a) Fever has been reported with overdose (Dagtekin et al, 2011).
b) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. One patient developed hyperthermia (temperature greater than 38 degrees C) (Moore et al, 2013).
c) CASE REPORT: Increased temperature related to leukopenia and sepsis has been reported following 10 days of lamotrigine therapy (Nicholson et al, 1995). Other drugs used by the patient included valproate sodium and propranolol.
d) CASE REPORT: A 45-year-old woman developed fever, rash, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure 14 days after beginning lamotrigine therapy (Schaub et al, 1994). Other medications included clonazepam and carbamazepine.

a) CASE REPORT: Tachycardia (150 bpm) was present in a 29-year-old man after intentionally ingesting an unknown number of 200 milligram lamotrigine tablets along with ethanol (Schwartz & Geller, 2007).
b) CASE REPORT: Increased pulse rate (120 BPM) in a 33-year-old woman following a 1500 to 2000 milligrams lamotrigine overdose (Harchelroad et al, 1994) and in a 26-year-old man following a 1350 milligram lamotrigine overdose (Buckley et al, 1993) have been reported.

a) A 10-year-old girl who was taking lamotrigine 22 mg/kg/day (plasma concentration 6.7 mcg/mL) presented with oculogyric crisis (a few to 20 episodes/day for 3 days; duration of each episode, 2 to 3 hours; associated symptoms: tremulousness, irritability) about a week after her lamotrigine dose was increased to 25 mg/kg/day (plasma concentration 15.8 mcg/mL). MRI revealed diffuse cerebral and cerebellar atrophy. Her symptoms resolved after lamotrigine dose was decreased to 20 mg/kg/day (plasma concentration 8.5 mcg/mL).
b) A 3-year-old boy who was taking lamotrigine 2 mg/kg/day (plasma concentration 2.1 mcg/mL) developed oculogyric crisis (1 episode/day for 1 month; duration of each episode, few seconds to 1 minute) after his lamotrigine dose was increased to 7.8 mg/kg/day. His symptoms resolved after decreasing the lamotrigine dose.
c) An 11-year-old boy who was taking lamotrigine 5.5 mg/kg/day for absence seizures, developed recurrent episodes of oculogyric crisis (5 to 7 episodes/day for 3 months; duration of each episode, 2 to 4 seconds) after his lamotrigine dose was increased to 7 mg/kg/day (plasma concentration 9.3 mcg/mL). His symptoms resolved after his lamotrigine dose was decreased to 4 mg/kg/day.

a) CASE REPORT: Two patients developed reversible downbeat nystagmus as a result of lamotrigine toxicity. Both patients had intractable epilepsy and developed oscillopsia and incoordination while taking lamotrigine in combination with other anticonvulsants. The first patient was taking lorazepam 1 mg twice daily, lamotrigine 100 milligrams four times daily, and gabapentin 400 milligrams three times daily. She had large amplitude downbeat nystagmus in the primary gaze, which became more pronounced in both right and left gaze. Downbeat nystagmus in down gaze and minimal nystagmus in up gaze were noted. In addition, she had moderate truncal ataxia. Serum lamotrigine levels peaked at 19.9 mcg/mL (therapeutic range 1-14 mcg/mL). After lamotrigine dose was reduced, her nystagmus resolved without further sequelae (AlKawi et al, 2005).
b) CASE REPORT: An 18-year-old woman with a history of epilepsy presented agitated, disoriented, noncooperative with a Glasgow Coma Scale (GCS) score of 12 about an hour after ingesting an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets. Physical examination revealed vertical nystagmus and myoclonia. She responded to questions with dysphasia within an hour of receiving IV lipid emulsion therapy (bolus of 100 mL and 0.5 mL/kg/min infusion for 2 hours; total dose, 3100 mL). She had a GCS score of 15 and mild dysarthria 4 hours later (Eren Cevik et al, 2014).

a) CASE REPORT: Dry mouth with thick secretions was reported in a 33-year-old woman following a 1500 to 2000 milligrams lamotrigine overdose (Harchelroad et al, 1994).

a) Premarketing studies have shown a minor incidence of increase in PR interval, not clinically significant, following therapeutic lamotrigine doses (Matsuo et al, 1993).
b) One study reported one case who had clinically insignificant first-degree heart block following therapeutic doses of lamotrigine (Betts et al, 1991).
c) BRUGADA-LIKE PATTERN

a) No ECG abnormalities were reported in an overdose involving greater than 4000 mg lamotrigine and a plasma lamotrigine concentration of 52 mcg/mL (Prod Info Lamictal(R), lamotrigine tablets, 2000).
b) Conduction disturbances were reported in 2 of 493 patients following lamotrigine overdose (Lofton & Klein-Schwartz, 2004).
c) CASE REPORT: A 50-year-old woman with a history of type 2 diabetes and bipolar disorder developed coma (Glasgow Coma Scale 7) approximately 2 hours after ingesting up to 3.5 g of lamotrigine. She was hemodynamically stable and a chest X-ray was normal. An ECG revealed sinus tachycardia and arterial blood gas analysis revealed FiO2 = 0.30, pH 7.36, PaCO2 39 mm Hg, PaO2 85 mm Hg, and base deficit -3 mmol/L. At this time, serum lamotrigine concentration was 27.1 mcg/mL (reference, 2 to 16 mcg/mL). She was treated with activated charcoal, IV magnesium and sodium bicarbonate. Four hours postadmission, another ECG revealed a widening of the QRS complex with left bundle branch block. All laboratory results, including troponin-I levels, were normal. Six hours postingestion, serum lamotrigine concentration increased to 29.7 mcg/mL. Despite supportive therapy, including sodium bicarbonate, the ECG did not improve. At this time, she was treated with an intravenous bolus (1.5 mL/kg) of 20% lipid emulsion and all symptoms resolved within a few minutes. She continued to receive lipids (0.5 mL/kg/min) for another 10 hours. She was discharged 2 days postingestion (Castanares-Zapatero et al, 2011).

