Is it safe to add Zyban (bupropion) to a combination treatment of fluoxetine, hydrocortisone, salme

Fråga: Is it safe to add Zyban (bupropion) to a combination treatment of fluoxetine, hydrocortisone, salmeterole, oxazepam, ramipril, desmopressine, levothyroxine and buspirone?

A physician is considering prescription of bupropion to a 52-year-old woman with obstructive lung disease, since other alternatives have not resulted in smoking cessation. About six years ago, the patient was operated for a craniopharyngioma. Sequelae include hypopituitarism, visual impairment and memory loss but no seizures. The patient has earlier been treated with Cipramil for depression, but did not respond well. She is now treated with Seroscand (fluoxetine) with good therapeutic response. Furthermore, the patient is treated with Buspar (buspirone), Hydrocortone (hydrocortisone), Levaxin (levothyroxin), Minirin (desmopressine), Pramace (ramipril), Seretide (salmeterol) and Sobril (oxazepam).

Sammanfattning: There are several possibilities of pharmacokinetic and pharmacodynamic drug interactions between bupropion and the patient´s other medications. In addition, bupropion is contraindicated in patients with a history of convulsion and previous or present CNS tumours and/or patients with increased risk of seizures. We therefore recommend this combination not be used.

Svar: Bupropion may theoretically interact both pharmacodynamically and pharmacokinetically with several drugs that the patient is administered, but so far there are limited clinical reports of drug interactions between bupropion and other drugs.

Bupropion is extensively metabolised in the liver by several different enzymes including cytochrome CYP2B6, CYP1A2 and CYP3A4 (1-2). Bupropion is mainly metabolised to its active metabolite hydroxybupropion by CYP2B6 (2). Other enzymes, such as CYP3A4, capable of bupropion hydroxylation are characterised by a lower affinity than CYP2B6. At high concentrations, CYP2E1 may contribute to the metabolism of bupropion, but this contribution is unlikely to be of clinical importance (3).

There are many substrates biotransformed partially by CYP2B6 in vitro, but few relatively specific CYP2B6 substrates have been identified (4). Among antidepressants tested as potential inhibitors of bupropion hydroxylation in vitro, paroxetine was the most potent inhibitor and fluoxetine was less active as inhibitor (3). Furthermore, the hydroxylation rate was reduced by citalopram. Bupropion and hydroxybupropion are known to inhibit CYP2D6 in vitro (1,3). However, the clinical relevance of this inhibition is not known. Fluoxetine is metabolised by CYP2D6 and also a strong inhibitor of the same enzyme and should hence be administered with caution (1,5). Three case reports indicate that fluoxetine inhibits the metabolism of bupropion resulting in severe adverse effects, psychosis, mania and seizures respectively (5). Since bupropion (1,2), buspirone (6) and ramipril (7) are all partly metabolised by CYP3A4, drug interactions between bupropion and the other substances are possible. However, no clinical reports of such drug interactions have been found in the literature.

Bupropion is a selective neural reuptake inhibitor of noradrenaline and dopamine and due to risk of pharmacodynamic interactions concomitant treatment with other antidepressive or antipsychotic agents is not recommended (8).

No reports on drug interactions between bupropion and oxazepam, desmopressin, levothyroxine, salmeterol or hydrocortisone have been found in the literature. Nor is there an obvious theoretical suspicion of such drug interactions.

In patients that previously have had or presently have tumours in the CNS and/or have an increased risk of seizures bupropion is contraindicated (8,9). Recently the Swedish medical product agency strongly stated that this drug should not be prescribed to patients with these conditions (9). 1 Drugline no 16931 (year 2000). 2 Drugline no 17408 (year 2000). 3 Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, Greenblatt DJ. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 2000;28:1176-83. 4 Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, Lindley CM. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 2000;28:1222-30.

5 Stockley IH. Drug interactions. 5th ed. London: The Pharmaceutical Press; 1999.
6 Drugline no 15933 (year 1999).
7 Drugline no 15522 (year 1997).
8 Zyban. Summary product characteristics. Medical Product Agency homepage (www.mpa.se)

9 Pressmeddelande från Läkemedelsverket, Zyban. http://www.mpa.se/press/press01/010601.shtml (2001-06-07)