Is the co-administration of phosphodiesterase 5 (PDE5) inhibitors for erectile dysfunction (ED) and

Fråga: Is the co-administration of phosphodiesterase 5 (PDE5) inhibitors for erectile dysfunction (ED) and alpha-adrenergic blockers for benign prostrate hypertrophy (BPH) safe?

This is a general question.

Sammanfattning: There is a potential for a, by all probabilities, dose dependent pharmacodynamic interaction between alpha-blockers and PDE5-inhibitors, which might occasionally cause significant hypotension. The clinical importance of this is not easy to evaluate. Use of the shorter acting drug sildenafil, rather than vardenafil or tadalafil, at the lowest effective dose, is prudent if the combination is used.

Svar: The co-administration of PDE5 inhibitors and organic nitrates is considered contraindicated due to a synergistic vasodilatatory effect, which is suspected to have caused fatal outcomes (1). The alpha-adrenergic blockers doxazosin, terazosin and alfuzosin are licenced in Sweden for the treatment of BPH. These drugs are also peripheral vasodilators, through their effect on the alpha-adrenergic receptor system. Thus, an adverse pharmacodynamic interaction between PDE5-inhibitors and these agents is theoretically possible.

According to the summary of product characteristics of sildenafil, some patients had symptomatic hypotension on co-administration of sildenafil and alpha-adrenergic blockers, particularly at doses of sildenafil exceeding 25 mg. Further details are not given (2).

On co-administration of tadalafil 20 mg and doxazosin 8 mg/d, a significant augmentation of the blood-pressure lowering effect of doxazosin was observed in healthy subjects. Several subjects experienced dizziness (3).

When vardenafil 5 mg was given in patients on terazosin therapy, some patients experienced standing systolic blood pressure <85 mmHg (4). Furthermore, in a study on the blood pressure reactions of 35 normotensive patients with ED, who were given vardenafil 10 mg, two out of three observed syncope episodes were in patients on concomitant doxazosin therapy (dose not specified) (5).

The manufacturers of vardenafil and tadalafil state that the coadministration of these drugs with alpha-adrenergic blockers is contraindicated (3,4). The manufacturer of sildenafil state that co-administration of doses in excess of 25 mg are contraindicated within 4 h of administering an alpha-blocker (2).

On the other hand, when combined data from 1137 patients enrolled in ED trials with sildenafil and receiving antihypertensive therapy were analysed, the 163 subjects receiving alpha-blockers had no episodes of hypotension, postural hypotension or syncope reported (6). Furthermore, in a study on 28 patients with "non-organic" ED, where montherapy with sildenafil 100 mg had failed, 14 were treated with concomitant doxazosin 4 mg qd and 14 with placebo. The blood-pressure reaction was similar in both groups. Patients with cardiovascular disease were excluded from the study (7).

A search in the files of the Swedish adverse drug reaction register did not identify any reports of hypotension, syncope or other cardiovascular adverse effects in patients treated with a combination of an alpha-adrenergic antagonist and a PDE5-inhibitor.

The data on the pharmacodynamic interactions between alpha-blockers and PDE5-inhibitors are to a large extent unpublished material, which has been accessed through the summaries of product characteristics for the respective drugs. Thus, it is difficult to quantify the importance of this effect on the basis of available information. Furthermore, epidemiological data do not imply this combination as a source of an important adverse interaction.

On theoretical ground, the combination should probably be avoided in patients with left ventricular dysfunction or other conditions which might inhibit the ability to compensate a loss of peripheral vascular resistance with increased cardiac output. The strategy of a supervised intake of sildenafil with blood pressure monitoring in patients on alpha-adrenoceptor blocking drugs, though prospectively unvalidated, may be considered as a support for decision-making in the individual case. Kloner RA. Novel phosphodiesterase type 5 inhibitors: assessing hemodynamic effects and safety parameters. Clin Cardiol 2004;27(suppl 1):I20-5.

Viagra SPC (Pfizer)
Cialis SPC (Lilly)
Levitra SPC (Bayer)

Pomara G, Morelli G, Pomara S, Taddei S, Ghiadoni L, Dinelli N, et al. Cardiovascular parameter changes in patients with erectile dysfunction using Pde inhibitors: a study with sildenafil and vardenafil. J Androl 2004;25(4):625-9. Prisant LM. Safety of treatment with sildenafil citrate for erectile dysfunction in men receiving different classes of antihypertensives. AJH 2000;13(4: part 2):129A-30A. de Rose AF, Giglio M, Traverso P, Lantieri P, Carmignani G. Combined oral therapy with sildenafil and doxazosin for the treatment of non-organic erectile dysfunction refractory to sildenafil monotherapy. Int J Impot Res 2002;14:50-3.