Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

In patients receiving medicinal products known to lower the seizure threshold, Zyban must only be used if there is a compelling clinical justification for which the potential medical benefit of smoking cessation outweighs the increased risk of seizure (see section 4.4).

The effect of bupropion on other medicinal products:

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 Zyban 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 Zyban should be carefully considered compared with the potential risks.

There have been post-marketing reports of serotonin syndrome, a potentially life-threatening condition, when Zyban is co-administered with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.4).

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 (see section 4.4).

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

Co-administration of digoxin with bupropion may decrease digoxin levels. Digoxin AUC 0–24 h 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.


The effect of other medicinal products on bupropion:
Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6 (see section 5.2). 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, 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.

Since bupropion is extensively metabolised, caution is advised when bupropion is co-administered with medicinal products known to induce metabolism (e.g. carbamazepine, phenytoin, ritonavir, efavirenz) or inhibit metabolism (e.g. valproate), as these may affect its clinical efficacy and safety.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20 to 80% (see section 5.2). Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers. Patients receiving any of these drugs with bupropion may need increased doses of bupropion but the maximum recommended dose of bupropion should not be exceeded.

Nicotine, administered transdermally by patches, did not affect the pharmacokinetics of bupropion and its metabolites.



Other interactions:
Smoking is associated with an increase in CYP1A2 activity. After cessation of smoking, reduced clearance of medicinal products metabolised by this enzyme, with subsequent increases in plasma levels, may occur. This may be particularly important for those medicinal products primarily metabolised by CYP1A2 with narrow therapeutic windows (e.g. theophylline, tacrine and clozapine).
The clinical consequences of smoking cessation on other medicinal products that are partially metabolised by CYP1A2 (e.g. imipramine, olanzapine, clomipramine, and fluvoxamine) are unknown.
In addition, limited data indicate that the metabolism of flecainide or pentazocine may also be induced by smoking.
Administration of Zyban 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 – see section 4.8) in patients receiving bupropion concurrently with either levodopa or amantadine.
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 Zyban treatment. The consumption of alcohol during Zyban treatment should be minimised or avoided.

Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by a different mechanism from bupropion, concomitant use of Zyban and monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.3) as there is an increased possibility of adverse reactions from their co-administration. At least 14 days should elapse between discontinuation of irreversible MAOIs and initiation of treatment with Zyban. For reversible MAOIs, a 24 hour period is sufficient.

Studies suggest that exposure to bupropion may be increased when sustained release bupropion tablets are taken with a high fat meal (see section 5.2).