Testosterone Cypionate and NSAIDs (Ibuprofen, Naproxen): Drug Interaction Guide

Is there a direct interaction between testosterone cypionate and ibuprofen or naproxen?

The Depo-Testosterone (testosterone cypionate, intramuscular) drug interactions section names three things: oral anticoagulants, whose effect androgens may increase; oxyphenbutazone, whose serum levels may rise; and diabetes medicines, whose requirement may fall [2]. The prescription ibuprofen label's drug interactions section covers ACE inhibitors, aspirin, diuretics, lithium, methotrexate, warfarin-type anticoagulants and H2 antagonists [1]. Neither section names the other drug.

There is no pharmacokinetic story here. Testosterone cypionate is an oil-soluble ester absorbed slowly from an intramuscular depot, with a half-life of about eight days [2]. Ibuprofen's half-life is 1.8 to 2.0 hours [1], and the naproxen label gives 12 to 17 hours. Neither label describes one drug changing the other's blood level.

We found no study that gave testosterone cypionate and ibuprofen or naproxen together and measured blood pressure, kidney function, bleeding or hormone levels. What follows is what each drug does on its own, from its label and from trials of that drug.

Blood pressure: both drugs push it up

The testosterone cypionate label says testosterone can increase blood pressure, which can increase cardiovascular risk over time, that blood pressure should be monitored periodically, and that testosterone products are not recommended in men with uncontrolled hypertension [2]. FDA reviewed the ambulatory blood pressure monitoring studies done for testosterone products and said the results confirmed a blood pressure increase with all testosterone products, class-wide [4].

The ibuprofen label says NSAIDs can lead to new hypertension or worsen existing hypertension, either of which may contribute to the increased incidence of cardiovascular events, and that blood pressure should be monitored closely when NSAID treatment starts and throughout the course [1]. It also says NSAIDs may blunt the effect of diuretics, ACE inhibitors and angiotensin receptor blockers [1].

Short-term NSAID trials do not show a uniform pressor effect. In a 1993 meta-analysis of 54 studies with 123 treatment arms and 1,324 participants, 92% of whom had hypertension, the effects on mean arterial pressure appeared only in hypertensive participants: indomethacin raised it by 3.59 mm Hg across 57 arms, while ibuprofen lowered it by 0.83 mm Hg across six arms [5].

Separately from blood pressure, NSAIDs increase the risk of serious thrombotic events including heart attack and stroke, which can be fatal, with risk that may appear early and rise with duration of use; they are contraindicated around coronary artery bypass graft surgery [1]. For context, the largest testosterone cardiovascular safety trial, TRAVERSE, tested a daily 1.62% testosterone gel rather than injections, in 5,246 men with hypogonadism and existing or high cardiovascular risk: major adverse cardiovascular events occurred in 7.0% on testosterone and 7.3% on placebo (hazard ratio 0.96, 95% CI 0.78 to 1.17) [6].

Fluid retention and edema

The Depo-Testosterone adverse reactions section lists retention of sodium, chloride, water, potassium, calcium and inorganic phosphates, and the warnings state that edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal or hepatic disease [2].

The NSAID labels list fluid retention and edema as well. The Coxib and traditional NSAID Trialists' Collaboration meta-analysis cited in the ibuprofen label found roughly a doubling of hospitalizations for heart failure with both selective and nonselective NSAIDs compared with placebo [1]. The ibuprofen label says to avoid ibuprofen in severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure, and to monitor for signs of worsening heart failure if it is used [1].

Kidneys: the NSAID side carries the risk

The NSAID labels tie their kidney effects to inhibition of renal prostaglandin synthesis [1]. The naproxen label says long-term NSAID use has caused renal papillary necrosis and that NSAIDs can reduce renal blood flow in people who depend on prostaglandins to maintain it. Its highest-risk list is impaired kidney function, dehydration, low blood volume, heart failure, liver dysfunction, use of diuretics or ACE inhibitors or ARBs, and older age. It also notes hyperkalemia has been reported with NSAIDs even without kidney impairment.

