Clinical Toxicology (2011) 49, 330–333
Ó 2011 Informa Healthcare USA, Inc.
ISSN 1556-3650 print/ISSN 1556-9519 online
DOI: 10.3109/15563650.2011.572555
SHORT REPORT
Complete heart block and death following lamotrigine overdose
LOREN K. FRENCH1, NATHANAEL J. MCKEOWN2, and ROBERT G. HENDRICKSON1
1
Emergency Department, Oregon Health & Science University, Portland 97239-3098, USA
2
Oregon Poison Center, Portland, Oregon 97239-3098, USA
Context. Lamotrigine is used for both seizure and psychiatric disorders. Overdoses typically follow a benign course. Case details. A
Clinical Toxicology Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 11/04/14
19-year-old male with bipolar disorder ingested 4 g of lamotrigine. The patient suffered from multiple seizures, charcoal aspiration,
respiratory arrest, prolongaton of the QRS interval on electrocardiogram, complete heart block, multiorgan failure and ultimately death.
Discussion. We describe the emergency department (ED) and ICU course for this patient and briefly review the toxic effects of
lamotrigine and the pharmacokinetics with and without hemodialysis.
Keywords Heart; CNS/psychological; Dialysis; Anticonvulsant
Introduction
Lamotrigine is a phenyltriazine that was initially introduced
For personal use only.
as an antiepileptic for adjunctive management of partial and
secondarily generalized tonic-clonic seizures.1 Since the
early 1990s, the clinical applications of lamotrigine have
expanded, and therapy for various psychiatric disorders is
commonplace.
Oral overdoses of lamotrigine have largely resulted in
benign outcomes, with reported symptoms including
drowsiness, vomiting, ataxia, vertigo, and tachycardia.2 In
rare instances, lamotrigine overdose has produced more
severe symptoms such as seizures, lengthening of the QRS
interval, and ventricular dysrhythmias.3–6
We report a unique case of lamotrigine overdose
associated with complete heart block and death with
confirmatory concentrations. In addition, we describe the
toxicokinetics of lamotrigine and the effect of hemodialysis
(HD) on lamotrigine concentrations.
Case report
A 19-year-old man presented to the emergency department
15 min after an intentional overdose of lamotrigine. The
patient ingested the medication in front of his mother at the
end of an argument. The mother witnessed the patient open
and ingest an entire bottle containing 4 g of lamotrigine. At
Received 17 January 2011; accepted 12 March 2011.
Address correspondence to Dr. Loren keith French M.D.,
Emergency Department, Oregon Health & Science University,
3181 SW Sam Jackson Park Rd, Mail Code CB550, Portland
97239-3098, USA. E-mail: frenchk@ohsu.edu
330
the time of the argument, he had no known previous access
to other medications, he did not appear intoxicated and was
not previously expressing any suicidality. Aside from
bipolar disorder, he was otherwise healthy and was not
prescribed any other medications.
His examination was notable for a heart rate of 123 bpm
and blood pressure of 139/77 mmHg. His respiratory rate
was 16 breaths/min and SaO2 was 100% on room air. He
was awake, alert and noted to be texting on his cell phone.
The patient was pale and shaky, but without focal
neurological defects. He was not noted to have mydriasis
or flushed skin and his speech was normal. Other than
tachycardia, the remainder of his examination was un-
remarkable.
Shortly after arrival, he received 50 g of activated
charcoal. Ten minutes later, he experienced a generalized
tonic-clonic seizure which terminated after the administra-
tion of 5 mg IV diazepam. An ECG was obtained, which
demonstrated a sinus tachycardia (HR 110 bpm) with a wide
QRS interval of 214 ms. A chest X-ray performed at that
time revealed an infiltrate that was suspicious for aspiration.
Fifteen minutes later, a second tonic-clonic seizure ensued
and again terminated after the administration of 5 mg IV
diazepam. His oxygen saturations remained 498% between
seizures, though not explicitly stated if he required assisted
ventilation for this period.
