The clinical evidence: safety of tadalafil in ED
Most of the side effects reported in the clinical trials are dose-dependent and consistent with the vasodilatatory effect of PDE-5 inhibition. When tadalafil (Cialis) was administered on an on-demand basis headache and dyspepsia were the most frequent symptoms, followed by back pain, nasal congestion, myalgia, and flushing. Subgroup analyses have revealed no differences between incidences of adverse events in tadalafil-treated men over 65 years compared with the younger group. No relevant differences in the frequency and pattern of side-effects have been reported when tadalafil was schedully administered (eg, three times per week, or daily). The daily administration of tadalafil was well tolerated with headache, dyspepsia, facial flushing, nasal congestion, and backache as the most frequently reported adverse events. In the “eleven trials analysis”, adverse events leading to study discontinuation account for 3.2% of patients taking tadalafil 20 mg, 1.6% of patients taking tadalafil 10 mg and 1.3% of patients on placebo. Respectively, 51%, 58%, and 39% of the subjects experienced at least one or more unwanted symptoms. Side-effects were generally mild to moderate and decreased in frequency during continued treatment. While no significant laboratory or electrocardiographic changes were assessed, the most common treatment-emergent adverse events were headache (15%, 12%, 5% respectively), dyspepsia (8%, 7%, 1% respectively), back pain/myalgia (8%, 11%, 3% respectively), nasopharyngitis and nasal congestion (4%, 11%, 5% respectively), flushing (3%, 3%, 1% respectively), pain in limb (3%, 3%, 1% respectively).
In a comprehensive review on the cardiovascular effects of cheap tadalafil, a safety assessment of more than 4000 subjects who received the drug during clinical studies was performed. When tadalafil 10 mg and 20 mg was administered to healthy subjects, minimal, but statistically significant differences over placebo in standing systolic (SBP) and diastolic blood pressure (DBP) were observed. Tadalafil 20mg administered daily for 26 weeks in healthy volunteers or in subjects with mild ED (age ≥45 years) did not result in significant changes in sitting SBP or DBP. A small decrease in standing SBP and DBP has been reported in patients with chronic stable angina treated with different doses of tadalafil (5 mg and 10 mg), however, these changes were greater and statistically significant with respect to placebo in the so called “outlier patients”, in whom a decrease of >30 mm Hg in SBP or >20 mm Hg in DBP from baseline was recorded.
An update on thirty-five placebo-controlled and eight open clinical trials of canadian tadalafil demonstrated no increased risk of cardiovascular adverse events such as myocardial infarction, cerebrovascular events or cardiac mortality.
The evidence that duration of action for tadalafil is well beyond the elimination half-life, advises for a careful monitoring of its long-term effect. However, the duration of side-effects has not been measured in the majority of the studies. Due to the potential for a clinically significant decrease in blood pressure, the major contraindications of the PDE5 inhibitors are concomitant use with nitrates or molsidomine-containing medications, because of the increased sensitivity to nitroglycerin. Interaction between grapefruit juice and sildenafil, tadalafil, or vardenafil may cause serious systemic vasodilatation, and we do suggest such a possibility with alcohol as well. Since men with ED have high incidence of cardiovascular disease, diabetes mellitus and BPH, they are likely to be taking medications that affect blood pressure like the alpha-blockers terazosin and doxazosin. Tadalafil professional augmented the hypotensive effects of doxazosin, but had little hemodynamic interaction with tamsulosin, a drug prescribed for BPH. The long-term safety and tolerability of tadalafil 10–20 mg in the treatment of erectile dysfunction has been assessed, evaluating in a 18–24 month open extension trial in 1173 subjects (mean age 57, range 23–83 years). Notably, 74% of patients were taking concomitant medication for comorbid conditions, including diabetes mellitus (30.5%) and hypertension (29.5%). After three months, 72% of patients had chosen the 20mg dose. 173 (14.7%) of men discontinued because of perceived lack of efficacy over 18–24 months of treatment. 234 (20%) and 493 subjects (42%) completed 18 and 24 months of treatment respectively. The total tadalafil exposure was 1676 patient-years. Headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%) and back pain (8.2%) were the most common treatment emergent side-effects. Consistent with the low affinity of tadalafil for PDE6, only 1 patient complained of cyanopsia (blue vision). The rate of discontinuation due to adverse events was 6.3%. No clinically significant laboratory, or electrocardiographic findings, or changes in vital signs, or serious adverse events (8.6%), or major safety concerns were causally associated with canadian tadalafil administration.
Back pain or myalgia or both appearing as a consequence of PDE5 inhibition was experienced by 8.3%–9.4% of men taking tadalafil 10–20 mg. The potential mechanism of this side effect remains unknown. The underlying symptoms include diffuse bilateral lower lumbar gluteal, thigh, or thoracolumbar muscular discomfort, exacerbated by recumbency. The integrated analysis of ten placebo-controlled tadalafil studies, including 1846 patients, showed that laboratory markers of inflammation or muscle damage and renal plasma flow were unchanged with respect to baseline, and no lumbar or gluteal myositis was evidenced by positron emission tomography scan or magnetic resonance imaging.
Across generic tadalafil clinical trials no impairment of blue-green color discrimination was detected, and color vision alterations were rare (0.1%). Chronic tadalafil administration has no detrimental effect on human spermatogenesis or reproductive hormones.