Cialis (Tadalafil) Monitoring for Older Adults (50 to 64): What Your Doctor Should Track

What the label asks a doctor to check first

The Cialis label says the evaluation of erectile dysfunction and of BPH should include an appropriate medical assessment to identify underlying causes, and that other urological conditions producing the same symptoms should be considered before treating BPH [1]. It also says doctors should weigh cardiovascular status, because sexual activity itself carries cardiac risk, and that Cialis should not be used in men for whom sexual activity is inadvisable because of their cardiovascular status [1].

The label names groups that were not included in its trials and for which 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, blood pressure below 90/50 mm Hg, or uncontrolled hypertension; and stroke within the last 6 months [1]. It advises caution in left ventricular outflow obstruction such as aortic stenosis, and in severely impaired autonomic control of blood pressure [1].

For context on the age group, men in the label's trials averaged 59 years in the as-needed ED studies (range 22 to 88), 58 years in the once-daily ED studies (range 21 to 82), and 63 years in the BPH and ED/BPH studies (range 44 to 93) [1].

Blood pressure: small alone, larger with alpha-blockers and alcohol

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]. Added to amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril or metoprolol, it produced small additional reductions in blood pressure compared with placebo [1].

Alpha-blockers also lower blood pressure, so combining them with Cialis can increase the risk of low blood pressure [1]. With doxazosin 8 mg daily, tadalafil 20 mg gave a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg (3.6 mm Hg supine), and in a second doxazosin study 16 of 24 subjects had a systolic reading below 85 mm Hg or a fall greater than 30 mm Hg after the morning tadalafil dose, against 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].

Alcohol also matters. Both alcohol and tadalafil are mild vasodilators, and the label says substantial alcohol (5 units or more) with Cialis can increase orthostatic signs and symptoms — higher heart rate, lower standing blood pressure, dizziness and headache [1]. Tadalafil did not change alcohol levels, and alcohol did not change tadalafil levels [1].

Kidney function: dose limits based on creatinine clearance

For as-needed use with a creatinine clearance of 30 to 50 mL/min, the label says start at 5 mg and take no more than 10 mg in any 48 hours; below 30 mL/min or on hemodialysis, the maximum is 5 mg in any 72 hours [1]. Once-daily use is not recommended below 30 mL/min or on dialysis; for BPH or ED with BPH and a creatinine clearance of 30 to 50 mL/min, the starting dose is 2.5 mg, with 5 mg considered depending on response [1].

Drugs@FDA lists the 2.5 mg tablet as discontinued, while the 5, 10 and 20 mg tablets are listed as prescription products [2].

Liver function and CYP3A4: the interactions that change the dose

Tadalafil's mean terminal half-life is 17.5 hours in healthy subjects, compared with about 4 hours for sildenafil, which is why one dose can still improve erectile function up to 36 hours later and why its interactions last longer [1]. With mild or moderate liver impairment (Child-Pugh A or B) the as-needed dose should not exceed 10 mg once a day; Child-Pugh C is not recommended [1].

The CYP3A4 numbers are large. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22%; 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 [1]. The label says erythromycin, itraconazole and grapefruit juice were not studied but would likely increase tadalafil exposure [1]. The label's caps with strong inhibitors are 10 mg every 72 hours as needed and 2.5 mg once daily [1].

In the other direction, rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak concentration by 46%; the label says no dose adjustment is needed, but that the efficacy of once-daily Cialis can be expected to fall by an unknown amount [1].

In the interactions tested, tadalafil did not change warfarin exposure or prothrombin time, potentiate aspirin-related bleeding time, or change midazolam, lovastatin or steady-state digoxin exposure [1]. The label also says tadalafil does not inhibit or induce CYP1A2, 3A4, 2C9, 2C19, 2D6 or 2E1, and that it added only about 3 beats per minute to the heart-rate rise from theophylline [1].

Nitrates: contraindicated, with a 48-hour emergency rule

Any form of organic nitrate, used regularly or intermittently, is contraindicated with Cialis because tadalafil potentiates the nitrate's blood-pressure-lowering effect [1]. For a life-threatening situation in which a nitrate is medically necessary, the label says at least 48 hours should pass after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with hemodynamic monitoring [1]. That is an emergency rule, not a timing guide for routine use.

The time course was measured in 150 men who took tadalafil 20 mg or placebo daily for 7 days and then received sublingual nitroglycerin 0.4 mg [3]. 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 [3]. The label adds that at 48 hours the interaction was not seen by most hemodynamic measures, although a few more tadalafil men had greater blood pressure falls [1].

Alpha-blockers: two different rules for ED and BPH

For BPH, the Cialis label does not recommend combining Cialis with an alpha-blocker, citing that efficacy of the combination has not been adequately studied and the risk of blood-pressure lowering. The label specifies stopping the alpha-blocker at least one day before starting once-daily Cialis for BPH [1].

For ED, the rule is different: a man who is stable on an alpha-blocker may use Cialis, starting at the lowest dose [1].

What to watch for between visits

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

Sudden vision loss in one or both eyes may be non-arteritic anterior ischemic optic neuropathy (NAION). The label puts the annual incidence of NAION at 2.5 to 11.8 cases per 100,000 in males aged 50 and older, and cites two observational case-crossover 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 the studies establish a causal relationship [1]. It says to stop Cialis and seek medical attention for such an event, advises caution with prior NAION and a crowded optic disc, and says use is not recommended in hereditary retinal disorders such as retinitis pigmentosa [1].

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

Common reactions are worth recognizing by timing. In the eight 12-week as-needed ED studies, back pain occurred in 6% of men on tadalafil 20 mg versus 3% on placebo, myalgia in 3% versus 1%, headache in 15% versus 5% and dyspepsia in 10% versus 1%, and back pain or myalgia usually began 12 to 24 hours after dosing and resolved within 48 hours [1]. Discontinuation for adverse events was 3.1% on 10 or 20 mg versus 1.4% on placebo [1]. In the three 12-week BPH and ED/BPH studies, dizziness was reported by 1.0% on tadalafil 5 mg versus 0.5% on placebo, and discontinuation was 3.6% versus 1.6% [1].

What the label does not settle

Low testosterone is not an approved use. The indications are ED, BPH, and ED with BPH [1]; Adcirca is a separately approved tadalafil 20 mg tablet for pulmonary arterial hypertension [4]. The label reports no adverse effect of tadalafil 10 or 20 mg on mean testosterone, luteinizing hormone or follicle-stimulating hormone concentrations versus placebo, which is a separate question from whether tadalafil treats low testosterone [1].

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