Cialis and Rivaroxaban Interaction: What Patients and Clinicians Need to Know

The short answer

The Cialis prescribing information lists three contraindications: any form of organic nitrate, guanylate cyclase stimulators such as riociguat, and a known serious hypersensitivity reaction to tadalafil [1]. Rivaroxaban is not one of them.

The label also addresses the metabolic pathway. It states that tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 enzymes, and that studies showed no inhibition or induction of CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 [1]. Rivaroxaban is a substrate of CYP3A4 and of the transporter P-glycoprotein [4]. The label statement therefore speaks to the CYP route only. No study has tested tadalafil with rivaroxaban, so the absence of a CYP effect does not establish that the combination has no interaction.

What tadalafil does to other drugs

The Cialis label shows what happens when a CYP3A4 inhibitor meets tadalafil. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and Cmax by 22%; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% and Cmax by 15% [1]. With a potent CYP3A4 inhibitor, the label caps Cialis at 10 mg no more often than every 72 hours for as-needed use and 2.5 mg for once-daily use [1].

In the reverse direction the label reports no such effect. Tadalafil did not change warfarin exposure or prothrombin time, did not potentiate the increase in bleeding time caused by aspirin, and did not alter midazolam, lovastatin or digoxin exposure [1]. Those are results for other drugs, not for rivaroxaban.

Bleeding with rivaroxaban

Rivaroxaban is an oral factor Xa inhibitor. ROCKET AF randomized 14,264 patients with nonvalvular atrial fibrillation to rivaroxaban 20 mg daily or dose-adjusted warfarin [2]. Major and nonmajor clinically relevant bleeding occurred in 14.9% per year on rivaroxaban and 14.5% per year on warfarin (hazard ratio 1.03, 95% CI 0.96 to 1.11, P=0.44) [2].

Those rates compare rivaroxaban with warfarin, not with tadalafil. The only bleeding finding in the Cialis label is that tadalafil did not potentiate aspirin's bleeding-time increase [1]. We found no study that measured bleeding in people taking tadalafil with rivaroxaban, so the aspirin result cannot be used to estimate what happens with this pair.

Blood pressure: the interactions the label documents

Tadalafil is a mild vasodilator. In healthy volunteers, 20 mg produced a mean maximal supine blood-pressure decrease of 1.6/0.8 mm Hg compared with placebo [1]. The larger falls come from specific partners named in the label.

Organic nitrates are contraindicated in any form [1]. The label's 48-hour figure is for emergencies only: where a nitrate is medically necessary in a life-threatening situation, 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 [1]. In a 150-man crossover study, standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil 20 mg daily than on placebo after sublingual nitroglycerin 0.4 mg at 4, 8 and 24 hours, with no difference at 48, 72 or 96 hours [3].

Alpha-blockers add to the effect. With doxazosin 8 mg daily, tadalafil 20 mg gave a placebo-subtracted maximal standing systolic fall of 9.8 mm Hg, and 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 tadalafil versus 6 on placebo [1]. With tamsulosin 0.4 mg the standing fall was 1.7 mm Hg at tadalafil 10 mg and 2.3 mm Hg at 20 mg [1]. For ED, the label says to be stable on the alpha-blocker first and start tadalafil at the lowest dose; for BPH it does not recommend the combination [1]. Antihypertensives produce small additional reductions, and 5 units or more of alcohol can add orthostatic symptoms such as dizziness and a rise in heart rate [1].

Renal dose limits for tadalafil

Kidney function changes tadalafil dosing. For as-needed use at a creatinine clearance of 30 to 50 mL/min, the label gives a 5 mg starting dose and a 10 mg maximum no more often than every 48 hours; below 30 mL/min or on hemodialysis, the maximum is 5 mg no more often than every 72 hours [1]. Once-daily use for ED is not recommended below 30 mL/min. For once-daily BPH or ED with BPH at 30 to 50 mL/min, the label recommends starting at 2.5 mg and considering 5 mg based on response [1].

Bottom line

The Cialis label does not list rivaroxaban as a contraindication, and it states that tadalafil is not expected to inhibit or induce the clearance of CYP-metabolized drugs [1]. Because the pair has not been studied, that statement does not settle whether they interact through other routes, such as transport or bleeding effects.