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Published: September 2001
Prescriber Update 22: 4-8
September 2001
Dr Michael Tatley, Medical Assessor, CARM, P O Box 913, Dunedin
The Centre for Adverse Reactions Monitoring (CARM) has recorded 218 reports of adverse reactions to bupropion (Zyban™) since its launch in New Zealand. The nature and number of reactions are of a similar pattern to that reported in Australia and the United Kingdom but on a smaller scale. Hypersensitivity and neuro-psychiatric reactions are most commonly reported. Bupropion is contraindicated in patients with a seizure disorder, and caution is required with other predisposing conditions or interacting medicines - check the data sheet. The Medicines Adverse Reactions Committee (MARC) advises prescribers that Zyban should only be considered as a second-line intervention and as part of a smoking cessation programme.
Bupropion (Zyban™), originally developed as an antidepressant, has recently been identified as a beneficial aid in smoking cessation therapy. In mid 2000, it was introduced in New Zealand for this latter indication. The mechanism by which bupropion acts as a smoking cessation aid is unclear, as is the exact mechanism of antidepressant activity.1 Recent media attention in the United Kingdom (UK) has focussed on reports of convulsions and deaths in patients who have taken bupropion, and questioned its safety profile.
Of the 126 cases of convulsions in bupropion users in the UK, half the patients had risk factors for seizures.2 In New Zealand, the Centre for Adverse Reactions Monitoring (CARM) has received two reports of convulsions. No apparent risk factors are known in these two cases and it has been difficult to establish causality due to incomplete information. These reports are a reminder about the potential for bupropion to precipitate seizures in predisposed patients.
Bupropion is contraindicated3 in patients:
Bupropion should be used with extreme caution3 in patients:
If patients are taking any medicines, check for interactions before prescribing bupropion. Details of interactions are in the Zyban data sheet which is on the Medsafe web site: www.medsafe.govt.nz/Profs/Datasheet/z/zybantab.htm
As at August 2001, CARM had recorded 218 reports of adverse reactions to bupropion. These were largely neuro-psychiatric and hypersensitivity reactions which, although not always serious, were severe enough for nearly all of these patients to discontinue treatment. Many of the neuro-psychiatric adverse events reported may be symptoms of nicotine withdrawal, making assessment of the reactions difficult. Hypersensitivity reactions accounted for 25% of reactions reported. Mean duration to onset of symptoms was 15 days for hypersensitivity reactions and 11 days for all others.
While reactions are more common at the higher dose of 300mg daily, 15% occurred at the 150mg daily dose including 70% of the reports of depression-type symptoms. Twenty-five reports (11%) were serious and required either treatment for the reaction or hospitalisation. Bupropion was the sole suspected medicine in 150 of the reports. In only one report was there evidence indicating the presence of known risk factors or potential drug interactions, suggesting that New Zealand prescribers are adhering to the prescribing information.
In comparison, the Adverse Drug Reactions Advisory Committee (ADRAC) in Australia4 has received 980 reports, and in the UK5 the Medicines Control Agency (MCA) has received 5,593 reports. The high numbers of reported reactions may be partly accounted for by the large number of patients using bupropion, as well as media attention and the higher reporting rate often seen for new medicines.
In Australia and the UK, where bupropion is subsidised, user numbers are around 250,000-300,0006 and 419,0002, respectively. Bupropion is not subsidised in New Zealand and our user population is estimated to be 23,000.7 The adverse reactions reporting rate in New Zealand is similar to that of Australia and the UK.
The most common adverse reactions reported to CARM are listed in the table below and involved hypersensitivity/skin (130 reactions), psychiatric changes (154 reactions) and nervous system (67 reactions). A similar pattern of reactions has been reported in Australia4 and the UK. 5
| Bupropion reactions reported most frequently in NZ | |
|---|---|
| Hypersensitivity/Skin | |
| Urticaria | 42 |
| Rash | 29 |
| Pruritis | 19 |
| Angiodema | 8 |
| Other | 32 |
| Psychiatric | |
| Insomnia | 35 |
| Depression | 28 |
| Anxiety | 23 |
| Depersonalisatoin | 12 |
| Other | 56 |
| Neurological | |
| Tremor | 22 |
| Headache | 21 |
| Ataxia | 6 |
| Other | 18 |
In the UK, there have been 37 deaths in patients taking bupropion. The contribution of the medicine to these deaths is unknown and many patients had underlying conditions that could provide alternative explanations including nine who were not on bupropion at the time of death.5
An ADRAC review8 of 15 reported deaths with bupropion in Australia found various causes of death and not a single consistent mode of death. In addition to being smokers, several patients had other existing risk factors for unexpected death such as alcohol abuse, diabetes or cardiomyopathy. In 10 of the 15 deaths, alternative contributing factors were identified that were at least as plausible as bupropion. Of the other five deaths, there was insufficient information to assess causality and in two of these cases further data are being sought.
ADRAC has also observed that smokers are already at increased risk of cardiovascular death and that early symptoms of cardiovascular disease may have prompted smoking cessation therapy with bupropion.4 In the single New Zealand report of non-fatal myocardial infarction, it has not yet been established whether there was pre-existing evidence of cardiovascular disease.
The Medicines Adverse Reactions Committee (MARC) is continuing to closely review the safety of bupropion
through the monitoring of CARM reports, as well as the experiences of overseas agencies. At present
MARC is satisfied that the risk:benefit ratio of bupropion is favourable when the medicine is used
appropriately as outlined in the Zyban data sheet, including observing all contraindications. However,
in view of the significant adverse events experienced in otherwise healthy individuals and the serious
nature of the international reports, MARC recommends that Zyban should only be considered as a
second-line intervention after unsuccessful trials with other smoking cessation treatments including
nicotine replacement therapy. Medsafe is working with the sponsor of Zyban to update the data
sheet to reflect this prescribing advice. MARC also advises that bupropion should only be used as part
of a comprehensive support programme for smoking cessation. Zyban information for patients is
available as a CMI (Consumer Medicine Information) on the Medsafe web site:
www.medsafe.govt.nz/Consumers/cmi/z/zyban.htm
Competing interests (author): none declared
Correspondence to Dr Michael Tatley, CARM, PO Box 913, Dunedin. E-mail: michael.tatley@stonebow.otago.ac.nz
