a) Mild hyperthermia (101 degrees F) developed in an 18-year-old woman who became combative after ingesting 9,000 milligrams of buPROPion (Storrow, 1994). A 31-year-old woman developed mild hyperthermia (38.5 degrees C), tachycardia and agitation after ingesting 4.5 g of sustained release buPROPion (Velez et al, 2002).
b) CASE REPORT: A 35-year-old man developed hyperthermia (41.4 degrees C) without muscle rigidity and signs of sepsis approximately 12 hours after intentionally ingesting 12 grams of buPROPion. During his hospital course, the patient also developed coma, cardiogenic shock, and status epilepticus. The hyperthermia persisted for 24 hours despite supportive therapy, but appeared to resolve with resolution of his seizures (Morazin et al, 2007).

a) Cardiovascular overdose effects include primarily tachycardia and rarely hypotension (Rivas-Coppola et al, 2015; Shenoi et al, 2011; Donnelly et al, 2010; Boora et al, 2010; Shepherd et al, 2004; Belson & Kelley, 2002; Ayers & Tobias, 2001) .
b) INCIDENCE: Sinus tachycardia was reported in 25 of 58 patients (52%) after overdose with buPROPion only (Spiller et al, 1994). None of these patients developed other dysrhythmias or hemodynamic compromise. In another series of 20 patients, tachycardia developed in 13 (76%) (Isbister & Balit, 2003). Tachycardia was reported in 20 out of 50 patients (40%) in another series (Colbridge et al, 2002). In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), tachycardia was reported in 26 patients (5.5%) (Shepherd, 2005).
c) CASE REPORTS: Sinus tachycardia, lasting 48 hours, was reported in a woman who also developed seizures following a 9000 mg overdose (Storrow, 1994). Sinus tachycardia, persistently low blood pressure and seizures were reported in an 18-year-old man following the ingestion of 7500 mg buPROPion (Bhattacharjee et al, 2001).
d) CASE REPORTS: Tachycardia has been reported in 3 patients following overdoses of 3000 mg, 4500 mg, and 4350 mg, respectively, of sustained release buPROPion. Symptoms resolved in all patients following aggressive benzodiazepine therapy (Weiner et al, 1998).
e) CASE REPORT (CHILD): A 3-year-old child developed persistent sinus tachycardia, hypotension, and recurrent seizures after ingesting 2400 mg of sustained-release buPROPion (140 mg/kg) . Following supportive therapy, the patient recovered without sequelae (Givens & Gabrysch, 2007).
f) CASE REPORT (CHILD): A 7-year-old child developed sinus tachycardia (140 to 155 bpm), visual and tactile hallucinations, agitation, and recurrent seizures after ingesting 1050 mg (48 mg/kg) of extended-release buPROPion. The patient recovered following supportive therapy (Spiller & Schaeffer, 2008).
g) CASE SERIES: According to a retrospective observational case series, involving 67 patients identified as having single-substance buPROPion exposures via insufflation, 47 patients (70.1%) developed tachycardia on arrival to a health care facility. The estimated mean insufflated buPROPion dose in 52 patients was 1500 mg (range, 100 to 9000 mg) (Lewis et al, 2014).
h) CASE REPORT: A 17-year-old girl intentionally ingested 2.4 mg of clonidine and 1500 mg buPROPion. Initially, she developed somnolence, miosis, and bradycardia (heart rate 39 beats/min). Over the next several hours, she was continually monitored and received supportive care. Approximately 23 hours post-ingestion, the patient developed tachycardia (peak heart rate 126 beats/minute), nausea, anxiety, mydriasis, and a generalized tonic-clonic seizure that lasted approximately 3 to 4 minutes. Over the next 8 hours, she continued to be tachycardic, hypertensive, and tremulous. With supportive care, her signs and symptoms resolved approximately 31 hours post-ingestion and, 2 days post-ingestion, she was discharged without sequelae to a psychiatric facility. It is suspected that manifestations of clonidine toxicity initially appeared, masking the toxic effects of buPROPion. Following the clearance of clonidine from the patient, buPROPion toxicity was then unmasked (Phillips et al, 2015).

a) CASE REPORT: Abnormal junctional rhythm was reported in one patient during clinical trials, but a cause-effect relationship was not established (Wenger & Stern, 1983).

