Cialis (Tadalafil) Geriatric Monitoring: What Clinicians and Patients Over 65 Need to Track

What actually changes after 65

One pharmacokinetic statement in the Cialis label is specific to age: after an oral dose, exposure (AUC) is 25% higher in healthy men aged 65 or older [1]. The label does not attach a separate starting dose to that number. Its dose reductions key off creatinine clearance, liver function and interacting drugs [1].

The mean terminal half-life is 17.5 hours in healthy subjects, and once-daily dosing reaches steady state in about 5 days at roughly 1.6 times single-dose exposure [1]. The label notes that once-daily use provides continuous plasma tadalafil levels and says to take that into account when weighing interactions with nitrates, alpha-blockers, antihypertensives and potent CYP3A4 inhibitors [1].

Kidney function is the dose lever to follow

Renal function, not age, decides the ceiling in the label.

• As-needed use for ED, creatinine clearance 30 to 50 mL/min: starting dose 5 mg, maximum 10 mg and not more often than every 48 hours [1].
• Creatinine clearance below 30 mL/min, or hemodialysis: maximum 5 mg and not more often than every 72 hours [1].
• Once-daily use: not recommended below 30 mL/min or on hemodialysis [1].
• Once daily for BPH, or for ED with BPH, at 30 to 50 mL/min: start 2.5 mg, with 5 mg considered depending on response [1].
• Mild or moderate liver impairment (Child-Pugh A or B): as-needed dose no higher than 10 mg; severe impairment (Child-Pugh C) is not recommended [1].

Blood pressure: the label's own numbers

In healthy volunteers, tadalafil 20 mg produced a mean maximal fall in supine blood pressure of 1.6/0.8 mm Hg compared with placebo [1]. With antihypertensives — amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril and metoprolol — the label reports small additional reductions in blood pressure compared with placebo [1].

Alpha-blockers are the sharper edge:

• Doxazosin 8 mg daily plus tadalafil 20 mg produced a placebo-subtracted mean maximal standing systolic fall of 9.8 mm Hg (supine 3.6 mm Hg); in a second doxazosin study, 16 of 24 men had a standing systolic reading below 85 mm Hg or a fall over 30 mm Hg after the morning tadalafil dose versus 6 on placebo [1].
• Tamsulosin 0.4 mg produced placebo-subtracted mean maximal standing systolic falls of 1.7 mm Hg with tadalafil 10 mg and 2.3 mm Hg with tadalafil 20 mg; with tadalafil 5 mg daily plus tamsulosin there were no outliers [1].
• Alfuzosin 10 mg plus tadalafil 20 mg produced a 4.4 mm Hg mean maximal standing systolic fall compared with placebo [1].

For ED, the label's rule is that the man be stable on the alpha-blocker first, with tadalafil started at the lowest dose [1]. For BPH, the label does not recommend combining tadalafil with an alpha-blocker, citing inadequately studied efficacy and the risk of blood pressure lowering [1].

Alcohol also matters. Five units or more with Cialis can increase orthostatic signs and symptoms — higher heart rate, lower standing blood pressure, dizziness and headache — although tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].

In the three 12-week BPH and ED/BPH trials (placebo n=576, tadalafil 5 mg n=581), dizziness was reported by 1.0% on tadalafil versus 0.5% on placebo [1].

Nitrates: the combination that cannot overlap

Any form of organic nitrate, taken regularly or intermittently, is contraindicated with Cialis [1]. The label gives one emergency rule: 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 under close medical supervision with hemodynamic monitoring [1].

A crossover study of 150 men looked at the time course: they took tadalafil 20 mg or placebo daily for 7 days and then sublingual nitroglycerin 0.4 mg. Standing systolic pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours (P<0.05), with no significant difference at 48, 72 and 96 hours [2]. Nitrates remain contraindicated; the 48-hour figure covers a life-threatening emergency, not routine spacing [1].