a) Severe sodium channel blockade after a massive lamotrigine overdose has been reported (Nogar et al, 2011).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. QRS prolongation (114 to 116 ms) developed in 2 patients (Moore et al, 2013).
b) CASE REPORT: A 19-year-old man with bipolar disorder ingested 4 g of lamotrigine and developed tachycardia (123 beats/min), multiple seizures, charcoal aspiration, respiratory failure, prolongation of the QRS interval (214 ms), and completed heart block. Despite supportive care, he developed sepsis and multiorgan failure and died 10 days postingestion (French et al, 2011).
c) Widening of the QRS complex (112 msec) was reported in a 26-year-old man following an overdose of 1350 mg lamotrigine. Two months later his QRS width had decreased to less than 100 ms (Buckley et al, 1993).
d) CASE REPORT: A 50-year-old woman with a history of type 2 diabetes and bipolar disorder developed coma (Glasgow Coma Scale 7) approximately 2 hours after ingesting up to 3.5 g of lamotrigine. She was hemodynamically stable and a chest X-ray was normal. An ECG revealed sinus tachycardia and arterial blood gas analysis revealed FiO2 = 0.30, pH 7.36, PaCO2 39 mm Hg, PaO2 85 mm Hg, and base deficit -3 mmol/L. At this time, serum lamotrigine concentration was 27.1 mcg/mL (reference, 2 to 16 mcg/mL). She was treated with activated charcoal, IV magnesium and sodium bicarbonate. Four hours postadmission, another ECG revealed a widening of the QRS complex with left bundle branch block. All laboratory results, including troponin-I levels, were normal and vital signs remained stable. Six hours postingestion, serum lamotrigine concentration increased to 29.7 mcg/mL. Despite supportive therapy, including sodium bicarbonate, the ECG did not improve. At this time, she was treated with an intravenous bolus (1.5 mL/kg) of 20% lipid emulsion and her QRS complexes narrowed within a few minutes. She continued to receive lipids (0.5 mL/kg/min) for another 10 hours. She was discharged 2 days postingestion (Castanares-Zapatero et al, 2011).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. QTc prolongation (463 to 586 ms) developed in 4 patients (Moore et al, 2013).

a) CASE REPORT: A 19-year-old man with bipolar disorder ingested 4 g of lamotrigine and developed tachycardia (123 beats/min), multiple seizures, charcoal aspiration, respiratory failure, prolongation of the QRS interval (214 ms), and completed heart block. Despite supportive care, he developed sepsis and multiorgan failure and died 10 days postingestion (French et al, 2011).

a) CASE REPORTS: Two children had hypotensive episodes, with blood pressure 77/45 mm Hg in one child, after addition of lamotrigine to their valproic acid regimen. Both children subsequently suffered multiorgan dysfunction, which reversed several days following discontinuation of their seizure medication (Chattergoon et al, 1997). This probably represents lamotrigine-associated anticonvulsant hypersensitivity syndrome (Schlienger et al, 1998).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. Hypertension (BP greater than 140 mmHg) developed in 4 patients (Moore et al, 2013).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. Tachycardia (greater than 100 beats/min) developed in 5 patients (Moore et al, 2013).
b) Tachycardia has been reported following overdoses (Castanares-Zapatero et al, 2011; French et al, 2011; Nwogbe et al, 2009; Lofton & Klein-Schwartz, 2004; Schwartz & Geller, 2007).
c) Tachycardia was reported in 21 out of 493 patients (4.3%) following lamotrigine overdose (Lofton & Klein-Schwartz, 2004).
d) CASE REPORT: A 29-year-old man presented with tachycardia (pulse 150 bpm) after an intentional ingestion of an unknown number of lamotrigine 200 mg tablets and ethanol (Schwartz & Geller, 2007).

a) Theoretically, aspiration can occur in a lethargic or comatose patient. Coma has rarely been reported following lamotrigine overdose (Prod Info LAMICTAL(R) oral tablets, chewable dispersible oral tablets, 2007).

a) Respiratory depression has been reported rarely following lamotrigine overdose (3 of 493 patients in one series) (Lofton & Klein-Schwartz, 2004).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. Tachypnea (greater than 24 breaths/min) developed in 4 patients (Moore et al, 2013).

a) Following overdoses, nystagmus may be a prominent neurologic effect (Close & Banks, 2010; Nwogbe et al, 2009; O'Donnell & Bateman, 2000). In a series of 493 lamotrigine overdoses, 8 patients (1.6%) developed nystagmus(Lofton & Klein-Schwartz, 2004).
b) CASE REPORT: Horizontal and vertical nystagmus was reported in a 26-year-old man one hour following ingestion of 1350 mg lamotrigine. Twenty-four hours later fine nystagmus and mild ataxia were evident (Buckley et al, 1993).
c) CASE REPORT: Following a stated overdose of 4500 mg lamotrigine (absorbed estimated dose of 2900 mg), a 32-year-old woman presented to the emergency department 4 hours later with marked ataxia and later developed rotational nystagmus in all directions of gaze. Over the next 48 hours the nystagmus improved, and she was discharged on the third day (O'Donnell & Bateman, 2000).
d) CASE REPORT: Two patients developed reversible downbeat nystagmus as a result of lamotrigine toxicity. Both patients had intractable epilepsy and developed oscillopsia and incoordination while taking lamotrigine in combination with other anticonvulsants. The first patient was taking lorazepam 1 milligram twice daily, lamotrigine 100 milligrams four times daily, and gabapentin 400 milligrams three times daily. She had large amplitude downbeat nystagmus in the primary gaze, which became more pronounced in both right and left gaze. Downbeat nystagmus in down gaze and minimal nystagmus in up gaze were noted. In addition, she had moderate truncal ataxia. Serum lamotrigine levels peaked at 19.9 mcg/mL (therapeutic range 1-14 mcg/mL). After lamotrigine dose was reduced, her nystagmus resolved without further sequelae (AlKawi et al, 2005).

a) CASE SERIES: Three children with no history of movement disorders developed oculogyric crisis (1 to 20 episodes per day; 2 seconds to several hours duration) after taking increasing doses of lamotrigine. All patients recovered following the reduction of lamotrigine doses (Veerapandiyan et al, 2011).

a) CASE REPORT: A 25-year-old man who was taking lamotrigine 400 mg/day (6 mg/kg/day; plasma concentration 12.1 mcg/mL) for generalized tonic-clonic seizures developed oculogyric crisis (2 to 3 episodes of sustained upward deviation of both eyes) after inadvertently ingesting 1600 mg/day (23.5 mg/kg/day; plasma concentration 16.5 mcg/mL) of lamotrigine during a 24-hour period. His symptoms resolved after his lamotrigine dose was decreased to 6 mg/kg/day (plasma concentration 7 mcg/mL) (Veerapandiyan et al, 2011).

a) The US Food and Drug Administration (FDA) has reported 40 cases of aseptic meningitis in adults and pediatric patients taking lamotrigine, with symptoms occurring 1 to 42 days (mean, 16 days) after starting lamotrigine. Hospitalization was required in 35 of 40 patients. In most cases symptoms resolved upon discontinuation of therapy. Rechallenge in 15 cases resulted in recurrence of more severe symptoms within a mean of 5 hr (range, 30 min to 24 hr). In cerebrospinal fluid analysis performed on 25 cases, there was predominance of neutrophils in most cases and a predominance of lymphocytes in one-third of cases. It is not known if the cases of aseptic meningitis are part of a hypersensitivity or a generalized drug reaction (U.S. Food and Drug Administration, 2010).

a) Absent accommodation developed 24 hours after an overdose of 1500 to 2000 mg lamotrigine (Harchelroad et al, 1994). The pupils were briskly reactive and bilaterally equal in size (4 mm).

a) Marked ataxia is commonly reported following overdoses in children and adults (Close & Banks, 2010; Oh et al, 2006; Nwogbe et al, 2009; Dinnerstein et al, 2007; Daana et al, 2007; O'Donnell & Bateman, 2000; Briassoulis et al, 1998; Stopforth, 1997; Reutens et al, 1993). In a series of 493 patients with lamotrigine overdose, 24 (4.9%) developed ataxia (Lofton & Klein-Schwartz, 2004).

