WARNINGS
NAPROSYN
RISK OF GI ULCERATION, BLEEDING AND PERFORATION WITH NSAID THERAPY
Serious gastrointestinal toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to 2 years' duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year.
Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date with naproxen have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
Physicians should consider alternative treatment to NSAIDs in patients who have experienced a serious gastrointestinal toxicity associated with NSAID use. For patients who require the use of an NSAID, coadministration of PREVACID 15 mg Delayed-Release Capsules with NSAIDs has been proven effective to reduce the risk of gastric ulcers associated with NSAID use in patients with a previous history of documented gastric ulcers. (See CLINICAL STUDIES, PREVACID®NapraPAC™ (375 or 500), Risk Reduction of NSAID-Associated Gastric Ulcer.)
PRECAUTIONS
GENERAL
NAPROSYN
NAPROXEN-CONTAINING PRODUCTS SUCH AS NAPROSYN® (NAPROXEN) TABLETS, EC-NAPROSYN® (NAPROXEN) DELAYED-RELEASE TABLETS, ANAPROX® /ANAPROX DS® (NAPROXEN SODIUM) TABLETS, NAPROSYN® (NAPROXEN) SUSPENSION, ALEVE® (NAPROXEN SODIUM), AND OTHER NAPROXEN PRODUCTS INCLUDING PREVACID® NapraPAC™ (375 or 500), SHOULD NOT BE USED CONCOMITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA AS THE NAPROXEN ANION.
NAPROSYN cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. If the steroid dose is reduced or eliminated during therapy, the steroid dosage should be reduced slowly 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 10 grams or less who are to receive long-term therapy should have hemoglobin values determined periodically.
The antipyretic and anti-inflammatory activities of the drug may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.
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.
PREVACID
Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.
INFORMATION FOR PATIENTS
Each convenience package of PREVACID® NapraPAC™ (375 or 500) contains sufficient product for seven days of treatment. Each daily dose consists of one PREVACID 15 mg capsule and two NAPROSYN tablets, either 375 mg or 500 mg. Take the PREVACID capsule and one NAPROSYN tablet in the morning before eating with a glass of water. Take the second NAPROSYN tablet in the evening with a glass of water.
NAPROSYN, like other drugs of this class, is not free of side effects. The side effects of this formulation can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. PREVACID when taken with naproxen has been shown to reduce the risk of NSAID-associated gastric ulcers in patients with a history of ulcer.
NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in the management of arthritis and have a major role in the treatment of pain. Naproxen as NAPROSYN is indicated for the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS) and likely benefits of naproxen treatment, particularly when it is used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen.
RENAL EFFECTS
NAPROSYN
As with other nonsteroidal anti-inflammatory drugs, long-term administration of naproxen to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis, hematuria, proteinuria and occasionally nephrotic syndrome associated with naproxen-containing products and other NSAIDs since they have been marketed.
A second form of renal toxicity has been seen in patients taking naproxen as well as other nonsteroidal anti-inflammatory drugs. In patients with prerenal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of nonsteroidal anti- inflammatory therapy is typically followed by recovery to the pretreatment state.
Naproxen and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with caution in patients with significantly impaired renal function, and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Caution should be used if the drug is given to patients with creatinine clearance of less than 20 mL/minute because accumulation of naproxen metabolites has been seen in such patients.
Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.
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.
HEPATIC FUNCTION
NAPROSYN
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. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 naproxen. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with naproxen 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 (eg, eosinophilia, rash, etc.), naproxen should be discontinued.
FLUID RETENTION AND EDEMA
NAPROSYN
Peripheral edema has been observed in some patients receiving naproxen.
LABORATORY TESTS
NAPROSYN
Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow patients chronically treated with naproxen for signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up and what they should do if certain signs and symptoms do appear (see WARNINGS, NAPROSYN Risk of GI Ulcerations, Bleeding and Perforation With NSAID Therapy).
