Naproxen

Adverse effects

Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset. Heavy use is associated with an increased risk of end-stage renal disease and kidney failure. Naproxen may cause muscle cramps in the legs in 3% of people.

In October 2020, the U.S. Food and Drug Administration (FDA) required the prescribing information to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.

Gastrointestinal

As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding. Naproxen should be taken orally with, or just after 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 U.S. markets, naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding. Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk. 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.

Cardiovascular

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. Naproxen is, however, associated with the smallest overall cardiovascular risks. 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.

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.

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.

NSAIDs such as naproxen may interfere with and reduce the efficacy of SSRI antidepressants, as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent, when taken together. Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution. 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). The risk is highest for people who are heavy drinkers.

Pharmacology

Mechanism of action

Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective NSAID.

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. An analysis of two clinical trials shows that naproxen's time to peak plasma concentration occurs between 2 and 4 hours after oral administration (the naproxen sodium formulation of the medication reaches peak plasma concentrations within 1–2 hours).

Pharmacogenetics

The pharmacogenetics of naproxen has been studied to better understand its adverse effects. 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. However, the study failed to account for differences in the activity of CYP2C9, a drug-metabolizing enzyme that is necessary for clearing naproxen. 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.

Chemistry

Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs. The free acid is an odorless, white to off-white crystalline substance. Naproxen free base is lipid-soluble and practically insoluble in water, while naproxen sodium and many other salts are freely soluble in water, often soluble in methanol, and sparingly soluble in alcohol; check the specific solubility of each salt before use. Naproxen has a melting point of 152–155 °C, while naproxen salts tend to have higher melting points.

Synthesis

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

Society and culture

Brand names

Naproxen and naproxen sodium are marketed under various brand names, including Accord, Aleve, Anaprox, Antalgin, Apranax, Eox, Feminax Ultra, Flanax, Inza, Maxidol, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, and Xenifar. It is also available as the combination naproxen/esomeprazole magnesium in delayed-release tablets under the brand name Vimovo.

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 of naproxen in the U.S. are mainly marketed by Bayer HealthCare, under the brand name Aleve, and as 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. 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 some provinces in Canada on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador; it subsequently became available OTC in British Columbia in January 2010 and Quebec in 2023.

Ecological effects

Naproxen has been found in groundwater and drinking water in concentrations high enough to have adverse effects on invertebrates, fungi, algae, bacteria and fishes. Naproxen is not thoroughly removed by conventional water treatment methods, and its degradation pathways in the environment are limited. Some methods more successfully remove naproxen from wastewater, including metal–organic complexes and porous carbon. Although the levels are generally low enough to not be acutely toxic, sub-lethal effects may still occur, such as reduced photosynthetic ability.

Research

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

Veterinary use

Horses

Naproxen is given by mouth 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). It is more effective for myositis than the commonly used NSAID phenylbutazone, and has shown especially good results for treatment of equine exertional rhabdomyolysis, a disease of muscle breakdown; it is less commonly used for musculoskeletal disease.