a) CASE REPORT: One hour after ingesting 1350 milligrams lamotrigine, a man presented with hypertonia and brisk reflexes. Twenty-four hours later the reflexes were normal and mild ataxia was present (Buckley et al, 1993).
b) CASE REPORT: Hypertonia, muscle weakness and ataxia was reported approximately 50 minutes after an ingestion of 800 milligrams in a 2-year-old child. Symptoms resolved within 24 hours and the child was discharged after 48 hours (Briassoulis et al, 1998).

a) CASE REPORT: Twenty-four hours following an overdose of 1500 to 2000 mg lamotrigine (also taking phenytoin and clorazepate), a woman presented with zero muscle stretch reflexes in her lower extremities. Reflexes returned to normal over the next 24 hours (Harchelroad et al, 1994).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. Hyperreflexia and intermittent myoclonus developed in 5 patients; inducible clonus developed in 2 patients (Moore et al, 2013).
b) CASE REPORTS: A 2-year-old boy experienced 2 generalized seizures 60 minutes after ingesting up to 43 mg/kg of lamotrigine. On admission, he had mild nystagmus, drowsiness, ataxia, hyperreflexia, and vomiting. Following supportive care, he recovered completely (Close & Banks, 2010).

a) CASE REPORT: Somnolence and ataxia were reported in a 45-year-old woman following a 2 week upward titration of therapeutic lamotrigine doses. No focal neurologic signs were present. Her neurological status improved over the next 2 weeks following discontinuation of lamotrigine (Schaub et al, 1994).

a) Drowsiness and obtundation have been reported following lamotrigine overdose (Close & Banks, 2010; Nwogbe et al, 2009; Dinnerstein et al, 2007; Daana et al, 2007).
b) In a series of 493 patients with lamotrigine exposure, drowsiness and lethargy were the most common toxic effects, developing in 103 (20.9%) patients. Slurred speech developed in 9 (1.8%) patients in this series (Lofton & Klein-Schwartz, 2004).
c) CASE REPORT: A woman presented with marked agitation, progressing over 4 hours to increasing lethargy, 4 hours after ingesting 1500 to 2000 milligrams of lamotrigine (other drugs included phenytoin and clorazepate). Dizziness and slurred speech were also reported. All symptoms resolved over 2 days with supportive treatment (Harchelroad et al, 1994).
d) CASE REPORT: A woman who ingested greater than 4000 milligrams lamotrigine experienced dizziness, headache and somnolence. She recovered without sequelae (Prod Info Lamictal(R), lamotrigine tablets, 2000).
e) CASE REPORT: A 17-year-old adolescent was reported to experience somnolence, dysarthria, ataxia, and lethargy following an overdose of lamotrigine (2000 milligrams) and gabapentin (12,000 milligrams). She fully recovered following supportive care (Stopforth, 1997).
f) CASE REPORT: A 3-year-old girl developed significant somnolence, a lacy reticular blanching rash and elevated liver function tests after ingesting forty-six 25 milligram tablets (1.150 grams) of lamotrigine. Plasma lamotrigine level was 25.3 mcg/mL (elevated above adult therapeutic levels). Following supportive treatment, she recovered without further sequelae (Zidd & Hack, 2004).

a) Coma has been reported rarely following lamotrigine overdose. In a series of 493 patients with lamotrigine exposure, 6 patients (1.2%) became comatose (Lofton & Klein-Schwartz, 2004).
b) CASE REPORT: A 46-year-old man with a history of bipolar disorder developed bilateral synchronous generalized myoclonus several hours after ingesting about 6000 mg of lamotrigine in a suicide attempt. Before arrival to the ED, he experienced 3 generalized seizures and presented comatose (Glasgow-Coma score (GCS) of 5/15) with spasticity in all 4 limbs. Laboratory results revealed an elevated lamotrigine concentration of 100 mcmol/L (therapeutic, 1 to 4 mcmol/L). EEG monitoring revealed no epileptiform discharges anytime during the myoclonic jerks. Following supportive care, including treatment with IV lorazepam, phenytoin, phenobarbital, midazolam, propofol, thiopental and mechanical ventilation, his symptoms gradually resolved. On day 3, another EEG was completely normal (Algahtani et al, 2014).
c) CASE REPORT: A 29 year-old man developed coma necessitating intubation after an intentional ingestion of an unknown amount of lamotrigine 200 milligram tablets and ethanol (190 mg/dL; normal < 10 mg/dL). The patient was extubated on the second hospital day, and made a full recovery with supportive care (Schwartz & Geller, 2007).
d) CASE REPORT: Coma, lasting 8 to 12 hours, was reported in a woman who ingested more than 4000 milligrams lamotrigine. She recovered without sequelae (Prod Info Lamictal(R), lamotrigine tablets, 2000).
e) CASE REPORT: A 50-year-old woman with a history of type 2 diabetes and bipolar disorder developed coma (Glasgow Coma Scale 7) approximately 2 hours after ingesting up to 3.5 g of lamotrigine. She recovered with supportive care and was discharged 2 days postingestion (Castanares-Zapatero et al, 2011).

a) CASE REPORT: Reversible encephalopathy associated with high lamotrigine blood levels (19 mg/L), with a concurrent urinary tract infection was reported in a 47-year-old woman. Concomitant medication included valproic acid, which remained at therapeutic blood levels. Symptoms included stupor, mutism, profound hemiplegia, urinary incontinence and primitive reflexes. Symptoms improved concurrent with a fall in lamotrigine levels after her lamotrigine dose was decreased from 400 milligrams/day to 75 milligrams/day (Hennessy & Wiles, 1996).

a) CASE REPORT: Encephalopathy with stupor (Glasgow coma scale 6) was reported in a 55-year-old woman with elevated serum lamotrigine concentration (32 milligrams/liter) after an intentional overdose of an unknown quantity of lamotrigine. Improvement of encephalopathy correlated with declining lamotrigine serum levels. Concurrent use of valproic acid may have contributed to the toxic effects of lamotrigine (Sbei & Campellone, 2001).

a) Seizures have been reported following high-dosage in children (Close & Banks, 2010; Guerrini et al, 1999).
b) CASE REPORT: Myoclonic status epilepticus was reported in an 8-year-old girl with Lennox-Gastaut syndrome when her 15 milligrams/kilogram/day dose of lamotrigine was increased to 20 milligrams/kilogram. An EEG revealed continuous myoclonus of cortical origin. Following discontinuation of lamotrigine, her seizures disappeared (Guerrini et al, 1999).

a) PEDIATRIC
b) ADULT

a) Disabling tremors with dysarthria and mild truncal ataxia have been reported in 3 patients following therapeutic doses of lamotrigine in combination with valproate sodium. Tremor resolved with reduction in dose of lamotrigine or valproate sodium (Reutens et al, 1993).

