Prevacid NapraPAC

lansoprazole and naproxen

Dosage Form: delayed-release capsules / tablets

Rx only

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).


• Prevacid NapraPAC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal (GI) Risk

• NSAIDs cause an increased risk of serious GI adverse events including bleeding and perforation of the stomach and intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Patients with a history of gastric and/or duodenal ulcers (especially patients with a history of bleeding or perforation) and geriatric patients are at greater risk for serious GI events (see WARNINGS and CLINICAL STUDIES, Risk Reduction of NSAID-Associated Gastric Ulcer(s)).

PREVACID® NapraPAC® 500 is a combination package containing two individual drug products: PREVACID® (lansoprazole) Delayed-Release Capsules, a proton pump inhibitor (PPI), and NAPROSYN® (naproxen tablets), a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The information described in this labeling concerns only the use of these products as indicated in this combination package and does not include all individual use information. For information on use of the components when dispensed as individual medications outside this combination package, please see the package inserts for PREVACID Delayed-Release Capsules and NAPROSYN Tablets.

Prevacid NapraPAC Description

Prevacid NapraPAC 500 is a combination package containing NAPROSYN 500 mg tablets and PREVACID 15 mg capsules.

NAPROSYN

Naproxen is a proprionic acid derivative related to the arylacetic acid group of NSAIDs. The chemical name for naproxen is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and naproxen has the following structure:

Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3.

Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8.

NAPROSYN (naproxen tablets) is available as yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone, and magnesium stearate.

PREVACID

The active ingredient in PREVACID Delayed-Release capsules is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3O2S with a molecular weight of 369.37. PREVACID has the following structure:

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.

Lansoprazole is stable when exposed to light for up to two months. The rate of degradation of the compound in aqueous solution increases with decreasing pH. The degradation half-life of the drug substance in aqueous solution at 25°C is approximately 0.5 hour at pH 5 and approximately 18 hours at pH 7.

PREVACID Delayed-Release capsules contain enteric-coated granules consisting of 15 mg of lansoprazole (active ingredient) and the following inactive ingredients: sugar sphere, sucrose, methacrylic acid copolymer, low substituted hydroxypropyl cellulose, starch, magnesium carbonate, talc, polyethylene glycol, titanium dioxide, polysorbate 80, hydroxypropyl cellulose, colloidal silicon dioxide, D&C Red No. 28, FD&C Blue No. 1, FD&C Green No. 3, and FD&C Red No. 40.

Prevacid NapraPAC - Clinical Pharmacology

Pharmacokinetics

NAPROSYN

Absorption

Naproxen is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. The elimination half-life of naproxen ranges from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life.

Distribution

Naproxen has a volume of distribution of 0.16 L per kg. At therapeutic levels, naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg per day, there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough concentrations at steady state were 36.5, 49.2 and 56.4 mg per L with 500, 1000, and 1500 mg daily doses of naproxen, respectively).

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of the maximum naproxen concentration in plasma (see PRECAUTIONS, Nursing Mothers).

Metabolism

Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites.

Excretion

The clearance of naproxen is 0.13 mL per min per kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate (see WARNINGS, Renal Effects).

Special Populations

Pediatric Patients

The combination of naproxen and lansoprazole has not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, PREVACID Special Populations – Pediatric Use).

Geriatric Patients

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is less than 1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear; although, it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients.

Race

Pharmacokinetic differences due to race have not been studied.

Hepatic Insufficiency

Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency.

Renal Insufficiency

Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency (see CLINICAL PHARMACOLOGY, PREVACID Special Populations - Renal Insufficiency). Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment – (creatinine clearance less than 30 mL per min – see WARNINGS, Renal Effects).

PREVACID

PREVACID Delayed-Release capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.

Absorption

The absorption of lansoprazole is rapid, with the mean Cmax occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both the Cmax and AUC are diminished by about 50 to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5 mcg per mL.

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+,K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Elimination

Following single-dose oral administration of PREVACID, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.

Special Populations

Pediatric Use

The combination of lansoprazole and naproxen has not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, NAPROSYN Special Populations – Pediatric Use).

Geriatric Use

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly.

Gender

In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results (see PRECAUTIONS, PREVACID Use in Women).

Renal Insufficiency

In patients with severe renal insufficiency, plasma protein binding decreased by 1% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function (see CLINICAL PHARMACOLOGY, NAPROSYN Special Populations - Renal Insufficiency).