a) Intraventricular conduction delays and sinus tachycardia have been reported following large overdose (Lung et al, 2012; Chao et al, 2012; Sirianni et al, 2008; Paris & Saucier, 1998; Shrier et al, 2000; Fresh et al, 1999). In a retrospective review of 7348 buPROPion-only overdoses, cardiovascular disturbances were extremely uncommon (Belson & Kelley, 2002).
b) CASE REPORT: Paris & Saucier (1998) reported sinus tachycardia and intraventricular conduction delays in a 32-year-old man following a 9 gram ingestion of buPROPion (Paris & Saucier, 1998). Initial ECG revealed supraventricular tachycardia (123 bpm) and QRS and QTc interval prolongation, 135 msec and 485 msec, respectively. Conduction delays resolved within 48 hours.
c) CASE REPORT: Four hours following the ingestion of 1500 mg of sustained-release buPROPion, an ECG revealed intraventricular conduction delay, with ventricular rate of 150 beats/min, QRS of 100 ms, and a QTc interval of 600 ms in a 16-year-old girl. Slow but consistent resolution of tachycardia and prolonged QT interval was reported on serial ECGs over the next 12 hours. Complete resolution occurred with no treatment (Shrier et al, 2000).
d) CASE REPORT: A 36-year-old woman was reported on ECG to have a QRS of 166 ms (QTc 587 ms) with a left bundle branch block pattern 12 hours following ingestion of 4.5 grams buPROPion. Her serum buPROPion level was 0.44 mg/L (therapeutic, 0.025-0.2 mg/L) at 16 hours post- ingestion. Progressive normalization of QRS width and rate was shown on serial ECGs (Fresh et al, 1999).
e) CASE REPORT: A 22-year-old patient who ingested 2000 to 2200 mg developed hypokalemia and nonspecific ST-T changes, but no QRS prolongation or other cardiac abnormalities (Wenger & Stern, 1983).
f) CASE REPORT: A 31-year-old woman developed agitation, tachycardia, mild hypertension (180/90), tremor, dystonia, increased muscle tone, hyperreflexia and clonus after ingesting 90 buPROPion tablets (13.5 g) with ethanol. She then developed coma and recurrent seizures (treated with diazepam, intubation and ventilation) and wide complex tachycardia which responded to adenosine (Tracey et al, 2002).
g) CASE SERIES: Patients (17) with buPROPion overdose had increased QTc intervals (461 +/- 43 msec) compared with controls (426 +/- 40 msec), however the mean uncorrected QT interval was not different between the two groups. Thirteen of the buPROPion patients (76%) had a QTc of more than 440 msec, but none developed dysrhythmias. The increased QTc may be due to overcorrection in patients with buPROPion induced tachycardia (Isbister & Balit, 2003)
h) CASE REPORTS: QRS widening occurred in two patients following intentional buPROPion overdose with elevated plasma levels. A 30-year-old man with bipolar disorder ingested a "full bottle" of buPROPion (dose unknown) and 8 hours after ingestion had sinus tachycardia with a QRS duration of 120 ms. Approximately, 4 hours post-ingestion, a 51-year-old woman had a QRS of 150 ms after taking 200 buPROPion sustained-release 150-mg tablets . In both cases, the QRS was within normal range within 72 hours of exposure, which correlated with normal plasma concentrations (Curry et al, 2005).
i) CASE REPORT: A 45-year-old woman developed QRS widening and QTc prolongation after ingesting 80 200-mg sustained-release buPROPion tablets as well as an unknown amount of over-the-counter "sleeping pills". Despite intravenous bolus administration of sodium bicarbonate (3 ampules), an ECG, performed 15 hours post-ingestion, revealed a QRS of 122 ms and a QTc of 608 ms. The patient's ECG abnormalities continued to persist for 24 hours. Following development of aspiration pneumonia and a complicated ICU stay, the patient was discharged 2 weeks post-ingestion (Wills et al, 2009).
j) CASE REPORT: A 17-year-old adolescent presented with a generalized seizure after intentionally ingesting 3000 mg of extended-release buPROPion. An initial ECG revealed sinus tachycardia (138 bpm), incomplete right bundle branch block, and a prolonged QT interval (QTc 563 msec). With supportive care, the patient recovered with resolution of his ECG abnormalities (Boora et al, 2010).
k) CASE REPORT: A 51-year-old woman, with a history of depression, presented to the emergency department with hypertension (144/95 mmHg), tachycardia (130 beats/min), and lethargy. After an initial ECG revealed a widened QRS complex, the patient was given sodium bicarbonate. Although a diphenhydramine overdose was suspected due to a report that an undetermined number of diphenhydramine tablets were missing, initial laboratory analysis revealed an elevated serum buPROPion concentration of 540 ng/mL. Over the next 2 hours, the patient's condition deteriorated with increasing lethargy, continued widening of the QRS complex despite sodium bicarbonate therapy, and hypotension refractory to vasopressors, calcium gluconate, and glucagon administration. Intravenous lipid emulsion therapy was then initiated. Within 30 minutes, the patient's hemodynamic status improved with an increase in blood pressure from 73/55 mmHg to 120/74 mmHg and a subsequent narrowing of her QRS complex (Livshits et al, 2011).
l) CASE REPORT: ECG abnormalities, including QTc interval prolongation (527 ms) and QRS interval widening (108 ms), metabolic acidosis, hypotension, and seizures were reported in a 14-year-old girl who ingested up to 9 g buPROPion and an unknown amount of hydroxyzine and citalopram in a suicide attempt. The patient recovered following intravenous lipid emulsion (ILE) therapy; however, lipemia, severe hypertriglyceridemia, and asymptomatic pancreatitis occurred secondary to ILE. With supportive care, the patient recovered and was transferred to a pediatric psychiatric unit 9 days post-admission (Bucklin et al, 2013).
m) CASE REPORT: A 30-year-old woman developed seizures, hypotension, metabolic acidosis, and sinus tachycardia after ingesting half of a bottle of extended-release buPROPion (exact amount ingested was not reported). An ECG revealed a prolonged QTc interval of 485 msec and a heart rate of 100 beats/min. A sodium bicarbonate infusion was initiated for treatment of the acidosis and prolonged QTc, and was discontinued following resolution of the acidosis. A repeat ECG revealed a wide complex tachycardia with a QRS of 220 msec and a QTc of 661 msec, and an IV bolus of amiodarone was administered followed by an amiodarone infusion. Despite treatment with amiodarone, the wide complex tachycardia persisted. Suspecting sodium channel toxicity due to the slow rate of the wide complex tachycardia, the amiodarone infusion was discontinued and sodium bicarbonate infusion was restarted. After beginning the sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex to 120 msec, a heart rate of 81 beats per minute, and a QTc of 604 msec (Franco, 2015).