a) Tremor developed in 9 of 493 (1.8%) patients with lamotrigine overdose (Lofton & Klein-Schwartz, 2004).
b) Tremor of the limbs was noted in a 2-year-old boy following an ingestion of sixteen 50 milligram tablets (800 milligrams) (Briassoulis et al, 1998).

a) CASE REPORT: Blepharospasm was reported in an adult after 4 months of therapy with lamotrigine, which was titrated up to 500 milligrams/day. The patient presented with persistent, involuntary eye blinking. Associated contractions of the platysma muscles in the cervical regions bilaterally were also noted. No other movement disorders were seen. About 4 weeks after cessation of lamotrigine, the blepharospasm resolved (Verma et al, 1999).

a) CASE REPORT: Severe choreatic dyskinesia was reported in a 23-year-old man within 2 hours following an intentional ingestion of an unknown quantity of lamotrigine. Agitation and rapid, intermittent, choreatic movements of the trunk and extremities were observed, with no seizure activity. The abnormal movements continued for the next 2 hours, but subsided during the first 12 hours of admission after administration of 2 mg lorazepam IV (Miller et al, 2008) (Miller & Levsky, 2008; Miller et al, 2001).

a) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. Agitation developed in 5 patients (Moore et al, 2013).
b) CASE REPORT: An 18-year-old woman with a history of epilepsy presented with agitation, disorientation and noncooperative with a Glasgow Coma Scale (GCS) score of 12 about an hour after ingesting an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets. Physical examination revealed vertical nystagmus and myoclonia. She responded to questions with dysphasia within an hour of receiving IV lipid emulsion therapy (bolus of 100 mL and 0.5 mL/kg/min infusion for 2 hours; total dose, 3100 mL). She had a GCS score of 15 and mild dysarthria 6 hours later (Eren Cevik et al, 2014).

a) Dizziness, headache, ataxia, and weakness have been reported with therapeutic doses (Betts et al, 1991; Jawad et al, 1989; Matsuo et al, 1993).
b) CASE REPORT: A 22-year-old woman treated with lamotrigine 275 mg twice daily monotherapy for epilepsy presented to the emergency department (ED) after sustaining a closed head injury and losing consciousness. She spontaneously recovered full consciousness within 1 hour of arrival at the ED. Nystagmus, symmetrically diminished deep tendon reflexes in all extremities, and mild ataxia were observed on examination. She reported increasing nausea, vertigo, and alterations in consciousness with falls for the preceding 2 months. Lamotrigine concentration was 20.4 mcg/mL (therapeutic 1 to 4 mcg/mL). Lamotrigine was discontinued and she was free of symptoms at a 6-month follow-up visit (Strimel et al, 2010).

a) Ataxia, drowsiness, confusion, and obtundation have been reported following lamotrigine overdose (Dinnerstein et al, 2007; Daana et al, 2007).
b) CASE REPORT: An 18-year-old woman with a history of epilepsy presented with agitation, disorientation and noncooperative with a Glasgow Coma Scale (GCS) score of 12 about an hour after ingesting an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets. Physical examination revealed vertical nystagmus and myoclonia. She responded to questions with dysphasia within an hour of receiving IV lipid emulsion therapy (bolus of 100 mL and 0.5 mL/kg/min infusion for 2 hours; total dose, 3100 mL). She had a GCS score of 15 and mild dysarthria 6 hours later (Eren Cevik et al, 2014).
c) CASE SERIES: In a retrospective, case series from 2003 to 2012, 57 cases of possible lamotrigine overdose, including 9 patients (6 adults and 3 children [ages: 1 year, 19 months, and 2 years]) with lamotrigine-only ingestions (median amount ingested: 2 g; range 0.5 to 13.5 g), were identified. The following CNS adverse effects were reported: seizures (n=3), depressed mental status (n=4), agitation (n=5), both agitation and depressed mental status (n=3), hyperreflexia and intermittent myoclonus (n=5), and inducible clonus (n=2). The average serum lamotrigine concentration from 7 patients was 35.4 mg/L (17 to 90 mg/L; therapeutic range: 3 to 14 mg/L) (Moore et al, 2013).
d) CASE REPORT: A 12-day-old infant experienced two episodes of tonic-clonic seizures 9 days apart, with no etiology determined despite extensive evaluation. Following control of the seizures, he developed stereotypical movements consisting of repeated non-purposeful thrashing movements of his arms, inability to fix or follow, irritability, loss of all social interaction and inability to feed. Urine toxicology results taken after the first seizure episode revealed elevated levels of benzodiazepines (lorazepam was administered for the patient's seizures) and lamotrigine. All previously stored serum samples were analyzed. Lamotrigine levels above 30 milligrams/liter were found, which suggested repeat poisoning. Following symptomatic treatment, he gradually returned to normal over the next 5 days and was placed in protective custody (Willis et al, 2007).
e) In a series of 493 patients with lamotrigine overdose, dizziness or vertigo developed in 22 (4.5%), confusion in 11 (2.2%), and agitation in 10 (2.0%) (Lofton & Klein-Schwartz, 2004). Headache has also been reported after overdose(Harchelroad et al, 1994; Prod Info Lamictal(R), lamotrigine tablets, 2000).

a) COMBINATION OVERDOSE: Features consistent with serotonin syndrome developed in a 44-year-old woman who ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g, and was found unconscious at home. After admission, a tonic-clonic seizure, rigidity, hyperreflexia, and reflex myocloni were observed. Laboratory results revealed sodium level of 129 mmol/L, creatinine kinase of 1915 Units/L, and creatine kinase-MB of 31 Units/L. Despite supportive therapy, including 8 hours of hemodialysis, her rigidity and hyperreflexia did not improve. Following treatment with an intravenous bolus (150 mL, 2.5 mL/kg) of 20% lipid emulsion, all symptoms resolved completely. On day 6, she was transferred to a psychiatric ward (Dagtekin et al, 2011).

a) Nausea, vomiting, anorexia and abdominal pain have been infrequently reported (Close & Banks, 2010; Oh et al, 2006; Jawad et al, 1989; Betts et al, 1991; Matsuo et al, 1993) but is likely to occur with elevated serum levels (Besag et al, 1998).

a) Nausea, vomiting, anorexia and abdominal pain are likely to occur with overdoses or elevated serum levels. In a series of 493 patients with lamotrigine overdose, 54 (11%) developed vomiting and 25 (5.1%) complained of nausea (Lofton & Klein-Schwartz, 2004; Besag et al, 1998).
b) CASE REPORT: A 19-month-old boy (weight: 11.4 kg) developed vomiting, confusion, slurred speech, and agitation after ingesting 400 mg of lamotrigine. Following supportive care, he recovered and was discharged home 24 hours after ingestion (Moore et al, 2013).

a) CASE REPORT: A 24-year-old woman presented with tachycardia, lethargy, dehydration, slurred speech, with cerebellar signs of nystagmus and ataxia 5 hours after ingesting 4200 mg of lamotrigine and two bottles of wine (blood ethanol 100 mg/dL). She developed upper abdominal pain and vomiting within 24 hours of admission with a serum amylase of 1043 Units/L (normal 0 to 110 Units/L). An abdominal ultrasound 2 days later revealed a thickened gall bladder wall, with some surrounding fluid and no evidence of gallstones. Following supportive care, she recovered completely and was discharged on day 5 (Nwogbe et al, 2009).