Hepatic Insufficiency

In patients with various degrees of chronic hepatic disease, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with severe hepatic disease should be considered.

Race

The pooled mean pharmacokinetic parameters of PREVACID from twelve U.S. Phase I studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of PREVACID in Asian subjects were approximately twice that seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.

Pharmacodynamics

NAPROSYN

Naproxen is a NSAID with analgesic and antipyretic properties. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

PREVACID

Mechanism of Action

PREVACID (lansoprazole) belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.

Antisecretory Activity

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than 3 and greater than 4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

The intragastric pH results of a five-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once daily lansoprazole are presented in Table 1.

Table 1: Mean Antisecretory Effects after single and multiple daily PREVACID dosing
		PREVACID
Parameter	Baseline Value	15 mg		30 mg
		Day 1	Day 5	Day 1	Day 5
NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%.
* (p<0.05) versus baseline only. † (p<0.05) versus baseline and lansoprazole 15 mg.
Mean 24-Hour pH	2.1	2.7*	4.0*	3.6†	4.9†
Mean Nighttime pH	1.9	2.4	3.0*	2.6	3.8†
% Time Gastric pH>3	18	33*	59*	51†	72†
% Time Gastric pH>4	12	22*	49*	41†	66†

After the initial dose in this study, increased gastric pH was seen within 1 to 2 hours with 30 mg of lansoprazole and 2 to 3 hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within 1 to 2 hours post-dosing with 15 mg of lansoprazole.

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses. There was no indication of rebound gastric acidity.

Enterochromaffin-like (ECL) Cell Effects

During lifetime exposure of rats with up to 150 mg per kg per day of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats (see PRECAUTIONS, PREVACID Carcinogenesis, Mutagenesis, Impairment of Fertility).

Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole.

Other Gastric Effects in Humans

Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.

Serum Gastrin Effects

In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral lansoprazole. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.

Endocrine Effects

Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function.

In 24-month carcinogenicity studies in Sprague-Dawley rats with daily lansoprazole dosages up to 150 mg per kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates.

Other Effects

No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after lansoprazole treatment (up to 180 mg per day) for up to 58 months.

After lifetime lansoprazole exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy were seen.

Clinical Studies

Risk Reduction of NSAID-Associated Gastric Ulcer(s)

A large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) 12-week study was conducted in patients who required chronic use of an NSAID and had a history of an endoscopically documented gastric ulcer. Patients were randomized to one of the following four treatment groups: PREVACID 15 mg per day, PREVACID 30 mg per day, misoprostol 200 micrograms QID, and placebo. Patients were allowed to take one or more NSAIDs and take concomitant low-dose aspirin (≤ 325 mg per day) during the study. Patients who had gastric ulcers, duodenal ulcers, erosive esophagitis, or ≥25 gastric/duodenal erosions on baseline upper endoscopy were excluded from participation. Patients had to be H. pylori negative by the CLO test and by histology testing.

A total of 537 patients were enrolled in the study, and 535 patients were treated. Patients ranged in age from 23 to 89 years (median age 60 years), with 65% female patients and 35% male patients. Race was distributed as follows: 90% Caucasian, 6% Black, and 4% other. Concomitant low-dose aspirin was used in about 20% of the patients. Additionally, about 99% of the patients had a prior history of a gastric ulcer and about 50% of the patients had a prior history of a duodenal ulcer.

The proportion of patients remaining free from gastric ulcers (diagnosed by upper endoscopy) at 4, 8, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo (see Table 2). The 30 mg dose of PREVACID demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer(s) than the 15 mg dose. In the 12 week study, no patient in any of the treatment groups developed a NSAID-associated serious GI complication (such as bleeding, perforation, or obstruction). However, this study was not designed to demonstrate risk reduction of NSAID-associated serious GI complications. Additionally, this study was not designed to demonstrate risk reduction of duodenal ulcers.

