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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.

Clinical trials conducted with tadalafil show it to be safe and generally
well tolerated. The most common treatment-emergent adverse events
reported in men receiving 20 mg of tadalafil are headache and dyspepsia,
which are mild or moderate in severity and transient in nature (18). Flushing
and myalgia have also been reported to occur with somewhat greater
frequency among men taking tadalafil than among those receiving placebo, but the incidence of flushing and myalgia among 804 men
taking up to 20 mg of tadalafil was 5% or less (Table 2). A similar profile of adverse events was observed in men with comorbid
diabetes. In these men, only dyspepsia occurred with significantly greater
frequency in men taking tadalafil (11%) than in men taking placebo (0%)
(p < 0.005). No clinically significant changes in the electrocardiogram,
vital signs, or blood chemistry have been observed with tadalafil.
Notably, there has been only one report of visual disturbance, consisting of
abnormal color vision, among men receiving tadalafil. As discussed
earlier, tadalafil lacks selectivity for the PDE6 isoenzyme, which may
explain the low incidence of visual disturbances. For this reason, tadalafil
as a therapy for ED has been suggested as an option in patients with retinopathy. In addition, no visual disturbances were reported among men
with comorbid diabetes, including those with diabetic retinopathy.

The recommended starting dose of tadalafil in most patients is 10 mg,
taken before anticipated sexual activity. The dose may be increased to
20 mg or decreased to 5 mg once per day, based on individual efficacy
and tolerability. No dose adjustment of tadalafil is required in patients
older than 65 yr age, in patients with diabetes, or in patients with mild
renal insufficiency.

Diabetes is a common comorbidity in men with ED. Several studies
have explored the effectiveness of tadalafil in this patient population. One study investigated men (n = 216) with type 1 or type 2 diabetes. Most men
in this study had moderate to severe ED (72%) and a diagnosis of type 2
diabetes (>90%), with more than 80% having only fair (HbA1C > 7.0–9.5%)
to poor (HbA1C > 9.5%) diabetes control. Nearly 40% of the patients also
had hypertension; 22% had microvascular complications, including retinopathy
or neuropathy; and 18% had hypercholesterolemia. Patients were
eligible whether or not they had responded to previous ED therapy, including
sildenafil.
As in studies of the general population of men with ED, studies of men
with comorbid diabetes (n = 216) benefited from using tadalafil. The erectile
function in most men improved significantly, with more than a six-point
(with 10 mg) or seven-point (with 20 mg) increase in scores for the EF
domain of the IIEF (compared with a 0.1 increase for placebo [p < 0.001])
at end point. Both doses of tadalafil, 10 and 20 mg, were superior to placebo
in improving successful vaginal penetration (SEP Q2). The end points
(change from baseline) were 30% (–4%), 57% (22%), and 54% (23%) for
placebo, 10 mg of tadalafil, and 20 mg of tadalafil, respectively.
Similarly, end-point scores for successful intercourse attempts (SEP
Q3) were more pronounced in patients receiving 20 mg of tadalafil, (51%)
or 10 mg (44%), vs 16% for those taking placebo (p < 0.001).
By the end of the 12-wk treatment period, 56% and 64% of men taking
10 and 20 mg, respectively, of tadalafil, compared with 25% receiving placebo, responded positively to the GAQ (p < 0.001). These benefits were
observed irrespective of the level of diabetes control. Many of the
patients in this study had long-standing, fairly advanced diabetes, and,
given the level of morbidity of the patient population, the effects of tadalafil
were clinically noteworthy.