a) CASE REPORT: A 21-year-old man developed significant elevations in liver enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum levels of 960 units/L and 347 units/L, respectively) after taking lamotrigine 200 mg/day for 2 months for schizophrenia. At the time of admission to the inpatient psychiatry unit for paranoid delusions, home medications included aripiprazole 15 mg/day and lamotrigine 200 mg/day; however, nonadherence to aripiprazole was reported by the patient's family. Liver enzymes 2 months prior to admission were normal (ALT and AST, 19 units/L). As serology and autoimmune tests ruled out other etiologies of hepatic injury, lamotrigine was determined to be causative factor and was not restarted at admission. Instead, the patient was restarted on aripiprazole, titrating up to 25 mg/day. Five days after stopping lamotrigine, AST was normal but ALT remained slightly elevated (102 units/L). The Naranjo Probability Scale indicated a probable causative relationship of lamotrigine and acute hepatotoxicity in this patient (Moeller et al, 2008).
b) CASE REPORT: Elevated liver enzymes (peaked at AST, 6079 International Units/L; ALT, 6900 IU/L; total bilirubin, 3.9 mg/dL; alkaline phosphatase, 149 IU/L; INR, 1.9) were reported in a 43-year-old woman after the addition of lamotrigine (50 mg/day) to oxcarbazepine 2 weeks before presentation. She presented with nausea, mild jaundice and a generalized erythematous pruritic macular rash. Following supportive care, she recovered completely and was discharged on day 3 (Su-Yin et al, 2008).
c) CASE REPORT: Elevated lactate dehydrogenase (6830 International Units/L) and aspartate aminotransferase (1200 International Units/L) were reported in a case of multiorgan dysfunction possibly due to therapeutic doses of lamotrigine (Schaub et al, 1994). Generalized seizures did not occur, but rhabdomyolysis was present.
d) CASE REPORT: Elevated AST (1,066 Units/L), ALT (279 Units/L), GGT (291 Units/L), and ALP (145 Units/L) serum levels were reported in an 11-year-old girl after the addition of lamotrigine to her valproic acid therapy. Multiorgan dysfunction developed, with rhabdomyolysis and no seizures. After discontinuation of her seizure medications, all abnormal serum levels returned to normal over 10 days (Chattergoon et al, 1997). This probably represents lamotrigine-associated anticonvulsant hypersensitivity syndrome.

a) CASE REPORT: A 3-year-old woman developed significant somnolence, a lacy reticular blanching rash and elevated liver function tests (serum AST 38 Units/L [normal range 10 to 31 Units/L]; ALP 332 Units/L [normal range 99 to 326 Units/L]) after ingesting forty-six 25 milligram tablets (1.150 grams) of lamotrigine. Plasma lamotrigine level was 25.3 mcg/mL (elevated above adult therapeutic levels). Following supportive treatment, she recovered without further sequelae (Zidd & Hack, 2004).

a) Slight elevations in plasma bilirubin have been reported with therapeutic lamotrigine doses (Cohen et al, 1987). The clinical significance of this is unknown.

a) CASE REPORT: Acute renal failure, in the absence of predisposing factors, occurred in a 45-year-old woman after 14 days of increasing lamotrigine doses as an add-on therapy for complex partial seizures. Carbamazepine and clonazepam had been used previously by this patient. Serum creatinine peaked at 500 micromoles per liter. Rhabdomyolysis developed and may have contributed to the renal failure. Generalized seizures were not reported (Schaub et al, 1994).

a) Hematuria was reported in 5% of patients receiving therapeutic doses of lamotrigine in clinical trials (Jawad et al, 1989).

a) Although uncommon, leukopenia has resulted from therapeutic dosages of lamotrigine.
b) CASE REPORT: A 35-year-old woman presented with leukopenia, which progressed to sepsis following 10 days of therapy with lamotrigine. Previously she had been stabilized on valproate sodium and propranolol. On admission to the hospital she was hypoxic, hypotensive and feverish, with a total white cell count of 0.6 X 10(9)/L. Following therapy, her condition stabilized and she fully recovered (Nicholson et al, 1995).
c) CASE REPORT: Agranulocytosis was reported in an 11-year-old girl 2 weeks after starting lamotrigine therapy (50 milligrams/day). No concomitant medications were taken. Lamotrigine was discontinued, and one week later her leucocyte count and proportion of neutrophils improved (de Camargo & Bode, 1999).

a) CASE REPORT: Disseminated intravascular coagulation has been reported in a 45-year-old woman after 2 weeks of upward titration of therapeutic lamotrigine doses. She had previously been maintained on carbamazepine and clonazepam for seizures with poor control prior to lamotrigine being added to her therapy.
b) CASE REPORTS: Two children developed multiorgan dysfunction with disseminated intravascular coagulation (DIC), with no concurrent seizures, within 2 weeks after adding lamotrigine to their valproic acid treatment regimen. Platelet and fibrinogen levels were markedly decreased in both patients. Both patients recovered with no sequelae several days after discontinuation of their seizure medications (Chattergoon et al, 1997). This probably represents lamotrigine-associated anticonvulsant hypersensitivity syndrome (Schlienger et al, 1998).

a) Anemia has been reported as an uncommon adverse effect of lamotrigine. Anemias appear to be reversible after discontinuation of lamotrigine. Patients with anemias were also taking other anticonvulsants, which may have contributed to the anemia (Esfahani & Dasheiff, 1997).
b) CASE REPORT: Lamotrigine-induced erythroblastopenic crisis was reported approximately 8 weeks after initiating lamotrigine therapy for a seizure condition in a 29-year-old woman with Diamond-Blackfan anemia, diagnosed at 4 months of age. Treatment with folinic acid resolved the erythroblastopenia while lamotrigine therapy was continued (Pulik et al, 2000).

a) Maculopapular and/or erythematous rashes have been reported with therapeutic doses of lamotrigine (Su-Yin et al, 2008; Betts et al, 1991; Jawad et al, 1989; Matsuo et al, 1993; Messenheimer et al, 1998). Rashes occurred in about 10% of lamotrigine patients as compared to 5% of patients receiving a placebo (Prod Info LAMICTAL(R) oral tablets, chewable dispersible oral tablets, 2007). The incidence of rash may be associated with increasing the lamotrigine dose and the use of combined drug therapy.

a) Rash was reported in 9 out of 493 patients (1.8%) following lamotrigine overdose (Lofton & Klein-Schwartz, 2004).
b) CASE REPORT: A 3-year-old girl developed significant somnolence, a lacy reticular blanching rash and elevated liver function tests after ingesting forty-six 25 mg tablets (1.150 grams) of lamotrigine. Plasma lamotrigine level was 25.3 mcg/mL (elevated above adult therapeutic levels). Following supportive treatment, she recovered without further sequelae (Zidd & Hack, 2004).