a) Orthostatic hypotension or dizziness may occur at therapeutic doses; two patients who fell backward did not have symptoms suggesting orthostatic hypotension, but had other signs of Parkinsonism (Szuba & Leuchter, 1992).

a) No reports of hypotension were observed in a retrospective case series of 58 buPROPion overdoses(Spiller et al, 1994).
b) A 18-year-old man developed sinus tachycardia and persistently low blood pressure (70/40 mmHg), in spite of fluid challenge, following an overdose of 7500 mg buPROPion and 24 tablets of a product containing acetaminophen, aspirin and caffeine (Bhattacharjee et al, 2001). Hypotension did not respond to dopamine but did resolve following an epinephrine infusion.
c) CASE REPORT (CHILD): A 3-year-old child developed persistent sinus tachycardia, hypotension, and recurrent seizures after ingesting 2400 mg of sustained-release buPROPion (140 mg/kg) . Following supportive therapy, the patient recovered without sequelae (Givens & Gabrysch, 2007).
d) CASE REPORT (INFANT): An 11-month-old infant developed generalized tonic-clonic seizures, tachycardia, metabolic acidosis, and, initially, hypertension (153/58 mmHg) after ingesting 30 300-mg sustained release buPROPion tablets. He was given activated charcoal, then vomited and aspirated, developed hypoxia and hypotension, and was subsequently refractory to vasopressor support, . Venoarterial extracorporeal membrane oxygenation (ECMO) was initiated approximately 21 hours post-ingestion, with immediate improvement of his metabolic acidosis, and gradual stabilization of his blood pressure (men arterial pressure 68 to 84 mmHg). Following discontinuation of ECMO 71 hours later, the patient's condition continued to improve, and he was subsequently discharged approximately 2 weeks post-admission, with no evidence of neurological sequelae at the 1-year follow-up (Shenoi et al, 2011).
e) CASE REPORT: Metabolic acidosis, ECG abnormalities, including QTc interval prolongation and QRS interval widening, hypotension, and seizures were reported in a 14-year-old girl who ingested up to 9 g buPROPion and an unknown amount of hydroxyzine and citalopram in a suicide attempt. The patient recovered following intravenous lipid emulsion (ILE) therapy; however, lipemia, severe hypertriglyceridemia, and asymptomatic pancreatitis occurred secondary to ILE. With supportive care, the patient recovered and was transferred to a pediatric psychiatric unit 9 days post-admission (Bucklin et al, 2013).

a) CASE REPORT: Following a massive overdose of 23 grams buPROPion, a 26-year-old man developed seizures, hypoxia, tachycardia progressing to bradycardia, and presented to the emergency department in cardiac arrest (2.5 hours post-ingestion). Aggressive resuscitation attempts were successful at returning pulse and blood pressure; however, the patient was declared brain dead and all life support systems were disconnected (Harris et al, 1997).
b) CASE REPORT: A 17-year-old girl presented with unresponsiveness and tachycardia approximately 6 hours after intentionally ingesting up to 7.95 grams of buPROPion and 4 grams of lamotrigine. An initial ECG revealed sinus tachycardia with prolonged QRS interval and a prolonged QTc interval. Approximately 10 hours post-ingestion, the patient developed a tonic-clonic seizure followed by cardiovascular collapse, characterized by pulseless wide complex rhythm. Following unsuccessful attempts at restoring sustained circulation with standard resuscitative measures, a 100 milliliter intravenous bolus of 20% lipid emulsion was administered. After administration of the lipid emulsion, the patient's cardiovascular status rapidly improved with gradual normalization of her neurologic function. She had a prolonged hospital course and was discharged on hospital day 24 to rehabilitation with mild memory deficits and fine motor incoordination (Sirianni et al, 2008).
c) CASE REPORT: After ingesting 80 tablets of metoprolol 25 mg and buPROPion 150 mg, a 50-year-old woman developed severe bradycardia and hypotension (HR 40 beats/min; mean arterial pressure 40 mmHg), refractory to calcium salts, catecholamines, and high-dose insulin. About 30 seconds after receiving 100 mL of 20% intravenous fat emulsion (IFE), she developed brady-asystolic arrest, but her pulse returned to normal after 3 minutes of cardiopulmonary resuscitation (CPR). Despite aggressive supportive care, her condition worsened and she died of multisystem organ failure on day 4. Although the exact cause of arrest in this patient is uncertain, several possible causes were suggested: IFE interaction with other resuscitation drugs, a sudden increase in absorption of drug in the GI tract, a brief lack of oxygen in the lipid-laden blood circulating in the coronary vessels contributing to the arrests, fatal ingestions of drugs regardless of therapy (Cole et al, 2014).
d) CASE REPORT/INFANT: Status epilepticus and apneic, pulseless cardiac arrest occurred in a 15-month-old girl following ingestion of an unknown amount of buPROPion. Following resuscitative measures, sinus rhythm was restored approximately 20 minutes later, and the patient's seizure activity eventually ceased following aggressive anticonvulsant therapy; however, she continued to deteriorate neurologically, demonstrating clinical signs of global hypoxic ischemic encephalopathy, including cortical blindness and spastic quadriparesis. A tracheostomy and gastric tube placement were needed. The infant developed permanent neurologic damage with ongoing symptomatic, refractory partial epilepsy that necessitated multiple medications (Rivas-Coppola et al, 2015).

