Anaprox (Naproxen Sodium)

ANAPROX® ANAPROX® DS

Roche

Naproxen Sodium

Analgesic – Anti-inflammatory

Action And Clinical Pharmacology: Naproxen sodium, has demonstrated analgesic, anti-inflammatory and antipyretic properties in human clinical studies and in classical animal test systems. It exhibits an anti-inflammatory effect even in adrenalectomized animals and therefore its action is not mediated through the pituitary-adrenal axis. It is not a corticosteroid. It inhibits prostaglandin synthetase, as do certain other nonsteroidal analgesic/anti-inflammatory agents. As with other agents, however, the exact mechanism of its anti-inflammatory and analgesic actions is not known.

Blood loss and gastroscopy studies with normal volunteers showed that daily administration of 1 100 mg of naproxen sodium caused significantly less gastric bleeding and erosion than 3 250 mg of ASA.

At the recommended dosage, the analgesic effect was shown to be comparable to that observed using 650 mg of ASA. The analgesic effect is obtained within 1 hour and can last at least 7 hours.

Naproxen sodium is freely soluble in water and is completely absorbed from the gastrointestinal tract. Plasma levels are obtained in patients within 20 minutes and peak levels in approximately 1 hour. It is extensively bound to plasma protein and has a plasma half-life of approximately 13 hours. The preferred route of excretion is via the urine with only 1% of the dose excreted in the feces.

Indications And Clinical Uses: The relief of mild to moderately severe pain, accompanied by inflammation in conditions such as musculoskeletal trauma and postdental extraction. It is also indicated for the relief of pain associated with postpartum cramping and dysmenorrhea.

Contra-Indications: Patients with active ulcers or active inflammatory diseases of the gastrointestinal tract. Patients who have shown hypersensitivity to it or to naproxen. Since cross-sensitivity has been demonstrated, naproxen sodium should not be given to patients in whom ASA or other nonsteroidal anti-inflammatory drugs induce the syndrome of asthma, rhinitis, or urticaria. Sometimes severe and occasionally fatal anaphylactoid reactions have occurred in such individuals.

Manufacturers’ Warnings In Clinical States: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) including naproxen sodium.

Naproxen sodium should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs). For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions).

Pregnancy and Lactation: Safety in pregnancy and lactation has not been established and its use during these events is therefore not recommended. Reproduction studies have been performed in rats, rabbits and mice. In rats, pregnancy was prolonged when naproxen sodium was given before the onset of labor; when it was given after the delivery process had begun, labor was protracted. Similar results have been found with other nonsteroidal anti-inflammatory agents and the evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis. Moreover, because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

The naproxen anion readily crosses the placental barrier. It has been found in the milk of lactating women at a concentration approximately 1% of that found in the plasma.

Precautions: Naproxen sodium should not be used concomitantly with the related drug naproxen since they circulate in plasma as the naproxen anion.

Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs naproxen sodium should be discontinued, an appropriate treatment instituted and patient closely monitored.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of naproxen sodium therapy when and if these adverse reactions appear.

Renal Effects: As with other nonsteroidal anti-inflammatory drugs, long-term administration of naproxen sodium to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, extracellular volume depletion, sodium restrictions, heart failure, liver dysfunction, those taking diuretics and the elderly. Assessment of renal function in these patients before and during therapy with naproxen sodium is recommended. Discontinuation of nonsteroidal anti-inflammatory therapy is typically followed by recovery to the pretreatment state.

Naproxen sodium and its metabolites are eliminated primarily by the kidneys, therefore, the drug should be used with great caution in patients with significantly impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. A reduction in daily dosage should be anticipated to avoid the possibility of excessive drug accumulation.

Naproxen sodium should not be used chronically in patients having baseline creatinine clearance less than 20 mL/minute. During long-term therapy, kidney function should be monitored periodically.

Fluid and Electrolyte Balance: Peripheral edema has been observed in some patients receiving naproxen sodium. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Although sodium retention has not been reported in metabolic studies, the drug should be used with caution in patients with fluid retention, hypertension or heart failure.

Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Each Anaprox tablet contains approximately 25 mg of sodium and each Anaprox DS tablet contains approximately 50 mg of sodium. This should be considered in patients whose overall intake of sodium must be markedly restricted.

It is possible that patients with questionable or compromised cardiac function may be at greater risk when taking naproxen sodium.

Anaphylactoid reactions to naproxen or naproxen sodium, whether of the true allergic type or the pharmacologic idiosyncratic (e.g., syndrome associated with the use of ASA) type, usually but not always occur in patients with a known history of such reactions. Therefore, careful questioning of patients for such things as asthma, nasal polyps, urticaria and hypotension associated nonsteroidal anti-inflammatory drugs before starting therapy is important. In addition, if such symptoms occur during therapy, treatment should be discontinued.

Geriatrics: One study indicates that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for naproxen sodium dosing is unknown, but caution is advised when high doses are required. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.

Patients with Impaired Liver Function: As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this drug as with other nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for naproxen sodium dosing is unknown, but caution is advised when high doses are required. It is prudent to use the lowest effective dose.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when naproxen sodium is administered.

Blood dyscrasias associated with the use of nonsteroidal anti-inflammatory drugs are rare, but could be associated with severe consequences.

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

Infection: The anti-inflammatory, antipyretic and analgesic effects of naproxen sodium may mask the usual signs of infection and the physician should be alert for development of infection in patients receiving naproxen sodium.

Ophthalmology: Because of adverse eye findings in animal studies with drugs of this class it is recommended that ophthalmic studies be carried out within a reasonable period of time after starting therapy and at periodic intervals thereafter if the drug is to be used for an extended period of time.

