Is there any interaction between sildenafil and sertraline? The background is a man, born 1969, wit

Fråga: Is there any interaction between sildenafil and sertraline? The background is a man, born 1969, with depression, anxiousness and impotence. No other diseases. Concomitant drugs are benzodiazepines such as zolpidem (Stilnoct) and alprazolam (Xanor).

Sammanfattning: Information about any interaction between sildenafil and sertraline is scarce. At the present moment it seems unlikely that an interaction can occur according to different metabolic pathways and according to the results of clinical trials.

Svar: Sildenafil is a new drug for impotence treatment. It is an orally active cyclic GMP-specific phosphodiesterase inhibitor. Sildenafil acts through inhibition of phosphodiesterase PDE5, which in turn causes increased levels of cGMP, smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil should not be given to patients who are using organic nitrates, with bad cardiovascular status or with hypotension. Main side effects include headache, flushing and dyspepsia.

Information from the company reveals that sildenafil is metabolised by CYP3A4 (major route) and by CYP2C9 (minor route). Clinical trials with patients indicate that drugs that are metabolised by CYP3A4, such as erythromycin, cimetidine, and ketoconazole (1) reduce the clearance of sildenafil. An 800-mg dose of cimetidine caused a 56 per cent increase in plasma sildenafil concentrations when co-administered with sildenafil. A single 100-mg dose of sildenafil administered with erythromycin at steady state (500 mg twice a day for 5 days) caused a 182 per cent increase in sildenafil AUC. It is stated that even stronger inhibitors of CYP3A4 such as ketoconazole (Fungoral), itraconazole (Sporanox) or mibrefadil (a calcium-blocker not registered in Sweden) would be expected to have still greater effects. Rifampin, on the other hand, induces CYP3A4 and may increase the clearance of sildenafil.

Sildenafil has one major metabolite, N-desmethyl sildenafil, with a pharmacological effect about 50 per cent of sildenafil. As it occurs at concentrations about 40 per cent of the parent compound it will contribute approximately to 20 per cent of the effect. Loop and potassium-sparing diuretics increase its AUC 62 per cent and non-specific beta-blockers 102 per cent. This interaction is not considered to be of clinical importance. Sildenafil is excreted mainly as metabolites in the faeces and to a lesser extent in the urine. Data from clinical trials has shown no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers (1).

In elderly patients, age >65, AUC is increased with 40 per cent. Hepatic impairment (cirrhosis) increases AUC with 80 per cent and severe renal impairment (clearance <30 ml/ml) increases AUC with 100 per cent. A starting dose of 25 mg should be considered in these patients.

Sertraline is a selective serotonin reuptake inhibitor and is a weak inhibitor of CYP2D6, CYP3A3/4 (3) in vitro but not in vivo (4), CYP2C9/10 and CYP1A2 (2). It is highly protein bound and interactions with other highly protein bound drugs could be expected, even if clinical data is limited (2).

A search in Medline did not reveal any reports of interaction between sildenafil and sertraline.