a) Serious rashes which have rarely been reported in association with lamotrigine treatment include Stevens-Johnson-Syndrome, angioedema, toxic epidermal necrolysis (TEN), and a rash complicated by hepatic, hematologic and other adverse effects(Prod Info LAMICTAL(R) oral tablets, chewable dispersible oral tablets, 2007; Messenheimer et al, 1998).
b) INCIDENCE: Approximately 0.8% (16 out of 1,983) pediatric patients developed a potentially life-threatening rash in the form of Stevens-Johnson Syndrome or TEN (Prod Info LAMICTAL(R) oral tablets, chewable dispersible oral tablets, 2007). Coadministration with valproate increases the incidence of serious rash to about 1.2% (Prod Info LAMICTAL(R) oral tablets, chewable dispersible oral tablets, 2007).
c) Short-term therapy with lamotrigine was associated with Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in a case-control study. Three cases were reported with either SJS or TEN following a range of therapy of 2 to 8 weeks. The risk is largely confined to the start of lamotrigine therapy (Rzany et al, 1999).
d) CASE REPORT: One study reported a case of Stevens-Johnson Syndrome associated with lamotrigine therapy in a 30-year-old man (Sachs et al, 1996). The syndrome developed 5 weeks after initiation of lamotrigine which was added to valproic acid therapy (2500 milligrams/day) and was diagnosed after a positive lymphocyte transformation reaction to the drug. The patient developed a skin eruption and had complaints of influenza-like symptoms.

a) CASE REPORTS: One study reported 3 cases of toxic epidermal necrolysis (TEN), verified by skin biopsies, which developed within 14 days of initiating lamotrigine therapy (Wadelius et al, 1996). All were treated in burn units of hospitals. The authors speculated immune sensitization occurred; however, all patients were also receiving valproic acid. The incidence of rash with lamotrigine is especially high when combined with valproic acid, but it is unknown if the risk of developing TEN is higher (Wadelius et al, 1996).
b) CASE REPORT: One study reported a case of TEN (confirmed by skin biopsy) in a 22-month-old man child after the addition of lamotrigine to his valproic acid therapy regimen (Vukelic et al, 1997). The seizure-free child developed a high fever and blistering rash which involved skin, conjunctivae, oral cavity and trachea. The authors suggested an interaction between valproic acid and lamotrigine may have resulted in toxic levels of lamotrigine.
c) CASE REPORT: One study reported a case of suspected TEN in a 74-year-old man possibly secondary to lamotrigine (Chaffin & Davis, 1997). Fourteen days after beginning lamotrigine therapy, the patient developed a rash, which progressed to TEN 4 days later. Other drug therapy included carbamazepine and clindamycin. Following treatment with hydrotherapy and discontinuation of lamotrigine and clindamycin, his symptoms improved and he was discharged 26 days after the rash developed.
d) CASE REPORT: A fatal case of TEN with multiple organ failure in a 54-year-old man, probably due to lamotrigine and possibly enhanced by valproic acid, is reported. Other contributing factors include concomitant allopurinol and captopril therapy for 4 years previously and initiation of valproic acid 3 months prior to the appearance of TEN. The patient developed TEN 4 weeks after starting lamotrigine therapy (Page et al, 1998).
e) Administration of lamotrigine in three patients with bipolar disorder resulted in the development of generalized maculopapular rashes that quickly progressed to TEN despite administration of corticosteroids. Two of the three patients developed respiratory distress requiring mechanical ventilation. All three patients gradually recovered with supportive care (Varghese et al, 2006).

a) CASE REPORT: A case of myopathy with elevated creatine kinase levels (7770 International Units/L) and myoglobin levels (3600 micrograms/liter) has been reported in the absence of generalized seizures following a 2 week period of lamotrigine initialization and increasing therapeutic doses in a 45-year-old woman (Schaub et al, 1994).
b) CASE REPORT: Rhabdomyolysis in the absence of seizures is reported in an 11-year-old woman 9 days after the addition of lamotrigine to her valproic regimen (valproic acid dose was halved). Serum creatine kinase level was reported to be 40,952 Units/L (normal <255 Units/L). Ten days after discontinuing both drugs, her creatine kinase levels returned to normal (Chattergoon et al, 1997). This probably represents lamotrigine-associated anticonvulsant hypersensitivity syndrome.

a) Rhabdomyolysis may develop in patients who develop prolonged seizures or coma after lamotrigine overdose (Schwartz & Geller, 2007).
b) COMBINATION OVERDOSE: A 44-year-old woman ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g, and was found unconscious at home. After admission, a tonic-clonic seizure, rigidity, hyperreflexia, and reflex myocloni were observed. Laboratory results revealed sodium level of 129 mmol/L, creatinine kinase of 1915 Units/L, and creatine kinase-MB of 31 Units/L. Despite supportive therapy, including 8 hours of hemodialysis, her rigidity and hyperreflexia did not improve. Following treatment with an intravenous bolus (150 mL, 2.5 mL/kg) of 20% lipid emulsion, all symptoms resolved completely. On day 6, she was transferred to a psychiatric ward (Dagtekin et al, 2011).

a) ANTICONVULSANT HYPERSENSITIVITY SYNDROME (AHS): consisting of fever, skin eruption or lymphadenopathy, and internal organ involvement has been associated with lamotrigine therapy in 26 reported cases. Effects appear similar to AHS induced by other aromatic anticonvulsants. Patients were reported to have fever (100%), exanthematous rashes (77%), eosinophilia (19%) and lymphadenopathy (12%). Four patients (15%) were reported with disseminated intravascular coagulopathy. The most commonly reported internal organ toxicities were hematologic and liver abnormalities in 69% and 65%, respectively, followed by renal (23%) and musculoskeletal (8%). Concomitant anticonvulsant drugs were used in all 26 cases (Schlienger et al, 1998).
b) CASE REPORTS: Two children had hypotensive episodes, with blood pressure 77/45 mmHg in one child, after addition of lamotrigine to their valproic acid regimen. Both children subsequently suffered multiorgan dysfunction (hepatotoxicity, rhabdomyolysis, disseminated intravascular coagulation) which reversed several days following discontinuation of their seizure medication (Chattergoon et al, 1997).
c) CASE REPORT: A 27-year-old woman developed multisystem hypersensitivity reaction, with DIC, fever, rash, and hepatic dysfunction, 11 days after starting lamotrigine therapy. Adjunctive therapy included phenobarbital. After stopping lamotrigine therapy, her condition improved spontaneously with no interventions other than steroid therapy (Sarris & Wong, 1999).
d) PSEUDOLYMPHOMA

a) CASE REPORT: An inadvertent overdose of lamotrigine (5 days of receiving four daily doses of 2700 milligrams) resulted in anticonvulsant hypersensitivity syndrome in a 49-year-old man. Effects included fever, maculopapular eruption, periorbital edema, leukocytosis, hepatitis and acute renal failure. Following drug discontinuation and administration of corticosteroids, symptoms and laboratory tests improved (Mylonakis et al, 1999).

a) Obtain an ECG and institute cardiac monitoring. Overdoses have resulted in ECG abnormalities, including widening QRS complex and PR prolongation (Buckley et al, 1993).

