Cialis (Tadalafil) for Adults 65 and Older: Caregiver Administration Guidance

What doses does the Cialis label give?

Cialis is a PDE5 inhibitor approved for erectile dysfunction (ED), for the signs and symptoms of benign prostatic hyperplasia (BPH), and for ED together with BPH [1]. The label sets the dose by indication, then adjusts it for kidney function, liver function and certain interacting drugs [1].

• ED, taken as needed: start at 10 mg before anticipated sexual activity; the dose may rise to 20 mg or fall to 5 mg depending on response and tolerability, and not more than once a day [1].
• ED, taken once daily: start at 2.5 mg at about the same time every day, regardless of when sexual activity happens, and the dose may go up to 5 mg [1].
• BPH, or ED with BPH: 5 mg once daily, at about the same time every day [1].
• The tablet may be taken with or without food, and the label says not to split it, so the whole dose is taken [1].

Two numbers shape caregiving. Tadalafil has a mean terminal half-life of about 17.5 hours, which is why one as-needed dose improves erectile function compared with placebo for up to 36 hours, with sexual stimulation still required [1]. Exposure (AUC) is about 25 percent higher in healthy men aged 65 or older than in younger men [1].

Is the dose different with kidney or liver problems?

Yes. The label gives specific ceilings [1].

What does giving the dose involve day to day?

For once-daily use, the label specifies a fixed daily dose regardless of sexual activity; steady state is reached within 5 days, with exposure about 1.6 times that of a single dose [1]. The label says once-daily use provides continuous plasma levels, which should be considered when evaluating interactions with nitrates, alpha-blockers, antihypertensives, strong CYP3A4 inhibitors and substantial alcohol [1].

For as-needed use, the label directs that the tablet be taken before anticipated sexual activity. Peak concentration occurs between 30 minutes and 6 hours after an oral dose, with a median of 2 hours, and absorption is not affected by food [1]. Knowing when the last as-needed dose was taken matters if anginal chest pain occurs: the label calls for immediate medical attention and sets a minimum interval before any nitrate is considered after a dose [1].

Tadalafil does not produce an erection by itself. The label's mechanism is that nitric oxide released during sexual stimulation raises cyclic GMP, and tadalafil slows the breakdown of that cyclic GMP, so there is no effect without sexual stimulation [1].

Nitrates: the contraindication that outranks everything

The Cialis label contraindicates the drug in anyone using any form of organic nitrate, taken regularly or intermittently, because tadalafil was shown to potentiate the hypotensive effect of nitrates [1]. Nitroglycerin and isosorbide are examples of nitrates. Riociguat, a guanylate cyclase stimulator, is also contraindicated [1].

The label handles the emergency case with a rule, not a workaround: in a life-threatening situation where a nitrate is medically necessary in someone who has taken Cialis, 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]. This is an emergency rule, not permission to combine the drugs.

A published study looked at the time course of the interaction. A total of 150 men took tadalafil 20 mg or placebo daily for 7 days, then received sublingual nitroglycerin 0.4 mg at set intervals in a crossover design; standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours [2]. The authors concluded that the interaction lasted 24 hours and was not seen at 48 hours, and that tadalafil should not be combined with organic nitrates [2].

The label also tells patients who develop anginal chest pain after taking Cialis to seek immediate medical attention [1].

Alpha-blockers, blood pressure medicines and alcohol

Alpha-blockers used for BPH or blood pressure lower blood pressure too, and the label says the effect is additive, with symptomatic hypotension such as fainting possible [1]. The label reports healthy-volunteer numbers. Tadalafil 20 mg with doxazosin 8 mg daily produced a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg (supine 3.6 mm Hg) [1]. 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 8 a.m. tadalafil, versus 6 on placebo [1]. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg on tadalafil 10 mg and 2.3 mm Hg on 20 mg, and there were no outlier readings when tadalafil 5 mg daily was combined with tamsulosin [1]. Alfuzosin 10 mg gave a 4.4 mm Hg standing fall with tadalafil 20 mg [1].

