Drug products: Alpoxen, Bonyl, Eox, Ipaflex, Miranax, Naprocur, Naprosyn, Naprosyn® Entero, Naproxen 2care4, Naproxen ABECE, Naproxen Apofri, Naproxen Bluefish, Naproxen Ebb, Naproxen Evolan, Naproxen Mylan, Naproxen NET, Naproxen Orifarm, Pronaxen, Pronaxen®, Vimovo
ATC code: M01AE02, M01AE52
Substances: naproxen, naproxen sodium
Men were at higher risk than women for gastric bleedings from NSAID treatment in a large retrospective study. Women had a higher risk of NSAID-induced liver affection in a small case-control study, while a large cohort study did not find any differences in risk between men and women. No sex differences in the risk of cardiovascular events have been shown. Published controlled studies on differences between men and women regarding the efficacy of naproxen are lacking. Studies have found women to have a higher free concentration if naproxen but the clinical significance of this is unclear.
The scientific literature indicates that pain behavior and pain perception may vary between men and women. This could be influenced by differences in pharmacokinetics, sex hormones, differences in stress response, or type of pain test. Also, many variables other than a person’s sex/gender account for individual differences in pain sensitivity. The prevalence of several clinical pain conditions is higher in women than in men, which suggests that either different clinical pain mechanisms may operate in men vs. women, or different or additional risk factors are relevant in one sex, or a combination of differences [1-3]. Therefore, sex differences of pain releasing medication might thus be difficult to interpret .
Plasma samples from patients (62 men, 173 women) with osteoarthritis treated with 750 mg naproxen, showed that women had 65% higher free concentration and 41% higher unbound fraction than men. However, no association between free concentration and effect or adverse events was found within the naproxen concentration ranges in this study . Another larger study found similar results (192 men, 433 women) . No sex differentiation in dosing is recommended by the manufacturer .
No studies with a clinically relevant sex analysis regarding the effects of naproxen have been found.
A nested control study estimated the risk of upper gastrointestinal complications associated with selective cox 2-inhibitors and non-selective NSAIDs (including diclofenac, ibuprofen, ketoprofen, naproxen) compared with non-use of NSAIDs. In all > 600 000 individuals contributed to >1 million person-years of observation and 726 upper gastrointestinal complications were identified. Male sex and high age carried a higher risk of complication and suggested a synergistic effect between these factors and NSAIDs on the risk of upper gastrointestinal complications. The risk for upper gastrointestinal complications differed between the various NSAIDs. Adjusted for male sex and age, the OR for ketoprofen was 3.4, compared to 2.2 for diclofenac, 4.0 for naproxen, and 1.6 for ibuprofen .
A retrospective cohort study (625 307 patients with 2 130 820 prescriptions, one third of these to men) found that incidence rates of NSAID-induced acute liver injury were similar for men and women and for the young and the elderly . However, a case-control study (136 men, 130 women) found an association between NSAID exposure and liver injury in women but not in men (OR 6.49 vs. 1.06). This may be due to differences in pharmacokinetics or levels of circulating hormone and/or more polypharmacy in women  or to a generally higher risk of drug-induced liver injury in women .
The large PRECISION trial (8636 men, 15445 women) compared the cardiovascular safety of celecoxib, naproxen, and ibuprofen. No sex differences were shown . A post-hoc study of the PRECISION trial (8591 men, 15 359 women) enrolled patients with known cardiovascular disease or risk factors as well as osteoarthritis or rheumatoid arthritis and required regular daily treatment with an NSAID. The risk score was designed to predict the 1-year occurrence of major toxicity including major adverse cardiovascular events, clinically significant gastrointestinal events, acute kidney injury, and death. Male sex and higher age were correlated to higher risk of major toxicities. However, sex-stratified data were not presented for each NSAID and therefore information about which of the studied substances caused the changes in effect and/or adverse events is lacking .
A meta-analysis evaluated NSAID use and the risk of Parkinson’s disease. Pooled risk ratios of Parkinson’s disease were similar in men and women using NSAID (men 0.79 (95%CI 0.69, 0.92); women 0.72 (95%CI 0.45, 1.15)) .
Studies on animal models shows that non-selective NSAIDs (diclofenac, ibuprofen, ketoprofen, ketorolac, naproxen) can affect implantation and ovulation and small clinical studies report that non-selective NSAIDS may cause decreased fertility in some women. However, the effect is reversible after treatment discontinuation [7, 15-18]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2021-12-13
Reviewed by: Carl-Olav Stiller, Diana Rydberg
Approved by: Karin Schenck-Gustafsson