Naproxen

Naproxen
Clinical data
Pronunciation /nəˈprɒksən/
Trade names Aleve, Naprosyn, Anaprox, Naprelan, Flanax, Aflaxen, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a681029
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    administration    		 Oral
    ATC code
    Legal status
    Legal status
    • AU: S2 (Pharmacy only) when in preparations that contain no more than 15 days' supply. Otherwise it is Schedule 4 (Prescription only).[2]
    • CA: OTC
    • UK: POM (Prescription only) Pharmacy medicine (P) only for treatment of primary dysmenorrhoea in women aged 15-50 years subject to a maximum single dose of 500mg, maximum daily dose of 750mg for a maximum of 3 days, and max pack size of 9x250mg tablets[3]
    • US: OTC
    Pharmacokinetic data
    Bioavailability 95% (oral)
    Protein binding 99%
    Metabolism Hepatic (to 6-desmethylnaproxen)
    Elimination half-life 12–17 hours (adults)[4]
    Excretion Renal
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.040.747 Edit this at Wikidata
    Chemical and physical data
    Formula C14H14O3
    Molar mass 230.259 g/mol
    3D model (JSmol)
    Melting point 152–154 °C (306–309 °F)
      (verify)

    Naproxen (brand names: Aleve, Naprosyn, and many others) is a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid class (the same class as ibuprofen) that relieves pain, fever, swelling, and stiffness.[5][6] It is a nonselective COX inhibitor, usually sold as the sodium salt. It is available in both an immediate release and extended release formulation. Naproxen is generally safe for use by breastfeeding mothers.

    Common adverse effects of naproxen include central nervous system effects (e.g. dizziness and headache), blood effects (e.g. bruising), allergic reactions (e.g. rash), and gastrointestinal complaints (e.g. heartburn and stomach ulcers). It has an intermediate risk of stomach ulcers compared to others drugs in the same class (NSAIDs). NSAIDs appear to increase the risk of serious cardiovascular events, though this risk appears to be less with naproxen compared to other NSAIDs. Serious drug interactions may occur in combinations with other drugs that affect the blood, or with drugs that also increase the risk of ulcers.

    As an NSAID, naproxen exerts its anti-inflammatory action by reducing the production of inflammatory mediators called prostaglandins. It is extensively metabolized by the liver to inactive metabolites.

    Medical uses

    250 mg tablet of naproxen
    220 mg tablet of naproxen sodium. Imprint L490 (upside-down). Round, light blue tablet.[7]

    Naproxen's medical uses are related to its mechanism of action as an anti-inflammatory compound. Naproxen is used to treat a variety of inflammatory conditions and symptoms that are due to excessive inflammation, such as pain and fever (naproxen has fever-reducing, or antipyretic, properties in addition to its anti-inflammatory activity). Notably, not all medications that reduce fever are anti-inflammatory compounds (such as paracetamol). Inflammatory sources of pain that may respond to naproxen's anti-inflammatory activity are conditions such as migraine, osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, and bursitis.[1]

    Because of its anti-inflammatory mechanism of action, one would not expect naproxen to be useful in treating non-inflammatory causes of pain (e.g., diabetic nerve pain).

    Naproxen is used as a "bridge therapy" in medication-overuse headache to wean patients off other medications.[8]

    Available formulations

    Naproxen is available as both an immediate release and as an extended release tablet. The extended release formulations (sometimes called "sustained release," or "enteric coated") take longer to take effect than the immediate release formulations, and therefore are less useful when immediate pain relief is desired. Extended release formulations are more useful for the treatment of chronic, or long-lasting, conditions, in which long-term pain relief is desirable.[7]

    Naproxen extended release 500 mg, back and front.

    Specific populations

    Pregnancy and lactation

    Small amounts of naproxen are excreted in breast milk.[1] However, adverse effects are uncommon in infants breastfed from mother taking naproxen.[9]

    Diagnostics

    Naproxen has been used to differentiate between infectious fevers and neoplastic or connective tissue disease-related fevers.[10] Although the literature is inconclusive, it is thought that naproxen may help differentiate between infectious fevers and neoplastic fevers by its efficacy in reducing them; in some studies, naproxen reduced neoplastic fevers far better than it reduced infectious fevers. This information could potentially be used to identify the etiology of the patient's fever, which can be complex in cancer patients (who are often at heightened risk for infection in the first place).[11]

    Adverse effects

    Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset.[1] Heavy use is associated with increased risk of end-stage renal disease and kidney failure.[12]

