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Tadalafil is a highly selective PDE5 inhibitor that is safe and efficacious
for the treatment of ED. Clinical evidence generally demonstrates
the favorable safety and efficacy profiles of the PDE5 inhibitors in most
patient populations, including men with stable ischemic heart disease
and those receiving therapy with antihypertensive agents (other than
a-blockers). These general properties also hold true for tadalafil, which
provides clinical benefits regardless of the cause or severity of ED and
may be safely used in men with comorbid conditions, such as diabetes
and hypertension in men following prostatectomy.
In both healthy men and those with cardiovascular disease, PDE5
inhibitors generally produce only mild vasodilation and minimal hemodynamic
effects and are not associated with increases in myocardial infarction
or death rates in controlled clinical trials. Clinical evidence with
tadalafil is consistent with this general statement, and it is important to note
that the majority of patients assessed at low cardiovascular risk may be
safely treated with tadalafil. Tadalafil is not associated with serious cardiovascular
adverse events, although, like other PDE5 inhibitors in its class,
its use is contraindicated in patients taking any form of organic nitrates.
When chest pain occurs more than 48 h after tadalafil administration,
however, nitrates may be used under close medical supervision. In addition,
tadalafil is contraindicated with the use of a blockers other than
0.4 mg of once-daily tamsulosin because of the potential for additive hypotensive
effects. There are no reports of increased risk of cardiovascular
mortality or morbidity after use of tadalafil, and the drug does not affect
exercise tolerance or time to ischemia during physical activity.
With its pharmacokinetic properties, which include a long duration of
action (up to 36 h), tadalafil represents a distinctly unique profile in the
pharmacotherapy of ED. The 36-h duration of action of tadalafil may
provide couples with increased flexibility by minimizing the need to schedule
sexual activity, thereby potentially increasing patient–partner satisfaction.
Additionally, the fact that neither the rate nor the extent of tadalafil
absorption is affected by the presence of high-fat food also translates into
increased flexibility for couples concerned about delayed onset of action
or reduced efficacy.

Although tadalafil, like other PDE5 inhibitors, is a vasodilator that may
augment the blood pressure-lowering effects of antihypertensive agents,
recent data show that tadalafil is safe in patients receiving two or more
concomitant antihypertensive agents. According to an analysis of
data from six placebo-controlled phase III studies of interactions between
tadalafil and commonly prescribed antihypertensive agents, a comparison
of patients receiving and not receiving antihypertensive therapy showed
comparable incidence rates of cardiovascular events. No statistically significant
differences were observed between tadalafil and placebo in the
mean changes in blood pressure from baseline in patients taking concomitant
antihypertensive therapy. Hypotension or postural hypotension was
not reported in any tadalafil-treated patients, compared with a report of
each in the placebo-treated patients. Additionally, syncope was reported in
one tadalafil-treated patient (0.1%) who was not receiving concomitant
antihypertensive medication and in two patients (1.9%) who received placebo
with concomitant antihypertensive agents. In clinical pharmacology
studies evaluating the combined efforts of tadalafil and various antihypertensive
agents on blood pressure, the additional blood pressure reduction
observed was generally mild, and there was no increase in hypotensive
symptoms. In addition, the studies demonstrated no difference in adverse
events in patients taking tadalafil with or without antihypertensive medications.

Another potential drug interaction exists between PDE5 inhibitors and
a blockers. In a drug-interaction study, when 20 mg of tadalafil was administered
to healthy subjects taking doxazosin (8 mg daily), an a1-adrenergic
blocker, there was a significant augmentation of the blood pressure-lowering effect of doxazosin. When 20 mg of tadalafil was administered to healthy
subjects taking 0.4-mg once-daily tamsulosin, a selective

Like other PDE5 inhibitors, clinical pharmacology studies show that
tadalafil (5–20 mg) potentiates the hypotensive effect of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the
NO-cGMP pathway. Therefore, administration of tadalafil to patients who
are using any form of organic nitrates, either regularly or intermittently, is
contraindicated.
Results of a recent placebo-controlled study to assess the degree of
interaction between nitroglycerin and tadalafil showed that 20 mg of
tadalafil enhanced the hypotensive effects of sublingual nitroglycerin
(NTG) for up to 24 h after tadalafil dosing. In this study, a significant
interaction between tadalafil and NTG was observed at each time point up
to and including 24 h. At 48 h, by most hemodynamic measures, the interaction
between tadalafil and NTG was not observed, although a few more
tadalafil subjects compared with those receiving placebo experienced a
decrease in blood pressure at this point in time. After 48 h, the interaction
was not detectable. In emergency situations in which nitrate administration
is deemed medically necessary, at least 48 h should elapse after the last
dose of tadalafil before nitrate administration is considered. In such circumstances,
nitrates should still only be administered under close medical
supervision and patient monitoring.

The long-term safety of tadalafil has been assessed in 1173 patients
enrolled in an ongoing, international, open-label study. Of the patients
enrolled, most (870) had been exposed to 10 or 20 mg of tadalafil daily
for at least 1 yr, with 991 being exposed to these dosages for more than
6 mo. Adverse events experienced by patients in the long-term study
generally reflected those observed in the shorter-term studies. Headache
and dyspepsia were the most frequently reported treatment-emergent
adverse events, with incidence rates of 15% and 11%, respectively. Other
adverse events reported with a frequency of 6 to 10% included infection,
back pain, rhinitis, flu syndrome, pain, and a need for surgical procedures.
Overall, tadalafil was associated with good safety and tolerability for
the treatment of ED in a broad range of patients using the drug for periods
up to 1 yr. Few subjects in this study discontinued use because of adverse
events.