Naproxen

3.18

log Kow = 3.18

3.18

-4.16

Practically odorless

Crystals from acetone-hexane

White to off-white crystalline powder

White to creamy white, crystalline powder; soluble in water and sparingly soluble in alcohol. /Naproxen sodium/

15.9

Slightly soluble in ether; soluble in methanol, chloroform

Soluble in 25 parts ethanol (96%), 20 parts methanol, 15 parts chloroform, 40 parts ether. Practically insoluble in water

Practically insoluble in water and freely soluble in alcohol.

In water, 15.9 mg/L at 25 °C

0.0159 mg/mL at 25 °C

When heated to decomposition it emits acrid smoke and fumes.

152°C

155 °C

Crystals from acetone; mp: 244-246 °C; specific optical rotation: -11 deg at 25 °C/D (in methanol) /Naproxen sodium salt/

153 °C

Specific optical rotation: +66 deg at 25 °C/D (in chloroform)

-4.83

Solid

Negative

0.22

10.5

Thermo LTQ

Electrospray ionization

ammonia (10nM)

4.18

4.15

pKa = 4.15

This chemical does not meet GHS hazard criteria for 0.7% (1 of 139) of reports.

Danger

H301 (42.4%): Toxic if swallowed [Danger Acute toxicity, oral]；H302 (57.6%): Harmful if swallowed [Warning Acute toxicity, oral]；H315 (56.1%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (55.4%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H335 (53.2%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]；H361 (49.6%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P261, P264, P264+P265, P270, P271, P280, P301+P316, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 139 reports by companies from 28 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 1 of 139 reports by companies.；There are 27 notifications provided by 138 of 139 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Status: Active Update: 21-09-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/16517

Naproxen: Does not have an individual approval but may be used under an appropriate group standard

IMAP assessments - 2-Naphthaleneacetic acid, 6-methoxy-.alpha.-methyl-, (S)-: Human health tier I assessment；IMAP assessments - 2-Naphthaleneacetic acid, 6-methoxy-.alpha.-methyl-, (S)-: Environment tier I assessment

Naproxen granules. ... Conditions of use -- (1) Horses. The drug is used for the relief of inflammation and associated pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the musculoskeletal system of the horse. (2)(i) For oral maintenance therapy following initial intravenous dosage ... (3) Not for use in horses intended for food. (4) Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Naproxen for injectiion. ... Indications for use: For the relief of inflammation and associated pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the musculoskeletal system of the horse. (3) Limitations: Not for use in horses intended for food. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl naproxen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl naproxen sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Naproxen sodium/

For more FDA Requirements (Complete) data for NAPROXEN (6 total), please visit the HSDB record page.

Brogden RN; Non-steroidal Anti-inflammatory Analgesics Other Than Salicylates. Drugs 32 (Suppl 4): 27-45 (1986). The largest group of non-narcotic analgesics are the arylalkanoic acid derivatives, comprising derivatives of arylacetic acid, propionic acid, heteraryl acetic acid and indole acetic acid.

Johnson AG et al; Adverse Drug Interactions With Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Recognition, management and avoidance.; Drug Saf 8 (2): 99-127 (1993). The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs remains unknown.

Todd PA, Clissold SP; Naproxen. A Reappraisal of its Pharmacology, and Therapeutic Use in Rheumatic Diseases and Pain States. Drugs 40 (1): 91-137 (1990). Naproxen is a nonsteroidal anti-inflammatory drug advocated for use in painful and inflammatory rheumatic and certain nonrheumatic conditions.

Acute Tox. 3 (42.4%)；Acute Tox. 4 (57.6%)；Skin Irrit. 2 (56.1%)；Eye Irrit. 2 (55.4%)；STOT SE 3 (53.2%)；Repr. 2 (49.6%)

Commercially available naproxen and naproxen sodium conventional tablets and naproxen delayed-release (enteric-coated) tablets should be stored in well-closed containers at 15 - 30 °C; the containers for the delayed-release tablets also should be light resistant. Extended-release naproxen sodium tablets should be stored in well-closed containers at 20 - 25 °C. Naproxen oral suspension should be stored in light-resistant containers at 15 - 30 °C, and temperatures exceeding 40 °C should be avoided. Naproxen conventional and delayed-release (enteric-coated) tablets should be stored in well-closed, light-resistant containers. Naproxen sodium tablets should be stored in well-closed containers.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

/Naproxen/ is excreted in milk of lactating women.

