Cialis (Tadalafil) Safety for Older Adults Aged 50 to 64

What actually changes between 50 and 64

The dose adjustments in the Cialis label are built around kidney function, liver function and drugs that change tadalafil levels [1]. In healthy men aged 65 or older, exposure (AUC) was 25% higher than in younger men [1].

Heart risk comes before dose

The label states that Cialis should not be used in men for whom sexual activity is inadvisable because of their cardiovascular status, since sexual activity itself carries cardiac risk [1]. Several groups were not included in the trials and are therefore not recommended for Cialis: myocardial infarction within the last 90 days, unstable angina or angina during intercourse, NYHA class 2 or greater heart failure within the last 6 months, uncontrolled arrhythmias, hypotension below 90/50 mm Hg, uncontrolled hypertension, and stroke within the last 6 months [1].

Tadalafil is a mild vasodilator. In a clinical pharmacology study, 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg compared with placebo in healthy subjects [1]. The label advises caution in left ventricular outflow obstruction such as aortic stenosis, and in severely impaired autonomic control of blood pressure [1]. It also says patients who develop anginal chest pain after taking Cialis should refrain from further sexual activity and seek immediate medical attention [1].

Nitrates: the contraindication that does not bend

Any form of organic nitrate, taken regularly or intermittently, is contraindicated with Cialis, because tadalafil potentiates the blood-pressure-lowering effect of nitrates [1]. The label gives one emergency exception: where a nitrate is medically necessary in a life-threatening situation, at least 48 hours should elapse after the last Cialis dose, and the nitrate should still be given only under close medical supervision with hemodynamic monitoring [1].

The time course was studied in a crossover study of 150 men who took tadalafil 20 mg or placebo daily for 7 days and then received sublingual nitroglycerin 0.4 mg [2]. 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 and 96 hours [2]. The authors concluded that the interaction lasted 24 hours and that tadalafil should not be combined with organic nitrates [2]. The label adds that at 48 hours a few more tadalafil men still had greater blood pressure falls, although most measures did not show the interaction [1]. Guanylate cyclase stimulators such as riociguat are contraindicated for the same reason [1].

Alpha-blockers and the prostate

Tadalafil and alpha-blockers both lower blood pressure, the effect is additive, and symptomatic hypotension such as fainting can occur [1]. In healthy volunteers, tadalafil 20 mg with doxazosin 8 mg daily produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg; in a second doxazosin study, 16 of 24 subjects had a systolic reading below 85 mm Hg or a fall over 30 mm Hg after tadalafil, versus 6 on placebo [1]. With tamsulosin 0.4 mg the standing falls were smaller, 1.7 mm Hg at tadalafil 10 mg and 2.3 mm Hg at 20 mg, and alfuzosin 10 mg gave 4.4 mm Hg with tadalafil 20 mg [1]. The published report of the doxazosin and tamsulosin crossover studies (18 men in each) found that 28% of those on doxazosin plus tadalafil had a standing systolic below 85 mm Hg versus 6% on doxazosin plus placebo, while no tamsulosin user fell below 85 mm Hg [3].

The label rules differ by indication. For ED, the Cialis label says men taking an alpha-blocker should already be stable on it before starting Cialis at the lowest dose [1]. For BPH, the label does not recommend combining Cialis with an alpha-blocker, citing inadequate study of the combination and the risk of blood pressure lowering; it states that an alpha-blocker taken for BPH should be stopped at least one day before once-daily Cialis for BPH is started [1].

Kidney and liver limits

At a creatinine clearance of 30 to 50 mL/min, as-needed Cialis starts at 5 mg with a maximum of 10 mg not more than once every 48 hours; once-daily Cialis for BPH or for ED with BPH starts at 2.5 mg and may be raised to 5 mg [1]. At a creatinine clearance below 30 mL/min or on hemodialysis, as-needed use is capped at 5 mg not more than once every 72 hours, and once-daily use is not recommended [1]. Exposure is about doubled in mild (51 to 80 mL/min) or moderate (31 to 50 mL/min) renal impairment after single 5 to 10 mg doses [1].

In mild or moderate liver impairment (Child-Pugh A or B), the as-needed dose should not exceed 10 mg once a day, and once-daily use has not been extensively evaluated [1]. Severe impairment (Child-Pugh C) is not recommended [1].

Medicines that change tadalafil levels

Tadalafil is metabolized mainly by CYP3A4 [1]. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure by 312% and peak concentration by 22%; ketoconazole 200 mg daily raised 10 mg exposure by 107% [1]. Ritonavir 200 mg twice daily raised 20 mg exposure by 124% with no change in peak concentration [1]. With a potent CYP3A4 inhibitor, the label caps as-needed Cialis at 10 mg every 72 hours and once-daily Cialis at 2.5 mg [1]. Erythromycin, itraconazole and grapefruit juice were not studied but would likely raise exposure, in the label's words [1].

In the other direction, rifampin 600 mg daily cut tadalafil 10 mg exposure by 88% and peak concentration by 46%; carbamazepine, phenytoin and phenobarbital would likely lower exposure [1]. The label calls for no dose adjustment but notes that the efficacy of once-daily Cialis may fall by an unknown amount [1]. Antihypertensives such as amlodipine, ARBs, bendroflumethiazide, enalapril and metoprolol produced small additional blood pressure reductions compared with placebo [1]. Substantial alcohol, 5 units or more, can increase orthostatic signs and symptoms with Cialis, although tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1]. Tadalafil did not change warfarin exposure or prothrombin time, and did not potentiate the bleeding time caused by aspirin [1].

Side effects in trials with mean ages of 58 to 63

The label's safety tables come from studies that overlap this age band closely: mean age 59 (range 22 to 88) in the eight as-needed ED studies, 58 (range 21 to 82) in the once-daily ED studies, and 63 (range 44 to 93) in the three BPH and ED-with-BPH studies [1]. The label notes that adverse reaction rates from clinical trials cannot be directly compared to rates in trials of another drug [1].

With 20 mg as needed, headache occurred in 15% 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 [1]. In the three trials of 5 mg once-daily Cialis for BPH and for ED with BPH, headache occurred in 4.1% of patients versus 2.3% on placebo, dyspepsia in 2.4% versus 0.2%, back pain in 2.4% versus 1.4%, and dizziness in 1.0% versus 0.5%, with discontinuation for adverse events of 3.6% versus 1.6% on placebo [1]. Back pain and myalgia usually begin 12 to 24 hours after dosing and typically resolve within 48 hours [1].

Eyes, ears and erections lasting more than four hours

Sudden vision loss in one or both eyes may 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 [1]. Two observational case-crossover studies suggested about a twofold 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 the reports nor these studies substantiate a causal relationship [1]. The annual incidence of NAION in the published literature is 2.5 to 11.8 cases per 100,000 in males aged 50 and older [1]. The label advises caution in men with prior NAION or a crowded optic disc, and does not recommend Cialis in hereditary retinal disorders such as retinitis pigmentosa [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 determine whether the hearing loss is directly related [1]. An erection lasting more than 4 hours, painful or not, needs emergency care; painful erections longer than 6 hours are priapism and can permanently damage erectile tissue [1].