Tadalafil significantly improves erectile function (EF), as assessed by
a variety of determinants of efficacy, including the following: the EF
domain of the International Index of Erectile Function (IIEF), which
classifies erectile function into five levels ranging from normal (26–30)
to severe (10) ; SEP Q2 and Q3 and the global assessment
questions (GAQ).
The SEP Q2 asks patients, “Were you able to insert your penis into your
partner’s vagina?” The SEP Q3 offers the key question, “Did your erection
last long enough for you to have successful intercourse?”The GAQ 1 and 2 are self administered at the end of the treatment period
during efficacy studies. For the GAQ 1, the patient is asked, “Has the
treatment you have been taking during the study improved your erections?”
GAQ then follows with Q2, “If ‘yes,’ has the treatment improved
your ability to engage in sexual activity?”. Using these assessment
tools, several studies have been conducted to determine the effectiveness
of tadalafil. Clinical trials have supported its efficacy and tolerability in a
broad population of men with ED.
The integrated analyses of randomized, double-blind, placebo-controlled
trials confirm the efficacy of tadalafil, particularly at doses of 10 and 20 mg,
according to a variety of end points. One integrated analysis
consisted of five trials including 1112 men, some with comorbidities of
hypertension or diabetes, and most with ED of more than 1-yr duration. After
a 4-wk, no-treatment baseline period, patients received fixed daily doses of
tadalafil (2.5–20 mg) or placebo in an at-home setting for the next 12 wk.
Patients were instructed to take the study medication as needed before sexual
intercourse, without restriction on food, alcohol use, or timing of sexual
activity. At the end point of these studies, the men responded to the GAQ,
which asked whether the treatment had improved their erections. Results
showed that the majority of men who received 10 or 20 mg of tadalafil felt
that treatment had improved their erections (p < 0.001) . Lower doses of tadalafil were less effective than 10 or 20 mg but still
elicited significantly more positive responses than placebo.
When EF was assessed by the EF domain of the IIEF, significant
improvement was observed at all doses of tadalafil (p < 0.001 vs placebo). Importantly, by the end point of the studies, normal erectile function
(defined by an IIEF EF domain score of 26 or more out of a possible 30)
was attained by 59% of men receiving 20 mg of tadalafil and 40% of men
receiving 10 mg of tadalafil, compared with 11% of those receiving placebo
(p < 0.001).
A subsequent analysis of 11 randomized, double-blind, 12-wk efficacy
trials conducted in more than 2000 patients indicated that tadalafil is effective
regardless of the baseline severity of ED. Thus, normal erectile function
was attained with 20 mg of tadalafil by 40% of men who had severe
ED at baseline (vs 3% for placebo control, p < 0.001).
In the integrated analysis of five trials, improved EF as measured by
SEP diary was accompanied by an increased number of successful
attempts at vaginal penetration (SEP Q2) and completion of intercourse
(SEP Q3). In this study, 57 to 80% of attempts at penetration were
successful in men receiving 5 to 20 mg of tadalafil, compared with 48%
in men receiving placebo (p < 0.001). More than twice the attempts at
intercourse were successful in men taking 20 mg of tadalafil than in men taking placebo (75% vs 32%, p < 0.001), with lower doses also being
effective.
In addition, the majority of men experienced successful intercourse after
taking their very first dose of tadalafil, 10 or 20 mg (56% and 67%, respectively,
vs 31% for placebo, p < 0.001). Moreover, even men with severe ED
experienced a 46 to 68% success rate for intercourse through the first four
doses of 10 or 20 mg of tadalafil (vs 20% for placebo, p < 0.001).
Overall, studies conducted in clinical settings that mimic real-life situations,
without restriction on food, alcohol, or timing of sexual activity,
show that tadalafil provides effective early treatment of ED irrespective of
its cause or severity. In addition, factors, such as age and ethnicity, do not
appear to influence the response to tadalafil. In the integrated analysis of
five randomized trials, the efficacy of tadalafil was similar in patients older
than 65 yr and in their younger counterparts. Tadalafil was similarly
effective in a study conducted in the United States and Puerto Rico, which
included men of diverse ethnic origin (73% white, 13% Hispanic, 13%
black, and 1% Asian) and in two primary US efficacy and safety trials
(78% white, 14% black, 7% Hispanic, and 1% other ethnicities).