Methotrexate is a cornerstone in the treatment of juvenile idiopathic arthritis. Although associated with many mild adverse effects, the short and long-term safety of methotrexate in juvenile idiopathic arthritis has been excellent. While many juvenile idiopathic arthritis children treated with methotrexate develop liver enzyme abnormalities, no cases of irreversible liver damage or of severe non-infectious hepatitis with Reye-like features have been reported in non-systemic juvenile idiopathic arthritis. /The investigators/ report a 2-year-old girl with oligoarthritis whose liver enzyme increased to greater than 45 times the upper limit of normal, and developed hypoglycemia and hyperammonemia after 10 months of methotrexate and naproxen therapy. An infectious and metabolic work-up for other causes was unremarkable. She recovered completely after folinic acid therapy; methotrexate and naproxen was not restarted. While very rare in juvenile idiopathic arthritis, methotrexate in synergism with naproxen can induce severe liver toxicity and it is important to screen children for liver enzyme abnormalities.

Because naproxen is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Although no clinically important drug interactions have been reported, patients receiving naproxen with any of these drugs should be observed for adverse effects.

Administration of naproxen with warfarin results in a slight increase in free warfarin in serum, but does not affect the hypoprothrombinemic effect of warfarin. Because naproxen may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (eg, streptokinase).

Results of a study in patients with diabetes mellitus showed no interference by naproxen on the effect of tolbutamide on plasma glucose concn.

For more Interactions (Complete) data for NAPROXEN (18 total), please visit the HSDB record page.

Serum aminotransferase levels can be elevated in as many as 4% of patients receiving prolonged courses of naproxen, particularly with high doses. Clinically apparent naproxen induced liver injury, however, is rare (approximately 1 in 10,000 new users), but convincing cases have been reported. The typical case resembles acute hepatitis and arises within 1 to 6 weeks of starting naproxen (Cases 1 and 2). The time to onset can be as long as 12 weeks, but convincing instances of liver injury arising after long term or intermittent low-dose use have not been described. The pattern of serum enzyme elevations can range from hepatocellular to cholestatic injury. Immunoallergic features and autoantibodies are not common, although rare cases of DRESS syndrome attributable to naproxen have been described including a syndrome of pulmonary infiltrates with eosinophilia (PIE). In most instances, recovery is rapid once naproxen is stopped. Rare instances of acute liver failure attributed to naproxen have been published, but the role of naproxen in these cases has not very convincingly shown. Reviews of hepatotoxicity often mention that naproxen is the least likely NSAID to cause serious liver injury.；Likelihood score: B (likely, but very rare cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a structure estimation method(2), indicates that naproxen is expected to have moderate mobility in soil(SRC). The pKa of naproxen is 4.15(3), indicating that this compound will almost entirely exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the acid exists as an anion and anions do not volatilize. Naproxen is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Naproxen is considered non-biodegradable(6).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a structure estimation method(2), indicates that naproxen is expected to adsorb to suspended solids and sediment(SRC). A pKa of 4.15(3) indicates naproxen will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 3.18(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Naproxen is considered non-biodegradable(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), naproxen, which has an estimated vapor pressure of 1.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase naproxen is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3 hours(SRC), calculated from its rate constant of 1.2X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Naproxen contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