a) CASE REPORT: A 35-year-old man intentionally ingested 12 grams of buPROPion and subsequently developed generalized seizures, progressing to status epilepticus, requiring continuous administration of barbiturates and benzodiazepines. Three hours post-ingestion, the patient also developed persistent hypotension (systolic less than 90 mmHg). An echocardiogram revealed global cardiac impairment with right and left ventricular hypokinesia without ventricular dilatation, indicative of cardiogenic shock. The ventricular shortening fraction was between 12% and 17% and cardiac output was estimated to be 2.8 L/min. Following dobutamine administration, an esophageal Doppler confirmed normalization of his cardiac output and a repeat echocardiogram showed global improvement of right and left systolic function. Despite the development of other complications, including hyperthermia and hepatic cytolysis, the patient gradually recovered with supportive care (Morazin et al, 2007). The authors speculated that high doses of barbiturates and benzodiazepines used to treat the patient's status epilepticus may have been contributory factors in the development of cardiogenic shock.

a) Animal experiments have shown changes in PR interval and QRS duration at concentrations 10 to 100 times that required for amitriptyline or imipramine (Wenger & Stern, 1983).

a) Massive overdose has resulted in seizures, cardiac arrest, severe hypoxia and mixed respiratory & metabolic acidosis during the initial phase of resuscitation (Harris et al, 1997).

a) Patients with no prior seizure history have developed seizures after daily doses of 600 to 900 mg. In one study, 2 of 4 patients receiving 800 mg or more daily developed seizures after 2 to 4 doses (Van Wyck Fleet et al, 1983).
b) INCIDENCE: A review of manufacturer's records on 37 cases of seizures during buPROPion therapy revealed an overall incidence of seizures of 0.8%. When patients receiving more than 450 mg/day were excluded, the incidence decreased to 0.35%, which increased to 0.48% after 2 years of therapy (Davidson, 1989).
c) Predisposing factors (diet, family history, abnormal baseline EEG, head injury, chronic ethanol use, possible withdrawal, other drugs that lower seizure threshold) are present in many patients who develop seizures on therapeutic doses (Johnston et al, 1991).

a) INCIDENCE: In one study, 12 of 58 patients (21%) with buPROPion only overdose developed seizures (Spiller et al, 1994). The manufacturer reports seizures occurring in approximately one third of all overdose cases (Prod Info WELLBUTRIN(R) oral tablets, 2005). Twelve (24%) of 50 buPROPion overdose patients in another series developed seizures (Colbridge et al, 2002). In most cases, seizures are of short duration and may not require ongoing treatment (Ayers & Tobias, 2001). In a retrospective review of 7348 buPROPion-only exposures, seizures were reported in 6% of all exposures. In children less than 6 years old, seizures were extremely rare (0.2%) compared to teens (15%) (Belson & Kelley, 2002). In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), seizures were reported in 4 patients (0.8%) with 1 patient who progressed to status epilepticus (Shepherd, 2005).
b) ONSET: Seizure activity usually develops within 1 to 8 hours post-ingestion after overdose (Ayers & Tobias, 2001). In one study, seizures occurred within 6 hours in most patients (Shepherd et al, 2004). Onset of seizures can be delayed after overdose with the sustained release products.
c) PRODROME: In one study, most patients developed persistent neurologic symptoms (ie, agitation, tremors, and hallucinations) prior to having a seizure (Shepherd et al, 2004).
d) According to a retrospective observational case series, involving 67 patients identified as having single-substance buPROPion exposures via insufflation, 20 patients (29.9%) experienced a seizure prior to presentation to the healthcare facility. The estimated mean insufflated buPROPion dose in 52 patients was 1500 mg (range, 100 to 9000 mg) (Lewis et al, 2014).
e) CASE SERIES: A retrospective case review of buPROPion exposures, reported to a poison center over a 7-year-period, identified 37 patients who were chronically taking buPROPion and had ingested at least 450 mg as a single agent supratherapeutic ingestion. Tablet formulation was identified in 35 of the 37 cases, with 29 (83%), 5 (14%), and 1 (3%) case(s) accounting for the XL, SR, and IR formulations, respectively. Out of the 37 patients, only 1 patient developed seizures after taking 300 mg of buPROPion SR twice daily for greater than 1 week. No seizures were reported in 32 patients following a single acute ingestion at a mean dose of 909 mg (range 600 to 2250 mg), Seizures were also not reported in 16 patients who had ingested a one-time buPROPion dose of 600 mg or less (Eggleston & Sullivan, 2015).
f) CASE REPORTS

