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Sustained release bupropion: Overdose and treatment
388
AMERICAN JOURNAL OF EMERGENCY MEDICINE [] Volume 20, Number 4 [] July 2002
11. Marras TK, Gutierrez C, Chan CK: Applying a prediction rule to identify low-risk patients with community-acquired pneumonia. Chest 2000;118:1339-1343
ATYPICAL SITE OF MYOCARDIALINFARCTION PAIN To the Editor:--I read with interest the correspondence letter by Adhiyaman et al ~ citing a case report in which an elderly man presented with pain in the nape of neck and inferior myocardial infarction but referred as possible subarachnoid hemorrhage. This case shows the diagnostic dilemmas faced by the clinicians particularly when conflicting diagnoses had been suggested beforehand. But I am disturbed by the clinical exclusion of subarachnoid hemorrhage and decision to proceed with thrombolysis. The absence of neck stiffness and hypertension does not necessarily rule out subarachnoid hemorrhage and in one series, neck stiffness and hypertension were present in only 21% and 34% of patients presenting at the emergency department. 2 Furthermore, approximately 25% of patients with subarachnoid haemorrhage have electrocardiographic changes consistent with myocardial infarction or ischemia. 3 The mechanism is unclear but sympathetic effects mediated by insular cortex may be responsible. Particularly fight sylvian fissure subarachnoid hemorrhage may have electrocardiographic consequences. 4 This case also raises 2 further issues. First, the benefits of thrombolysis in inferior myocardial infarction, although proven beyond doubt, are marginal when compared with anterior myocardial infaction and left bundle branch block and there is a case for withholding thrombolysis in doubtful cases. 5,6 Second, there is an obvious difficulty in counseling the patients in these scenarios and helping the patients to take an informed decision. It would be interesting to know whether the suspicion of subarachnoid hemorrhage and the potential catastrophic consequences of thrombolysis if it were to be had been discussed with the patient. RAMACHANDRANSIVAKUMAR,MD Department qf Care of Elderly Lister Hospital Stevenage, UK
References 1. Adhiyaman V, Ganeshram KN, Sivaramalingam M, et al: Acute myocardial infarction presenting as subarachnoid haemorrhage. Am J Emerg Med 2002;20:55 2. Seet CM" Clinical presentation of patients with subarachnoid haemorrhage at a local emergency department. Singapore Med J 1999;40:383-5 3. Zaroff JG, Rordorf GA, Newell JB, et al: Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery 1999;44:34-9 4. Hirashima Y, Takashima S, Matsumura N, et al: Right sylvian fissure subarachnoid hemorrhage has electrocardiographic consequences. Stroke 2001 ;32:2278-81 5. Schroder K, Wegscheider K, Neuhaus K-L, et al: Significance of initial ST segment changes for thrombolytic treatment in first inferior myocardial infarction. Heart 1997;77:506-11 6. Tobe TJM: Is thrombolytic treatment in acute inferior myocardial infarction really better than conventional treatment? Br Heart J 1995;73:108-9
Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2004-0037535.00/0 doi:10.1053/ajem.2002.33961
SUSTAINED RELEASE BUPROPION: OVERDOSE AND TREATMENT To the Editor:--Overdose of the immediate release form of bupropion has been well studied, t-4 As the new sustained release form became available in 1996, it nearly replaced the immediate release form in the prescribing habits of today's physicians. The intentional overdose and treatment of sustained release bupropion have been less well described despite this noted prescribing popularity. ~ Adverse effects with bupropion include lethargy, tachycardia, tremors, seizures, and vomiting. A 3-year multicenter analysis revealed the incidence of seizures in overdose with the immediate release form to be 21%. 1 In this report, 86% of pure bupropion overdoses received treatment with activated charcoal. Although in some of these cases (47%) also received gastric lavage, there was no methodology to or discussion of the adequacy of treatment. The following case illustrates a typical bupropion overdose. New treatment recommendations are based on data suggesting possible pill bezoar formation. A 47-year-old white woman was found unresponsive at approximately 7.30 AM on the day of admission. She took approximately 25 to 28 tablets of sustained release bupropion 150 mg over about 1 hour starting around 4 AM. She was not taking this medication at the time of the overdose. Naloxone 2 mg IV was given with no change in her status. On ED arrival, gastric lavage revealed no pill fragments. Pertinent laboratory data revealed normal electrolytes and a metabolic acidosis (CO 2 total 15 mmol/mL). The plasma bupropion level on admission, 3 hours postingestion was 2,200 ng/mL and 24 hours postingestion was 57 ng/mL (Gas Chromatography, National Medical Services, Willow Grove, PA). She was given activated charcoal 30 grams in sorbitol through a nasogastric tube. After 30 minutes in the ED, the patient had a tonic-clonic seizure lasting about 60 seconds resolving spontaneously. No further seizures were noted. Through the first 24 hours, 4 additional doses of activated charcoal 30 grams in sorbitol were given at 6 hour intervals. The patient had no neurologic complications after the initial seizure and recovered uneventfully. Although no such published data exist, it is anticipated that adverse effects from overdose with sustained release bupropion would be similar to those with the immediate release form. Despite reports of fatal overdose, most cases of bupropion overdose recover without long-term effects. 