Primary adverse effects for naproxen include dyspepsia, nausea, dizziness, elevated liver enzymes, increased blood pressure, diminished renal function, rash, increased bleeding risk, and GI ulcers. Serious but rare adverse effects include blood dyscrasias, Stevens-Johnson syndrome, myocardial infarction, stroke, heart failure, and anaphylaxis. The following are several mechanisms of the above adverse effects:；GI Effects: COX-1 and COX-2 inhibition lead to decreased prostaglandin synthesis in the gastric mucosa. The prostaglandins maintain mucosal integrity, therefore decreased synthesis causes reduced protection to the tissue. However, studies indicate COX-1 has a more significant effect on the integrity of the mucosa; consequently, selective COX-2 inhibitors such as Celecoxib do not have as much of an effect on gastric tissue.；Renal Effects: Prostaglandins produced by both COX-1 and COX-2 are important regulators of renal function, hemodynamics, and sodium and water reabsorption in the kidneys. When renal blood flow is dependent upon prostaglandin synthesis, NSAID administration can significantly decrease renal blood flow, leading to acute kidney injury and renal failure. Also, alterations in sodium and water reabsorption may increase blood pressure, especially in patients with pre-existing hypertension.；Platelet Effects: Platelet aggregation inhibition with naproxen is due to the dose-dependent inhibition of COX-1 in platelets. This action leads to decreased levels of platelet thromboxane A2 and an increase in bleeding time. This inhibition is reversible upon discontinuation of naproxen. Despite the known inhibition of platelet function, studies examining an increase in clinical bleeding time have shown mixed results.

EXPERIMENTAL: /Naproxen/ is excreted in milk of lactating women.

EXPERIMENTAL: Detectable in breast milk about 1% of plasma concentration. /from Table II/

POTENTIAL ADVERSE EFFECTS ON FETUS: Use in late pregnancy should be avoided. May constrict ductus arteriosus in utero or inhibit or prolong labor as result of inhibition of prostaglandin synthetase. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Detectable in breast milk about 1% of plasma concentration. The American Academy of Pediatrics considers drug safe for breast-feeding. FDA Category: B (B = Studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; or animal studies have shown an adverse effect (other than a decrease in fertility), but controlled studies in pregnant women have not demonstrated a risk to the fetus in the first trimester and there is no evidence of a risk in later trimesters.) /from Table II/

Naproxen crosses the placenta. Naproxen is also distributed into milk in concn of about 1% of simultaneous maternal plasma drug concn.

Naproxen overdose is common due to its OTC availability, but the overdose is usually mild in severity, and serious adverse effects from overdose are rare. There is no available antidote for naproxen overdose; however, monitoring vital signs and supportive care is recommended. The role of activated charcoal is uncertain due to time constraints and unclear benefits, and there is no role for hemodialysis due to naproxen's high degree of protein binding. However, ingestion of large amounts of Naproxen can lead to severe toxicity causing seizures and metabolic acidosis, which can potentially cause renal failure. Therefore, although hemodialysis is not generally recommended, it can correct acid-base disturbances and provide additional support to those with renal impairment in specific situations.

/AQUATIC SPECIES/ ...Bioassays assessing acute and chronic effects on four organisms were conducted on four high-use drugs: Acetaminophen, ibuprofen, naproxen, and salicylic acid (metabolite of acetyl salicylic acid). Results indicated no negative effects except for the chronic algal (Selanastrum capricornutum) growth test on ibuprofen (no-observed-effect concentration, 10 ug/L; lowest-observed-effect concentration, 32 ug/L). Effects of these four compounds on invertebrates and plants in the receiving environments are unlikely based on the concentrations measured.

/AQUATIC SPECIES/ The occurrence of pharmaceuticals in the environment is of great concern and only few data are available about the adverse effects of such molecules and their derivatives on non-target aquatic organisms. This study was designed to assess the toxic potential of Naproxen, a nonsteroidal anti-inflammatory, Naproxen Na, its freely water soluble sodium salt and their photoproducts in the aquatic environment. Bioassays were performed on algae, rotifers and microcrustaceans to assess acute and chronic toxicity. Furthermore, possible genotoxic effects of photoderivatives were investigated using SOS chromotest and Ames fluctuation test. The results showed that photoproducts were more toxic than the parent compounds both for acute and chronic values, while genotoxic and mutagenic effects were not found. These findings suggested the opportunity to consider derivatives in ecotoxicology assessment of drugs.

