigine; Lamictal; Lamitrin; Lamolep; Plexxo; India: Lamepil; Lametec; Indon.: Lamictal; Irl.: Lamictal; Larig; Israel: Lamictal; Lamodex; Lamogine; Ital.: Lamictal; Malaysia: Lamictal; Lamotrix; Mex.: Lamdra; Lamictal; Limatic; Protalgine; Neth.: Lamictal; Lamitor; Lamochem†; Lamomont; Lamotifi; Plexxo†; Symla; Norw.: Lamictal; NZ: Lamictal; Mogine; Philipp.: Lamictal; Pol.: Danoptin; Epilactal; Lamia; Lamilept; Lamitrin; Lamotrihexal; Lamotrix; Plexxo; Triginet; Port.: Lamictal; Rus.: Convulsan (Конвульсан); Lamictal (Ламиктал); Lamitor (Ламитор); Lamolep (Ламолеп); S.Afr.: Epitec; Lamictin; Lamitor; Singapore: Lamictal; Spain: Crisomet; Labileno; Lamictal; Swed.: Lamictal; Switz.: Lamictal; Thai.: Lamictal; Turk.: Lamictal; UK: Lamictal; USA: Epitrogine; Lamictal; Venez.: Epifon†; Lamictal.
Published November 01, 2018.