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

a) Administer sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg by intravenous bolus, repeated as needed. Maintain arterial pH between 7.45 and 7.55. Monitor serial ECGs and arterial blood gases frequently.

a) LIDOCAINE/INDICATIONS
b) LIDOCAINE/DOSE
c) LIDOCAINE/MAJOR ADVERSE REACTIONS
d) LIDOCAINE/MONITORING PARAMETERS

a) CASE REPORT: A 48-year-old woman, with a medical history of depression and gastric bypass surgery, as well as a remote history of seizure disorder, presented to the ED unconscious with one episode of tonic-clonic seizure after ingesting about 7.5 g of lamotrigine (lamotrigine concentration: 74.7 mcg/mL). Her vital signs included a heart rate of 131 beats/min, blood pressure of 107/68 mmHg, temperature of 99.4 degrees F, and a respiratory rate of 16 breaths/min. She was treated with supportive care and was intubated with rocuronium. An ECG revealed a narrow-complex sinus tachycardia, with a QRS duration of 106 msec. She developed a one-minute tonic-clonic seizure about 2.5 hours after presentation and received a 2 mg bolus of lorazepam. At this time, a second ECG revealed normal sinus rhythm, a heart rate of 86 beats/min, a QRS duration of 110 msec, and a small R-wave in aVR. Despite treatment with 2 boluses of sodium bicarbonate, her QRS duration did not change and she remained hemodynamically unstable. She developed status epilepticus 10 minutes later and an ECG showed a wide-complex tachycardia, and she became pulseless. She received sodium bicarbonate, 360 mL of 20% lipid emulsion, lidocaine, amiodarone, and 2 g calcium chloride during 45 minutes of resuscitation. Her pulses were reestablished with QRS narrowing with each defibrillation, but were widened again with recurrent seizure activity. Following the termination of seizures with vecuronium, she was finally stabilized. An ECG after resuscitation revealed a junctional tachycardia with a 3 mm R-wave in aVR. She was treated with fosphenytoin and propofol in the ICU, and was gradually weaned from sedation over 3 days when it was observed that the patient had extensor posturing. A MRI revealed brain edema consistent with anoxic injury and her family elected to withdraw care 4 days after presentation (Nogar et al, 2011).

a) Osmotic diuretic used in the management of rhabdomyolysis and myoglobinuria (Zimmerman & Shen, 2013).

a) ADULT: TEST DOSE: (for patients with marked oliguria or those with inadequate renal function) 0.2 g/kg IV as a 15% to 25% solution infused over 3 to 5 minutes to produce a urine flow of at least 30 to 50 mL/hr; a second test dose may be given if urine flow does not increase within 2 to 3 hours. The patient should be reevaluated if there is inadequate response following the second test dose (Prod Info MANNITOL intravenous injection, 2009). TREATMENT DOSE: 50 to 100 g IV as a 15% to 25% solution may be used. The rate should be adjusted to maintain urinary output at 30 to 50 mL/hour (Prod Info mannitol IV injection, urologic irrigation, 2006) OR 300 to 400 mg/kg or up to 100 g IV administered as a single dose (Prod Info MANNITOL intravenous injection, 2009).
b) PEDIATRIC: Dosing has not been established in patients less than 12 years of age(Prod Info Mannitol intravenous injection, 2009). TEST DOSE (for patients with marked oliguria or those with inadequate renal function): 0.2 g/kg or 6 g/m(2) body surface area IV as a 15% to 25% solution infused over 3 to 5 minutes to produce a urine flow of at least 30 to 50 mL/hr; a second test dose may be given if urine flow does not increase; TREATMENT DOSE: 0.25 to 2 g/kg or 60 g/m(2) body surface area IV as a 15% to 20% solution over 2 to 6 hours; do not repeat dose for persistent oliguria (Prod Info MANNITOL intravenous injection, 2009).

a) Fluid and electrolyte imbalance, in particular sodium and potassium; expansion of the extracellular fluid volume leading to pulmonary edema or CHF exacerbations(Prod Info MANNITOL intravenous injection, 2009).

a) Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia; do not add to whole blood for transfusions(Prod Info Mannitol intravenous injection, 2009); enhanced neuromuscular blockade observed with tubocurarine(Miller et al, 1976).

a) Renal function, urine output, fluid balance, serum potassium, serum sodium, and serum osmolality (Prod Info Mannitol intravenous injection, 2009).

a) Safety and efficacy in patients under 2 years were not established (Prod Info LAMICTAL ODT(R) oral disintegrating tablets, 2014; Prod Info LAMICTAL(R) oral tablets, oral chewable dispersible tablets, 2014).

a) ORAL CHEWABLE DISPERSAL, DISINTEGRATING, AND IMMEDIATE-RELEASE TABLETS: 0.15 mg/kg to 0.6 mg/kg orally daily in divided doses; gradually increased to a maintenance dose up to 15 mg/kg daily; MAX: 400 mg/day in 2 divided doses (Prod Info LAMICTAL ODT(R) oral disintegrating tablets, 2014; Prod Info LAMICTAL(R) oral tablets, oral chewable dispersible tablets, 2014).
b) ADMINISTRATION: ONLY use whole tablets; round down to the nearest whole tablet (Prod Info LAMICTAL ODT(R) oral disintegrating tablets, 2014; Prod Info LAMICTAL(R) oral tablets, oral chewable dispersible tablets, 2014).

a) ORAL CHEWABLE DISPERSAL, DISINTEGRATING, AND IMMEDIATE-RELEASE TABLETS: 25 mg orally daily or every other day or 50 mg orally daily; gradually increased to a maintenance dose up to 500 mg/day (in divided doses) (Prod Info LAMICTAL ODT(R) oral disintegrating tablets, 2014; Prod Info LAMICTAL(R) oral tablets, oral chewable dispersible tablets, 2014).
b) ORAL EXTENDED-RELEASE TABLETS: 25 mg orally every other day or daily or 50 mg orally daily; gradually increased to a maintenance dose up to 600 mg daily (Prod Info LAMICTAL(R) XR(TM) oral extended release tablets, 2013).

