Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID increases the risk of serious gastrointestinal events (see GI WARNINGS and CLINICAL STUDIES, Risk Reduction of NSAID-Associated Gastric Ulcer(s)).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

NSAIDs, including NAPROSYN, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPROSYN, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. NAPROSYN should be used with caution in patients with fluid retention, hypertension, or heart failure.

NSAIDs, including NAPROSYN, can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed.

NSAIDs should be prescribed with extreme caution in those with a prior history of GI bleeding, ulcer disease, or geriatric patients. Patients with a prior history of peptic ulcer disease and/or GI bleedingwho use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, use of multiple NSAIDS, smoking, use of alcohol, advanced age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with PREVACID NapraPAC, the lowest effective NAPROSYN dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of PREVACID NapraPAC until a serious GI adverse event is ruled out.

Physicians should consider alternative treatment to NSAIDs in high risk patients (including patients who have experienced a serious NSAID-associated GI complication). For patients who require the use of NAPROSYN, coadministration with 15 mg of PREVACID Delayed-Release Capsules has been proven effective to reduce the risk of NSAID-associated gastric ulcers in patients with a previous history of documented gastric ulcer(s) (see CLINICAL STUDIES, Risk Reduction of NSAID-Associated Gastric Ulcer(s).)

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate acute renal failure. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, geriatric patients, patients taking diuretics, and ACE inhibitors. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state (see WARNINGS, Advanced Renal Disease).

No information is available from controlled clinical studies regarding the use of NAPROSYN in patients with advanced renal disease. Therefore, treatment with NAPROSYN is not recommended in these patients with advanced renal disease .

Anaphylactoid reactions may occur in patients without known prior exposure to NAPROSYN and/or PREVACID.

NAPROSYN should not be given to patients with the aspirin triad ¾ a symptom complex that typically occurs in asthmatic patients, with or without nasal polyps, who experience rhinitis or severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS Aspirin-Sensitive Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

NAPROSYN can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

In late pregnancy, as with other NSAIDs, NAPROSYN should be avoided because it may cause premature closure of the ductus arteriosus.

NAPROSYN

NAPROSYN cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids 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 pharmacological activity of NAPROSYN in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.

Because of adverse eye findings in animal studies with NSAIDs, it is recommended that an ophthalmic exam be performed if any visual change occurs.

Elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN. These liver test abnormalities may worsen, may remain unchanged, or may resolve with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Elevations of ALT or AST approximately three or more times the upper limit of normal have been reported in approximately 1% of patients receiving NSAIDs in clinical trials. In addition, rare cases of severe hepatic reactions (including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure), some of them with fatal outcomes, have been reported.

While on therapy with NAPROSYN, 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 a severe hepatic reaction.

If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), NAPROSYN should be discontinued.

Consider the use of a lower NAPROSYN dose in patients with the following conditions (since the plasma concentration of unbound naproxen is increased in these patients): chronic alcoholic liver disease, hypoproteinemia, and abnormal plasma proteins.

Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including NAPROSYN, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving NAPROSYN who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity between aspirin and other NSAIDs has been reported in these patients, NAPROSYN should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

PREVACID

Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.

Each package of PREVACID NapraPAC contains sufficient product for seven days of treatment. Each daily dose consists of one PREVACID 15 mg capsule and two NAPROSYN tablets, either 250 mg, 375 mg, or 500 mg. In the morning before eating, take the PREVACID capsule and one NAPROSYN tablet with a glass of water. In the evening, take the second NAPROSYN tablet with a glass of water.

1. NAPROSYN, like other NSAIDs, may cause serious cardiovascular (CV) side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS).

2. NAPROSYN, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. For patients who require the use of an NSAID, coadministration with 15 mg of PREVACID Delayed-Release Capsules has been proven effective to reduce the risk of NSAID-associated gastric ulcers in patients with a previous history of documented gastric ulcers (see CLINICAL STUDIES, Risk Reduction of NSAID-Associated Gastric Ulcer(s).)

Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).

3. NAPROSYN can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.

5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid Reactions).

7. In late pregnancy, as with other NSAIDs, NAPROSYN should be avoided because it may cause premature closure of the ductus arteriosus.

8. Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo, or depression during therapy with NAPROSYN.

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile (including liver enzymes and kidney tests) checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop; systemic manifestations occur (e.g., eosinophilia, rash, etc.); or if abnormal liver tests persist or worsen, PREVACID NapraPAC should be discontinued.

NAPROSYN

A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen 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 with oral lansoprazole doses of 5 to 150 mg/kg/day ¾ 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 (BSA)] exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In addition, in a one-year toxicity study, testicular interstitial cell adenoma occurred in 1 of 30 rats treated with 50 mg/kg/day of lansoprazole (13 times the recommended human dose based on BSA).

In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on BSA. 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 BSA) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on BSA) 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 BSA).

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 BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy Category C

PREVACID NapraPAC

There are no adequate and well-controlled studies of PREVACID NapraPAC in pregnant women. Because animal reproduction studies are not always predictive of human response, PREVACID NapraPAC should not be used during pregnancy unless clearly needed.

NAPROSYN

Reproduction studies of naproxen 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 naproxen. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of naproxen in pregnant women. NAPROSYN should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

PREVACID

Teratology studies have been performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day (40 times the recommended human dose based on BSA) and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

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 effects of NSAIDs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

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 PREVACID NapraPAC on labor and delivery in pregnant women are unknown.

PREVACID NapraPAC

No PREVACID NapraPAC studies were conducted in nursing mothers. Since prostaglandin-inhibiting drugs (including NAPROSYN) may have adverse effects on neonates, the use of PREVACID NapraPAC in nursing mothers should be avoided.

NAPROSYN

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration 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 lansoprazole, taking into account the importance of lansoprazole to the mother.

PREVACID NapraPAC

The safety and effectiveness of PREVACID NapraPAC in pediatric patients have not been established.

NAPROSYN

Geriatric patients are at a greater risk of developing serious NSAID-associated events (e.g., GI bleeding) compared to younger patients. Additionally, geriatric patients do not tolerate GI bleeding as well as younger patients. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS, Gastrointestinal Effects ¾ Risk of Ulceration, Bleeding, and Perforation). Caution is advised when high NSAID doses are required. As with other drugs used in geriatric patients, it is prudent to use the lowest effective dose.

Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored with chronic naproxen administration. Geriatric patients may be at a greater risk for thedevelopment of renal toxicity precipitated by reduced prostaglandin formation during administration of NSAIDs (see WARNINGS, Renal Effects).

Although the total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in geriatric patients.

PREVACID

The incidence rates of PREVACID-associated adverse events and laboratory test abnormalities are similar to those seen in younger patients. For geriatric patients, dosage and administration of PREVACID need not be altered.

PREVACID

Over 4,000 women were treated with PREVACID. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse events in females were similar to those seen in males.

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