Naproxen

Available formulations

Naproxen sodium is available as both an immediate-release and 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.

Pregnancy and lactation

As with all non-steroidal anti-inflammatory medications (NSAIDs), naproxen use should be avoided in pregnancy due to the importance of prostaglandins in vascular and renal function in the fetus. NSAIDs should especially be avoided in the third trimester. Small amounts of naproxen are excreted in breast milk.[13] However, adverse effects are uncommon in infants breastfed from a mother taking naproxen.[16]

Gastrointestinal

As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding.[21] Naproxen should be taken orally with, or just after food, to decrease the risk of gastrointestinal side effects.[22] Persons with a history of ulcers or inflammatory bowel disease should consult a doctor before taking naproxen.[22] In U.S. markets, naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding.[13] Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk.[23] 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.[24][25]

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.[26] Naproxen is, however, associated with the smallest overall cardiovascular risks.[27][28] 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.[27]

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.[28]

Mechanism of action

Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective NSAID.[32][33][34][35][36]

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.[37] 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).[38]

Pharmacogenetics

The pharmacogenetics of naproxen has been studied to better understand its adverse effects.[39] 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.[39] However, the study failed to account for differences in the activity of CYP2C9, a drug-metabolizing enzyme that is necessary for clearing naproxen.[39] 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.[39]

Synthesis

Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:[41]

• Scale Synthesis of S-naproxen.svg

Brand names

Naproxen and naproxen sodium are marketed under various brand names, including Accord, Aleve,[42] Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, and Xenifar.[43] It is also available as the combination naproxen/esomeprazole magnesium in delayed-release tablets under the brand name Vimovo.[43][44]

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 generic store brand formulations in 220mg tablets.[45] In Australia, packets of 275mg tablets of naproxen sodium are Schedule 2 pharmacy medicines, with a maximum daily dose of five tablets or 1375mg. In the United Kingdom, 250mg 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.[46] In the Netherlands, 220mg and 275mg tablets are available OTC in drugstores, 550mg is OTC only at pharmacies. Aleve became available over the counter in some provinces in Canada[47] on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador;[48] it subsequently became available OTC in British Columbia in January 2010[49] and Quebec in 2023.[50]

Horses

Naproxen is given by mouth to horses at a dose of 10mg/kg and has shown to have a wide safety margin (no toxicity when given at three times the recommended dose for 42 days).[59] It is more effective for myositis than the commonly used NSAID phenylbutazone, and has shown especially good results for treatment of equine exertional rhabdomyolysis,[60] a disease of muscle breakdown; it is less commonly used for musculoskeletal disease.