Naproxen (naproxen 375 mg) Dailymed

Precautions

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General

Naproxen-containing products such as naproxen and naproxen sodium, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion.

Naproxen and naproxen sodium cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically.

Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with naproxen or naproxen sodium and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately (see WARNINGS; Cardiovascular Thrombotic Events).

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop naproxen or naproxen sodium and seek immediate medical therapy (see WARNINGS; Hepatotoxicity).

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS; Heart Failure and Edema).

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see CONTRAINDICATION, WARNINGS; Anaphylactic Reactions).

Serious Skin Reactions

Advise patients to stop naproxen or naproxen sodium immediately if they develop any type of rash and to contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions).

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including VOLTAREN, may be associated with a reversible delay in ovulation (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility).

Fetal Toxicity

Inform pregnant women to avoid use of naproxen or naproxen sodium and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus).

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of naproxen and naproxen sodium with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS;: Gastrointestinal Bleeding, Ulceration, and Perforation, PRECAUTIONS; Drug Interactions). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with naproxen and naproxen sodium until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions).

Activities Requiring Alertness

Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen.

Masking of Inflammation and Fever

The pharmacological activity of naproxen or naproxen sodium in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity).

Drug Interactions

See Table 1 for clinically significant drug interactions with naproxen.

Table 1: Clinically Significant Drug Interactions with naproxen

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Drug/Laboratory Test Interactions

Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found.

Mutagenesis

Studies to evaluate the mutagenic potential of naproxen or naproxen sodium tablets have not been completed.

Impairment of fertility

Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area).

Pregnancy

Risk Summary

Use of NSAIDs, including naproxen and naproxen sodium tablets, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including naproxen, in pregnant women starting at 30 weeks of gestation (third trimester) (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus).

There are no adequate and well-controlled studies of naproxen or naproxen sodium tablets in pregnant women.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies in rats, rabbit, 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 the 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 such as naproxen, resulted in increased pre- and post-implantation loss.

Data

Human Data

There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided.

Animal Data

Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. 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 such as naproxen, resulted in increased pre- and postimplantation loss.

Labor and Delivery

There are no studies on the effects of naproxen or naproxen sodium tablets during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Nursing Mothers

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naproxen or naproxen sodium tablets and any potential adverse effects on the breastfed infant from the naproxen or naproxen sodium tablets or from the underlying maternal condition.

Females and Males of Reproductive Potential

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation.

Consider withdrawal of NSAIDs, including naproxen and naproxen sodium tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION ). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION ), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS; Laboratory Monitoring).

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.

Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Toxicity and Hyperkalemia).