a) A 48-year-old woman developed cardiac arrest with significant conduction disturbances and status epilepticus after ingesting about 7.5 g of lamotrigine (lamotrigine concentration: 74.7 mcg/mL; therapeutic range: 3 to 14 mcg/mL). Despite intensive supportive care, a MRI obtained 3 days after admission revealed brain edema consistent with anoxic injury and her family elected to withdraw care 4 days after presentation (Nogar et al, 2011).
b) A 19-year-old man with bipolar disorder ingested 4 g of lamotrigine (blood concentration, 35.7 mcg/mL, 19 hours post-ingestion) and developed tachycardia (123 beats/min), multiple seizures, charcoal aspiration, respiratory failure, prolongation of the QRS interval (214 ms), and completed heart block. Despite supportive care, he developed sepsis and multiorgan failure and died 10 days post-ingestion (French et al, 2011).
c) A 50-year-old woman with a history of type 2 diabetes and bipolar disorder developed coma and widening of QRS with left bundle branch block after ingesting up to 3.5 g of lamotrigine. Despite supportive therapy, including activated charcoal, IV magnesium, and sodium bicarbonate, the ECG did not improve. Serum lamotrigine concentrations were 27.1 mcg/mL (reference, 2 to 16 mcg/mL) and 29.7 mcg/mL, 2 and 6 hours postingestion, respectively. Following treatment with an intravenous bolus (1.5 mL/kg) of 20% lipid emulsion, all symptoms resolved within a few minutes. She continued to receive lipids (0.5 mL/kg/min) for another 10 hours. She was discharged 2 days postingestion (Castanares-Zapatero et al, 2011).
d) COMBINATION OVERDOSE: A woman who ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g developed coma, seizures, rigidity, and hyperreflexia. Plasma concentrations of lamotrigine, diazepam, and venlafaxine were 42.4 mg/L (therapeutic range, 1 to 4 mg/L), 560 mcg/L (therapeutic range, 200 to 500 mcg/L), and 1254 mcg/L (therapeutic range, 30 to 150 mcg/L), respectively. Following treatment with lipid emulsion, all symptoms resolved completely (Dagtekin et al, 2011).
e) Serum lamotrigine concentrations above 13 mcg/mL have been associated with a steep increase in adverse effects, such as tremor (Froscher et al, 2002).
f) A 25-year-old man who was taking lamotrigine 400 mg/day (6 mg/kg/day; plasma concentration 12.1 mcg/mL) for generalized tonic-clonic seizures developed oculogyric crisis (2 to 3 episodes of sustained upward deviation of both eyes) after inadvertently ingesting 1600 mg/day (23.5 mg/kg/day; plasma concentration 16.5 mcg/mL) of lamotrigine during a 24-hour period. His symptoms resolved after his lamotrigine dose was decreased to 6 mg/kg/day (plasma concentration 7 mcg/mL) (Veerapandiyan et al, 2011).
g) A serum level of 25.2 mcg/mL was reported on initial presentation to the emergency department of a 29-year-old man who intentionally ingested an unknown number of 200 milligram lamotrigine tablets and ethanol (191 mg/dL; normal less than 10 mg/dL). This value most likely does not represent the peak lamotrigine concentration since it is uncertain when the ingestion occurred; it is estimated they it may have been up to 12 hours prior to presentation (Schwartz & Geller, 2007).
h) Serum level of 52 micrograms/milliliter (a ten-fold increase over normal therapeutic values) was reported four hours following an acute ingestion of greater than 4000 milligrams lamotrigine in an adult woman (Prod Info Lamictal(R), lamotrigine tablets, 2000).
i) STATUS EPILEPTICUS- Approximately 1 to 2 hours after ingesting 4.1 grams of lamotrigine, a 42-year-old woman with a history of focal seizures developed secondarily generalized status epilepticus. The lamotrigine concentrations were: 47.4 micrograms/milliliter (on admission), 15.8 micrograms/milliliter (on day 2), 3.2 micrograms/milliliter (on day 3), and 0.8 micrograms/milliliter (on day 4) (Dinnerstein et al, 2007).
j) Harchelroad et al (1994) reported serum lamotrigine levels of 52.5 micrograms/milliliter at 28 hours post-ingestion in a 33-year-old woman who ingested 1500 to 2000 milligrams (Harchelroad et al, 1994).
k) Lamotrigine serum levels at 3 and 17 hours post-ingestion were 17.4 and 6.4 micrograms/milliliter respectively following an acute overdose of 1350 milligrams in a 26-year-old man (Buckley et al, 1993).
l) Serum lamotrigine level of 19.3 micrograms/milliliter was associated with marked sedation, fatigue, and decreased cognition in a 17-year-old girl (Kaufman & Gerner, 1998).
m) Peak serum lamotrigine concentration of 35.8 milligrams/liter was reported following a stated overdose of 4500 milligrams (absorbed estimated dose of 2900 milligrams) in a 32-year-old woman. The patient survived, with clinical manifestations of rotary nystagmus and marked ataxia which improved over 2 days (O'Donnell & Bateman, 2000).
n) Following ingestion of an unknown quantity of lamotrigine, a serum level of 62.4 micrograms/milliliter was reported at 24 hours after admission in a 23-year-old man. The overdose was associated with severe choreatic dyskinesia which improved following an injection of lorazepam (Miller et al, 2001).
o) A lamotrigine serum level of 32 milligrams/liter was reported following deliberate ingestion of an unknown quantity of lamotrigine and valproic acid. Encephalopathy resulted, with improvement correlating with declining lamotrigine serum levels. It was suggested that valproic acid may have potentiated toxicity by decreasing hepatic clearance of lamotrigine (Sbei & Campellone, 2001).
p) Two patients developed reversible downbeat nystagmus as a result of lamotrigine toxicity. Both patients had intractable epilepsy and developed oscillopsia and incoordination while taking lamotrigine (patient one took 100 milligrams four times daily; patient two took 200 milligrams every morning, 100 milligrams at noon, 200 milligrams every evening) in combination with other anticonvulsants (eg; gabapentin or valproic acid). Serum lamotrigine levels peaked at 19.9 micrograms/milliliter (therapeutic range 1-14 micrograms/milliliter) in patient one and peaked at 27 micrograms/milliliter (therapeutic range 4-18 micrograms/milliliter using a different laboratory) in patient two (AlKawi et al, 2005).

a) OCULOGYRIC CRISIS: Three children with no history of movement disorders developed oculogyric crisis (1 to 20 episodes per day; 2 seconds to several hours duration) after taking increasing doses of lamotrigine. All patients recovered following the reduction of lamotrigine doses (Veerapandiyan et al, 2011).
b) A plasma lamotrigine level of 35 milligrams/liter (above 30 milligrams/liter in several previously stored samples) was reported in a 12-day-old infant after receiving an unknown amount of lamotrigine. He experienced tonic-clonic seizures, and other neurological symptoms. Following symptomatic treatment, he gradually returned to normal over the next 5 days (Willis et al, 2007).
c) One study reported that plasma levels equal to or greater than 8 micrograms/milliliter have been well tolerated by pediatric patients (Uvebrant & Bauziene, 1994).
d) Plasma lamotrigine level of 25.3 micrograms/milliliter (elevated above adult therapeutic levels) was reported in a 3-year-old after ingesting forty-six 25 milligram tablets (1.150 grams) of lamotrigine. Following supportive treatment, she recovered without further sequelae (Zidd & Hack, 2004).
e) Peak plasma level of 3.8 milligrams/liter was reported in a 2-year-old boy after an ingestion of 800 milligrams (Briassoulis et al, 1998).

a) 245 mg/kg (RTECS, 2001)

a) 205 mg/kg (RTECS, 2001)