Initial laboratory data, obtained at the time of the first
seizure, included a WBC of 27.9 K/uL, hemoglobin of
13.9 g/dL, and platelet count of 245 K/uL. A complete
metabolic panel was normal with the following exceptions:
potassium 3.5 mEq/L (3.6–5.1 mEq/L), glucose 79 mg/dL
(84–110 mg/dL), and total protein 8.1 g/dL (6.1–7.9 g/dL).
Serum bicarbonate concentration was 26 mmol/L.
Salicylates, ethanol, and acetaminophen were undetectable.

Additional testing for drugs of abuse was negative for
cocaine, tricyclic antidepressants, amphetamines,
propoxyphene, phencyclidine, barbiturates, cannabinoids,
methadone, and opiates.
Following the second seizure, the patient underwent
orogastric lavage. Following lavage, the patient was endo-
tracheally intubated by an anesthesiologist for depression of
mental status. No mention of the contents of the gastric
effluent was noted, however, charcoal was visualized in the
airway at the time of intubation, thus increasing the suspicion
of aspiration of gastric contents. Three minutes later, the
patient became pulseless and received one minute of chest
compression and 1 mg IV epinephrine with return of
spontaneous circulation. The post-intubation arterial blood
Clinical Toxicology Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 11/04/14
gas demonstrated a pH of 6.92, pCO2 70 mmHg, and pO2
115 mmHg, while on 100% FiO2 revealing both a respiratory
and metabolic acidosis. At this time, two ampules (50 mL) of
8.4% sodium bicarbonate were infused, and arrangements for
transfer to a tertiary care hospital were made. No repeat ECG
was performed. A repeat chest X-ray revealed an enlarging
infiltrate that was again suspicious for aspiration.
A repeat ECG at the receiving facility noted persistent QRS
prolongation (210 ms) (Fig. 1). Several hours after arrival to
the tertiary care facility, the patient developed complete heart
block requiring transvenous pacemaker placement. During
this time, serum chemistries were: sodium 152 mmol/L,
For personal use only.
potassium 3.8 mmol/L, chloride 116 mmol/L, bicarbonate
21 mmol/L, glucose 312 mg/dL, BUN 18 mg/dL and
creatinine 1.9 mg/dL. Arterial blood gas demonstrated a pH
of 7.18, pCO2 45 mmHg, and pO2 88 mmHg. Once
ventricular capture was obtained, an echocardiogram was
performed and a left ventricular ejection fracture of 520%
was measured. HD was performed on the second day of
admission (74 h post-ingestion) secondary to acute renal
failure from rhabdomyolysis (CK 23,039 U/L). An electro-
encephalogram (EEG) obtained on the second day of
admission demonstrated diffuse encephalopathy without
seizure activity, however, it remains unknown if he was
having non-convulsive seizures prior to this time. The first
lamotrigine concentration drawn at 19 h post-ingestion was
Fig 1. Initial ECG on arrival to tertiary care facility demonstrating
QRS prolongation (210 ms).
Clinical Toxicology vol. 49 no. 4 2011
Fatal lamotrigine overdose 331
35.7 mcg/mL (therapeutic reference range 3–14 mcg/mL).
Lamotrigine was detectable in the serum for over 8 days
despite five sessions of HD (Fig. 2). Over the next several
days, the patient developed Staphylococcal and Klebsiella
pneumonia and disseminated intravascular coagulation. On
the tenth day of admission, the patient’s family, understanding
his grave prognosis, wished to withdraw support and the
patient expired soon after.
