What drug interactions may occur when fluoxetine is added to the following treatment: warfarin, fur

Fråga: What drug interactions may occur when fluoxetine is added to the following treatment: warfarin, furosemide, metoprolol, spironolactone, ramipril and digoxin?

The question concerns a 53-year-old man treated with ordinary doses of the above mentioned drugs.

Sammanfattning: Fluoxetine can be expected to inhibit the metabolism of metoprolol via the CYP2D6 enzyme, with increased betablockade as a result. There are few case reports indicating a possible interaction with warfarin and a single case report suggesting an interaction between fluoxetine and digoxin. Both serotonin reuptake inhibitors and diuretics may cause hyponatremia. These interactions may be handled with careful clinical monitoring of the patient, in combination with a dose reduction of metoprolol and laboratory monitoring of INR, digoxin concentrations and serum sodium. However, an alternative antidepressant, for example citalopram or sertraline, with a shorter half-life and less propensity for drug interactions can also be considered.

Svar: Fluoxetine, a selective serotonine reuptake inhibitor, is also a potent inhibitor of the drug metabolising enzyme CYP2D6 and possibly of other cytochrome enzymes, eg CYP3A4. With continuous treatment, fluoxetine inhibits its own metabolism, resulting in a very long half-life of seven days for the mother compound and up to four weeks for one of its active metabolites, S-norfluoxetine.

Fluoxetine is known to interact with most other antidepressants and many neuroleptics, as well as with metoprolol and other lipophilic betablockers, all of which are metabolised via CYP2D6 (1-3).

A few case reports describe an interaction between fluoxetine and warfarin, leading to elevated INR (international normalised ratio) and, in one case, fatal cerebral bleeding (2-5).

Hyponatremia has been reported as a rare side-effect to fluoxetine in elderly patients and caution is advised when combining fluoxetine and diuretics (2, 6).

Elevated serum digoxin concentrations after starting fluoxetine treatment have been reported in a 93-year-old woman (7).

We found no documentation supporting an interaction between ramipril and fluoxetine. 1 Belpaire FM, Wijnant P, Temmerman A, Rasmussen BB, Brosen K: The oxidative metabolism of metoprolol in human liver microsomes: inhibition by the selective serotonin reuptake inhibitors. Eur J Clin Pharmacol 1998; 54: 261-264

2 Hansen and Horn´s Drug interactions analysis and management. Applied Therapeutics Inc. 1997. p. 293-296, 298, 463
3 Stockley IH. Drug interactions. 4th ed. London: The Pharmaceutical Press; 1996. p. 434, 263
4 Drugline no 12973 (year 1996)
5 Dent LA, Orrock MW: Warfarin-fluoxetine and diazepam-fluoxetine interaction. Pharmacotherapy 1997; 17: 170-172
6 Drugline no 14807 (year 1998)

7 Leibovitz A, Bilchinsky T, Gil I, Habot B: Elevated serum digoxin level associated with coadministered fluoxetine. Arch Intern Med 1998; 158: 1152-1153