NAPRELAN (Page 4 of 5)

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

DRUG/LABORATORY TEST INTERACTIONS

Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined.

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-dinitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artificially 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.

Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (50 mg/m2 , 100 mg/m2 , and 150 mg/m2). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found.

PREGNANCY

Teratogenic Effects. Pregnancy Category C.

Reproduction studies have been performed in rats at 20mg/kg/day (125 mg/m2 /day, 0.23 times the human systemic exposure) rabbits at 20mg/kg/day (220 mg/m2 /day, 0.27 times the human systemic exposure) and mice at 170mg/kg/day (510 mg/m2 /day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predicitve of human response, NAPRELAN® Tablets should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Nonteratogenic effects

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 effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester should be avoided.

LABOR AND DELIVERY

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPRELAN® on labor and delivery in pregnant women are unknown.

NURSING MOTHERS

The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.

PEDIATRIC USE

No pediatric studies have performed with NAPRELAN® Tablets, thus safety of NAPRELAN® Tablets in pediatric populations has not been established.

GERIATRIC USE

Clinical studies of NAPRELAN® Tablets did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Aging may affect the pharmacokinetics of naproxen. 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. Elderly or debilitated patients seem to tolerate GI ulcerations and bleeding less well than other individuals taking NSAIDs (see WARNINGS, RISK of GI Ulceration, Bleeding And Perforation With NSAID Therapy). Additionally, elderly patients may be more sensitive to dose-dependent reduction in renal prostaglandin formation while taking NSAIDs (see WARNINGS, Renal Effects).

ADVERSE REACTIONS

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% — 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.

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