====== Lamotrigine ====== ===== DRUGS INCLUDED IN THIS CATEGORY ===== Lamotrigine is available in standard oral, chewable, disintegrating mucous membrane and extended release forms. ===== OVERVIEW ===== Lamotrigine overdose most commonly leads to rash and mild to moderate CNS effects (sedation, delirium, nystagmus, ataxia, involuntary movements) but is occasionally complicated by seizures and severe cardiac sodium channel blockade with refractory ventricular [[:wikitox:3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|arrhythmias]]. Treatment is largely limited to providing supportive care, but sustained release overdoses and early presentations of large overdoses might benefit from activated charcoal. Clearance of lamotrigine may possibly be enhanced with repeated doses of activated charcoal or hemodialysis but the indications and clinical benefit from these interventions are unknown. ===== MECHANISM OF TOXIC EFFECTS ===== Lamotrigine blocks voltage-gated sodium channels in a rate-dependent manner. In contrast to many sodium channel blocking drugs, alkalinisation does not appear to have favourable effects on the extent of block (Lazar //et al.// 2015). It has numerous other pharmacological actions at both therapeutic and overdose concentrations which are of unclear significance. Notably, it is a reversible non-selective monoamine oxidase inhibitor (Southam //et al.// 2005), although, puzzlingly, interactions with SSRIs causing severe serotonin toxicity have not been reported. The CNS and cardiovascular effects observed in overdose may be related to the sodium channel blocking effect, although other features of the toxicity of lamotrigine (rash, delirium, abnormal movements) are different from other sodium channel blocking drugs. ===== KINETICS IN OVERDOSE ===== ==== Absorption ==== Absorption is rapid and complete after ingestion of the standard release preparation in therapeutic doses with peak concentrations occurring around 2–3 hours later. There are limited data on pharmacokinetics in overdose but sustained release formulations would be expected to be slowly absorbed and potentially form pharmacobezoar. ==== Distribution ==== Lamotrigine distributes widely with a volume of distribution of 0.9 to 1.2 L/kg. It is about 55% bound to serum proteins. These factors mean it would theoretically be possible to significantly increase elimination with [[:wikitox:3.2.3.1.2_charcoal_haemoperfusion|haemodialysis]]. Although this has not been documented in overdose, in therapeutic use about 20% of lamotrigine is removed with 4 hours of intermittent haemodialysis, and the elimination half-life in renal failure is reduced three-fold by dialysis. ==== Metabolism - Elimination ==== The elimination half-life of lamotrigine is 25–50 hours in chronic therapeutic doses, with longer half-lives reported with both renal and hepatic failure (which may reflect altered distribution or clearance). Lamotrigine is metabolised in the liver, primarily by glucuronidation (UGT1A4 and UGT2B7)(Rowland //et al.// 2006). Valproate is known to substantially decrease clearance and it is likely there are other drugs that might interact via this mechanism. ===== CLINICAL EFFECTS ===== ==== Central nervous system effects ==== The most common effects are related to disturbance of neuronal transmission. Nystagmus, ataxia, agitation and sedation may occur. Involuntary movements such as hemiballismus, choreoathetosis and myoclonus are a notable feature in some patients. Paradoxical seizures may also occur (French //et al.// 2011; Moore //et al.// 2013; Nogar //et al.// 2011). CNS effects after co-ingestion with noradrenaline (norepinephrine), dopamine or serotonin reuptake inhibitors (e.g. antidepressants, bupropion, amphetamines) are potentially more serious, given the MAO inhibiting effects of lamotrigine found in vivo. ==== Cardiac effects ==== Hypotension is common but is likely to be due to CNS effects and dehydration rather than direct cardiac effects in most cases. QRS prolongation, heart block and ventricular arrhythmias may occur, and indicate a severe overdose (French //et al.// 2011; Nogar //et al.// 2011). Note the sodium channel blockade has been reported __not__ to respond to alkalinisation in laboratory (Lazar //et al.// 2015) or clinical settings (French //et al.// 2011; Nogar //et al.// 2011). ===== INVESTIGATIONS ===== ==== Blood concentrations ==== === Conversion factor === * mg/L x 3.91 = µmol/L * µmol/L x 0.256 = mg/L Lamotrigine concentrations are not generally monitored in patients. The therapeutic range is sometimes quoted as 3 to 14 mg/L (12–55 µmol/L), although earlier studies aimed for much lower trough concentrations (1 to 4 mg/L) (Chong and Dupuis 2002). There is little evidence to indicate what concentrations are of concern, overdoses with concentrations of 17, 26 and 90 mg/L have reported ECG changes (Buckley //et al.// 1993; Moore //et al.// 2013; Sirianni //et al.// 2008), and concentrations as low as 36 and 75 mg/L have been measured after cardiac arrests (French //et al.// 2011; Nogar //et al.