A three-year multi-center retrospective analysis of overdoses of bupropion immediate-release reported to six regional poison control centers (Spiller et al, Am J Emerg Med (1994) 12:43-45) reported that sinus tachycadia occurred in 25 of 58 patients (43%) but no other arrhythmias or conduction defects were found.  Seizures occurred in 12 patients (21%).  The mean ingestion of patients experiencing seizures was 3078 mg, whereas the mean ingestion of patients not experiencing seizures was 2148 mg.  Time to onset of seizures ranged from on to eight hours (mean-4 hours).  Multiple seizures occurred in two of these patients.  The significance and prevalence of this hypokalemia is unknown.  Benzodiazepines were effected in stopping the convulsions in seven of eight cases when they were used.  In the eighth case, follow-up use of diphenylhydantoin successfully terminated the seizure.  Lethargy and tremors were also seen frequently following overdose.  Other CNS effects seen in overdose were confusion, lightheadedness, hallucinations, and paresthesias.  Coma was observed in two of nine patients who ingested both bupropion and a benzodiazepine.  The only patient in the series who experienced hypotension required a two-hour dopamine infusion and intubation.  All of this group of patients recovered without physical sequelae.

 

In the only case of bupropion immediate-release overdose detailed in the emergency medicine literature, an 18-year-old female took nine grams of bupropion without concomitant medications or substances.  This produced combativeness, and sinus tachycardia without conduction abnormality, followed by a 45 second tonic-clonic seizure that abated with administration of 10 mg of intravenous diazepam.  She was further treated with oral intubation, gastric lavage, activated charcoal, and sorbitol.  The patient was extubated in 24 hours and her tachycardia resolved aftr 48 hours.  There was no further seizure activity.  Two fatal overdose cases (a 37-year-old male and a 60-year-old female) in which bupropion immediate-release was the major toxicology finding were reported to have followed overdoses of less than ten grams bupropion.  In both cases blood level of 4.0 mg/L – more than forty times the expected plasma concentrations in patients – were found.

 

8.6                            Summary of Important Adverse Events Considered Drug Related

 

8.6.1                       Seizures

 

Although the sponsor reported no seizures as having occurred during the testing of bupropion sustained-release in protocols 203 and 205, seizures did arise in open trial 208.  As noted in section 8.5.5, in protocol 208 bupropion sustained-release was associated with an observed seizure rate of 0.10% with an upper 95% confidence limit of 0.19%.  The incidence of seizure with bupropion sustained-release doses of up to 300 mg/day, when administered to subjects without known risk-factors that might increase seizure incidence, appears to be similar to that of other commercially-available antidepressants.

 

By contrast, the immediate-release formulation of bupropion has been well described to being associated with seizures.  The immediate-release compound has been associated with seizures in approximately 0.4 per cent of patients treated at doses up to 450 mg/day.  This incidence may be two to four times greater than that of other marketed antidepressants.  The estimated seizure risk increases almost tenfold at doses between 450 and 600 mg/day.  The risk of seizure from immediate-release bupropion appears to be strongly associated with dose and the presence of predisposing factors, including history of head trauma or seizure, central nervous system tumor, history of bulimia or anorexia nervosa, or concomitant intake of medications known to lower the seizure threshold.  Sudden and large increases in doses were thought to contribute to increased risk of seizure.

 

8.6.2                       Allergic Phenomena

 

Eighteen patients (2.6% of 693 total bupropion sustained-release-treatment patients) in protocols 203 and 205 discontinued bupropion sustained-release due to rash, pruritus, or urticaria.  In protocol 208’s eight-week treatment phase.  44 patients (1.4% of 3100 bupropion sustained-release-treated patients) discontinued due to those allergic phenomena.  Only two out of 245 (0.9%) patients in the placebo-treated groups of protocols 203 and 205

 

 

Bupropion Sustained-Release Clinical Review               41

 

 

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