    Gastrointestinal adverse effects

    As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding.[13] Naproxen should be taken orally with food to decrease the risk of gastrointestinal side effects. Persons with a history of ulcers or inflammatory bowel disease should consult a doctor before taking naproxen. In the U.S., naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding.[1] Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk.[14] To reduce stomach ulceration risk, it is often combined with a proton-pump inhibitor (a medication that reduces stomach acid production) during long-term treatment of those with pre-existing stomach ulcers or a history of developing stomach ulcers while on NSAIDs.[5][6]

    Cardiovascular adverse effects

    COX-2 selective and nonselective NSAIDs have been linked to increases in the number of serious and potentially fatal cardiovascular events, such as myocardial infarctions and strokes.[15] Naproxen is, however, associated with the smallest overall cardiovascular risks.[16][17] Cardiovascular risk must be considered when prescribing any nonsteroidal anti-inflammatory drug. The drug had roughly 50% of the associated risk of stroke compared with ibuprofen, and was also associated with a reduced number of myocardial infarctions compared with control groups.[16]

    A study found that high-dose naproxen induced near-complete suppression of platelet thromboxane throughout the dosing interval and appeared not to increase cardiovascular disease (CVD) risk, whereas other non-aspirin high-dose NSAID regimens had only transient effects on platelet COX-1 and were associated with a small but definite vascular hazard. Conversely, naproxen was associated with higher rates of upper gastrointestinal bleeding complications compared with other NSAIDs.[17]

    Interactions

    Drug–drug interactions

    Naproxen may interact with antidepressants, lithium, methotrexate, probenecid, warfarin and other blood thinners, heart or blood pressure medications, including diuretics, or steroid medicines such as prednisone.[1]

    NSAIDs such as naproxen may interfere with and reduce the efficacy of SSRI antidepressants,[18] as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent when taken together.[19] Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution.[19]

    Drug–food interactions

    Alcohol consumption increases the risk of gastrointestinal bleeding when combined with NSAIDs like naproxen in a dose-dependent manner (that is, the higher the dose of naproxen, the higher the risk of bleeding).[20] The risk is highest for people who are heavy drinkers.[20]

    Pharmacology

    Mechanism of action

    Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective coxib.[21][22][23][24][25] This results in the inhibition of prostaglandin synthesis. Prostaglandins act as signaling molecules in the body, inducing inflammation. Thus, by inhibiting COX-1/2, naproxen induces an anti-inflammatory effect.

    Pharmacokinetics

    Naproxen is a minor substrate of CYP1A2 and CYP2C9. It is extensively metabolized in the liver to 6-O-desmethylnaproxen, and both the parent drug and the desmethyl metabolite undergo further metabolism to their respective acylglucuronide conjugated metabolites.[26] An analysis of two clinical trials shows that naproxen's time to peak plasma concentration occurs between 2–4 hours after oral administration, though naproxen sodium reaches peak plasma concentrations within 1–2 hours.[4]

    Pharmacogenetics

    The pharmacogenetics of naproxen has been studied in an effort to better understand its adverse effects.[27] In 1998, a small pharmacokinetic (PK) study failed to show that differences in a patient's ability to clear naproxen from the body could account for differences in a patient's risk of experiencing the adverse effect of a serious gastrointestinal bleed while taking naproxen.[27] However, the study failed to account for differences in the activity of CYP2C9, a drug metabolizing enzyme responsible for clearing naproxen.[27] Studies on the relationship between CYP2C9 genotype and NSAID-induced gastrointestinal bleeds have shown that genetic variants in CYP2C9 that reduce the clearance of major CYP2C9 substrates (like naproxen) increase the risk of NSAID-induced gastrointestinal bleeds, especially for homozygous defective variants.[27]

    As of October 2017, there are no recommendations for routine CYP2C9 testing for naproxen.[28]

    Chemistry

    Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs.[29] The free acid is an odorless, white to off-white crystalline substance. It is lipid-soluble and practically insoluble in water. It has a melting point of 152–155 °C.

    Synthesis

    Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:[30]

    Society and culture

    Brand names

    Naproxen and naproxen sodium are marketed under various brand names, including: Synflex, Aleve, Accord, Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, MotriMax, and Xenobid. It is also available as the combination naproxen/esomeprazole magnesium in delayed release tablets under the brand name Vimovo.[31]