// 2011). Yet, many with similar concentrations have had unremarkable courses. ==== Biochemistry and Haematology ==== There are no expected electrolyte abnormalities in lamotrigine overdose although these would generally be measured. Rhabdomyolysis and coagulopathy have occasionally been reported as late complications, but it is unclear if these relate to lamotrigine or were secondary complications. ==== ECG ==== Marked ECG abnormalities are unusual but prolonged QRS duration is fairly common. Refractory ventricular arrhythmias have been observed in lamotrigine overdose, but the risk factors for these rare cases are poorly defined (French //et al.// 2011; Nogar //et al.// 2011). ===== DIFFERENTIAL DIAGNOSIS ===== The differential diagnosis would depend on the dominant clinical feature. Other sodium channel blocking drugs should be considered in the presence of seizures and QRS prolongation. The abnormal movements could possibly be confused with those associated with serotonin toxicity or dopamine agonist/antagonists. ===== TREATMENT ===== ==== Supportive ==== Maintenance of the airway and ventilation is the first priority in unconscious overdose patients. IV access (with IV fluids [normal saline]) should be secured as soon as possible in order to have access for the treatment of seizures or arrhythmias. The following would indicate the need for intensive care admission: * Need for intubation or ventilation ([[:wikitox:3.2.3.1.2_charcoal_haemoperfusion|GCS]] < 9; high pCO2; for decontamination, etc.) * Abnormal ECG (QRS > 100 ms, PR > 200 ms or heart block, arrhythmias) ==== GI Decontamination ==== Oral [[:wikitox:3.2.2.2.3_activated_charcoal|activated charcoal]] should be considered in large overdoses (while the risk of toxicity is low, serious cases are often refractory to treatment). Repeat-dose activated charcoal should also be given to unconscious patients. ==== Treatment of specific complications ==== === Delirium / abnormal movements === Given the mechanism is poorly understood, treatment with oral or intravenous [[:wikitox:benzodiazepines|]] is probably the safest option (in adults: Diazepam 5 to 10 mg, repeated as necessary). === Seizures === [[:wikitox:status_epilepticus_and_treatment_of_seizures|Seizures]] should be treated with intravenous [[:wikitox:benzodiazepines|]] (in adults: Diazepam 5 to 10 mg, repeated if necessary every 15 to 20 minutes). [[:wikitox:barbiturates|Phenobarbitone]] (15 mg/kg) can be used if seizures are refractory to benzodiazepines. Avoid phenytoin which is also a sodium channel blocking drug. ==== Arrhythmias ==== Ventricular arrhythmias are the usual cause of in-hospital deaths. Ventricular arrhythmias should be treated with lignocaine (lidocaine). Other [[:wikitox:3.4.3.4_antiarrhythmics|class I antiarrhythmic drugs]], [[:wikitox:magnesium_treatment|magnesium]], [[:wikitox:3.4.3.4.2_beta_blockers|beta-blockers]] and amiodarone are likely to exacerbate cardiac toxicity (convert ventricular arrhythmias into asystole). The pH can be corrected, but sodium bicarbonate and alkalinisation are not effective treatments for the cardiac toxicity in theory or practice. ===== Elimination enhancement ===== [[:wikitox:3.2.2.2.3.1_repeated_doses_of_activated_charcoal|Multiple doses of activated charcoal]] would be expected to moderately increase the clearance of lamotrigine (Buckley //et al.// 1993). High-flux haemodialysis would also be expected to significantly enhance lamotrigine elimination, although reports in the overdose setting are absent, and this would be difficult in the setting of severe cardiac toxicity, when it would be most indicated. ===== LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP ===== Long term sequelae have not been reported and no follow up is required after resolution of the clinical signs & ECG findings unless the patient has been profoundly hypotensive. ===== REFERENCES ===== Buckley, N. A., Whyte, I. M., and Dawson, A. H. (1993). Self-poisoning with lamotrigine. //Lancet// 342(8886-8887), 1552-1553 Chong, E., and Dupuis, L. L. (2002). Therapeutic drug monitoring of lamotrigine. //Ann. Pharmacother.// 36(5), 917-920 French, L. K., Mckeown, N. J., and Hendrickson, R. G. (2011). Complete heart block and death following lamotrigine overdose. //Clin. Toxicol. (Phila)// 49(4), 330-333 Lazar, A., Lenkey, N., Pesti, K., Fodor, L., and Mike, A. (2015). Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway. //Front Pharmacol.// 6, 210 Moore, P. W., Donovan, J. W., Burkhart, K. K., and Haggerty, D. (2013). A case series of patients with lamotrigine toxicity at one center from 2003 to 2012. //Clin. Toxicol. (Phila)// 51(7), 545-549 Nogar, J. N., Minns, A. B., Savaser, D. J., and Ly, B. T. (2011). Severe sodium channel blockade and cardiovascular collapse due to a massive lamotrigine overdose. //Clin. Toxicol. (Phila)// 49(9), 854-857. Rowland, A., Elliot, D. J., Williams, J. A., Mackenzie, P. I., Dickinson, R. G., and Miners, J. O. (2006). In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. //Drug Metab Dispos.// 34 (6), 1055-1062 Sirianni, A. J., Osterhoudt, K. C., Calello, D. P., Muller, A. A., Waterhouse, M. R., Goodkin, M. B., Weinberg, G. L., and Henretig, F. M. (2008). Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. //Ann. Emerg. Med.// 51(4), 412-5, 415 Southam, E., Pereira, R., Stratton, S. C., Sargent, R., Ford, A. J., Butterfield, L. J., Wheable, J. D., Beckett, S. R., Roe, C., Marsden, C. A., and Hagan, R. M. (2005). Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo. //Eur. J. Pharmacol.// 519(3), 237-245