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Classification: A

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.

Additional information

The prevalence of several clinical pain conditions is higher in women than in men. Differences in pharmacokinetics, sex hormones, stress response, or socio-cultural aspects may be of importance [1-3]. Therefore, sex and gender differences of pain medications are difficult to interpret [4].

Pharmacokinetics and dosing

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 [5]. Another larger study found similar results (192 men, 433 women) [6]. No sex differentiation in dosing is recommended by the manufacturer [7].


No studies with a clinically relevant sex analysis regarding the effects of naproxen have been found.

Adverse effects

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 [8].

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 [9]. 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 [10] or to a generally higher risk of drug-induced liver injury in women [11].

The large PRECISION trial (8636 men, 15445 women) compared the cardiovascular safety of celecoxib, naproxen, and ibuprofen. No sex differences were shown [12]. 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 [13].

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)) [14].

Reproductive health issues

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).

Updated: 2022-12-22

Date of litterature search: 2021-12-13


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  2. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013;111(1):52-8. PubMed
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  12. Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med. 2016;375(26):2519-29. PubMed
  13. Solomon DH, Shao M, Wolski K, Nissen S, Husni ME, Paynter N. Derivation and Validation of a Major Toxicity Risk Score Among Nonsteroidal Antiinflammatory Drug Users Based on Data From a Randomized Controlled Trial. Arthritis Rheumatol. 2019;71(8):1225-1231. PubMed
  14. Samii A, Etminan M, Wiens MO, Jafari S. NSAID use and the risk of Parkinson's disease: systematic review and meta-analysis of observational studies. Drugs Aging. 2009;26:769-79. PubMed
  15. Salman S, Sherif B, and Al-Zohyri A. OP0131 Effects of Some Non Steroidal Anti-Inflammatory Drugs on Ovulation in Women with Mild Musculoskeletal Pain. Annals of the Rheumatic Diseases. 2015;74(suppl 2):117-118. länk
  16. Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link?. Drug Saf. 2002;25:545-51. PubMed
  17. Uhler ML, Hsu JW, Fisher SG, Zinaman MJ. The effect of nonsteroidal anti-inflammatory drugs on ovulation: a prospective, randomized clinical trial. Fertil Steril. 2001;76(5):957-61. PubMed
  18. Matyas RA, Mumford SL, Schliep KC, Ahrens KA, Sjaarda LA, Perkins NJ et al. Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod. 2015;30(7):1714-23. PubMed
  19. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk
  20. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.] länk

Authors: Alan Fotoohi, Linnéa Karlsson Lind

Reviewed by: Carl-Olav Stiller, Diana Rydberg

Approved by: Karin Schenck-Gustafsson