Tadalafil (Generic) and NSAIDs (Ibuprofen, Naproxen): Drug Interaction Guide

Is there an interaction between tadalafil and ibuprofen or naproxen?

For Cialis tablets, the prescribing information does not list ibuprofen, naproxen or other NSAIDs in its drug interactions section [1].

Tadalafil is a CYP3A4 substrate. The Cialis label limits the dose with strong CYP3A4 inhibitors such as ketoconazole and ritonavir; CYP3A4 inducers such as rifampin may reduce tadalafil exposure, but the label says no dose adjustment is warranted [1]. NSAIDs are not part of that list. What remains is the NSAID's own profile: ibuprofen and naproxen are effective pain and arthritis drugs, but their labels describe bleeding, cardiovascular and kidney risks that exist whether or not tadalafil is being taken [2].

What the Cialis label covers

Cialis 5, 10 and 20 mg tablets are listed as prescription products; the Cialis 2.5 mg tablet is listed as discontinued [5]. Generic tadalafil tablets, including 2.5 mg tablets, follow the Cialis indications: erectile dysfunction, the signs and symptoms of benign prostatic hyperplasia, and the two together [1][5]. Its listed interactions are nitrates and guanylate cyclase stimulators such as riociguat (both contraindicated), alpha-blockers, antihypertensives, alcohol, CYP3A4 inhibitors and inducers, and antacids [1].

NSAIDs appear once in the Cialis label, in the adverse reactions section: when treatment was needed for tadalafil-related back pain or myalgia, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective [1].

What the NSAID side of the pair carries

Every prescription NSAID, ibuprofen and naproxen included, carries a boxed warning for serious cardiovascular thrombotic events, including heart attack and stroke, which can be fatal and may occur early in treatment [2]. The same boxed warning covers serious gastrointestinal bleeding, ulceration and perforation, which can happen at any time and without warning symptoms [2].

The labels put numbers on the GI risk: serious upper GI ulcers, bleeding or perforation occurred in about 1% of patients treated for 3 to 6 months and about 2% to 4% treated for a year, and only one in five patients with a serious upper GI event has symptoms [2]. A past ulcer or GI bleed raises the risk of a bleed more than 10-fold [2].

In the Coxib and traditional NSAID Trialists' meta-analysis of 280 placebo-controlled trials (124,513 participants), upper GI complications rose about four-fold with these drugs: rate ratio 3.97 (95% CI 2.22 to 7.10) for ibuprofen and 4.22 (2.71 to 6.56) for naproxen [6]. Heart failure hospitalizations were roughly doubled with NSAIDs compared with placebo [2]. None of those figures comes from tadalafil; they belong to the NSAID [2][6].

Prescription ibuprofen labeling says to use the lowest effective dose for the shortest duration consistent with individual treatment goals [2].

Bleeding: does tadalafil add to it?

The Cialis label measures the effect directly: tadalafil did not potentiate the increase in bleeding time caused by aspirin [1].

What clearly raises bleeding risk is an NSAID combined with an anticoagulant. In EINSTEIN trial data from 8,246 patients with venous thromboembolism, adding an NSAID during anticoagulation gave major bleeding of 6.5 vs 2.0 per 100 patient-years (HR 2.37, 95% CI 1.51 to 3.75), with clinically relevant bleeding at HR 1.77 (1.46 to 2.14) [3]. The ibuprofen label says the effects of warfarin and NSAIDs on GI bleeding are synergistic, so users of both have a higher risk of serious GI bleeding than users of either alone, and it notes that although short-term studies did not show an effect on prothrombin time, bleeding has been reported [2].

Kidneys and blood pressure

NSAIDs block prostaglandin production, and their labels tie the kidney and diuretic effects to that inhibition [2]. The highest-risk groups listed are people with impaired kidney function, dehydration, low blood volume, heart failure or liver dysfunction, people taking diuretics or ACE inhibitors or ARBs, and older adults; hyperkalemia has been reported even without kidney impairment, and NSAIDs can cause fluid retention and edema [2]. A meta-analysis of five observational studies found pooled acute kidney injury risk ratios for traditional NSAIDs ranging from 1.58 to 2.11 [7].

Tadalafil has its own kidney dose limits. For as-needed use at a creatinine clearance of 30 to 50 mL/min, the label says to start at 5 mg with a maximum of 10 mg not more often than every 48 hours; below 30 mL/min or on hemodialysis, the maximum is 5 mg not more often than every 72 hours and once-daily use is not recommended [1].

On blood pressure, the two drugs act in opposite directions. Tadalafil 20 mg lowered supine blood pressure by a mean maximal 1.6/0.8 mm Hg versus placebo in healthy volunteers [1]. NSAIDs can start or worsen hypertension and blunt the effect of diuretics, ACE inhibitors and ARBs [2], and a meta-analysis of randomized trials found NSAIDs raised supine mean blood pressure by 5.0 mm Hg (95% CI 1.2 to 8.7) [8].

For context on a related kidney combination: in 487,372 UK antihypertensive users, an NSAID plus a diuretic plus an ACE inhibitor or ARB carried an acute kidney injury rate ratio of 1.31 (1.12 to 1.53), rising to 1.82 (1.35 to 2.46) in the first 30 days; an NSAID plus only one of those drugs was not associated with a higher rate overall [9]. Tadalafil is not one of those drugs.

Low-dose aspirin for heart protection

The ibuprofen label reports interference with aspirin's antiplatelet effect when ibuprofen 400 mg three times daily was given with enteric-coated low-dose aspirin, and the interaction was present even with once-daily ibuprofen 400 mg, particularly when ibuprofen was taken before aspirin; immediate-release low-dose aspirin taken at least 2 hours before once-daily ibuprofen reduced it, but that finding cannot be extended to enteric-coated aspirin [2]. In the 2001 crossover study in healthy volunteers, ibuprofen given before aspirin blocked aspirin's platelet inhibition, while rofecoxib, acetaminophen and diclofenac did not [4]. The label advises considering a non-interfering NSAID or a non-NSAID analgesic for people taking low-dose aspirin for heart protection [2].