/AQUATIC SPECIES/ The ecotoxicity of the nonsteroidal anti-inflammatory drugs (NSAIDs) diclofenac, ibuprofen, naproxen, and acetylsalicylic acid (ASA) has been evaluated using acute Daphnia and algal tests. Toxicities were relatively low, with half-maximal effective concentration (EC50) values obtained using Daphnia in the range from 68 to 166 mg/L and from 72 to 626 mg/L in the algal test. Acute effects of these substances seem to be quite improbable. The quantitative structure-activity relationships (QSAR) approach showed that all substances act by nonpolar narcosis; thus, the higher the n-octanol/water partitioning coefficient (log Kow) of the substances, the higher is their toxicity. Mixture toxicity of the compounds could be accurately predicted using the concept of concentration addition. Toxicity of the mixture was considerable, even at concentrations at which the single substances showed no or only very slight effects, with some deviations in the Daphnia test, which could be explained by incompatibility of the very steep dose-response curves and the probit analysis of the data. Because pharmaceuticals in the aquatic environment occur usually as mixtures, an accurate prediction of the mixture toxicity is indispensable for environmental risk assessment.

The average daily load of naproxen into Lake Greifensee, Switzerland from 3 wastewater treatment plants, specifically Moenchaltorf, Uster, and Mauer, was 1.34, 3.11, and 1.61 g/day, respectively, sampled between August 16, 1999 to October 22, 1999(1). The compound was detected, not quantified in sewage sludge from the Iona Island, British Columbia, Canada municipal wastewater treatment plant, sampled in 1982(2). Naproxen concentrations ranged from not detected to 120 ng/L in effluent from sewage treatment plants in Berlin, Germany; it was not detected sewage treatment plant eflluent in Greece(3). Naproxen was detected in sewage treatment plant effluents at concentrations of 1.73 and 0.51 ug/L (France), 0.29, 0.41, and 5.22 ug/L (Italy), and 2.15 ug/L (Sweden). A range of 0.3 to 0.42 ug/L was reported for effluents sampled in Germany and Switzerland(4). Levels in 2 effluent samples from the Jefferson Parish East Bank Wastewater Treatment Plant in New Orleans, LA, were 106 and 81 ng/L in February and March, 2002, respectively(5).

Naproxen concentrations in final effluents of eight municipal sewage treatment plants, Atlantic Canada, sampled in 2003(1). [Table#4552]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of naproxen can be estimated to be 330(SRC). According to a classification scheme(2), this estimated Koc value suggests that naproxen is expected to have moderate mobility in soil. The pKa of naproxen is 4.15(3), indicating that this compound will almost entirely exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ Most cases of naproxen overdosage have been reported in adults. Adverse GI effects (e.g., heartburn, vomiting) and seizures usually occur in these patients; drowsiness and prolongation of clotting time also may occur. The incidence of adverse effects in adults may differ from those in children since rash and prolonged bleeding time appear to occur more frequently in children while other reactions occur more frequently in adults; the incidence of adverse GI and CNS effects are similar.

/SIGNS AND SYMPTOMS/ Toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, urticaria, alopecia, erythema nodosum, fixed drug eruption, lichen planus, and pustular reaction have been reported during postmarketing experience.

/SIGNS AND SYMPTOMS/ Long-term use may be associated with an increased risk of cardiovascular and cerebrovascular events.

/SIGNS AND SYMPTOMS/ Pseudoporphyria, a cutaneous disorder characterized by skin fragility, vesiculation, and scarring, has been reported as a side effect of naproxen therapy in children with juvenile rheumatoid arthritis. ... The results of a 6-month prospective study to determine the prevalence of pseudoporphyria in our juvenile rheumatoid arthritis population /are presented/. All the patients with pseudoporphyria had received naproxen for > or = 4 weeks at the time of the study. Of the patients treated with naproxen, 12% (9/74) developed this complication. No patient had significant elevation of free erythrocyte protoporphyrin, excluding the diagnosis of true erythropoietic protoporphyria. We conclude that pseudoporphyria is a common side effect of naproxen therapy in children with juvenile rheumatoid arthritis, even in geographic areas without high sun exposure. Because of the risk of facial scarring with pseudoporphyria, physicians and parents of children with juvenile rheumatoid arthritis should be aware of this complication.

