Cialis Dosing in Renal Impairment: A Clinician's Guide to Tadalafil and Kidney Disease

What the Cialis Label Says at Each Creatinine Clearance

The Cialis label sets its renal dosing tiers by creatinine clearance in mL/min [1].

Creatinine clearance 30 to 50 mL/min

As-needed use: the recommended starting dose is 5 mg, not more than once per day, and the maximum dose is 10 mg not more than once in every 48 hours [1].

Once-daily use for BPH, or for ED with BPH: the starting dose is 2.5 mg, and an increase to 5 mg may be considered based on individual response [1].

Below 30 mL/min, or on hemodialysis

The maximum dose is 5 mg, not more than once in every 72 hours [1]. Once-daily use is not recommended at this level of kidney function or on dialysis [1].

Above 50 mL/min

The label's renal dosing tiers start at 30 to 50 mL/min, and it gives no separate renal dose limits above that [1]. The standard doses are 10 mg as needed, adjustable to 20 mg or down to 5 mg, not more than once a day; 2.5 mg once daily for ED, adjustable to 5 mg; and 5 mg once daily for BPH or for ED with BPH [1]. Exposure in mild impairment (creatinine clearance 51 to 80 mL/min) was about twice that in healthy subjects [2].

Why Kidney Function Changes Tadalafil Exposure

Tadalafil is metabolized mainly by CYP3A4, and it is excreted about 61% in feces and 36% in urine as metabolites [1]. Its mean terminal half-life is 17.5 hours, with a 5th to 95th percentile range of 11.5 to 29.6 hours; mean oral clearance is 2.48 L/h and apparent volume of distribution is 62.6 L, and once-daily dosing reaches steady state by day 5 with 1.6-fold accumulation [3].

A pharmacokinetic study of six single-dose studies found exposure in people with mild or moderate renal insufficiency was approximately twice that in healthy subjects [2]. In end-stage renal failure, the mean AUC of the major metabolite (total methylcatechol glucuronide) was three times the mean for healthy subjects, and hemodialysis contributed negligibly to elimination of either tadalafil or the metabolite; in that study a 10 mg dose was not well tolerated by subjects with moderate renal dysfunction [2]. Exposure is also about 25% higher in people aged 65 or older [2].

For the creatinine clearance ranges above, the label sets lower doses and longer intervals between doses [1].

Does Tadalafil Improve Kidney Function?

The clearest renal data with tadalafil come from a small trial in people with heart and kidney problems. Twenty subjects with pre-heart failure and renal impairment were randomized 2:1 to tadalafil at a goal dose of 20 mg daily or placebo for 12 weeks [4]. Long-term tadalafil did not improve glomerular filtration rate: the median increase was 2.0 mL/min in the tadalafil group versus 13.5 mL/min in the placebo group (P=0.54), with no difference in urinary sodium or cGMP excretion after a saline load [4]. The authors concluded the results do not support PDE5 inhibition to improve the renal response in this population [4].

The Cialis label reports that during clinical trials, diagnostic testing for people with back pain or myalgia, including measures for renal damage, revealed no evidence of medically significant underlying pathology [1].

Once-Daily Use, BPH and the 2.5 mg Tablet

Cialis 5 mg once daily is approved for the signs and symptoms of BPH and for ED with BPH [1]. When Cialis is used with finasteride to start BPH treatment, the label recommends use for up to 26 weeks [1].

Drugs@FDA lists the Cialis 2.5 mg tablet as discontinued, while the 5, 10 and 20 mg tablets are listed as prescription products [5]. The Cialis label specifies a 2.5 mg daily starting dose for BPH or ED with BPH at a creatinine clearance of 30 to 50 mL/min [1]. The label says not to split the tablets; the entire dose should be taken [1].

Interactions to Check

Nitrates

Any form of organic nitrate, taken regularly or intermittently, is contraindicated with Cialis [1]. Where a nitrate is medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last Cialis dose before it is considered, and then only under close medical supervision with hemodynamic monitoring [1]. In a crossover study of 150 men given tadalafil 20 mg or placebo daily for 7 days and then sublingual nitroglycerin 0.4 mg, 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 [6].

Alpha-blockers

Tadalafil and alpha-blockers are both vasodilators, and the blood pressure effect is additive [1]. For ED, the label says to be stable on the alpha-blocker first and to start Cialis at the lowest dose [1]. For BPH, the label does not recommend combining Cialis with an alpha-blocker, and says a person taking an alpha-blocker for BPH should stop it at least one day before starting once-daily Cialis for BPH [1].

CYP3A4 inhibitors

Ketoconazole 400 mg daily raised single-dose tadalafil 20 mg AUC by 312% and Cmax by 22%; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107%; ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% [1]. With potent CYP3A4 inhibitors such as ketoconazole or ritonavir, the label limits as-needed Cialis to 10 mg no more often than every 72 hours and once-daily Cialis to 2.5 mg [1].

CYP3A4 inducers

Rifampin 600 mg daily reduced tadalafil 10 mg AUC by 88% and Cmax by 46% [1]. The label calls for no dose adjustment, but notes that the reduced exposure can be anticipated to decrease the efficacy of once-daily Cialis by an amount that is unknown [1].

Alcohol

Both alcohol and tadalafil are mild vasodilators, and substantial alcohol (5 units or more) with Cialis can increase orthostatic signs and symptoms, including higher heart rate, lower standing blood pressure, dizziness and headache [1].

Adcirca Is a Separate Tadalafil Product

Adcirca is a separate tadalafil product approved for pulmonary arterial hypertension [7]. Its label has its own renal rules: for mild or moderate impairment (creatinine clearance 31 to 80 mL/min) it advises starting at 20 mg once daily, and for severe impairment it advises avoiding Adcirca. The Cialis label says combining Cialis with other PDE5 inhibitors has not been studied [1].

What to Watch For

In healthy volunteers, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg compared with placebo [1]. In the eight placebo-controlled as-needed ED studies, the most common adverse reactions at 20 mg versus placebo were headache (15% vs 5%), dyspepsia (10% vs 1%), back pain (6% vs 3%), myalgia (3% vs 1%), nasal congestion (3% vs 1%) and flushing (3% vs 1%) [1]. Back pain and myalgia generally began 12 to 24 hours after dosing and typically resolved within 48 hours [1].

The label says an erection lasting more than 4 hours, painful or not, needs emergency medical attention [1]. It also says to stop Cialis and seek medical care for a sudden loss of vision in one or both eyes, which may be non-arteritic anterior ischemic optic neuropathy, and for a sudden decrease or loss of hearing [1].