a) Paresthesias, light-headedness, slurred speech, lethargy and confusion are common; coma has been reported in mixed overdoses, but is rare after single ingestions of buPROPion (Donnelly et al, 2010; Boora et al, 2010; Sirianni et al, 2008; Prod Info WELLBUTRIN(R) oral tablets, 2005; Ayers & Tobias, 2001; Bhattacharjee et al, 2001; Spiller et al, 1994; Storrow, 1994; Wenger & Stern, 1983) .
b) CASE REPORT: A 35-year-old man became comatose (Glasgow Coma Score of 3), as well as developing status epilepticus and cardiogenic shock, after intentionally ingesting 12 grams of buPROPion. Following supportive care, the patient gradually recovered (Morazin et al, 2007).
c) According to a retrospective observational case series, involving 67 patients identified as having single-substance buPROPion exposures via insufflation, drowsiness/lethargy and a syncopal episode were reported in 6% and 3% of patients, respectively. Drowsiness, lethargy, and syncope were reported in 7.5% of patients who did not have a prehospital seizure. The estimated mean insufflated buPROPion dose in 52 patients was 1500 mg (range, 100 to 9000 mg) (Lewis et al, 2014).

a) Tremor is a common effect in higher therapeutic doses (400 to 600 mg/day), occurring in 8 of 16 patients in one study (Dufresne et al, 1985).

a) INCIDENCE: Tremor was reported in 14 of 58 overdose (24%) cases (Spiller et al, 1994). Tremor has been reported in 10% to 14% of buPROPion overdose patients in other case series (Colbridge et al, 2002; Belson & Kelley, 2002). In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), tremor was reported in 34 patients (7.1%) (Shepherd, 2005).
b) According to a retrospective observational case series, involving 67 patients identified as having single-substance buPROPion exposures via insufflation, 7 patients (10.4%) experienced tremor/movement disorder. Tremors or movement disorders were reported in 13 patients (19.4%) who did not have a prehospital seizure. The estimated mean insufflated buPROPion dose in 52 patients was 1500 mg (range, 100 to 9000 mg) (Lewis et al, 2014).

a) Vivid dreaming, visual hallucination, and altered time sense were described in patients receiving high doses (greater than 450 mg/day) (Becker & Dufresne, 1982).
b) Organic mental disorders (including 1 case of auditory hallucinations) were reported in 3 patients with bipolar mood disorder taking buPROPion (Ames et al, 1992).

a) Auditory and visual hallucinations have been described frequently following buPROPion overdose (Thorpe et al, 2010; Donnelly et al, 2010; Prod Info WELLBUTRIN(R) oral tablets, 2005; Shepherd et al, 2004; Mainie et al, 2001). Hallucinations developed in 4 of 58 overdose cases (Spiller et al, 1994). Visual hallucinations were reported in a 14-year-old following the ingestion of up to 3000 mg of buPROPion (Ayers & Tobias, 2001) and in a 45-year-old woman who ingested 16 grams of sustained-release buPROPion as well as an unknown amount of over-the-counter "sleeping pills" (Wills et al, 2009). In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), hallucinations were reported in 2 patients (0.4%) (Shepherd, 2005).
b) CASE REPORT (CHILD): Visual and tactile hallucinations occurred in a 7-year-old child following ingestion of 1050 mg (48 mg/kg) of extended release buPROPion (Spiller & Schaeffer, 2008).
c) CASE REPORT (ADOLESCENT): A 17-year-old experienced visual and tactile hallucinations after intentionally ingesting 2100 mg of extended-release buPROPion (Boora et al, 2010).

a) Agitation and excitement are common adverse effects during treatment.

a) Initial agitation and restless may occur following an overdose (Wills et al, 2009). In severe cases, this may progress to an altered mental state and possible coma (Bhattacharjee et al, 2001; Mainie et al, 2001). Paris & Saucier (1998) reported an adult with agitation, combativeness, and prolonged delirium after a 9 gram overdose(Paris & Saucier, 1998).
b) A brief episode of agitation and combativeness 18 hours post-ingestion (up to 3000 mg buPROPion) was reported in a 14-year-old (Ayers & Tobias, 2001). In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), agitation was reported in 39 patients (8.2%) (Shepherd, 2005).
c) According to a retrospective observational case series, involving 67 patients identified as having single-substance buPROPion exposures via insufflation, 7 patients (10.4%) experienced agitation/anxiety. The estimated mean insufflated buPROPion dose in 52 patients was 1500 mg (range, 100 to 9000 mg) (Lewis et al, 2014).

a) A parkinsonian syndrome was reported in 2 patients, manifesting as falling backwards (Szuba & Leuchter, 1992).

a) CASE REPORT: Catatonia is reported in a 19-year-old man on the fifth day of buPROPion therapy (75 mg 3 times daily). Increased muscle tone, mutism, posturing, and unresponsiveness were noted. BuPROPion therapy was stopped and electroconvulsive treatments were begun (Jackson et al, 1992).

a) In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), dizziness was reported in 35 patients (7.4%) and drowsiness in 29 patients (6.1%) (Shepherd, 2005).

