Cialis (Tadalafil) Safety for Adults Aged 30 to 49

What the trials show for this age range

The eight primary 12-week placebo-controlled studies of Cialis taken as needed for ED enrolled men aged 22 to 88, mean age 59 [1]. Separately, an integrated analysis of five 12-week tadalafil trials included 1,112 men, mean age 59, range 22 to 82; 81% of men on tadalafil 20 mg reported improved erections versus 35% on placebo (P<0.001), with headache and dyspepsia the most common adverse events [2].

The label reports 25% higher tadalafil exposure in healthy men aged 65 or older and more diarrhea among Cialis-treated patients aged 65 or older in as-needed ED studies, but it gives no side-effect rates specifically for men aged 30 to 49 [1].

Side effects and how often they occur

In the eight as-needed ED studies, headache was reported by 5% of men on placebo and by 11% on tadalafil 10 mg and 15% on 20 mg; dyspepsia by 1% on placebo and 8% and 10%; back pain by 3% on placebo and 5% and 6%; myalgia by 1% on placebo and 4% and 3%; nasal congestion by 1% on placebo and 3% and 3%; and flushing by 1% on placebo and 3% and 3% [1]. Discontinuation because of adverse events was 3.1% on 10 or 20 mg versus 1.4% on placebo [1].

Back pain and myalgia generally begin 12 to 24 hours after a dose and typically resolve within 48 hours [1]. The label describes diffuse, bilateral discomfort in the lower back, buttocks, thighs or thoracolumbar area, worse when lying down, usually mild or moderate, sometimes needing acetaminophen or an NSAID; about 0.5% of men taking Cialis as needed stopped because of it [1].

Once-daily use has its own numbers. In three 12-week once-daily ED studies, headache was reported by 5% on placebo, 3% on tadalafil 2.5 mg and 6% on tadalafil 5 mg. Across three once-daily ED trials lasting 12 or 24 weeks, 2.8% on placebo and 4.1% on tadalafil stopped treatment because of adverse events [1]. In three 12-week studies of 5 mg once daily for BPH or for ED with BPH, headache was 2.3% on placebo versus 4.1%, dyspepsia 0.2% versus 2.4%, back pain 1.4% versus 2.4% and dizziness 0.5% versus 1.0% [1].

Nitrates

Any form of organic nitrate, used regularly or intermittently, is contraindicated with Cialis, because tadalafil was shown to potentiate the blood-pressure-lowering effect of nitrates [1].

A 150-man crossover study gave tadalafil 20 mg or placebo daily for seven days, then sublingual nitroglycerin 0.4 mg. Standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil than on placebo at 4, 8 and 24 hours (P<0.05), with no difference at 48, 72 and 96 hours [3].

The label's only timing statement is an emergency rule: where a nitrate is medically necessary in a life-threatening situation, at least 48 hours should have elapsed since the last Cialis dose, and the nitrate should still be given only under close medical supervision with hemodynamic monitoring [1]. That is not a safe-timing guide for planned use.

Alpha-blockers and blood pressure

Tadalafil and alpha-blockers both lower blood pressure, the effect is additive, and symptomatic hypotension such as fainting can occur [1]. With doxazosin 8 mg daily plus tadalafil 20 mg, the placebo-subtracted maximal fall in standing systolic pressure was 9.8 mm Hg (3.6 mm Hg supine) [1]. In a second doxazosin study, 16 of 24 men had a systolic reading below 85 mm Hg or a fall of more than 30 mm Hg after 8 a.m. tadalafil, versus 6 on placebo [1]. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg with tadalafil 10 mg and 2.3 mm Hg with 20 mg; with alfuzosin 10 mg it was 4.4 mm Hg with tadalafil 20 mg [1].

The label's rules differ by indication. For ED, the label says a man should already be stable on the alpha-blocker and Cialis should start at the lowest dose [1]. For BPH, the label does not recommend combining Cialis with an alpha-blocker at all, because the combination's efficacy has not been adequately studied and blood pressure can fall, and it directs that an alpha-blocker taken for BPH be stopped at least one day before starting once-daily Cialis for BPH [1].

On its own, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo in healthy volunteers [1]. Clinical pharmacology studies with amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril and metoprolol found small additional reductions [1].

Medicines that change tadalafil levels

Tadalafil is metabolized mainly by CYP3A4 [1]. Ketoconazole 400 mg daily raised single-dose tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22%; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% and peak by 15% [1]. Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% with no change in peak, while ritonavir 500 or 600 mg twice daily raised AUC by 32% with a 30% fall in peak [1]. Erythromycin, itraconazole and grapefruit juice were not studied, but the label states they would likely increase tadalafil exposure [1].

With a CYP3A4 inhibitor, the Cialis label caps as-needed use at 10 mg no more often than every 72 hours and once-daily use at 2.5 mg [1]. In the other direction, rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak by 46%; the label calls for no dose adjustment but notes that once-daily Cialis may become less effective by an unknown amount [1].

Alcohol

Both alcohol and tadalafil are mild vasodilators [1]. Substantial alcohol — 5 units or more — taken with Cialis can increase orthostatic signs and symptoms, including a rise in heart rate, a fall in standing blood pressure, dizziness and headache [1]. Tadalafil did not change alcohol levels, and alcohol did not change tadalafil levels [1].

Vision, hearing and prolonged erection

The label also warns about sudden vision loss, sudden hearing loss and prolonged erections [1]. Sudden loss of vision in one or both eyes can be non-arteritic anterior ischemic optic neuropathy (NAION), reported rarely after marketing with all PDE5 inhibitors; the label says to stop Cialis and seek medical attention, and to use it cautiously in men with prior NAION or a crowded optic disc; it is not recommended for people with hereditary retinal disorders such as retinitis pigmentosa [1]. The background annual incidence of NAION in men aged 50 or older is 2.5 to 11.8 cases per 100,000, and two observational case-crossover studies suggested roughly a doubling of risk (2.15, 95% CI 1.06 to 4.34; and 2.27, 95% CI 0.99 to 5.20); the label states that neither the reports nor these studies substantiate a causal relationship [1]. In vitro, tadalafil is about 700-fold more potent for PDE5 than for PDE6, the retinal enzyme [1].

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported; the label says to stop Cialis and seek prompt medical attention, and that it cannot be determined whether the hearing loss is directly related to the drug [1].

An erection lasting more than 4 hours, painful or not, needs emergency care, and painful erections longer than 6 hours are priapism that can permanently damage erectile tissue [1]. The label advises caution in men with sickle cell anemia, multiple myeloma, leukemia, or penile deformity such as angulation, cavernosal fibrosis or Peyronie's disease [1].

Kidney and liver limits

For as-needed use, a creatinine clearance of 30 to 50 mL/min means a starting dose of 5 mg and a maximum of 10 mg no more often than every 48 hours; 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 [1]. For BPH or ED with BPH at 30 to 50 mL/min, the label starts at 2.5 mg and allows 5 mg [1].

In mild or moderate liver impairment (Child-Pugh A or B), the as-needed dose should not exceed 10 mg, and in severe impairment (Child-Pugh C) Cialis is not recommended [1].

Once daily or as needed

Improvement in erectile function was shown up to 36 hours after an as-needed dose, which is not the same as a 36-hour erection — sexual stimulation is still required [1]. The Cialis label says to take the entire dose without splitting the tablet [1]. Headache and dyspepsia rates were lower in the once-daily ED studies than in the 20 mg as-needed arm, but those were separate studies, and the label cautions that adverse reaction rates from trials run under different conditions cannot be directly compared [1]. No boxed warning applies to Cialis [1].