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Clinical record

• A 35-year-old man, previously well with no known allergies, presented to the emergency department 17 days after starting bupropion (Zyban) to assist him in giving up smoking. He had been taking no other medication before his presentation.

• Five days before presentation, he complained of discomfort in his throat, and two days later he developed an urticarial rash on his trunk and limbs, joint pain and swelling, and sweating. He had seen his general practitioner three times in the three days before presenting to the emergency department, and was treated with promethazine and prednisolone (50 mg Day 1, 25 mg Day 2, 25 mg Day 3) and cessation of bupropion. Despite this treatment, his symptoms progressed. His rash became more extensive and he started vomiting.

• At presentation to the emergency department, he had a temperature of 37.6ºC, a diffuse urticarial rash on his trunk and limbs, swelling of the metacarpophalangeal joints and interphalangeal joints, and tender wrists, knees and ankles. Testing with a urine dipstick showed red blood cells (RBC) and 5 g/L protein in his urine. Investigation revealed normal serum electrolyte, urea and creatinine levels. He had neutrophilia of 13.3 x 10⁹/L (normal, 2-8 x 10⁹/L), erythrocyte sedimentation rate of 18 mm/h (normal, < 15 mm/h), C-reactive protein level of 218 mg/L (normal, < 8 mg/L), and gamma glutamate transferase level of 72 U/L (normal, < 43 U/L), but results of other liver function tests were normal. Urine microscopy showed > 10⁸ RBC/L (normal, < 10⁷ RBC/L). Tests for antinuclear antibody, antibodies to dsDNA, antibodies to extractable nuclear antigens, antineutrophil cytoplasmic antibodies, immune complexes, and rheumatoid factor were negative. His immunoglobulin and complement levels were normal. An immunoelectrophoretogram showed raised acute phase reactants. A skin biopsy was consistent with urticaria. There was no evidence of vasculitis.

• The man was admitted to hospital and treated with prednisolone (50 mg/day) and antihistamines. A repeat urine analysis showed resolution of the haematuria and proteinuria. He developed angioedema of his lip which settled over two days. He was discharged two days after admission on a 10-day steroid taper and a non-steroidal anti-inflammatory drug, and he made a slow recovery over the following two weeks.

Discussion of bupropion

Bupropion hydrochloride is a selective inhibitor of neuronal uptake of catecholamines (noradrenaline and dopamine). The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown; however, it is presumed that this effect is mediated in part by noradrenergic or dopaminergic mechanisms.¹

Pharmacokinetic studies suggest that both bupropion and its major active metabolite, hydroxybupropion, bind to plasma and cell-surface proteins at a significant level (84% and 77%, respectively). The elimination half-life of bupropion and hydroxybupropion is about 20 hours, and steady-state levels for bupropion and its metabolites are reached within eight days (GlaxoSmith Kline, Therapeutic Goods Administration registration submission).

A number of clinical trials have shown that bupropion leads to smoking abstinence for a four-week period in more patients than placebo or nicotine transdermal systems, with an optimal dose response at 300 mg/day.^1,2 In addition, bupropion helps patients maintain continuous abstinence for six months, and reduces subjective symptoms of cigarette craving and nicotine withdrawal symptoms.^1,2 It is also associated with less weight gain.^1-4

Adverse reactions associated with bupropion include headaches, agitation, insomnia, dry mouth, and seizures.⁴ Bupropion should not be administered to patients with one or more conditions predisposing to a lower seizure threshold, such as a history of seizures, head trauma, tumour of the central nervous system, or other medications known to lower the seizure threshold. A less frequent but significant adverse event seen with administration of bupropion is a hypersensitivity reaction. This occurs at a rate of about 3% (GlaxoSmithKline, Therapeutic Goods Administration registration submission) and most commonly manifests as pruritus, urticaria and/or angioedema; however, some patients present with symptoms suggestive of a serum-sickness-like reaction. These patients usually develop symptoms about 10-20 days after starting bupropion. Their initial symptom is usually an urticarial rash. Over the following days they develop malaise, polyarthralgia/polyarthritis, and fever. Seven patients with the serum-sickness illness have been reported.^5-9 There was no evidence of nephritis or complement pathway activation reported in these patients.

A serum-sickness-like reaction to a drug is believed to be an immune-complex-mediated illness precipitated by the drug acting as a hapten in a protein-hapten complex. As a high proportion of bupropion binds to protein, it is possible that in some individuals the protein-hapten complex will provoke an immune response, with antibody production. The presence of urticaria in 3% of individuals receiving bupropion suggests the antibodies produced can activate anaphylatoxins such as C3a or C5a, which lead to mast cell and basophil degranulation. Alternatively, the drug might directly activate mast cells or induce specific IgE which activates the mast cells; however, skinprick testing with the drug in our patient provided no evidence for these pathways. It is surprising that we and others⁸ have not been able to find evidence of complement protein activation or immune complexes in these patients. The absence of circulating immune complexes may be due to the immune complexes being predominantly cell-bound. A serum-sickness-like reaction usually resolves after antigen withdrawal, over about 14 days. Some patients may require hospitalisation.

The adverse events with bupropion highlight the importance of postmarketing surveillance of new therapeutic agents, especially those that are used in a large number of people in a short period, as is the case with bupropion.

References

1. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997; 337: 1195-1202.
2. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999; 340: 685-691.
3. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation (Cochrane Review). Cochrane Database Syst Rev 2000; CD000031.
4. Holm KJ, Spencer CM. Bupropion: a review of its use in the management of smoking cessation. Drugs 2000; 59: 1007-1024.
5. McLean SE, Pirie SD. A 30-year-old woman with a generalised rash. J Emerg Nurs 1999; 25: 575-576.
6. Tripathi A, Greenberger PA. Bupropion hydrochloride induced serum sickness-like reaction. Ann Allergy Asthma Immunol 1999; 83: 165-166.
7. Yolles JC, Armenta WA, Alao AO. Serum sickness induced by bupropion. Ann Pharm 1999; 33: 931-933.
8. McCollom RA, Elbe DHT, Ritchie AH. Bupropion-induced serum sickness-like reaction. Ann Pharm 2000; 34: 471-473.
9. Peloso PM, Baillie C. Serum sickness-like reaction with bupropion. JAMA 1999; 282: 1817.

©MJA 2001
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