DRUG INTERACTIONS
NAPROSYN
The use of NSAIDs in patients who are receiving ACE inhibitors may potentiate renal disease states (see PRECAUTIONS, NAPROSYN Renal Effects).
In vitro studies have shown that naproxen anion, because of its affinity for protein, may displace from their binding sites other drugs that are also albumin-bound (see CLINICAL PHARMACOLOGY, NAPROSYN Pharmacokinetics).
Theoretically, the naproxen anion itself could likewise be displaced. Short-term controlled studies failed to show that taking the drug significantly affects prothrombin times when administered to individuals on coumarin-type anticoagulants. Caution is advised nonetheless, since interactions have been seen with other nonsteroidal agents of this class. Similarly, patients receiving the drug and a hydantoin, sulfonamide or sulfonylurea should be observed for signs of toxicity to these drugs (see CLINICAL STUDIES, NAPROSYN General Information).
Concomitant administration of naproxen and aspirin is not recommended because naproxen is displaced from its binding sites during the concomitant administration of aspirin, resulting in lower plasma concentrations and peak plasma levels.
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 has also been reported. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers.
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Caution should be used if naproxen is administered concomitantly with methotrexate. Naproxen, and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly increasing the toxicity of methotrexate.
PREVACID
Lansoprazole is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood levels.
In a study of healthy subjects neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including lansoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin.
In a single-dose crossover study examining lansoprazole 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate. Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. In clinical trials, antacids were administered concomitantly with PREVACID Delayed-Release Capsules; this did not interfere with its effect.
Lansoprazole causes a profound and long-lasting inhibition of gastric acid secretion; therefore, it is theoretically possible that lansoprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, digoxin).
DRUG/LABORATORY TEST INTERACTIONS
NAPROSYN
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 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.
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
NAPROSYN
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 (50, 100, 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.
PREVACID
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with doses of 5 to 150 mg/kg/day, about 1 to 40 times the exposure on a body surface (mg/m2) basis, of a 50-kg person of average height (1.46 m2 body surface area) given the recommended human dose of 30 mg/day (22.2 mg/m2). Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day (4 to 40 times the recommended human dose based on body surface area) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg/kg/day (13 times the recommended human dose based on body surface area) in a 1-year toxicity study.
In a 24-month carcinogenicity study, CD-1 mice were treated orally with doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on body surface area. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on body surface area) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on body surface area) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on body surface area).
Lansoprazole was not genotoxic in the Ames test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test. It was positive in in vitro human lymphocyte chromosomal aberration assays.
Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.
PREGNANCY: TERATOGENIC EFFECTS
Pregnancy Category B
PREVACID® NapraPAC™ (375 or 500)
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREVACID® NapraPAC™ (375 or 500) should not be used during pregnancy unless clearly needed.
NAPROSYN
Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/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 predictive of human response, naproxen should not be used during pregnancy unless clearly needed.
PREVACID
Teratology studies have been performed in pregnant rats at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.
NONTERATOGENIC EFFECTS
NAPROSYN
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 ductus arteriosus), use during third trimester should be avoided.
NURSING MOTHERS
PREVACID® NapraPAC™ (375 or 500)
No studies were conducted in this population with PREVACID® NapraPAC™, however, because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use of PREVACID® NapraPAC™ (375 or 500) in nursing mothers should be avoided.
NAPROSYN
The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.
PREVACID
Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions in nursing infants from lansoprazole, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
PREVACID® NapraPAC™ (375 or 500)
The safety and effectiveness of PREVACID® NapraPAC™ (375 or 500) in pediatric patients have not been established.
GERIATRIC USE
NAPROSYN
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.
PREVACID
The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in younger patients. For elderly patients, dosage and administration of lansoprazole need not be altered.
USE IN WOMEN
PREVACID
Over 4,000 women were treated with lansoprazole. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse events were also similar to those seen in males.
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