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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.

Common extrinsic factors appear to exert no influence on the pharmacokinetics
of tadalafil. For example, in a clinical pharmacology study
conducted in 18 healthy subjects, on the effect of food on tadalafil absorption,
the mean plasma tadalafil concentration was similar among subjects
who received a single 20-mg dose of tadalafil after eating a high-fat
meal and among subjects who fasted, indicating that tadalafil may be
taken with or without food. This study also demonstrated that the presence
of high-fat food affects neither the rate nor the extent of tadalafil
absorption.
Other drug interactions do exert influence on the pharmacokinetics of
tadalafil. For example, since tadalafil is metabolized predominantly by
CYP3A4 in the liver, the dosage should be limited to 10 mg not more than
once every 72 h in patients taking potent inhibitors of CYP3A4, such as
ritonavir and ketoconazole. In addition, drugs that induce CYP3A4, such
as rifampin (600 mg daily), reduce tadalafil exposure. Although specific
interactions have not been studied, other CYP3A4 inducers, such as carbamazepine,
phenytoin, and phenobarbital, would likely decrease tadalafil
exposure. No dose adjustment is warranted, however.
In addition, tadalafil did not potentiate the increase in bleeding time
caused by aspirin. Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of
absorption of tadalafil without altering exposure AUC to tadalafil, and no
dose adjustment is warranted.

Studies conducted in 421 men, either healthy or with mild ED, have
found no evidence that tadalafil has adverse effects on spermatogenesis.
Tadalafil had no clinically relevant effect on sperm concentration, sperm
count per ejaculate, sperm motility, or sperm morphology. Similarly,
tadalafil has no effect on serum levels of testosterone, luteinizing hormone,
or follicle-stimulating hormone.