For more Human Toxicity Excerpts (Complete) data for NAPROXEN (34 total), please visit the HSDB record page.

Naproxen's production and use as an analgesic(1) may result in its release to the environment through various waste streams(SRC).

Status: Active Update: 21-09-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/16517

Naproxen: Does not have an individual approval but may be used under an appropriate group standard

Naproxen granules. ... Conditions of use -- (1) Horses. The drug is used for the relief of inflammation and associated pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the musculoskeletal system of the horse. (2)(i) For oral maintenance therapy following initial intravenous dosage ... (3) Not for use in horses intended for food. (4) Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Naproxen for injectiion. ... Indications for use: For the relief of inflammation and associated pain and lameness exhibited with arthritis, as well as myositis and other soft tissue diseases of the musculoskeletal system of the horse. (3) Limitations: Not for use in horses intended for food. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl naproxen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl naproxen sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Naproxen sodium/

For more FDA Requirements (Complete) data for NAPROXEN (6 total), please visit the HSDB record page.

M01AE02

G - Genito urinary system and sex hormones；G02 - Other gynecologicals；G02C - Other gynecologicals；G02CC - Antiinflammatory products for vaginal administration；G02CC02 - Naproxen

M - Musculo-skeletal system；M01 - Antiinflammatory and antirheumatic products；M01A - Antiinflammatory and antirheumatic products, non-steroids；M01AE - Propionic acid derivatives；M01AE02 - Naproxen

M - Musculo-skeletal system；M02 - Topical products for joint and muscular pain；M02A - Topical products for joint and muscular pain；M02AA - Antiinflammatory preparations, non-steroids for topical use；M02AA12 - Naproxen

QM - Musculo-skeletal system；QM02 - Topical products for joint and muscular pain；QM02A - Topical products for joint and muscular pain；QM02AA - Antiinflammatory preparations, non-steroids for topical use；QM02AA12 - Naproxen

QM - Musculo-skeletal system；QM01 - Antiinflammatory and antirheumatic products；QM01A - Antiinflammatory and antirheumatic products, non-steroids；QM01AE - Propionic acid derivatives；QM01AE02 - Naproxen

Naproxen is highly protein bound with >99% of the drug bound to albumin at therapeutic levels.

Naproxen is an established non-selective NSAID and is useful as an analgesic, anti-inflammatory and antipyretic. Similar to other NSAIDs, the pharmacological activity of naproxen can be attributed to the inhibition of cyclo-oxygenase, which in turn reduces prostaglandin synthesis in various tissues and fluids including the synovial fluid, gastric mucosa, and the blood. Although naproxen is an effective analgesic, it can have unintended deleterious effects in the patient. For instance, naproxen can adversely affect blood pressure control. A study found that use of naproxen induced an increase in blood pressure, although the increase was not as significant as that found with ibuprofen use. Further, studies have found that the risk of upper gastrointestinal bleeding is on average four-fold higher for individuals taking NSAIDs. Other factors that increase the risk of upper gastrointestinal bleeding include concurrent use of corticosteroids or anticoagulants, and a history of gastrointestinal ulcers.

As with other non-selective NSAIDs, naproxen exerts it's clinical effects by blocking COX-1 and COX-2 enzymes leading to decreased prostaglandin synthesis. Although both enzymes contribute to prostaglandin production, they have unique functional differences. The COX-1 enzymes is constitutively active and can be found in normal tissues such as the stomach lining, while the COX-2 enzyme is inducible and produces prostaglandins that mediate pain, fever and inflammation. The COX-2 enzyme mediates the desired antipyretic, analgesic and anti-inflammatory properties offered by Naproxen, while undesired adverse effects such as gastrointestinal upset and renal toxicities are linked to the COX-1 enzyme.

