naproxen (Rx, OTC)

1-10%

Abdominal pain (3-9%)

Constipation (3-9%)

Dizziness (3-9%)

Drowsiness (3-9%)

Headache (3-9%)

Heartburn (3-9%)

Nausea (3-9%)

Edema (3-9%)

GI bleeding (1-4%)

GI perforation (1-4%)

Lightneadedness (<3%)

GI ulcers (1-4%)

Fluid retention (3-9%)

Diarrhea (1-3%)

Stomatitis (<3%)

Diverticulitis (1-3%)

Dyspnea (3-9%)

Hearing disturbances (<3%)

<1%

Meaningful (3 × upper limit of normal) elevation of serum alanine aminotransferase or aspartate aminotransferase

Contraindications

Absolute: Aspirin allergy; perioperative pain in setting of coronary artery bypass graft (CABG) surgery

Relative: Bleeding disorders, delayed esophageal transit, hepatic disease, peptic ulcer, renal impairment, stomatitis, late pregnancy (may cause premature closure of ductus arteriosus)

Cautions

Use caution in congestive heart failure (CHF), hypertension, renal/hepatic impairment, or aspirin sensitive asthma

May increase risk of aseptic meningitis, especially in patients with systemic lupus erythematosis and mixed connective tissue disorders

Prolonged use may increase risk of adverse cardiovascular events

May cause anaphylactoid reactions, even in patients with no prior exposure to NSAIDs

Long-term administration of NSAIDs may result in renal papillary necrosis and other renal injury; patients at greatest risk include elderly individuals, those with impaired renal function, hypovolemia, heart failure, liver dysfunction, or salt depletion, and those taking diuretics, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers

May cause drowsiness, dizziness, and blurred vision

Platelet aggregation and adhesion may be decreased; may prolong bleeding time; monitor closely patients with coagulation disorders

Patient should ask a doctor or pharmacist, before taking this medication, if under a doctor's care for any serious condition, taking aspirin for heart attack or stroke (drug may decrease benefit of aspirin), or if taking any other drug

May increase risk of hyperkalemia in the elderly, renal disease, or diabetics, especially when used concomitantly with drugs that increase hyperkalemia

May cause serious skin reactions including exfoliative dermatitis, toxic epidermal syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis; discontinue therapy at first sign of skin rash

May cause new-onset of hypertension; monitor blood pressure closely throughout therapy

OTC use not for children <12 years

Withhold for at least 4-6 half-lives prior to surgery or dental procedure

Heart failure risk

• NSAIDS have the potential to trigger HF by prostaglandin inhibition that leads to sodium and water retention, increased systemic vascular resistance, and blunted response to diuretics
• NSAIDS should be avoided or withdrawn whenever possible
• Heart failure: risk is higher if you administer more than directed or for longer than directed
• AHA/ACC Heart Failure Guidelines; Circulation. 2016; 134

Drug reaction with eosinophilia and systemic symptoms

• Drug Reaction reported in patients taking NSAIDs; some of these events have been fatal or life-threatening; DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling
• Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis; sometimes symptoms of DRESS may resemble an acute viral infection
• Eosinophilia is often present; because this disorder is variable in its presentation, other organ systems not noted here may be involved
• Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, discontinue therapy and evaluate the patient immediately

Pregnancy

Use of NSAIDs can cause premature closure of fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment

Because of these risks, limit dose and duration of use between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy

Use of NSAIDs at about 30 weeks gestation or later in pregnancy increases risk of premature closure of fetal ductus arteriosus

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive

Animal data

• In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times maximum recommended human daily dose of 1500 mg/day, respectively
• Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization
• In animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre-and post-implantation loss; prostaglandins also have been shown to have an important role in fetal kidney development; in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses
• Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs can cause premature closure of fetal ductus arteriosus
• If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit use to lowest effective dose and shortest duration possible; if treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios; if oligohydramnios occurs, discontinue therapy and follow up according to clinical practice
• There are no studies on effects of therapy during labor or delivery; in animal studies, NSAIDS inhibit prostaglandin synthesis, cause delayed parturition, and increase incidence of stillbirth

Lactation

Based on available published clinical data, drug may be present in human milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits synthesis of prostaglandins in body tissues by inhibiting at least 2 cyclooxygenase (COX) isoenzymes, COX-1 and COX-2

May inhibit chemotaxis, alter lymphocyte activity, decrease proinflammatory cytokine activity, and inhibit neutrophil aggregation; these effects may contribute to anti-inflammatory activity

Absorption

Bioavailability: 95%

Onset: 30-60 min

Duration: < 12 hr

Peak serum time: 1-4 hr (tablets); 2-12 hr (delayed release empty stomach); 4-24 hr (delayed relase with food)

Peak plasma concentration: 62-96 mcg/mL

Distribution

Protein bound: <99%

Vd: 0.16 L/kg

Metabolism

Metabolized in liver via conjugation

Metabolites: 6-Desmethylnaproxen, glucuronide conjugates

Enzymes inhibited: COX-1, COX-2

Elimination

Half-life: 12-17 hr

Dialyzable: No value

Clearance: 0.13 mL/min/kg

Excretion: Urine (95%), feces (<3%)