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

Drug Interactions: The naproxen anion may displace from their binding sites other drugs which are also albumin-bound and may lead to drug interactions. For example, in patients receiving bishydroxycoumarin or warfarin, the addition of naproxen sodium could prolong the prothrombin time. These patients should, therefore, be under careful observation. Similarly, patients receiving naproxen sodium and a hydantoin, sulfonamide or sulfonylurea should be observed for signs of toxicity to these drugs.

The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations have also been reported.

Naproxen sodium and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta blockers.

The rate of absorption of naproxen sodium is altered by concomitant administration of antacids but is not adversely influenced by the presence of food. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.

Caution is advised in the concomitant administration of naproxen sodium and methotrexate since naproxen and other nonsteroidal anti-inflammatory agents have been reported to reduce the tubular secretion of methotrexate in an animal model, thereby possibly enhancing its toxicity.

Laboratory Tests: Naproxen sodium decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

The administration of naproxen sodium 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 artifactually altered, it is suggested that naproxen sodium therapy be temporarily discontinued 48 hours before adrenal function tests are performed.

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

Children: The safety and efficacy of this drug in children has not been established and its use in children is therefore not recommended.

Adverse Reactions: The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

Adverse reactions reported in controlled clinical trials are listed below. (1) Denotes incidence of reported reaction between 3% and 9%. (2) Denotes incidence of reported reactions between 1% and 3%. Reactions occurring in less than 1% of the patients during controlled clinical trials and through voluntary reports since marketing are unmarked.

Gastrointestinal: heartburn (1), constipation (1), abdominal pain (1), nausea (1), diarrhea (2), dyspepsia (2), stomatitis (2), diverticulitis (2), gastrointestinal bleeding, hematemesis, melena, peptic ulceration with or without bleeding and/or perforation, vomiting, ulcerative stomatitis.

CNS: headache (1), dizziness (1), drowsiness (1), lightheadedness (2), vertigo (2), depression (2) and fatigue (2). Occasionally patients had to discontinue treatment because of the severity of some of these complaints (headache and dizziness). Other adverse effects were inability to concentrate, malaise, myalgia, insomnia and cognitive dysfunction (i.e. decreased attention span, loss of short-term memory, difficulty with calculations).

Skin: pruritus (1), ecchymoses (1), skin eruptions (1), sweating (2), purpura (2), alopecia, urticaria, skin rash, erythema multiforme, Stevens-Johnson syndrome, epidermal necrolysis, photosensitive dermatitis, exfoliative dermatitis and erythema nodosum.

Hepatic Changes: abnormal liver function tests, jaundice, cholestasis and hepatitis.

Cardiovascular Reactions: dyspnea (1), peripheral edema (1), palpitations (2), congestive heart failure and vasculitis.

Renal: glomerular nephritis, hematuria, interstitial nephritis, nephrotic syndrome, nephropathy and tubular necrosis.

Hematologic: eosinophilia, granulocytopenia, leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia and hemolytic anemia.

Special Senses: tinnitus (1), hearing disturbances (2), hearing impairment and visual disturbances.

Others: thirst (2), muscle weakness, anaphylactoid reactions, menstrual disorders, pyrexia (chills and fever), angioneurotic edema, hyperglycemia, hypoglycemia, hepatitis and eosinophilic pneumonitis.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Significant overdosage may be characterized by drowsiness, heartburn, indigestion, nausea or vomiting. No evidence of toxicity or late sequelae have been reported 5 to 15 months after ingestion for 3 to 7 days of doses up to 3 000 mg of naproxen. One patient ingested a single dose of 25 g naproxen and experienced mild nausea and indigestion. It is not known what dose of the drug would be life threatening. The oral LD50 of the drug is 543 mg/kg in rats, 1 234 mg/kg in mice, 4 110 mg/kg in hamsters and greater than 1 000 mg/kg in dogs.

Should a patient ingest a large number of naproxen sodium tablets, the stomach may be emptied and usual supportive measures employed. Animal studies suggest that the prompt administration of 5 g of activated charcoal would tend to reduce markedly the absorption of the drug. In dogs, 0.5 g/kg of charcoal was effective in reducing the plasma levels of naproxen when given after the drug. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. However, hemodialysis may still be appropriate in the management of renal failure.

Dosage And Administration: The recommended starting dose of Anaprox for adults is two 275 mg tablets, followed by one 275 mg tablet every 6 to 8 hours, as required. The total daily dose should not exceed 1 375 mg. Alternatively, one Anaprox DS tablet (550 mg) given twice daily may be used.

Availability And Storage: Anaprox: Each oval-shaped, blue film-coated tablet, engraved on one side NPS-275, contains: naproxen sodium 275 mg. Nonmedicinal ingredients: FD&C Blue No. 2 aluminum lake, hydroxypropyl methycellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. Bisulfite-, erythrosine-, gluten-, lactose-, sorbitol-, tartrazine- and xylitol-free. Bottles of 100 and 500.

Anaprox DS: Each oblong, dark blue, film-coated tablet, engraved on one side NPS 550, break scored on both sides, contains: naproxen sodium 550 mg. Nonmedicinal ingredients: FD&C Blue No. 2 aluminum lake, hydroxypropyl methycellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. Bisulfite-, erythrosine-, gluten-, lactose-, sorbitol-, tartrazine- and xylitol-free. Bottles of 100 and 500.

Store at room temperature (15 to 30°C) in a well-closed container, protected from light.

ANAPROX® ANAPROX® DS Roche Naproxen Sodium Analgesic – Anti-inflammatory

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