Naproxen has pharmacologic actions similar to those of other prototypical nonsteroidal anti-inflammatory agents (NSAIAs). The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis. Naproxen inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 (PGHS-1) and -2 (PGHS-2), respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway. Naproxen, like other prototypical NSAIAs, inhibits both COX-1 and COX-2. Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.

The anti-inflammatory, analgesic, and antipyretic effects of naproxen and other nonsteroidal anti-inflammatory agents (NSAIAs), including selective inhibitors of COX-2 (e.g., celecoxib, rofecoxib), appear to result from inhibition of prostaglandin synthesis. While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors. Naproxen stabilizes lysosomal membranes and inhibits the response of neutrophils to chemotactic stimuli. The drug does not possess glucocorticoid or adrenocorticoid-stimulating properties.

Naproxen lowers body temperature in patients with fever. Although the mechanism of the antipyretic effect of nonsteroidal anti-inflammatory agents is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.

Naproxen-induced inhibition of prostaglandin synthesis may result in decreased frequency and intensity of uterine contractility. Prostaglandins E2 and F2alpha increase the amplitude and frequency of uterine contractions in pregnant women; current evidence suggests that primary dysmenorrhea is also mediated by these prostaglandins. Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined. Blood concentrations of a metabolite of prostaglandin F2alpha have been found to decrease in women with dysmenorrhea who were receiving naproxen. Therapy with naproxen has been effective in relieving menstrual pain and has reduced blood loss in women with menorrhagia, probably by inhibiting the formation of these prostaglandins. Administration of naproxen during late pregnancy may prolong gestation by inhibiting uterine contractions.

The elimination half-life of naproxen is reported to be 12-17 hours.

The reported elimination half-life in dogs is 34-72 hr.

In healthy adults, the plasma half-life of naproxen reportedly ranges from 10-20 hr. The manufacturer state that the plasma half-life of naproxen is about 13 hr. The plasma half-life and elimination of the drug appear to be similar in children and adults.

The pharmacokinetics of naproxen, its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid (O-desmethylnaproxen), and their acyl glucuronides were studied in 10 subjects (ages 20-50 yr) who received an oral dose of 500 mg naproxen. Mean half-life of naproxen in 9 subjects was 24.7 hr. A half-life of 7.4 hr in the 10th subject was considered an extraordinary case. ...

Naproxen is heavily metabolized in the liver and undergoes both Phase I and Phase II metabolism. The first step involves demethylation of naproxen via CYP 1A2, 2C8, and 2C9. Both naproxen and desmethylnaproxen proceed to Phase II metabolism; however, desmethylnaproxen can form both acyl and phenolic glucoronide products, while naproxen only produces the acyl glucuronide. The acyl glucuronidation process involves UGT 1A1, 1A3, 1A6, 1A7, 1A9, 1A10 and 2B7, while phenolic glucuronidation is catalyzed by UGT 1A1, 1A7,1A9, and 1A10. Desmethylnaproxen also undergoes sulphation which is mediated by SULT 1A1, 1B1 and 1E1.

Naproxen is extensively metabolized in the liver to 6-desmethylnaproxen. Approximately 95% of the drug is excreted in urine as unchanged naproxen (less than 1%) and 6-desmethylnaproxen (less than 1%) and their glucuronide or other conjugates (66-92%). Some data suggest that renal excretion of unchanged naproxen may be negligible or absent; previously reported concentrations of unchanged drug may reflect rapid hydrolysis of conjugates during collection, storage, and handling of urine samples. The half-life of naproxen metabolites and conjugates is shorter than 12 hours. Naproxen metabolites may accumulate in patients with renal impairment. Elimination of naproxen is reduced in patients with severe renal impairment. A small amount (less than 5%) of the drug is excreted in feces.