    Access restrictions

    Syntex first marketed naproxen in 1976 as the prescription drug Naprosyn. They first marketed naproxen sodium under the brand name Anaprox in 1980. It remains a prescription-only drug in much of the world. In the United States, the Food and Drug Administration (FDA) approved it as an over-the-counter (OTC) drug in 1994. OTC preparations in the U.S. are mainly marketed by Bayer HealthCare under the brand name Aleve and generic store brand formulations in 220 mg tablets. In Australia, packets of 275 mg tablets of naproxen sodium are Schedule 2 pharmacy medicines, with a maximum daily dose of five tablets or 1375 mg. In the United Kingdom, 250 mg tablets of naproxen were approved for OTC sale under the brand name Feminax Ultra in 2008, for the treatment of primary dysmenorrhoea in women aged 15 to 50.[32] In the Netherlands, 220 mg and 275 mg tablets are available OTC in drugstores, 550 mg is OTC only at pharmacies. Aleve became available over the counter in most provinces in Canada on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador;[33] it subsequently became available OTC in British Columbia in January 2010.[34]

    Research

    Naproxen may have antiviral activity against influenza. In laboratory research, it blocks the RNA-binding groove of the nucleoprotein of the virus, preventing formation of the ribonucleoprotein complex—thus taking the viral nucleoproteins out of circulation.[35]

    Veterinary use

    Use in horses

    Naproxen is given orally to horses at a dose of 10 mg/kg, and has shown to have a wide safety margin (no toxicity when given at three times the recommended dose for 42 days).[36] It is more effective for myositis than the commonly used NSAID phenylbutazone, and has shown especially good results for treatment of equine exertional rhabdomyolysis,[37] a disease of muscle breakdown, but is less commonly used for musculoskeletal disease.

