Interactions

Active ingredient Bupropion interacts in the following cases:

CYP2D6 substrates

Although not metabolised by the CYP2D6 isoenzyme, bupropion and its main metabolite, hydroxybupropion, inhibit the CYP2D6 pathway. Co-administration of bupropion hydrochloride and desipramine to healthy volunteers known to be extensive metabolisers of the CYP2D6 isoenzyme resulted in large (2- to 5-fold) increases in the Cmax and AUC of desipramine. Inhibition of CYP2D6 was present for at least 7 days after the last dose of bupropion hydrochloride.

Concomitant therapy with medicinal products with narrow therapeutic indices that are predominantly metabolised by CYP2D6 should be initiated at the lower end of the dose range of the concomitant medicinal product. Such medicinal products include certain antidepressants (e.g. desipramine, imipramine, paroxetine), antipsychotics (e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), and Type 1C antiarrhythmics (e.g. propafanone, flecainide). If bupropion is added to the treatment regimen of a patient already receiving such a medicinal product, the need to decrease the dose of the original medicinal product should be considered. In these cases the expected benefit of treatment with bupropion should be carefully considered compared with the potential risks.

Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g. tamoxifen), may have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion.

Hepatic impairment

Bupropion is extensively metabolised in the liver to active metabolites, which are further metabolised. No statistically significant differences in the pharmacokinetics of bupropion were observed in patients with mild to moderate hepatic cirrhosis compared with healthy volunteers, but bupropion plasma levels showed a higher variability between individual patients. Therefore bupropion should be used with caution in patients with mild to moderate hepatic impairment and 150 mg once a day is the recommended dose in these patients. All patients with hepatic impairment should be closely monitored for possible undesirable effects (e.g. insomnia, dry mouth) that could indicate high drug or metabolite levels.

Bupropion should be used with caution in patients with hepatic impairment. Because of increased variability in the pharmacokinetics in patients with mild to moderate impairment the recommended dose in these patients is 150mg once a day.

Renal impairment

Bupropion is mainly excreted into urine as its metabolites. Therefore 150 mg once a day is the recommended dose in patients with renal impairment, as bupropion and its active metabolites may accumulate to a greater extent than usual. The patient should be closely monitored for possible undesirable effects that could indicate high drug or metabolite levels.

Bupropion should be used with caution in patients with renal insufficiency. The recommended dose in these patients is 150mg once a day.

CYP2B6 isoenzyme substrates, inhibitors, inducers

Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6. Co-administration of medicinal products that may affect the metabolism of bupropion via CYP2B6 isoenzyme (e.g. CYP2B6 substrates: cyclophosphamide, ifosfamide, and CYP2B6 inhibitors: orphenadrine, ticlopidine, clopidogrel), may result in increased bupropion plasma levels and lower levels of active metabolite hydroxy-bupropion. The clinical consequences of the inhibition of the metabolism of bupropion via CYP2B6 enzyme and the consequent changes in the bupropion-hydroxybupropion ratio are currently unknown.

Alcohol

Although clinical data do not identify a pharmacokinetic interaction between bupropion and alcohol, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during bupropion treatment. The consumption of alcohol during bupropion treatment should be minimised or avoided.

Lactation

Bupropion and its metabolites are excreted in human breast milk. A decision on whether to abstain from breast-feeding or to abstain from therapy with bupropion should be made taking into account the benefit of breast-feeding to the newborn/infant and the benefit of bupropion therapy to the mother.

Pregnancy

Some epidemiological studies of pregnancy outcomes following maternal exposure to bupropion in the first trimester have reported an association with increased risk of certain congenital cardiovascular malformations specifically ventricular septal defects and left outflow tract heart defects. These findings are not consistent across studies. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Bupropion should not be used in pregnancy. Pregnant women should be encouraged to quit smoking without the use of pharmacotherapy.

Citalopram

Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.

Digoxin

Co-administration of digoxin with bupropion may decrease digoxin levels. Digoxin AUC0–24h was decreased and renal clearance was increased in healthy volunteers, based on a cross-study comparison. Clinicians should be aware that digoxin levels may rise on discontinuation of bupropion and the patient should be monitored for possible digoxin toxicity.

Levodopa, amantadine

Administration of bupropion to patients receiving either levodopa or amantadine concurrently should be undertaken with caution. Limited clinical data suggest a higher incidence of undesirable effects (e.g. nausea, vomiting, and neuropsychiatric events) in patients receiving bupropion concurrently with either levodopa or amantadine.

Effects on ability to drive and use machines

As with other CNS acting drugs bupropion may affect ability to perform tasks that require judgement or motor and cognitive skills. Bupropion has also been reported to cause dizziness and lightheadedness. Patients should therefore exercise caution before driving or use of machinery until they are reasonably certain bupropion does not adversely affect their performance.

Efavirenz

Efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers.

Pregnancy

Some epidemiological studies of pregnancy outcomes following maternal exposure to bupropion in the first trimester have reported an association with increased risk of certain congenital cardiovascular malformations specifically ventricular septal defects and left outflow tract heart defects. These findings are not consistent across studies. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Bupropion should not be used in pregnancy. Pregnant women should be encouraged to quit smoking without the use of pharmacotherapy.

Nursing Mothers

Bupropion and its metabolites are excreted in human breast milk. A decision on whether to abstain from breast-feeding or to abstain from therapy with bupropion should be made taking into account the benefit of breast-feeding to the newborn/infant and the benefit of bupropion therapy to the mother.

Carcinogenesis, Mutagenesis and Fertility

Fertility

There are no data on the effect of bupropion on human fertility. A reproductive study in rats revealed no evidence of impaired fertility.

Effects on Ability to Drive and Use Machines

As with other CNS acting drugs bupropion may affect ability to perform tasks that require judgement or motor and cognitive skills. Bupropion has also been reported to cause dizziness and lightheadedness. Patients should therefore exercise caution before driving or use of machinery until they are reasonably certain bupropion does not adversely affect their performance.