The pharmacokinetics of naproxen, its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid (O-desmethylnaproxen), and their acyl glucuronides were studied in 10 subjects (ages 20-50 yr) who received an oral dose of 500 mg naproxen. Mean half-life of naproxen in 9 subjects was 24.7 h. A half-life of 7.4 h in the 10th subject was considered an extraordinary case. Naproxen acyl glucuronide accounted for 50.8% of the dose, its isomerized conjugate isoglucuronide for 6.5%, O-desmethylnaproxen acyl glucuronide for 14.3%, and its isoglucuronide for 5.5%. Excretion of naproxen and O-desmethylnaproxen was negligible. Plasma protein binding was 98% for naproxen, 100% for O-desmethylnaproxen, 92% for naproxen acyl glucuronide, 66% for naproxen isoglucuronide, 72% for O-desmethylnaproxen acyl glucuronide, and 42% for O-desmethylnaproxen isoglucuronide. It was concluded that naproxen is O-desmethylated and parent drug and metabolite are conjugated into acyl glucuronides.

Naproxen has known human metabolites that include (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-[(2S)-2-(6-methoxynaphthalen-2-yl)propanoyl]oxyoxane-2-carboxylic acid and O-Desmethylnaproxen.

57Y76R9ATQ

NAPROXEN

Mechanisms of Action [MoA] - Cyclooxygenase Inhibitors

Chemical Structure [CS] - Anti-Inflammatory Agents, Non-Steroidal

Established Pharmacologic Class [EPC] - Nonsteroidal Anti-inflammatory Drug

Naproxen is a Nonsteroidal Anti-inflammatory Drug. The mechanism of action of naproxen is as a Cyclooxygenase Inhibitor.

Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.

Agents that increase uric acid excretion by the kidney (URICOSURIC AGENTS), decrease uric acid production (antihyperuricemics), or alleviate the pain and inflammation of acute attacks of gout.

Compounds or agents that combine with cyclooxygenase (PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES) and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of eicosanoids, prostaglandins, and thromboxanes.

Naproxen is available as a free acid and sodium salt. At comparable doses, (naproxen 500 mg = naproxen sodium 550 mg) they differ slightly in their rates of absorption, but otherwise they are therapeutically and pharmacologically equivalent. Naproxen sodium achieves a peak plasma concentration after 1 hour, while peak plasma concentration is observed after 2 hours with naproxen (free acid). There are no differences between the 2 forms in the post-absorption phase pharmacokinetics. The difference in initial absorption should be considered when treating acute pain, since naproxen sodium may offer a quicker onset of action. The mean Cmax for the various formulations (immediate release, enteric coated, controlled release etc.) of naproxen are comparable and range from 94 mcg/mL to 97.4 mcg/mL. In one pharmacokinetic study, the mean Tmax of naproxen 500 mg (immediate release) given every 12 hours over 5 days was 3 hours, compared to a mean Tmax of 5 hours for Naprelan 1000 mg (controlled release) given every 24 hours over 5 days. In this same study, the AUC0-24hr was 1446mcgxhr/mL for naproxen immediate release and 1448 mcgxhr/mL for the controlled release formulation. A separate study comparing the pharmacokinetics of Naprosyn tablets and EC-Naprosyn observed the following values: Tmax and AUC0-12hrs of EC-Naprosyn were 4 hours and 845 mcgxhr/mL respectively, and Tmax and AUC0-12hrs values of Naprosyn were 1.9 hours and 767 mcgxhr/mL respectively. When given in combination with sumatriptan the Cmax of naproxen is roughly 36% lower compared to naproxen sodium 550 mg tablets, and the median Tmax is 5 hours. Based on the AUC and Cmax of naproxen, Vimovo (naproxen/esomeprazole combination product) and enteric-coated naproxen may be considered bioequivalent. Overall, naproxen is rapidly and completely absorbed when administered orally and rectally. Food may contribute to a delay in the absorption of orally administered naproxen, but will not affect the extent of absorp

After oral administration, about 95% of naproxen and it's metabolites can be recovered in the urine with 66-92% recovered as conjugated metabolite and less than 1% recovered as naproxen or desmethylnaproxen. Less than 5% of naproxen is excreted in the feces.