a) CASE REPORT: A 15-year-old boy developed agitation, tachycardia, hypertension, flushed skin, dry mucous membranes, mydriasis, hyperreflexia, and clonus and extreme rigidity in the lower extremities only, consistent with serotonin syndrome, after reportedly ingesting 10 300-mg sustained-release buPROPion tablets. The patient also experienced visual hallucinations. With supportive therapy, the patient's symptoms resolved within 36 hours post-ingestion (Thorpe et al, 2010).

a) INCIDENCE: Vomiting developed in 8 of 58 overdose cases (14%) in another study (Spiller et al, 1994). In another series of 50 patients, vomiting was reported in 6 (12%) (Colbridge et al, 2002).
b) Overdose of sustained-release or extended-release buPROPion has resulted in vomiting within 7 hours of ingestion (Wills et al, 2009; Spiller & Schaeffer, 2008; Givens & Gabrysch, 2007; Weiner et al, 1998).
c) In a retrospective review of 476 patients who ingested 75 to 1500 mg of buPROPion (median and mode 300 mg for all dosage and sustained-release forms), nausea and/or vomiting were reported in 32 patients (6.7%) (Shepherd, 2005).

a) CASE REPORT: An 18-year-old woman intentionally ingested approximately 30 4.5 g sustained release buPROPion tablets (Wellbutrin SR). Activated charcoal was given one hour after ingestion. Over the next few hours the patient became increasingly agitated and had a witnessed tonic-clonic seizure. Seven hours after exposure the patient vomited a 15 to 20 pill bezoar in a small amount of gastric fluid. The patient was observed for 23 hours with no further symptoms reported (Aalund et al, 2003).

a) CASE REPORT: A 35-year-old man developed hepatic cytolysis with elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations up to 10 times and 14 times the upper limit of normal, respectively, approximately 48 hours after intentionally ingesting 12 grams of buPROPion. Liver injury may have been secondary to cardiogenic shock that developed in this patient. There was no elevation of bilirubin and the liver enzyme concentrations spontaneously normalized after one week (Morazin et al, 2007).

a) Hepatotoxicity consisting of hepatocellular hypertrophy and focal nodular hyperplasia was observed in rats after chronic administration. In addition, there was an increase in liver weight in both rats and dogs, apparently related to hepatic enzyme induction (Tucker, 1983).

a) Clitoral priapism of 24-hour duration was reported in a 50-year-old woman two days after starting buPROPion therapy (100 mg twice daily) (Levenson, 1995).

a) CASE REPORT (INFANT): An 11-month-old infant developed generalized tonic-clonic seizures, tachycardia, metabolic acidosis, and, initially, hypertension (153/58 mmHg) after ingesting 30 300-mg sustained release buPROPion tablets. He was given activated charcoal, then vomited and aspirated, developed hypoxia and hypotension, and was subsequently refractory to vasopressor support . Venoarterial extracorporeal membrane oxygenation (ECMO) was initiated approximately 21 hours post-ingestion, with immediate improvement of his metabolic acidosis, and gradual stabilization of his blood pressure (mean arterial pressure 68 to 84 mmHg). Following discontinuation of ECMO 71 hours later, the patient's condition continued to improve, and he was subsequently discharged approximately 2 weeks post-admission, with no evidence of neurological sequelae at the 1-year follow-up (Shenoi et al, 2011).
b) CASE REPORT: Severe metabolic acidosis (pH 6.82; PaCO2 54.8 kPa; PaO2 85 kPa; HCO3 9.2 mmol/L) was reported in an 18-year-old woman who ingested 2.85 g sustained-release buPROPion. The metabolic acidosis resolved with supportive care (Chao et al, 2012).
c) CASE REPORT: Hypokalemic, hyperchloremic metabolic acidosis was reported in a 17-year-old girl who ingested approximately 30 150-mg sustained-release buPROPion tablets in a suicide attempt. In addition to the metabolic acidosis, the patient experienced a seizure at presentation to the emergency department, and developed hypocalcemia, and hypoglycemia; however, she remained hemodynamically and neurologically stable throughout her hospital course. With supportive therapy, the patient's metabolic abnormalities normalized and she was referred for psychiatric assessment (Wilson et al, 2013).
d) CASE REPORT: Metabolic acidosis (pH 6.91, pCO2 96 mmHg, HCO3 19 mmol/L), ECG abnormalities, including QTc interval prolongation and QRS interval widening, hypotension, and seizures were reported in a 14-year-old girl who ingested up to 9 g buPROPion and an unknown amount of hydroxyzine and citalopram in a suicide attempt. The patient recovered following intravenous lipid emulsion (ILE) therapy; however, lipemia, severe hypertriglyceridemia, and asymptomatic pancreatitis occurred secondary to ILE. With supportive care, the patient recovered and was transferred to a pediatric psychiatric unit 9 days post-admission (Bucklin et al, 2013).
e) CASE REPORT/INFANT: Metabolic acidosis (pH 7.08, HCO3 15 mmol/L, base excess -11) was reported in a 15-month-old girl following ingestion of an unknown amount of buPROPion (Rivas-Coppola et al, 2015).

a) CASE REPORT: A case of eosinophilia is described in a 72-year-old woman with no other predisposing causes five days after initiation of buPROPion therapy. The eosinophil count peaked at 0.60 fraction of 1.00 with the count returning to normal after drug cessation (Malesker et al, 1995).

a) CHRONIC TOXICITY

a) CASE REPORT: Hypoglycemia (49 mg/dL) was reported in a 17-year-old girl who ingested approximately 30 150-mg sustained-release buPROPion tablets in a suicide attempt (Wilson et al, 2013).

a) Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity and serum sickness have been reported with buPROPion therapy (Davis et al, 2001).

a) Continuous cardiac monitoring following a massive ingestion is recommended. Monitor for neurological signs of seizure and CNS depression.

