Naprelan (naproxen) Side Effects, Warnings, and Interactions

Naprelan (naproxen) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate pain, inflammation, and fever. Naproxen is common and available over-the-counter (OTC) and as a generic or under different brand names like Aleve, Anaprox, and Naprosyn.

Common side effects of naproxen include rash, ringing in the ears, headaches, dizziness, drowsiness, abdominal pain, nausea, diarrhea, constipation, heartburn, fluid retention, and shortness of breath.

Serious side effects of naproxen include fluid retention, blood clots, heart attacks, high blood pressure (hypertension), and heart failure.

Drug interactions of naproxen include lithium, blood pressure medications, methotrexate, aminoglycosides, anticoagulants, cyclosporine, and furosemide and thiazide diuretics.

NSAIDs such as naproxen may cause a fetal birth defect called ductus arteriosus (early closure of two major blood vessels of the heart and lung) in the third trimester of pregnancy. NSAIDs should be avoided during this last part of pregnancy.

A small amount of naproxen is excreted in breast milk. Because the concentration in breast milk is low, breastfeeding while taking naproxen probably is not harmful to the infant.

The most common side effects from naproxen are:

• rash,
• ringing in the ears,
• headaches,
• dizziness,
• drowsiness, abdominal pain, nausea,
• diarrhea,
• constipation,
• heartburn,
• fluid retention, and
• shortness of breath.

Other important side effects include:

• fluid retention,
• blood clots,
• heart attacks,
• hypertension, and
• heart failure.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

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.

As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors. The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship between drug usage and these adverse events.

In those reactions listed as “Probable Causal Relationship” there is at least one case for each adverse reaction where there is evidence to suggest that there is a causal relationship between drug usage and the reported event. The adverse reactions reported were based on the results from two double-blind controlled clinical trials of three months duration with an additional nine month open-label extension. A total of 542 patients received Naprelan Tablets either in the double-blind period or in the nine month open-label extension.

Of these 542 patients, 232 received Naprelan Tablets, 167 were initially treated with Naprosyn® and 143 were initially treated with placebo. Adverse reactions reported by patients who received Naprelan Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with Naprelan Tablets are italicized.

The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). The incidence of other adverse events occurring in 3% to 9% of the patients are marked with an asterisk.

Those reactions occurring in less than 3% of the patients are unmarked.

Incidence greater Than 1% (Probable Causal Relationship)

Body as a Whole - Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%).

Gastrointestinal - Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn*, stomatitis.

Hematologic - Anemia, ecchymosis.

Respiratory - Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased.

Renal - Urinary tract infection*, cystitis.

Dermatologic - Skin rash*, skin eruptions*, ecchymoses*, purpura.

Metabolic and Nutrition - Peripheral edema, hyperglycemia.

Central Nervous System - Dizziness, paresthesia, insomnia, drowsiness*, lightheadedness.

Cardiovascular - Hypertension, edema*, dyspnea*, palpitations.

Musculoskeletal - Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder.

Special Senses - Tinnitus*, hearing disturbances, visual disturbances.

General - Thirst.

Incidence Less Than 1% (Probable Causal Relationship)

Body as a Whole - Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis, edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic.

Gastrointestinal - Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess, cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis, jaundice, pancreatitis, necrosis.

Renal - Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder, pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia, metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal, urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis.

Hematologic - Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC, thrombocytopenia, agranulocytosis, granulocytopenia.

Central Nervous System - Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo, amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural, paralysis, dream abnormalities, inability to concentrate, muscle weakness.

Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia, dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus, urticaria, neoplasm skin, photosensitive dermatitis, photosensitivity reactions resembling porphyria cutaneous tarda, epidermolysis bullosa.

Special Senses - Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation disorder, otitis media, pain eye.

Cardiovascular - Angina pectoris, coronary artery disease, myocardial infarction, deep thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG, heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart failure.

Respiratory - Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia, respiratory distress, respiratory disorder, eosinophilic pneumonitis.

Musculoskeletal - Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain, ptosis, spasm general, bursitis.

Metabolic and Nutrition - Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis, BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT increase, SGPT increase, weight decrease.

General - Anaphylactoid reactions, angioneurotic edema, menstrual disorders, hypoglycemia, pyrexia (chills and fevers).

Incidence Less Than 1% (Causal Relationship Unknown)

Other adverse reactions listed in the naproxen package label, but not reported by those who received Naprelan Tablets are shown in italics. These observations are being listed as alerting information to the physician.

Hematologic - Aplastic anemia, hemolytic anemia.

Central Nervous System - Aseptic meningitis, cognitive dysfunction.

Dermatologic - Epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.

Gastrointestinal - Non-peptic GI ulceration, ulcerative stomatitis.

Cardiovascular - Vasculitis.

See Table 1 for clinically significant drug interactions with naproxen.

Table 1: Clinically Significant Drug Interactions with Naproxen

Drug/Laboratory Test Interactions