Discussion
Lamotrigine is a phenyltriazine anticonvulsant that may
cause QRS prolongation, seizures, and altered mental status
in overdose.2,6,7
Lamotrigine exerts its antiepileptic effect through inhibition
of voltage-gated sodium channels.1 While the primary target is
neuronal tissue, lamotrigine has the potential to block cardiac
sodium channels as well. Consequently, wide complex
rhythms have been described, though infrequently, following
lamotrigine use in both therapeutic4 and overdoses.2,7
Common symptoms following overdose include drowsi-
ness, vomiting, nausea, ataxia, vertigo, and tachycardia.2
Other reported complications include seizures,6 anticonvul-
sant hypersensitivity syndrome,3 respiratory depression,7
and choreiform dyskinesia.8
Lamotrigine has an oral bioavailability of 98%. N-
glucuronidation is the primary means of metabolism and
there are no known metabolically active metabolites in
humans. Daily dosing of lamotrigine depends on the
indication but should not exceed 500 mg/day. In therapeutic
doses, the time to peak concentration is approximately 2.5 h
and the elimination half-life is approximately 25 h (range
14–50). Lamotrigine has no appreciable interaction with the
human cytochrome P450 system.9
Management of the patient with lamotrigine intoxication
is primarily supportive. Activated charcoal has shown to
Fig 2. Lamotrigine concentration vs. time from ingestion graph.
Arrows indicate HD in relation to time from ingestion. HD was run
for 3 h in all instances except the last two which ran for 2.5 h.
 332 L.K. French et al.
decrease lamotrigine absorption and accelerate its elimina-
tion.10 However, since overdose may cause sedation,
respiratory depression, and seizures, a cautious approach
may be warranted. As with most toxins, benzodiazepines are
the first line therapy for seizures.
Given the propensity for sodium channel blockade,
sodium bicarbonate therapy is physiologically sound, and
case reports have demonstrated narrowing of the QRS
complex following sodium bicarbonate administration.4 In
this case, an electrocardiogram (EKG) was not promptly
repeated following bolus administration of sodium bicarbo-
nate, thus conclusions regarding its effectiveness cannot be
made.
We documented a prolonged and highly variable half-life
Clinical Toxicology Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 11/04/14
for lamotrigine in our case of acute overdose (half-life
range: 16.6–630.0 h). There may be several explanations for
this observation. It is possible that lamotrigine had
prolonged absorption. However, lamotrigine has never been
described to form pharmacobezoars and it has no appreci-
able opioid or antimuscarinic effect and no known inhibition
of gastric emptying. We documented a prolonged half-life
for 8 days after ingestion, which would be a significantly
long period to be explained by slowed gastric emptying
alone. There was an increase in lamotrigine concentration
between 90 and 109 h that may imply continued absorption,
however, the concentration increase was small
For personal use only.
(1.2 mcg/mL) and is likely within the standard error for
the test and may simply reflect a concentration plateau.
Therefore, it is most likely that the prolonged half-life of
lamotrigine in our case was due to a decrease in elimination.
Valproic acid may inhibit N-glucuronidation and has been
demonstrated to slow elimination of lamotrigine. In this
case, the patient was not taking valproic acid, had no access
to valproic acid and had a witnessed ingestion, making co-
ingestion unlikely. Gilbert’s syndrome could potentially
slow elimination of lamotrigine, however, this patient had a
normal unconjugated bilirubin concentration during his
hospitalization and lacks history of this disorder. Unfortu-
nately, the toxicokinetics of lamotrigine are not well
described and it remains unclear if metabolism is saturated
or if pharmacokinetic properties are altered in another way
in overdose.11
The pharmacokinetics of lamotrigine in therapeutic doses,
including small molecular weight (256.09 g/mol), small
volume of distribution (Vd: 1.2 L/kg), and low protein
binding (55%), predict that lamotrigine should be cleared
moderately by HD. At therapeutic dosing, HD does appear
to increase lamotrigine clearance. Patients on HD from
chronic renal failure have shorter lamotrigine half-lives than
those who are not on HD (59.6 vs. 12.2 h), though large
individual variation was noted.12 In our case, the half-life of
lamotrigine with once daily dialysis ranged from 16.6 to
60.6 h with a mean of 42.3 h. In one instance, the
concentration increased after HD. The half-life of lamo-
trigine in our patient prior to HD was infinite and may have
reflected continued absorption early after the overdose. The
half-life without HD after the initial few days ranged from
60.1 to 101 h with a mean of 80.7 h. Further study using HD
clearance rates and dialysate concentrations, which were
limitations in this case, may further clarify if HD is an
appropriate modality in the treatment of acute severe
lamotrigine toxicity.