1-4.6-9 Common to overdose with bupropion are tonic-clonic seizures estimated to occur in approximately 20% of individuals. 1 The mechanism for these seizures appears unclear. The data comparing the 2 forms reveals that the sustained release form has a lower incidence of seizures for comparable prescribed doses, l°,H However, there are no data to suggest a decrease incidence of seizures in patients with sustained release bupropion overdose. Sigg reported recurrent seizures from sustained release bupropion overdose. This patient experienced a second tonicclonic seizure 10 hours after the first one. 8 Similarly, Shrethra et al described a case of reoccurring tonic-clonic seizures after an overdose with sustained release bupropion. 9 Although the reason for these recurrent seizures is not clear, it is proposed that delayed absorption could account for this because of tablet bezoar formation after multiple tablet ingestion. This could
Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2004-0038535.00/0 doi:10.1053/ajem.2002.31136
389
• CORRESPONDENCE
result in a prolonged and/or inconsistent release of bupropion from the tablet matrix. 8 Various reports have listed similar treatment patterns of bupropion overdose usually involving gastric lavage, oral activated charcoal, or both. 2,2 The Poisindex (Micromedex Inc., Englewood, CO) recommends gastric lavage if done within 1 hour of the ingestion followed by an unspecified dose of activated charcoal. In this case, the plasma bupropion level obtained 24 hours postingestion was significantly lower than the level obtained at admission. Although the pharmacokinetics of overdose can be different from that of chronic daily dosing, this difference in plasma levels seems greater than one would expect based on a normal metabolic clearance and distribution of this amount of parent drug. 1° Sustained release bupropion is completely absorbed by 3 hours) 2 In this patient, gastric lavage and administration of activated charcoal occurred 3 hours postingestion. Based on this information, it would seem unlikely that either lavage or charcoal would have altered the plasma levels this much. If pill bezoar formation occurred as postulated and delayed absorption existed in this patient, activated charcoal administered intermittently over the first 24 hours could have further decreased drug absorption via whole bowel irrigation. Although optimal timing of the initial dose of activated charcoal remains uncertain, it is agreed that early administration is important. In addition to the standard Poisindex treatment for bupropion overdose, the authors recommend a new treatment protocol by expanding the use of activated charcoal. Recommended is the administration of charcoal (30 grams) given at 6 hour intervals for 24 hours postingestion. Administration of charcoal at intervals over the first 24 hours postingestion
may significantly decrease the overall incidence of overdose related effects. ROBERTS. WHITE,MD Department of Family and Community Medicine JOSHUAR. LANGFORD,AB Rockford Rockford, 1L
References 1. Spiller HA, Ramoska EA, Krenzalok EP, et al: Bupropion overdose: A 3-year multi-center retrospective analysis. Am J Emerg Med 1994;12:43-5 2. Storrow AB: Bupropion overdose and seizure. Am J Emerg Med 1994; 12:183-4 3. Harris CR, Gualtieri J, Stark G: Fatal bupropion overdose. J Toxicol Clin Toxicol 1997;35:321-4 4. Paris PA, Saucier JR: ECG Conduction delays associated with massive bupropion overdose. Clin Toxicol 1998;36:595-8 5. Sandow N: The Top 200 Prescriptions for 1998, 1999, and 2000. Available at http://www.rxlist.com. Accessed May 2002 6. Shrier M, Diaz JE, Tsarouhas N: Cardiotoxicity associated with bupropion overdose. Ann Emerg Med 2000;35:100 7. Fresh L, Donovan FL, Burkart K, et al: Bupropion toxicity causes wide complex tachycardia. J Toxicol Clin Toxicol 1999;37: 635 8. Sigg T: Recurrent seizures from sustained-release bupropion. J Toxicol Clin Toxicol 1999;37:634 9. Shretha M, Greenberg M: Status epilepticus secondary to bupropion overdose. J Toxicol Clin Toxicol 1999;37:634-5 10. Dunner DL, Zisook S, Billow AA, et ah A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry 1998;59:366-73 11. Product Information for Wellbutrin Tablets and Wellbutrin SR Tablets. Research Triangle Park, NC, Glaxo Wellcome Inc.
