Effects on Blood Pressure When Administered with Nitrates

In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use tadalafil in patients taking any form of nitrates [see Contraindications (4.1)]. 

A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). A significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood–pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable. [See Contraindications (4.1)]. 

Effects on Blood Pressure 

The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1.

a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at a similar frequency to alcohol alone. 

b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination. Some patients had symptoms associated with the decrease in blood pressure including syncope.

Figure 1: Effects of Tadalafil on Blood Pressure

Effects on Cardiac Electrophysiology

The effect of a single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double–blinded, placebo, and active–controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two–sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two–sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with a 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute. 

Effects on Exercise Stress Testing

The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise–induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post– exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood–pressure–lowering effects of nitrates. 

Effects on Vision

Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients). 

Effects on Sperm Characteristics

Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo. 

Dose-Response Relationship

Dose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm-5 and -209 dynes*sec*cm-5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively.