Concurrent use of bupropion with CYP2B6 inhibitors, nelfinavir, ritonavir and efavirenz

Bupropion (Wellbutrin, Zyban) is an antidepressant that can also be used as a smoking cessation aid. It is an attractive agent for use in the HIV-infected population as it is well tolerated, has a low anticholinergic adverse effect profile, and is less likely to result in the sexual side-effects often associated with selective serotonin reuptake inhibitors [1]. Seizures are a worrying adverse effect of bupropion, with the risk increasing with increasing concentrations of the drug [2]. The incidence of generalized tonic–clonic seizures associated with the sustained release formulation of bupropion increases from 0.1% with the use of 100–300 mg a day to 0.4% when a dose of 400 mg a day is used. Furthermore, the estimated incidence of seizures with the immediate release formulation of bupropion increases almost 10-fold between 450 and 600 mg a day [2]. In the setting of bupropion overdose, seizures were seen in 21% of patients [3]. As bupropion is extensively metabolized by the liver, the potential for inadvertent overdose as a result of a drug interaction exists. Bupropion metabolism is mediated primarily by the 2B6 isoenzyme of the cytochrome P450 system [4]. In-vitro data indicate that the antiretroviral drugs, nelfinavir, ritonavir and efavirenz, are capable of inhibiting the activity of this enzyme at concentrations that are attainable in vivo [5]. The potential thus exists for a serious drug interaction and the eliciting of seizures when these antiretroviral drugs are co-administered with bupropion. Despite warnings surrounding the concomitant use of these antiretroviral drugs with bupropion, these combinations have occasionally been used in clinical practice. This case series aimed to document the clinical consequences of the co-administration of bupropion with nelfinavir, ritonavir and efavirenz in the HIV clinic setting. HIV-infected patients who had used either ritonavir, nelfinavir or efavirenz with bupropion at an HIV specialty primary care clinic of St Michael's Hospital, Toronto, Canada were identified from a voluntary observational database. A thorough review of the chart of patients identified as receiving bupropion with a CYP2B6 inhibitor was retrospectively performed to obtain the patient's age, sex, concomitant antiretroviral drugs and other medications, co-mordities, previous history of seizure disorders, hepatic or renal dysfunction, date of initiation of antiretroviral drugs and bupropion (including doses used, indications for use, duration of use), and any subsequent adverse effects following co-administration over a 6-month follow-up period, if available. Ten patients were identified as having taken bupropion with either nelfinavir, ritonavir, or efavirenz. Patient no. 2 took bupropion with both nelfinavir and efavirenz on different occasions to make up a total of 11 cases. Six patients had taken bupropion with nelfinavir, two patients had taken bupropion with ritonavir, and three patients had taken bupropion with efavirenz. The results are summarized in Table 1.Table 1: Description of the concurrent use of bupropion and nelfinavir, ritonavir or efavirenz.All patients were men, with a median age of 42 years (range 35–66). None of the patients had a history of seizures or seizure disorders. Other predisposing risk factors for seizures were identified in eight out of 10 patients, mostly involving the use of a concomitant medication that could lower the seizure threshold. The median duration of the concomitant use of bupropion with either nelfinavir, ritonavir, or efavirenz was 8 months, and ranged from 3 weeks to 2 years. Bupropion was used in doses of 150 mg a day to 150 mg twice a day. The antiretroviral drugs were used in their usual therapeutic doses, except for ritonavir, which was used in its protease-inhibitor boosting dose of 100 mg twice a day. No episodes of seizures were documented in any of the medical records for patients who took bupropion with the CYP2B6 inhibitors during the period of concomitant use. Although no episodes of sf seizures were observed in this case series, the numbers of patients who had been exposed to bupropion with either nelfinavir, ritonavir, or efavirenz were small and the lack of seizure incidence may reflect the low rate of seizures reported with bupropion in the literature. The absence of the occurrence of seizures would suggest that the risk of seizure with the concomitant use of bupropion and either nelfinavir, ritonavir, or efavirenz may be comparable to the estimates given for the general low-risk population. However, these data are preliminary, and would be strengthened by further work, such as pharmacokinetic measurements and prospective surveillance. No patients in the series were receiving ritonavir at doses above 100 mg twice a day, making it impossible to make any inferences about the safety of combined bupropion and higher doses of ritonavir [6,7]. The combination of ritonavir and bupropion should thus be used with caution at low doses and avoided if possible if higher doses are used. No seizures were observed in 11 cases of the combined use of bupropion with the CYP2B6 inhibitors, nelfinavir, ritonavir, or efavirenz. A study of a larger sample of patients who had used these combinations would be beneficial in confirming these preliminary results.

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