Actos (Pioglitazone) and Tadalafil Interaction: What Patients and Clinicians Need to Know

Is there a direct interaction between pioglitazone and tadalafil?

The tadalafil information on this page comes from the Cialis label (erectile dysfunction and benign prostatic hyperplasia). Adcirca is a separate 20 mg tadalafil product for pulmonary arterial hypertension with its own label [2][4].

Pioglitazone is metabolized mainly by CYP2C8, with a minor contribution from CYP3A4 [3]. Tadalafil is metabolized mainly by CYP3A4, and the Cialis label says tadalafil does not inhibit or induce CYP3A4 [2]. The pioglitazone label's drug interaction section covers strong CYP2C8 inhibitors such as gemfibrozil, CYP2C8 inducers such as rifampin, and topiramate; the label separately addresses hypoglycemia risk with insulin or sulfonylureas [1]. It does not list tadalafil. The Cialis label's interaction section names nitrates, alpha-blockers, antihypertensives, alcohol, and CYP3A4 inhibitors or inducers; it does not list pioglitazone [2].

Blood pressure and fluid retention

Pioglitazone's label focuses on fluid retention and heart failure; it gives no combined hypotension warning with tadalafil [1]. The label says pioglitazone can cause dose-related edema and can cause or worsen congestive heart failure; it says to monitor for rapid weight gain, shortness of breath and edema after starting and after each dose increase [1]. In PROactive, hospitalized heart failure occurred in 5.7% (149/2,605) of patients on pioglitazone and 4.1% (108/2,633) on placebo [1].

Tadalafil is a mild systemic vasodilator. In healthy volunteers, tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6 over 0.8 mm Hg compared with placebo [2]. The Cialis label reports small additional blood-pressure reductions when tadalafil is given with amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril or metoprolol [2]. The label also warns that alpha-blockers can add to tadalafil's blood-pressure-lowering effect and may cause symptomatic hypotension, and that substantial alcohol, 5 units or more, can increase orthostatic signs and symptoms [2].

Heart failure is where the two labels overlap

Pioglitazone is not recommended in symptomatic heart failure, and starting it in established NYHA class III or IV heart failure is contraindicated [1]. The Cialis label says tadalafil is not recommended in NYHA class 2 or greater heart failure within the last 6 months [2]. It also says tadalafil is not recommended after a heart attack within 90 days, in unstable angina or angina during intercourse, uncontrolled arrhythmia, blood pressure below 90/50 mm Hg, uncontrolled hypertension, or stroke within 6 months [2].

These are separate label limits, not a pharmacokinetic interaction.

What does the tadalafil label say about nitrates?

Any form of organic nitrate, regular or intermittent, is contraindicated with Cialis [2]. In a life-threatening situation where a nitrate is medically necessary, the label says at least 48 hours should elapse after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with hemodynamic monitoring [2]. A 150-man crossover study found the interaction with sublingual nitroglycerin was still significant at 24 hours and was not seen at 48 hours [5].

Pioglitazone's label does not list nitrates as an interaction [1].

Doses and organ function

The pioglitazone label starts at 15 mg or 30 mg once daily and titrates to a maximum of 45 mg; for NYHA class I or II heart failure the starting dose is 15 mg [1]. The label says to obtain liver tests before starting, and it lists no renal dose adjustment [1].

The Cialis label for ED as needed starts at 10 mg, with a range of 5 to 20 mg and a maximum of one dose per day [2]. Once-daily ED starts at 2.5 mg and may increase to 5 mg; BPH uses 5 mg once daily [2]. For creatinine clearance 30 to 50 mL/min, as-needed dosing starts at 5 mg and is limited to 10 mg every 48 hours [2]. For creatinine clearance below 30 mL/min or dialysis, the maximum is 5 mg every 72 hours and once-daily use is not recommended [2]. Severe liver impairment is not recommended [2].

What to watch for

Pioglitazone's boxed warning directs prescribers to monitor patients for excessive rapid weight gain, shortness of breath and edema after starting or increasing the dose [1]. In a 16-week add-on trial, edema occurred in 17.6% of patients on pioglitazone 30 mg plus insulin versus 7.0% on placebo plus insulin [1].

The Cialis label says to seek emergency care for an erection lasting more than 4 hours, whether painful or not [2]. It says to stop tadalafil and seek medical care for sudden vision loss in one or both eyes or sudden decrease or loss of hearing [2].