The label's rules are these. For ED in a man already taking an alpha-blocker, he should be stable on the alpha-blocker first and Cialis should start at the lowest dose [1]. For BPH, the label does not recommend combining Cialis with an alpha-blocker, because the efficacy of the combination has not been adequately studied and because of the risk of blood pressure lowering [1]. With other antihypertensives (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, metoprolol) the label describes small additional blood pressure reductions compared with placebo [1]. In healthy volunteers, tadalafil 20 mg alone lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo [1].

Alcohol is a mild vasodilator like tadalafil. The label says substantial alcohol, meaning 5 units or more, can increase orthostatic signs and symptoms including a rise in heart rate, a fall in standing blood pressure, dizziness and headache; tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].

Which prescriptions change tadalafil exposure?

Tadalafil is metabolized mainly by CYP3A4, so inhibitors raise exposure and inducers lower it [1]. Ketoconazole 400 mg daily raised tadalafil 20 mg AUC by 312 percent and peak concentration by 22 percent; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107 percent [1]. Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124 percent with no change in peak concentration [1]. Erythromycin, itraconazole and grapefruit juice were not studied, but the label says they would likely increase exposure [1].

In the other direction, rifampin 600 mg daily cut tadalafil 10 mg AUC by 88 percent and peak concentration by 46 percent; carbamazepine, phenytoin and phenobarbital would likely lower exposure but were not studied [1]. The label calls for no dose adjustment with inducers, but notes that the efficacy of once-daily Cialis may fall by an unknown amount [1].

What side effects is a caregiver likely to notice?

In the eight 12-week placebo-controlled trials of as-needed Cialis for ED, the reported rates for 10 mg and 20 mg versus placebo were: headache 11 percent and 15 percent versus 5 percent; dyspepsia 8 percent and 10 percent versus 1 percent; back pain 5 percent and 6 percent versus 3 percent; myalgia 4 percent and 3 percent versus 1 percent; nasal congestion 3 percent and 3 percent versus 1 percent; flushing 3 percent and 3 percent versus 1 percent; pain in limb 3 percent and 3 percent versus 1 percent [1]. Discontinuation for adverse events was 3.1 percent on 10 or 20 mg versus 1.4 percent on placebo [1].

In the three 12-week trials of 5 mg once daily for BPH or ED with BPH, the rates were headache 4.1 percent versus 2.3 percent on placebo, dyspepsia 2.4 percent versus 0.2 percent, back pain 2.4 percent versus 1.4 percent, nasopharyngitis 2.1 percent versus 1.6 percent and dizziness 1.0 percent versus 0.5 percent; discontinuation was 3.6 percent on tadalafil versus 1.6 percent on placebo [1].

Back pain and muscle pain generally began 12 to 24 hours after dosing and typically resolved within 48 hours; the label says that when treatment was needed, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective [1].

When does the label say to get emergency care?

• An erection lasting more than 4 hours, painful or not, needs emergency treatment [1]. The label defines priapism as painful erections lasting more than 6 hours and says that untreated it can cause irreversible damage to erectile tissue [1].
• Sudden vision loss in one or both eyes may be non-arteritic anterior ischemic optic neuropathy; the label directs patients to stop Cialis and seek medical attention [1]. The label puts the annual incidence of that condition at 2.5 to 11.8 cases per 100,000 in males aged 50 and older, and reports two observational studies suggesting roughly a 2-fold risk (2.15, 95% CI 1.06 to 4.34, and 2.27, 95% CI 0.99 to 5.20), while stating that neither the reports nor those studies substantiate a causal relationship [1].
• Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, is a reason to stop Cialis and seek prompt medical attention, according to the label [1].
• Anginal chest pain after a dose means immediate medical attention [1].

Does the person's heart condition change anything?

The label says treatments for ED, including Cialis, should not be used in men for whom sexual activity is inadvisable because of underlying cardiovascular status [1]. It lists groups that were not included in the trials and for whom Cialis is therefore not recommended: 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 or uncontrolled hypertension, and stroke within the last 6 months [1]. It also advises caution in left ventricular outflow obstruction such as aortic stenosis, and in severely impaired autonomic control of blood pressure [1].