Bupropion (Zyban SR)

5 September 2001

Bupropion (Zyban SR) was first marketed in Australia late in 2000 as a short-term aid to giving up smoking and has had very high usage. It was initially developed as an antidepressant. It is a selective inhibitor of the neuronal re-uptake of catecholamines in the brain but its mechanism to enhance the ability to quit smoking is unknown.

New medicines achieve registration on the basis of experience in relatively limited numbers of patients and some uncommon or rare adverse reactions to the drug become recognised only after usage has grown, which may take years. In contrast, the very high usage of bupropion in a short time has highlighted several possible adverse effects, some of which may be severe.

The assessment of reactions to bupropion use is difficult because many patients experience the effects of nicotine withdrawal in addition to the effects of bupropion. Since November 2000 the Adverse Drug Reactions Advisory Committee (ADRAC) has received 1237 Australian reports of suspected adverse reactions in connection with the use of Zyban SR. In 1215 of these, Zyban SR was implicated as the sole suspected drug. The more commonly reported problems involved skin reactions (499 reports), psychiatric disturbances (427), the nervous system (406), and the gastrointestinal tract (258) as indicated in Table 1 below.

Table 1: More commonly reported reactions with Bupropion
Adverse Reaction No. of Reports
Skin
Urticaria 289
Other rashes 137
Other itch 73
Neurological
Headache 116
Dizziness/ataxia 108
Convulsions/twitching 74
Tremor 71
Paraesthesia/hypoaesthesia 64
Psychiatric
Insomnia 115
Agitation 81
Depression 72
Anxiety 69
Gastrointestinal
Nausea 128
Vomiting 44
Other
Facial/angioedema 89
Chest pain 79
Serum sickness 63
Shortness of breath 51
Increased sweating 41

The profile of the drug is dominated by hypersensitivity reactions and neurological and psychiatric effects.

The majority of hypersensitivity reactions involve relatively minor skin reactions but there have also been reports of facial oedema or angioedema and serum sickness-like reactions. The latter describe a syndrome of a skin rash or urticaria with joint pain or swelling. The delayed onset ranging from 5 to 44 days (median: 16 days) after commencement of bupropion is also consistent with a serum sickness-like syndrome. In at least 30 of the cases, steroids were given.

Bupropion can cause seizures and is contraindicated in patients with epilepsy. It should be used with great caution in those with a predisposition to seizures including those abusing alcohol or taking another medication that can lower the seizure threshold. This includes most antidepressant and antipsychotic drugs, insulin, oral hypoglycaemic drugs and anorectic products.

Care also needs to be taken in prescribing bupropion for patients with a history of psychiatric conditions, and especially those taking drug therapy, because of the possibilities of interactions or additive effects. These are identified in the product information.

Recent media coverage has highlighted a small number of Australian reports to ADRAC of suspected adverse reactions to bupropion where the patient died. As at 22 June 2001, there had been 18 such reports in patients aged from 30 years to 69 years. The duration of exposure to bupropion ranged from a single dose to 10 weeks in 15 patients: two died three days after ceasing the drug. The death of a patient may be caused by a drug or may be coincidental. Smokers are at increased risk of cardiovascular death and early symptoms of cardiovascular disease may prompt therapy with bupropion.

An ADRAC review of the 18 reports has found that there were a variety of reported 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. Eleven of the 18 patients had an alternative explanation for death that was at least as plausible as a possible effect of bupropion. In four reports, the available information was very limited and it was not possible to assess the cause of death. Further information is being sought on three cases to aid assessment of the cause of death.

ADRAC will review each report with a fatal outcome as additional information becomes available. As with all such reports, ADRAC seeks detailed follow-up information including post-mortem and coronial reports to aid in assessment of the individual cases. ADRAC meets every six to seven weeks and is keeping the drug's safety under close review.