1) CASE SERIES: In a retrospective chart review of 407 buPROPion ingestions in children less than 6 years of age from 4 regional poison centers, no neurological or cardiovascular effects were reported in children with ingestions of less than 10 mg/kg. Two children ingested an estimated 900 mg of buPROPion with one remaining asymptomatic and the other child (estimated dose 64 mg/kg), a one-year old, developed vomiting, agitation, and tachycardia (maximum heart rate 152 bpm) (Spiller et al, 2010). Children who have ingested buPROPion, as the sole agent, at doses of 10 mg/kg or less can be managed at home ; however, children who have ingested doses greater than 10 mg/kg should be referred to a healthcare facility. In this study, the incidence of seizure after unintentional buPROPion ingestion in children less than 6 years was 0.7% (Spiller et al, 2010; Beuhler et al, 2010).

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) CASE REPORT (CHILD): A 3-year-old child, who ingested 2400 mg of sustained-release buPROPion and subsequently experienced recurrent seizures, developed aspiration pneumonia following decontamination with whole bowel irrigation (WBI). A chest x-ray revealed a right lower lobe infiltrate; nasopharyngeal suction of his esophagus returned approximately 400 milliliters of the polyethylene glycol and electrolyte solution used for WBI. Over the next several hours, his respiratory status continued to deteriorate requiring mechanical ventilation. With supportive therapy, the patient gradually recovered and he was discharged without sequelae (Givens & Gabrysch, 2007).

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) 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) Complete resolution of QRS and QTc prolongation on serial ECGs has been reported even in the absence of drug therapy following buPROPion overdoses (Shrier et al, 2000; Fresh et al, 1999).

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

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

a) If patient is severely agitated, sedate with IV benzodiazepines.

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) CHILD: 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).

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) CHILD: 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

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) A 17-year-old girl developed seizures and cardiovascular collapse after intentionally ingesting up to 7.95 grams buPROPion and 4 grams lamotrigine. Following unsuccessful attempts at restoring sustained circulation with standard resuscitative measures (for 70 minutes), a 100 milliliter intravenous bolus of 20% lipid emulsion was administered. After administration of the lipid emulsion, the patient's cardiovascular status rapidly improved with gradual normalization of her neurologic function (Sirianni et al, 2008).
b) A 51-year-old woman, with a history of depression, presented to the emergency department with hypertension (144/95 mmHg), tachycardia (130 bpm), and lethargy. After an initial ECG revealed a widened QRS complex, the patient was given sodium bicarbonate. Although a diphenhydramine overdose was suspected due to a report that an undetermined number of diphenhydramine tablets were missing, initial laboratory analysis revealed an elevated serum buPROPion concentration of 540 ng/mL. Over the next 2 hours, the patient's condition deteriorated with increasing lethargy, continued widening of the QRS complex despite sodium bicarbonate therapy, and hypotension refractory to vasopressors, calcium gluconate, and glucagon administration. Intravenous lipid emulsion therapy was then initiated at a bolus dose of 1.5 mL/kg 20% lipid emulsion given over 1 minute, followed by a repeat bolus of 1.5 mL/kg 5 minutes later and an infusion of 0.25 mL/kg/min for 1 hour. Within 30 minutes, the patient's hemodynamic status improved with an increase in blood pressure from 73/55 mmHg to 120/74 mmHg and a subsequent narrowing of her QRS complex. Although the patient's hospital course was complicated with development of sustained unstable ventricular tachycardia, requiring cardioversion, persistent hypotension, necessitating another bolus dose of IV lipid emulsion, cardiogenic shock, aspiration pneumonia, sepsis, transient hepatic failure, and acute renal failure necessitating hemodialysis, she gradually recovered with supportive care and was discharged on hospital day 26 (Livshits et al, 2011).
c) Metabolic acidosis, ECG abnormalities, including QTc interval prolongation and QRS interval widening, hypotension, and seizures were reported in a 14-year-old girl who ingested up to 9 g buPROPion and an unknown amount of hydroxyzine and citalopram in a suicide attempt. Because of worsening hypotension and development of a junctional cardiac rhythm, the patient was started on intravenous lipid emulsion therapy (ILE), receiving 2 100-mL (1.16 mL/kg) boluses, followed by an ILE infusion at 0.25 mL/kg/min over 1 hour. This infusion was repeated 3 times for a total dose of 46 mL/kg in less than 12 hours. The patient's hemodynamic status improved following ILE therapy; however, lipemia, severe hypertriglyceridemia, and asymptomatic pancreatitis occurred secondary to ILE. With supportive care, the patient recovered and was transferred to a pediatric psychiatric unit 9 days post-admission (Bucklin et al, 2013).
d) After ingesting 80 tablets of metoprolol 25 mg and buPROPion 150 mg, a 50-year-old woman developed severe bradycardia and hypotension (HR 40 beats/min; mean arterial pressure 40 mmHg), refractory to calcium salts, catecholamines, and high-dose insulin. About 30 seconds after receiving 100 mL of 20% intravenous fat emulsion (IFE), she developed brady-asystolic arrest, but her pulse returned to normal after 3 minutes of cardiopulmonary resuscitation (CPR). Despite aggressive supportive care, her condition worsened and she died of multisystem organ failure on day 4. Although the exact cause of arrest in this patient is uncertain, several possible causes were suggested: IFE interaction with other resuscitation drugs, a sudden increase in absorption of drug in the GI tract, a brief lack of oxygen in the lipid-laden blood circulating in the coronary vessels contributing to the arrests, fatal ingestions of drugs regardless of therapy (Cole et al, 2014).