    References

    1. 1 2 3 4 5 6 "Naproxen". Drugs.com. 2017. Retrieved 7 February 2017.
    2. ↑ Gill, A, ed. (July 2013). Standard for the Uniform Scheduling of Medicines and Poisons No. 4 (PDF). The Poisons Standard 2013. Therapeutic Goods Administration. ISBN 978-1-74241-895-7.
    3. ↑ "NAPROXEN". British National Formulary.
    4. 1 2 Angiolillo DJ, Weisman SM (April 2017). "Clinical Pharmacology and Cardiovascular Safety of Naproxen". American Journal of Cardiovascular Drugs. 17 (2): 97–107. doi:10.1007/s40256-016-0200-5. PMC 5340840. PMID 27826802.
    5. 1 2 Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
    6. 1 2 Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 665, 673. ISBN 978-0-85711-084-8.
    7. 1 2 "L490 (Naproxen 220 mg)". drugs.com. Drugs.com. Retrieved 17 May 2017.
    8. ↑ Garza I, Schwedt TJ. "Diagnosis and Management of Chronic Daily Headache". medscape.com. WebMD LLC. Retrieved 17 May 2017.
    9. ↑ "LACTMED: NAPROXEN". TOXNET. NIH. Retrieved 21 July 2017.
    10. ↑ Zell JA, Chang JC (November 2005). "Neoplastic fever: a neglected paraneoplastic syndrome". Supportive Care in Cancer. 13 (11): 870–7. doi:10.1007/s00520-005-0825-4. PMID 15864658.
    11. ↑ Kudlowitz D. "Neoplastic Fever: Pathophysiology, Clinical Features, And Diagnostic Assessment". Clinical Correlations. New York University. Retrieved 4 May 2017.
    12. ↑ Risk of Kidney Failure Associated with the Use of Acetaminophen, Aspirin, and Nonsteroidal Antiinflammatory Drugs. The New England Journal of Medicine.
    13. ↑ "Naproxen". PubMed Health. 1 September 2008. Archived from the original on 22 July 2010.
    14. ↑ Richy F, Bruyere O, Ethgen O, Rabenda V, Bouvenot G, Audran M, Herrero-Beaumont G, Moore A, Eliakim R, Haim M, Reginster JY (July 2004). "Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach". Annals of the Rheumatic Diseases. 63 (7): 759–66. doi:10.1136/ard.2003.015925. PMC 1755051. PMID 15194568.
    15. ↑ Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Wang Q, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Bao W, Lincoff AM (December 2016). "Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis". The New England Journal of Medicine. 375 (26): 2519–29. doi:10.1056/NEJMoa1611593. PMID 27959716.
    16. 1 2 Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P (January 2011). "Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis". BMJ. 342: c7086. doi:10.1136/bmj.c7086. PMC 3019238. PMID 21224324. c7086.
    17. 1 2 Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C (August 2013). "Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials". Lancet. 382 (9894): 769–79. doi:10.1016/S0140-6736(13)60900-9. PMC 3778977. PMID 23726390.
    18. ↑ Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P (May 2011). "Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans". Proceedings of the National Academy of Sciences of the United States of America. 108 (22): 9262–7. Bibcode:2011PNAS..108.9262W. doi:10.1073/pnas.1104836108. PMC 3107316. PMID 21518864.
    19. 1 2 Turner MS, May DB, Arthur RR, Xiong GL (March 2007). "Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks". Journal of Internal Medicine. 261 (3): 205–13. doi:10.1111/j.1365-2796.2006.01720.x. PMID 17305643.
    20. 1 2 Pfau PR, Lichenstein GR (November 1999). "NSAIDs and alcohol: never the twain shall mix?". The American Journal of Gastroenterology. 94 (11): 3098–101. doi:10.1111/j.1572-0241.1999.03098.x. PMID 10566697.
    21. ↑ Duggan KC, Walters MJ, Musee J, Harp JM, Kiefer JR, Oates JA, Marnett LJ (November 2010). "Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen". The Journal of Biological Chemistry. 285 (45): 34950–9. doi:10.1074/jbc.M110.162982. PMC 2966109. PMID 20810665.
    22. ↑ Hinz B, Cheremina O, Besz D, Zlotnick S, Brune K (April 2008). "Impact of naproxen sodium at over-the-counter doses on cyclooxygenase isoforms in human volunteers". International Journal of Clinical Pharmacology and Therapeutics. 46 (4): 180–6. doi:10.5414/CPP46180. PMID 18397691.
    23. ↑ Van Hecken A, Schwartz JI, Depré M, De Lepeleire I, Dallob A, Tanaka W, Wynants K, Buntinx A, Arnout J, Wong PH, Ebel DL, Gertz BJ, De Schepper PJ (October 2000). "Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers". Journal of Clinical Pharmacology. 40 (10): 1109–20. Bibcode:1991JClP...31..928S. doi:10.1177/009127000004001005 (inactive 2018-09-11). PMID 11028250.
    24. ↑ Gross GJ, Moore J (July 2004). "Effect of COX-1/COX-2 inhibition versus selective COX-2 inhibition on coronary vasodilator responses to arachidonic acid and acetylcholine". Pharmacology. 71 (3): 135–42. doi:10.1159/000077447. PMID 15161995.
    25. ↑ Hawkey CJ (October 2001). "COX-1 and COX-2 inhibitors". Best Practice & Research. Clinical Gastroenterology. 15 (5): 801–20. doi:10.1053/bega.2001.0236. PMID 11566042.
    26. ↑ Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP, Vree JB, Guelen PJ (August 1993). "Pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans". Biopharmaceutics & Drug Disposition. 14 (6): 491–502. doi:10.1002/bdd.2510140605. PMID 8218967.
    27. 1 2 3 4 Rodrigues AD (November 2005). "Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same?". Drug Metabolism and Disposition. 33 (11): 1567–75. doi:10.1124/dmd.105.006452. PMID 16118328.
    28. ↑ "CYP2C9". pharmgkb.org. PharmGKB. Retrieved 17 May 2017.
    29. ↑ el Mouelhi M, Ruelius HW, Fenselau C, Dulik DM (1987). "Species-dependent enantioselective glucuronidation of three 2-arylpropionic acids. Naproxen, ibuprofen, and benoxaprofen". Drug Metabolism and Disposition. 15 (6): 767–72. PMID 2893700.
    30. ↑ Harrington PJ, Lodewijk E (1997). "Twenty Years of Naproxen Technology". Org. Process Res. Dev. 1 (1): 72–76. doi:10.1021/op960009e.
    31. ↑ "Vimovo". vimovo.com. 11 March 2015.
    32. ↑ "Medicines regulator approves availability of a new OTC medicine for period pain" (Press release). Medicines and Healthcare products Regulatory Agency (MHRA). 1 April 2008. Archived from the original (PDF) on 21 September 2013.
    33. ↑ "Aleve – Welcome to Canada, Eh!" (PDF) (Press release). Bayer Health Care. 14 July 2009. Retrieved 24 March 2012.
    34. ↑ "Aleve – Helping British Columbians with Joint and Arthritis Pain Get Back to Doing the Activities They Love". newswire.ca. 28 January 2010.
    35. ↑ Lejal N, Tarus B, Bouguyon E, Chenavas S, Bertho N, Delmas B, Ruigrok RW, Di Primo C, Slama-Schwok A (May 2013). "Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus". Antimicrobial Agents and Chemotherapy. 57 (5): 2231–42. doi:10.1128/AAC.02335-12. PMC 3632891. PMID 23459490. Lay summary – EurekAlert!.
    36. ↑ McIlwraith CW, Frisbie DD, Kawcak CE. Nonsteroidal Anti-Inflammatory Drugs. Proc. AAEP 2001 (47): 182-187.
    37. ↑ May SA, Lees P. Nonsteroidal anti-inflammatory drugs. In McIlwraith CW, Trotter GW, eds. Joint disease in the horse. Philadelphia: WB Saunders, 1996;223–237.
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