Guanylate cyclase stimulators such as riociguat are also contraindicated, because the combination may potentiate hypotension [1].

Drugs that change tadalafil levels

Tadalafil is metabolized mainly by CYP3A4 [1].

• Ketoconazole 400 mg daily raised tadalafil 20 mg AUC by 312% (peak concentration 22% higher); ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% [1].
• Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% with no change in peak concentration; 500 or 600 mg twice daily raised AUC by 32% with peak concentration down 30% [1].
• Erythromycin, itraconazole and grapefruit juice were not studied, but the label says they would likely increase tadalafil exposure [1].
• With potent CYP3A4 inhibitors such as ketoconazole or ritonavir, the Cialis label limits as-needed use to 10 mg no more often than every 72 hours and once-daily use to 2.5 mg [1].
• Rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak concentration by 46%; the label calls for no dose adjustment but notes that once-daily efficacy may fall by an unknown amount [1].

Vision, hearing and priapism

Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely after marketing with all PDE5 inhibitors. Based on published literature, the annual incidence is 2.5 to 11.8 cases per 100,000 in males aged 50 and older [1]. Two observational case-crossover studies suggested roughly a 2-fold increase in risk, with estimates of 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]. The label says to stop and seek medical care for sudden vision loss in one or both eyes, advises caution with prior NAION and a crowded optic disc, and does not recommend use in hereditary retinal disorders such as retinitis pigmentosa [1].

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported, and the label says it cannot tell whether it is directly related [1].

An erection lasting over 4 hours, painful or not, needs emergency care; painful erections over 6 hours are priapism and can permanently damage erectile tissue [1]. Caution applies with sickle cell anemia, multiple myeloma, leukemia, or penile deformity such as angulation, cavernosal fibrosis or Peyronie's disease [1].

Back pain and myalgia: timing is the clue

In the as-needed ED trials, back pain was reported by 3% on placebo versus 3%, 5% and 6% at 5, 10 and 20 mg, and myalgia by 1% versus 1%, 4% and 3% [1]. Back pain or myalgia generally began 12 to 24 hours after dosing and typically resolved within 48 hours [1]. The discomfort was described as diffuse bilateral lower lumbar, gluteal, thigh or thoracolumbar pain, worse when lying down, and diagnostic testing for inflammation, muscle injury or renal damage found no evidence of medically significant underlying pathology [1]. About 0.5% of on-demand users stopped treatment because of back pain or myalgia [1].

The label also notes that in the as-needed ED studies diarrhea was reported more frequently in patients aged 65 and older [1].

Falls: what is documented and what is not

Falls are not an outcome the label reports. What the label does document is: dizziness in 1.0% versus 0.5% on placebo in the BPH and ED/BPH trials [1], orthostatic symptoms with five or more units of alcohol [1], additive blood pressure lowering with alpha-blockers, including fainting [1], and a caution that men with severely impaired autonomic control of blood pressure may be particularly sensitive to vasodilators [1].

Cardiovascular exclusions that matter more with age

The label does not recommend tadalafil in men with a myocardial infarction within 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, or stroke within 6 months, because these groups were not included in the clinical trials [1]. Sexual activity itself carries cardiac risk, and the label says tadalafil should not be used in men for whom sexual activity is inadvisable because of cardiovascular status [1]. Caution is advised in left ventricular outflow obstruction such as aortic stenosis [1].

The label's checkpoints in one list

• Creatinine clearance, which sets the dose cap and the dosing interval [1].
• Blood pressure effects with an alpha-blocker, an antihypertensive or substantial alcohol [1].
• Nitrates, which are contraindicated, with a 48-hour rule that applies only to a life-threatening emergency [1].
• CYP3A4 inhibitors and inducers, which changed tadalafil AUC by +312% (ketoconazole) to -88% (rifampin) in the label's studies [1].
• Vision and hearing changes, and any erection lasting over 4 hours [1].
• Back, gluteal or thigh pain that starts the day after a dose [1].