AMERICAN JOURNAL OF EMERGENCY MEDICINE [] Volume 20, Number 4 [] July 2002
11. Marras TK, Gutierrez C, Chan CK: Applying a prediction rule to identify low-risk patients with community-acquired pneumonia. Chest 2000;118:1339-1343
ATYPICAL SITE OF MYOCARDIALINFARCTION PAIN To the Editor:--I read with interest the correspondence letter by Adhiyaman et al ~ citing a case report in which an elderly man presented with pain in the nape of neck and inferior myocardial infarction but referred as possible subarachnoid hemorrhage. This case shows the diagnostic dilemmas faced by the clinicians particularly when conflicting diagnoses had been suggested beforehand. But I am disturbed by the clinical exclusion of subarachnoid hemorrhage and decision to proceed with thrombolysis. The absence of neck stiffness and hypertension does not necessarily rule out subarachnoid hemorrhage and in one series, neck stiffness and hypertension were present in only 21% and 34% of patients presenting at the emergency department. 2 Furthermore, approximately 25% of patients with subarachnoid haemorrhage have electrocardiographic changes consistent with myocardial infarction or ischemia. 3 The mechanism is unclear but sympathetic effects mediated by insular cortex may be responsible. Particularly fight sylvian fissure subarachnoid hemorrhage may have electrocardiographic consequences. 4 This case also raises 2 further issues. First, the benefits of thrombolysis in inferior myocardial infarction, although proven beyond doubt, are marginal when compared with anterior myocardial infaction and left bundle branch block and there is a case for withholding thrombolysis in doubtful cases. 5,6 Second, there is an obvious difficulty in counseling the patients in these scenarios and helping the patients to take an informed decision. It would be interesting to know whether the suspicion of subarachnoid hemorrhage and the potential catastrophic consequences of thrombolysis if it were to be had been discussed with the patient. RAMACHANDRANSIVAKUMAR,MD Department qf Care of Elderly Lister Hospital Stevenage, UK
References 1. Adhiyaman V, Ganeshram KN, Sivaramalingam M, et al: Acute myocardial infarction presenting as subarachnoid haemorrhage. Am J Emerg Med 2002;20:55 2. Seet CM" Clinical presentation of patients with subarachnoid haemorrhage at a local emergency department. Singapore Med J 1999;40:383-5 3. Zaroff JG, Rordorf GA, Newell JB, et al: Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery 1999;44:34-9 4. Hirashima Y, Takashima S, Matsumura N, et al: Right sylvian fissure subarachnoid hemorrhage has electrocardiographic consequences. Stroke 2001 ;32:2278-81 5. Schroder K, Wegscheider K, Neuhaus K-L, et al: Significance of initial ST segment changes for thrombolytic treatment in first inferior myocardial infarction. Heart 1997;77:506-11 6. Tobe TJM: Is thrombolytic treatment in acute inferior myocardial infarction really better than conventional treatment? Br Heart J 1995;73:108-9
Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2004-0037535.00/0 doi:10.1053/ajem.2002.33961
SUSTAINED RELEASE BUPROPION: OVERDOSE AND TREATMENT To the Editor:--Overdose of the immediate release form of bupropion has been well studied, t-4 As the new sustained release form became available in 1996, it nearly replaced the immediate release form in the prescribing habits of today's physicians. The intentional overdose and treatment of sustained release bupropion have been less well described despite this noted prescribing popularity. ~ Adverse effects with bupropion include lethargy, tachycardia, tremors, seizures, and vomiting. A 3-year multicenter analysis revealed the incidence of seizures in overdose with the immediate release form to be 21%. 1 In this report, 86% of pure bupropion overdoses received treatment with activated charcoal. Although in some of these cases (47%) also received gastric lavage, there was no methodology to or discussion of the adequacy of treatment. The following case illustrates a typical bupropion overdose. New treatment recommendations are based on data suggesting possible pill bezoar formation. A 47-year-old white woman was found unresponsive at approximately 7.30 AM on the day of admission. She took approximately 25 to 28 tablets of sustained release bupropion 150 mg over about 1 hour starting around 4 AM. She was not taking this medication at the time of the overdose. Naloxone 2 mg IV was given with no change in her status. On ED arrival, gastric lavage revealed no pill fragments. Pertinent laboratory data revealed normal electrolytes and a metabolic acidosis (CO 2 total 15 mmol/mL). The plasma bupropion level on admission, 3 hours postingestion was 2,200 ng/mL and 24 hours postingestion was 57 ng/mL (Gas Chromatography, National Medical Services, Willow Grove, PA). She was given activated charcoal 30 grams in sorbitol through a nasogastric tube. After 30 minutes in the ED, the patient had a tonic-clonic seizure lasting about 60 seconds resolving spontaneously. No further seizures were noted. Through the first 24 hours, 4 additional doses of activated charcoal 30 grams in sorbitol were given at 6 hour intervals. The patient had no neurologic complications after the initial seizure and recovered uneventfully. Although no such published data exist, it is anticipated that adverse effects from overdose with sustained release bupropion would be similar to those with the immediate release form. Despite reports of fatal overdose, most cases of bupropion overdose recover without long-term effects. 