Complete heart block is a novel finding in lamotrigine
toxicity. While conduction abnormalities are encountered
following ingestions of many xenobiotics, concomitant
metabolic derangements may further suppress myocardial
function and contribute to cardiac toxicity. Acidosis,
hypoxia, and hypotension may have played a critical role
in the segue from conduction delay to conduction block in
this patient.
In this case, the patient clearly ingested lamotrigine, as
this action was directly witnessed by his mother. The dose
and the quantitative concentrations are consistent with his
tachycardia, seizures, and QRS prolongation. However, we
did consider other unreported intoxicants that may cause
seizure, heart block, and QRS widening, specifically cyclic
antidepressants, diphenhydramine, and cocaine. The patient
did not appear intoxicated at the time of his ingestion and he
had no appreciable antimuscarinic findings on his initial
examination in the Emergency Department (ED) or at any
other time during his hospitalization. In addition, his
immunoassay was negative for tricyclic antidepressants
(TCAs) and cocaine. Given the findings of an elevated
lamotrigine concentration, his symptom complex consistent
with lamotrigine toxicity, and his witnessed ingestion, we
feel that it is unlikely that there was a co-ingestant to explain
his symptoms.
Conclusion
We describe a case of lamotrigine overdose complicated by
seizures, wide-complex tachycardia, complete heart block, and
death. While the majority of lamotrigine overdoses reported in
the literature appear to follow a relatively benign course, our
case demonstrates the potential seriousness of these ingestions.
Further studies using HD clearance rates are needed before
definitive conclusions regarding the efficacy of HD in
lamotrigine overdose can be made.
Declaration of interest
The authors report no conflict of interest. The authors alone
are responsible for the content and writing of this paper.
References
1. Fitton A, Goa KL. Lamotrigine. An update of its pharmacology and
therapeutic use in epilepsy. Drugs 1995; 50:691–713.
2. Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity
reported to poison centers. Ann Pharmacother 2004; 38:1811–1815.
3. Mylonakis E, Vittorio CC, Hollik DA. Lamotrigine overdose presen-
ting as anticonvulsant hypersensitivity syndrome. Ann Pharmacother
1999; 33:557–559.
4. Herold TJS. Lamotrigine as a possible cause of QRS prolongation in a
patient with known seizure disorder. Can J Emerg Med 2006; 8:
361–364.
Clinical Toxicology vol. 49 no. 4 2011

5. Reimers A, Reinholt G. Acute Lamotrigine overdose in an adolescent.
Ther Drug Monit 2007; 29:669–670.
6. Close BR, Banks CJ. Seizures secondary to lamotrigine toxicity in a
two-year old. Ann Pharacother 2010; 44:1112–1115.
7. Wade FJ, Dang CV, Nelson L, Wasserberger J. Emergency complica-
tions of the newer anticonvulsants. J Emer Med 2010; 38:231–237.
8. Miller MA, Levsky ME. Choreiform dyskinesia following isolated
lamotrigine overdose. J Child Neurol 2008; 23:243.
9. Doyon, S. Goldfrank’s Toxicologic Emergencies. 8th ed. New York:
McGraw-Hill; 2006. Chapter 47, pp. 713–745.
Clinical Toxicology Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 11/04/14
For personal use only.
Clinical Toxicology vol. 49 no. 4 2011
Fatal lamotrigine overdose 333
10. Keranen T, Sorri A, Moilanen E, Ylitalo P. Effects of charcoal on the
absorption and elimination of the antiepileptic drugs lamotrigine and
oxcarbazepine. Arzneimittelforschung 2010; 60:421–426.
11. Rowland, A, Elliot DJ, Williams JA, Mackenzie PI, Dickinson RG,
Miners JO. In vitro characterization of lamotrigine N2-
glucoronidation and the lamotrigine-valproic acid interaction. Drug
Metab Dispos 2006; 34:1055–1062.
12. Fillastre JP, Taburet AM, Fialaire A, Etienne I, Bidault R, Singlas E.
Pharmacokinetics of lamotrigine in patients with renal impairment:
influence of haemodialysis. Drugs Exp Clin Res 1993; 19:25–32.