One pattern worth knowing about is an NSAID added to a diuretic plus an ACE inhibitor or ARB. In a UK nested case-control study of 487,372 antihypertensive users with 2,215 acute kidney injury cases, that three-drug combination carried a rate ratio of 1.31 (95% CI 1.12 to 1.53), rising to 1.82 (1.35 to 2.46) in the first 30 days, while an NSAID with just one of those drugs was not associated with a higher overall rate [7].

On the testosterone side, the cypionate label's kidney-related content concerns edema in men with pre-existing renal disease; it also lists serious cardiac, hepatic or renal disease among its contraindications [2]. It does not describe kidney injury of its own.

Bleeding: a boxed warning on one side, clotting-factor effects on the other

Every prescription NSAID carries a boxed warning for serious gastrointestinal bleeding, ulceration and perforation, which can be fatal and can occur at any time without warning symptoms [1]. The numbers in the labeling: serious upper GI ulcers, gross bleeding or perforation in about 1% of patients treated for 3 to 6 months and about 2% to 4% of those treated for a year, and only one in five patients with a serious upper GI event has symptoms [1]. A past ulcer or GI bleed raises the risk more than 10-fold, and oral corticosteroids, anticoagulants, longer treatment, smoking, alcohol and older age raise it too [1]. Taking two NSAIDs together adds GI toxicity with little added benefit and is not recommended.

The testosterone cypionate label approaches bleeding from a different direction. Its adverse reactions list includes suppression of clotting factors II, V, VII and X and bleeding in patients on concomitant anticoagulant therapy, and its drug interactions section says androgens may increase sensitivity to oral anticoagulants, so the anticoagulant dose may need to be reduced [2]. 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 [1].

Hematocrit: what testosterone does to the blood count

Testosterone raises red cell mass. Across 29 placebo-controlled randomized trials in 3,393 men, intramuscular testosterone enanthate or cypionate raised mean hematocrit by 4.0% (95% CI 2.9 to 5.1) versus placebo, significantly more than the 1.4% seen with patches [3]. In a retrospective review of 178 hypogonadal men followed for three years at one center, hematocrit above 50% occurred in 66.7% of men on injectable testosterone, 12.8% on gels and 35.1% on pellets, although the injection group was younger (mean 42.5 versus about 54 years) and started with a higher hematocrit [8]. A review of the erythrocytosis literature concludes the risk is well established with testosterone therapy and that short-acting injectable formulations have the highest incidence [9].

The ibuprofen label lists decreases in hemoglobin and hematocrit among its less frequent hematologic adverse reactions [1]. The Depo-Testosterone label says to check hemoglobin and hematocrit periodically during long-term use [2].

Ibuprofen versus naproxen

Both carry the same boxed warnings and class warnings for fluid retention, kidney effects and GI bleeding. Their half-lives differ: about two hours for ibuprofen [1] and 12 to 17 hours for naproxen (naproxen label).

In the CNT Collaboration meta-analysis of individual participant data, naproxen did not significantly raise major vascular events (rate ratio 0.93, 95% CI 0.69 to 1.27) while ibuprofen raised major coronary events (2.22, 95% CI 1.10 to 4.48); upper GI complications rose with both, at 4.22 for naproxen and 3.97 for ibuprofen [10]. In PRECISION, 24,081 arthritis patients at increased cardiovascular risk took celecoxib (mean 209 mg a day), naproxen (852 mg) or ibuprofen (2045 mg) for a mean of 20.3 months, and the primary cardiovascular outcome occurred in 2.3%, 2.5% and 2.7% respectively, with celecoxib noninferior to both [11].

One labeling point that catches people out: Aleve is naproxen sodium 220 mg, equal to 200 mg naproxen, so it counts as a naproxen product. The naproxen labeling says not to combine naproxen products.

Aspirin and the Depo-Testosterone label

The ibuprofen label notes that people taking low-dose aspirin for heart protection who need an analgesic should consider an NSAID that does not interfere with aspirin's antiplatelet effect, or a non-NSAID analgesic, because ibuprofen taken before aspirin can block aspirin's antiplatelet effect [1][12]. The Depo-Testosterone label also identifies testosterone as a Schedule III controlled substance [2].