1) Seizures developed in 41 (11%) cases, of which 9 had more than one episode, and one had status epilepticus. Ingestions of 2.5 g were more likely to result in seizures and the average time of onset ranged from 1 to 14 hours (mean 4.3 +/- 3.2 hours). Of note, all patients (except one) that developed seizures had a prodrome phase which included persistent neurologic findings (ie, agitation, tremors, and hallucinations). The one individual that had no evidence of neurologic deficits was monitored for 5 hours than discharged from the emergency department, and had a seizure 4 hours later. In this study, benzodiazepines were successfully used to treat buPROPion-induced seizures (Shepherd et al, 2004).

1) Week one: 1 tablet in the morning
2) Week two: 1 tablet in the morning and 1 tablet in the evening
3) Week three: 2 tablets in the morning and 1 tablet in the evening
4) Week four and onward: 2 tablets in the morning and 2 tablets in the evening (MAXIMUM dose)

a) Oral, immediate release: 2 hours (Prod Info WELLBUTRIN(R) oral film-coated tablets, 2011).

a) Aplenzin(R): Oral: 5 hours (Prod Info APLENZIN(R) oral extended-release tablets, 2012).
b) Forfivo XL(R): Oral, extended-release: 5 hours (Prod Info FORFIVO XL oral extended-release tablets, 2011).
c) Wellbutrin XL(R): Oral, extended-release: 5 hours (Prod Info WELLBUTRIN XL(R) extended-release oral tablets, 2009).

a) Oral, sustained-release: 3 hours (Prod Info WELLBUTRIN SR(R) oral sustained-release tablets, 2011a; Prod Info ZYBAN(R) Oral Tablets, 2008; Prod Info ZYBAN(R) Oral Tablets, 2008; Hsyu et al, 1997).

a) An 18-year-old woman had a buPROPion level of 400 nanograms/milliliter 7 hours after ingesting 9,000 milligrams (Storrow, 1994). Clinical effects included confusion, tachycardia and seizures.
b) A post mortem blood buPROPion level of 0.7 milligrams/liter was reported in a 38-year-old woman after a mixed ingestion of buPROPion and ethanol (Ramcharitar et al, 1992).
c) A four hour serum buPROPion level was reported as 220 nanograms/milliliter following an ingestion of 4500 milligrams sustained-release buPROPion in a 19-year-old female. Clinical effects included vomiting, tremulousness and tachycardia; symptoms improved following intravenous lorazepam (Weiner et al, 1998).
d) A 16-hour serum buPROPion level was reported as 0.44 milligrams/liter (therapeutic 0.025-0.2 milligrams/liter) in a 36-year-old female who ingested 4.5 grams of buPROPion (Fresh et al, 1999).
e) A 20.5-hour serum buPROPion and hydroxy-buPROPion metabolite level was reported as 446 and 3212 nanograms/milliliter, respectively, in a 26-year-old male following an ingestion of approximately 23 grams of buPROPion. At 33.5 hours post-ingestion, levels of buPROPion and its metabolite were reported as 135 and 3109 nanograms/milliliter, respectively. The patient developed severe hypoxia and respiratory acidosis during the initial phase of cardiac resuscitation that led to his death (Harris et al, 1997).
f) The plasma and urinary buPROPion concentrations in a 35-year-old man, obtained approximately 4 hours following intentional ingestion of 12 grams buPROPion, were 1.40 mg/L and 30 mg/L, respectively (Morazin et al, 2007).
g) The plasma buPROPion level in a 45-year-old woman, obtained 14 hours following ingestion of 80 200-mg sustained release tablets, was 1.3 mg/L (reference range, 0.025 to 0.1 mg/L). Toxic effects in this patient included agitation, hallucinations, seizures, and QRS prolongation (Wills et al, 2009).
h) The peak plasma buPROPion concentration in a 23-year-old man, obtained 8.25 hours following ingestion of 5700 mg sustained-release tablets, was 1.145 mg/L (Donnelly et al, 2010).

a) POST-MORTEM CONCENTRATIONS: Post-mortem serum buPROPion concentrations ranged from 3.1 mg/L to greater than 20 mg/L in 4 patients (one 16-year-old and 3 adults) following sustained-release buPROPion overdose ingestions in doses ranging from 5.4 to 9 grams (Spiller et al, 2008).

a) 230 mg/kg (Budavari, 1996)

a) 575 mg/kg (Budavari, 1996)
b) 544 mg/kg (RTECS, 2001)

a) 210 mg/kg (Budavari, 1996)

a) 600 mg/kg (Budavari, 1996)