1-4.6-9 Common to overdose with bupropion are tonic-clonic seizures estimated to occur in approximately 20% of individuals. 1 The mechanism for these seizures appears unclear. The data comparing the 2 forms reveals that the sustained release form has a lower incidence of seizures for comparable prescribed doses, l°,H However, there are no data to suggest a decrease incidence of seizures in patients with sustained release bupropion overdose. Sigg reported recurrent seizures from sustained release bupropion overdose. This patient experienced a second tonicclonic seizure 10 hours after the first one. 8 Similarly, Shrethra et al described a case of reoccurring tonic-clonic seizures after an overdose with sustained release bupropion. 9 Although the reason for these recurrent seizures is not clear, it is proposed that delayed absorption could account for this because of tablet bezoar formation after multiple tablet ingestion. This could
Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2004-0038535.00/0 doi:10.1053/ajem.2002.31136
389
• CORRESPONDENCE
result in a prolonged and/or inconsistent release of bupropion from the tablet matrix. 8 Various reports have listed similar treatment patterns of bupropion overdose usually involving gastric lavage, oral activated charcoal, or both. 2,2 The Poisindex (Micromedex Inc., Englewood, CO) recommends gastric lavage if done within 1 hour of the ingestion followed by an unspecified dose of activated charcoal. In this case, the plasma bupropion level obtained 24 hours postingestion was significantly lower than the level obtained at admission. Although the pharmacokinetics of overdose can be different from that of chronic daily dosing, this difference in plasma levels seems greater than one would expect based on a normal metabolic clearance and distribution of this amount of parent drug. 1° Sustained release bupropion is completely absorbed by 3 hours) 2 In this patient, gastric lavage and administration of activated charcoal occurred 3 hours postingestion. Based on this information, it would seem unlikely that either lavage or charcoal would have altered the plasma levels this much. If pill bezoar formation occurred as postulated and delayed absorption existed in this patient, activated charcoal administered intermittently over the first 24 hours could have further decreased drug absorption via whole bowel irrigation. Although optimal timing of the initial dose of activated charcoal remains uncertain, it is agreed that early administration is important. In addition to the standard Poisindex treatment for bupropion overdose, the authors recommend a new treatment protocol by expanding the use of activated charcoal. Recommended is the administration of charcoal (30 grams) given at 6 hour intervals for 24 hours postingestion. Administration of charcoal at intervals over the first 24 hours postingestion
may significantly decrease the overall incidence of overdose related effects. ROBERTS. WHITE,MD Department of Family and Community Medicine JOSHUAR. LANGFORD,AB Rockford Rockford, 1L
References 1. Spiller HA, Ramoska EA, Krenzalok EP, et al: Bupropion overdose: A 3-year multi-center retrospective analysis. Am J Emerg Med 1994;12:43-5 2. Storrow AB: Bupropion overdose and seizure. Am J Emerg Med 1994; 12:183-4 3. Harris CR, Gualtieri J, Stark G: Fatal bupropion overdose. J Toxicol Clin Toxicol 1997;35:321-4 4. Paris PA, Saucier JR: ECG Conduction delays associated with massive bupropion overdose. Clin Toxicol 1998;36:595-8 5. Sandow N: The Top 200 Prescriptions for 1998, 1999, and 2000. Available at http://www.rxlist.com. Accessed May 2002 6. Shrier M, Diaz JE, Tsarouhas N: Cardiotoxicity associated with bupropion overdose. Ann Emerg Med 2000;35:100 7. Fresh L, Donovan FL, Burkart K, et al: Bupropion toxicity causes wide complex tachycardia. J Toxicol Clin Toxicol 1999;37: 635 8. Sigg T: Recurrent seizures from sustained-release bupropion. J Toxicol Clin Toxicol 1999;37:634 9. Shretha M, Greenberg M: Status epilepticus secondary to bupropion overdose. J Toxicol Clin Toxicol 1999;37:634-5 10. Dunner DL, Zisook S, Billow AA, et ah A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry 1998;59:366-73 11. Product Information for Wellbutrin Tablets and Wellbutrin SR Tablets. Research Triangle Park, NC, Glaxo Wellcome Inc.