Prescription Drug Information: Naproxen Sodium (Page 3 of 7)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract.

A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen.

In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults.

In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were:

Gastrointestinal (GI) Experiences, including: heartburn * , abdominal pain * , nausea * , constipation * , diarrhea, dyspepsia, stomatitis

Central Nervous System: headache * , dizziness * , drowsiness * , lightheadedness, vertigo

Dermatologic: pruritus (itching) * , skin eruptions * , ecchymoses * , sweating, purpura

Special Senses: tinnitus * , visual disturbances, hearing disturbances

Cardiovascular: edema * , palpitations

General: dyspnea * , thirst

* Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked.

In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients.

Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting

General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes

The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials.

Gastrointestinal: pancreatitis, vomiting
Hepatobiliary: jaundice
Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis
Nervous System: inability to concentrate Dermatologic: skin rashes

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized.

Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)

Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema

Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease).

Hepatobiliary: abnormal liver function tests, hepatitis (some cases have been fatal)

Hemic and Lymphatic: eosinophilia, leucopenia, granulocytopenia, hemolytic anemia, aplastic anemia

Metabolic and Nutritional: hyperglycemia, hypoglycemia

Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions

Respiratory: eosinophilic pneumonitis, asthma

Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema

Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine

Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients.

Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death

Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction

Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation

Hepatobiliary: hepatitis, liver failure

Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations

Respiratory: asthma, respiratory depression, pneumonia

Dermatologic: exfoliative dermatitis

Special Senses: blurred vision, conjunctivitis

Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria

7 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 have 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 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 and Precautions (5.12) ].

Aspirin

Clinical Impact:

A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen ( see 12.2 Pharmacodynamics). There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period.

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 and Precautions (5.2) ].

Intervention:

Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate.

Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.12) ].

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 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 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 and Precautions (5.6) ].
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 sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].

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 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 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 sodium and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine

Clinical Impact:

Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.

Intervention:

During concomitant use of 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 and Precautions (5.2) ].

Intervention:

The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.

Pemetrexed

Clinical Impact:

Concomitant use of 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 sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min 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 sodium is not recommended.

Cholestyramine

Clinical Impact:

Concomitant administration of cholestyramine can delay the absorption of naproxen.

Intervention:

Concomitant administration of cholestyramine with 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 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 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.

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