Zetia and Tadalafil Interaction: What Patients and Clinicians Need to Know

Does ezetimibe interact with tadalafil?

Neither label lists the other drug, and neither sets a dose change or a timing gap for the pair [1][2]. The Zetia label singles out cyclosporine, fibrates and bile acid sequestrants for management [1]. The Cialis label covers nitrates, alpha-blockers, antihypertensives, alcohol, CYP3A4 inhibitors and CYP3A4 inducers [2].

Ezetimibe is a cholesterol absorption inhibitor, and the label covers single-ingredient Zetia 10 mg tablets, not combination products such as ezetimibe/simvastatin or bempedoic acid/ezetimibe, which have their own labels [1]. Tadalafil is a PDE5 inhibitor sold as Cialis for erectile dysfunction and benign prostatic hyperplasia, and as Adcirca for pulmonary arterial hypertension at a different strength and dose [2][3].

What the Zetia label flags

• Cyclosporine. Taking both raises ezetimibe and cyclosporine concentrations, and the rise in ezetimibe exposure may be greater in people with severe renal insufficiency. The label says to monitor cyclosporine concentrations [1].
• Fibrates. Fenofibrate and ezetimibe can both increase cholesterol excretion into bile, which can lead to gallstones. The label does not recommend combining ezetimibe with fibrates other than fenofibrate, and says gallbladder studies are indicated if cholelithiasis is suspected [1]. In the fenofibrate combination trial, cholecystectomy rates were 0.6% with fenofibrate alone and 1.7% with ezetimibe plus fenofibrate [1].
• Bile acid sequestrants. Cholestyramine lowers ezetimibe exposure, which may reduce efficacy. The Zetia label says to take ezetimibe at least 2 hours before or 4 hours after a bile acid sequestrant [1].

What the Cialis label flags

• Nitrates. Contraindicated with any form of organic nitrate, taken regularly or intermittently [2].
• Guanylate cyclase stimulators such as riociguat: contraindicated [2].
• Alpha-blockers. Both lower blood pressure and the effect is additive. For erectile dysfunction, the label says to be stable on the alpha-blocker first and start tadalafil at the lowest dose; for BPH, the label does not recommend combining Cialis with an alpha-blocker [2].
• CYP3A4 inhibitors such as ketoconazole and ritonavir. Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% [2]. The Cialis label limits as-needed tadalafil to 10 mg every 72 hours and once-daily tadalafil to 2.5 mg when a CYP3A4 inhibitor is used [2].
• CYP3A4 inducers such as rifampin. Rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak concentration by 46%; the label calls for no dose adjustment but notes that once-daily Cialis may work less well by an unknown amount [2].
• Antihypertensives and alcohol. Small additional blood pressure reductions occurred with amlodipine, ARBs, bendroflumethiazide, enalapril and metoprolol. Substantial alcohol (5 units or more) can increase dizziness, headache and standing blood pressure drops [2].

Two different clearance routes

Ezetimibe is rapidly conjugated to an active glucuronide in the small intestine and liver, a phase II reaction, with minimal oxidative (phase I) metabolism. The glucuronide makes up 80% to 90% of drug in plasma, and ezetimibe and its glucuronide are eliminated with a half-life of about 22 hours [1].

Tadalafil is a CYP3A4 substrate with a mean terminal half-life of 17.5 hours in healthy subjects [2]. The Cialis label states that tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 [2]. Neither label attributes a clearance effect to the other drug [1][2].

The tadalafil interaction that carries the real risk

The Cialis label contraindicates any organic nitrate because tadalafil potentiates the blood-pressure-lowering effect of nitrates [2]. It also gives an emergency rule: where a nitrate is medically necessary in a life-threatening situation, at least 48 hours should pass after the last Cialis dose, and the nitrate should still be given only under close medical supervision with hemodynamic monitoring [2]. That is an emergency exception, not a way to use the two together routinely.

A 150-man crossover study examined the time course: tadalafil 20 mg daily for 7 days, then sublingual nitroglycerin 0.4 mg. Standing systolic blood pressure fell below 85 mm Hg in more men on tadalafil than on placebo at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours [4]. The Zetia label does not list nitrates as an interaction [1].

What to watch on each drug

The Zetia label warns about liver enzymes and muscle effects. Consecutive transaminase rises of 3 times the upper limit of normal or more occurred in 1.3% of patients taking ezetimibe with a statin versus 0.4% taking a statin alone, and the label says to test liver enzymes as clinically indicated and to consider stopping ezetimibe if ALT or AST stays at that level or above [1]. Myopathy and rhabdomyolysis are possible; in postmarketing reports most patients who developed rhabdomyolysis were also taking a statin or another agent such as a fibrate, and if myopathy is suspected the label says to stop ezetimibe and other interacting medicines as appropriate [1].

The Cialis label warns that tadalafil adds to the blood-pressure-lowering effect of alpha-blockers, antihypertensives and substantial alcohol [2]. It says patients should seek emergency care for an erection lasting more than 4 hours [2], and should stop Cialis and seek medical attention for sudden vision loss in one or both eyes or sudden decrease or loss of hearing [2].

Organ-impairment limits that stand on their own

Each drug has its own organ-impairment limits, which do not depend on the other being in the regimen. Ezetimibe is not recommended in moderate or severe hepatic impairment (Child-Pugh B or C), where exposure rises about 3- to 4-fold [1]. The Cialis label caps as-needed dosing at 10 mg in mild or moderate hepatic impairment and does not recommend use in severe impairment [2].