Naproxen has a volume of distribution of 0.16 L/kg.

Naproxen is cleared at a rate of 0.13 mL/min/kg.

Oral absorption of naproxen in dogs is rapid, with peak plasma concentration reached in 0.5-3 hr. The reported elimination half-life in dogs is 34-72 hr. Naproxen is highly protein bound (>99.0%). In dogs, naproxen is primarily eliminated through the bile, whereas in other species, the primary route of elimination is through the kidneys. The long half-life of naproxen in dogs appears to be due to its extensive enterohepatic recirculation.

After therapeutic doses, naproxen is more than 99% bound to plasma proteins. When naproxen binding sites become saturated (at twice daily doses of 500 mg or more), plasma free drug concentrations increase and may result in increased urinary clearance rates. Therefore, plasma naproxen concentrations tend to plateau when dosage exceeds 500 mg twice daily. In a study in patients with severe renal failure, binding of naproxen to serum proteins was decreased compared to healthy adults; the decreased binding may have accounted for an increase in metabolism and apparent volume of distribution of the drug observed in these patients. In patients with chronic alcoholic liver disease, total plasma concentrations of naproxen are decreased while concentrations of the unbound drug are increased.

Epidermis；Kidney；Liver

Membrane

Naproxen Action Pathway

Anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and sodium salt are used to treat rheumatoid arthritis and other musculoskeletal disorders, dysmmenorrhea, and acute gout.

Non-steroidal anti-inflammatory drug

THERAP CAT: Anti-inflammatory; analgesic; antipyretic

THERAP CAT (VET): Anti-inflammatory

For more Uses (Complete) data for NAPROXEN (6 total), please visit the HSDB record page.

Use (kg) in Switzerland (2009): >1000；Use (kg; approx.) in Germany (2009): >10000；Use (kg; exact) in Germany (2009): 14733；Use (kg) in USA (2002): 248000；Use (kg) in France (2004): 37332；Consumption (g per capita) in Switzerland (2009): 0.13；Consumption (g per capita; approx.) in Germany (2009): 0.12；Consumption (g per capita; exact) in Germany (2009): 0.18；Consumption (g per capita) in the USA (2002): 0.88；Consumption (g per capita) in France (2004): 0.62；Excretion rate: 0.1；Calculated removal (%): 83.7

(2S)-2-(6-hydroxynaphthalen-2-yl)propanoic acid

(2S)-2-(5-chloro-6-methoxynaphthalen-2-yl)propanoic acid

(2S)-2-(5-bromo-6-methoxynaphthalen-2-yl)propanoic acid

(2S)-2-(5-iodo-6-methoxynaphthalen-2-yl)propanoic acid

For more Impurities (Complete) data for NAPROXEN (14 total), please visit the HSDB record page.

Three consecutive /phase transfer catalysis/ reactions (esterification, C-alkylation, and hydrolysis) are used to convert phenylacetic acid derivatives to compounds such as ibuprofen and naproxen.

The major pharmaceutical products based on 2-naphthol /include/ ... the antirheumatic naproxen, produced via 2-methoxynaphthalene.

Naproxen, an antirheumatic, is ... prepared from 2-naphthol by the Friedel-Crafts acylation of 2-methoxynaphthalene and subsequent Willgerodt-Kindler reaction. The S-configuration which is obtained from its racemic mixture with the alkaloid cinchonidine is the effective isomer.

Preparation: J. H. Fried, I. T. Harrison, ZA 6707597; eidem, US 3904682; eidem, US 4009197 (1968, 1975, 1977 all to Syntex).

Table: Naproxen Preparations [Table#4553]

Table: Naproxen Combination Preparations [Table#4554]

Table: Naproxen Sodium Preparations [Table#4555]

Table: Naproxen Sodium Combination Preparations [Table#4556]

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients

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