Table 2: Proportion of Patients Remaining Free of Gastric Ulcers*
	PREVACID	PREVACID	Misoprostol	Placebo
	15 mg daily	30 mg daily	200 mcg QID
Week	(N=121)	(N=116)	(N=106)	(N=112)
(p<0.001) PREVACID 15 mg daily versus placebo; PREVACID 30 mg daily versus placebo; and misoprostol 200 mcg QID versus placebo.
(p<0.05) Misoprostol 200 mcg QID versus PREVACID 15 mg daily; and misoprostol 200 mcg QID versus PREVACID 30 mg daily
* % = Life Table Estimate
4	90%	92%	96%	66%
8	86%	88%	95%	60%
12	80%	82%	93%	51%

Of the 537 patients in the double-blind, placebo- and misoprostol-controlled study, a retrospective subset analysis of 119 patients – whose NSAIDs were naproxen or naproxen and aspirin – was performed. Patients ranged in age from 37 to 84 years (median age 58 years) with 61% female patients and 39% male patients. Race was distributed as follows: 88% Caucasian, 8% Black, and 4% other. Concomitant low-dose aspirin was used in 15% of the patients. Of the 61 patients in the two PREVACID treatment groups: 5, 54, and 2 patients received less than 750 mg, 750 to 1000 mg, and greater than 1000 mg of daily naproxen, respectively.

The proportion of patients remaining free from gastric ulcer (diagnosed by upper endoscopy) at 4, 8, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo (see Table 3). The 30 mg dose of PREVACID demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcers than the 15 mg dose.

Table 3: Proportion of Patients (whose NSAIDs were Naproxen or Naproxen and Aspirin) Remaining Free of Gastric Ulcers*
	PREVACID	PREVACID	Misoprostol	Placebo
	15 mg daily	30 mg daily	200 mcg QID
Week	(N=37)	(N=24)	(N=28)	(N=30)
(p<0.001) PREVACID 15 mg daily versus placebo; PREVACID 30 mg daily versus placebo; and misoprostol 200 mcg QID versus placebo.
* % = Life Table Estimate
4	91%	83%	88%	52%
8	89%	83%	88%	52%
12	89%	83%	83%	33%

NAPROSYN

General Information

Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity, or duration of rheumatoid arthritis.

In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease.

In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg twice daily (1500 mg per day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were GI events.

In clinical studies in patients with rheumatoid arthritis or osteoarthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder GI adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin.

In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects.

Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a "steroid-sparing" effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone.

In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin.

Geriatric Patients

The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.

Indications and Usage for Prevacid NapraPAC

Carefully consider the potential benefits and risks of Prevacid NapraPAC and other treatment options before deciding to use Prevacid NapraPAC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Prevacid NapraPAC is indicated for reducing the risk of NSAID-associated gastric ulcers in patients with a history of documented gastric ulcer(s) who require the use of an NSAID for treatment of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and/or ankylosing spondylitis (see CLINICAL STUDIES and DOSAGE AND ADMINISTRATION). Controlled studies did not extend beyond 12 weeks.

Contraindications

Prevacid NapraPAC is contraindicated in patients with known severe hypersensitivity to any component of the formulations of PREVACID (lansoprazole), NAPROSYN (naproxen), or the over-the-counter products containing naproxen.

Prevacid NapraPAC is contraindicated in patients who have experienced aspirin- or NSAID-related asthma, urticaria, or allergic-type reactions. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS –Preexisting Asthma).

Prevacid NapraPAC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Warnings

CARDIOVASCULAR EFFECTS

Cardiovascular Thrombotic Events

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 does increase the risk of serious GI 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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

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.

Congestive Heart Failure and Edema

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.

GI Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including NAPROSYN, can cause serious GI adverse events including inflammation, 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 in patients treated with NSAIDs. 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 to 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. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who 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, smoking, use of alcohol, older 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. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

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)).

Epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper GI bleeding. In two studies, concurrent use of an NSAID or aspirin potentiated the risk of bleeding (see PRECAUTIONS: Drug Interactions). Although these studies focused on upper GI bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

Renal Effects

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 overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics, and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state (see WARNINGS, Advanced Renal Disease).

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. If NAPROSYN therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, 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. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Skin Reactions

NSAIDs, including 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.

Pregnancy

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

Precautions

General

NAPROSYN

Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and other naproxen products, including Prevacid NapraPAC, 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. 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 drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPROSYN. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory 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. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions (including jaundice, and fatal fulminant hepatitis, liver necrosis, and hepatic failure), some of them with fatal outcomes, have been reported.

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 NAPROSYN.

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

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.

Hematological Effects

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 pla