Cialis (Tadalafil) Sexual Function Impact: Clinical Evidence, Dosing, and What to Expect

How tadalafil changes an erection

During sexual stimulation, nitric oxide raises cyclic GMP in the smooth muscle of the penis, which relaxes that muscle and increases blood flow. Tadalafil inhibits phosphodiesterase type 5 (PDE5), the enzyme that breaks cGMP down, so cGMP stays elevated longer. Because the drug acts only on that stimulated pathway, it has no effect without sexual stimulation [1].

PDE5 is also present in prostate, bladder and pulmonary vascular smooth muscle, and the label states that the mechanism by which tadalafil reduces BPH symptoms has not been established [1]. In vitro, tadalafil is about 700-fold more potent against PDE5 than against PDE6, the retinal enzyme, and 14-fold and 40-fold more potent against PDE5 than against two forms of PDE11; PDE11 inhibition has no defined clinical consequence in humans [1].

How much does it improve erectile function?

In the five 12-week double-blind trials pooled by Brock and colleagues, 1,112 men aged 22 to 82 with mild to severe ED of various causes took placebo or tadalafil 2.5, 5, 10 or 20 mg as needed. With 20 mg, the IIEF erectile function domain score rose by a mean 7.9 points from baseline, 75% of intercourse attempts were successfully completed, and 81% of men reported improved erections at endpoint against 35% on placebo, with P<0.001 for each comparison. Headache and dyspepsia were the most common adverse events [2].

Once-daily dosing was tested in a separate trial that randomized 268 men to placebo, tadalafil 5 mg or tadalafil 10 mg daily for 12 weeks. The IIEF erectile function score changed by 0.9, 9.7 and 9.4 points respectively, successful completion of intercourse improved by 13.2, 45.5 and 50.1 percentage points, and 28.3%, 84.5% and 84.6% of men reported improved erections, all significant versus placebo at P<0.001 [3].

Does Cialis really last 36 hours?

The label does not say Cialis keeps a man erect for 36 hours. It says Cialis taken as needed improves erectile function compared with placebo up to 36 hours after dosing, and that sexual stimulation is still required [1]. The label links the window to the pharmacokinetics: mean terminal half-life is 17.5 hours, and peak plasma concentration is reached a median of 2 hours after a tablet, within a range of 30 minutes to 6 hours [1]. An erection lasting more than 4 hours, painful or not, calls for emergency care, and a painful erection longer than 6 hours is priapism that can irreversibly damage erectile tissue [1].

Testosterone

The results described above cover erectile function and completion of intercourse. The label reports a laboratory finding: tadalafil 10 or 20 mg had no adverse effect on mean testosterone, luteinizing hormone or follicle-stimulating hormone concentrations compared with placebo [1]. Tadalafil is approved for ED, BPH and ED with BPH, not for low testosterone [1].

Dosing: as needed or once daily

The Cialis label starts as-needed dosing at 10 mg before anticipated sexual activity, adjusted to 20 mg or down to 5 mg by response and tolerability, with a maximum of one dose per day. For once-daily ED use, the label's starting dose is 2.5 mg at about the same time each day regardless of when sex is planned, increased to 5 mg if needed. For BPH, or for ED with BPH, the label's dose is 5 mg once daily at about the same time every day. The label says the tablets may be taken with or without food and are not to be split [1]. With once-daily use, steady state is reached within 5 days and exposure is about 1.6-fold that of a single dose [1].

The label sets limits for reduced kidney or liver function. For people with creatinine clearance of 30 to 50 mL/min, the Cialis label specifies a 5 mg starting dose for as-needed use and a maximum of 10 mg no more than once every 48 hours [1]. Below 30 mL/min or on hemodialysis, the maximum is 5 mg no more often than every 72 hours, and once-daily use is not recommended. For BPH or ED with BPH at 30 to 50 mL/min, the label specifies a 2.5 mg start with 5 mg considered. Mild or moderate liver impairment caps as-needed dosing at 10 mg, and severe impairment is not recommended [1]. With strong CYP3A4 inhibitors such as ketoconazole or ritonavir, the as-needed maximum is 10 mg every 72 hours and the once-daily maximum is 2.5 mg; ketoconazole 400 mg daily raised tadalafil 20 mg exposure by 312% [1].

BPH and erectile function together

Cialis 5 mg once daily is approved both for the signs and symptoms of BPH and for ED with BPH [1]. In a 12-week trial of men aged 45 or older with an IPSS of 13 or higher, tadalafil 5 mg once daily (n=161) lowered the IPSS by 5.6 points versus 3.6 on placebo (P=0.004), an effect apparent after 1 week and significant by week 4, without a significant change in peak urine flow or post-void residual volume; the trial also reported a significant improvement on the IIEF erectile function domain [4].

Two label rules matter here. For BPH, the label does not recommend combining Cialis with an alpha-blocker, because efficacy of the combination has not been adequately studied and both drugs lower blood pressure. For ED, the label says a man who is stable on an alpha-blocker may start tadalafil at the lowest dose [1]. When Cialis is started together with finasteride for BPH, the label recommends use for up to 26 weeks [1].

What to watch for

In the as-needed ED trials, headache occurred in 15% of men on tadalafil 20 mg versus 5% on placebo, dyspepsia in 10% versus 1%, back pain in 6% versus 3%, myalgia in 3% versus 1%, nasal congestion in 3% versus 1%, flushing in 3% versus 1%, and limb pain in 3% versus 1%. Discontinuation for adverse events was 3.1% on 10 or 20 mg versus 1.4% on placebo. Back pain and myalgia usually began 12 to 24 hours after dosing and resolved within 48 hours [1]. On once-daily 5 mg for BPH or ED with BPH, headache was 4.1% versus 2.3% on placebo and dyspepsia 2.4% versus 0.2% [1].

Any organic nitrate, used regularly or intermittently, is contraindicated with Cialis because tadalafil potentiates the blood-pressure-lowering effect [1]. In a 150-man crossover study, men took tadalafil 20 mg or placebo daily for 7 days and then sublingual nitroglycerin 0.4 mg; standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours (P<0.05), with no difference at 48, 72 or 96 hours [5]. The label adds that at 48 hours a few more tadalafil men still had greater blood pressure falls [1]. The label's emergency provision is that if a nitrate is medically necessary in a life-threatening situation, at least 48 hours should pass after the last Cialis dose and the nitrate should be given with close medical supervision and hemodynamic monitoring [1].

Sudden vision loss in one or both eyes can be non-arteritic anterior ischemic optic neuropathy, reported rarely after marketing with all PDE5 inhibitors, and the label says to stop Cialis and get medical care [1]. Two observational case-crossover studies suggested roughly a 2-fold risk, with estimates of 2.15 (95% CI 1.06 to 4.34) and 2.27 (95% CI 0.99 to 5.20), and the label states that neither those reports nor the studies establish a causal relationship [1]. Alcohol and tadalafil are both mild vasodilators; 5 units or more with Cialis can increase orthostatic signs and symptoms such as raised heart rate, lower standing blood pressure, dizziness and headache, though tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].

The Cialis label says ED treatment should not be used when sexual activity is inadvisable because of cardiovascular status [1]. Groups not studied, and therefore not recommended, include myocardial infarction within 90 days, unstable angina or angina during intercourse, NYHA class 2 or greater heart failure within 6 months, uncontrolled arrhythmia, blood pressure below 90/50 mm Hg or uncontrolled hypertension, and stroke within 6 months. In healthy volunteers, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo [1].

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