prevacid naprapac 250 (lansoprazole and naproxen)
prevacid naprapac 375 (lansoprazole and naproxen)
prevacid naprapac 500 (lansoprazole and naproxen)
[TAP Pharmaceutical Products Inc.]
PREVACID® NapraPAC™ (250, 375 or 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 250 is a combination package containing NAPROSYN 250 mg tablets and PREVACID 15 mg capsules. PREVACID NapraPAC 375 is a combination package containing NAPROSYN 375 mg tablets and PREVACID 15 mg capsules. PREVACID NapraPAC 500 is a combination package containing NAPROSYN 500 mg tablets and PREVACID 15 mg capsules.
Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs (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 is available as yellow tablets containing 250 mg of naproxen, pink tablets containing 375 mg of naproxen, and yellow tablets containing 500 mg of naproxen for oral administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone, and magnesium stearate.
The active ingredient in PREVACID 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 5.0 and approximately 18 hours at pH 7.0.
PREVACID capsules contain enteric-coated granules consisting of 15 mg of lansoprazole (active ingredient) and the following inactive ingredients: hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium carbonate, methacrylic acid copolymer, starch, talc, sugar sphere, sucrose, polyethylene glycol, polysorbate 80, and titanium dioxide. Components of the gelatin capsule include gelatin, titanium dioxide, D&C Red No. 28, FD&C Blue No. 1, FD&C Green No. 3, and FD&C Red No. 40 (inactive ingredients).
Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. After administration of naproxen 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.
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is a less than dose-proportional increase in plasma levels (due to an increase in clearance caused by saturation of plasma protein binding at higher doses). The mean trough concentrations at steady state were 36.5, 49.2 and 56.4 mg/L with the once daily administration of 500, 1000, and 1500 mg 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 the plasma (see PRECAUTIONS, Nursing Mothers).
Naproxen is extensively metabolized to 6-O-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes.
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-O-desmethyl naproxen (<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. In patients with renal failure metabolites may accumulate (see WARNINGS, Renal Effects).
The combination of naproxen and lansoprazole has not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, PREVACID Special Populations – Pediatric Use).
Studies indicate that the total plasma concentration of naproxen is unchanged in the elderly. The unbound plasma fraction of naproxen is increased in the elderly; however, it represents only < 1% of the total naproxen plasma concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of the total naproxen plasma 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.
Pharmacokinetic differences due to race have not been studied.
Naproxen pharmacokinetics has not been determined in subjects with hepatic 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 <30 mL/min – (see WARNINGS, Renal Effects).
PREVACID 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.
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 50-70% 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.
Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is consistent over the concentration range of 0.05 to 5.0 μg/mL.
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.
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.
The combination of lansoprazole and naproxen has not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, NAPROSYN Special Populations – Pediatric 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.
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).
In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-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).
In patients with various degrees of chronic hepatic disease, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2-7.2 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.
The pooled 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.
NAPROSYN (naproxen) is a nonsteroidal anti-inflammatory drug (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 (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.
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 >3 and >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.
|Parameter||Baseline Value||15 mg||30 mg|
|Day 1||Day 5||Day 1||Day 5|
|NOTE: An intragastric pH of >4 reflects a reduction in gastric acid by 99%.|
|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 1-2 hours with 30 mg of lansoprazole and 2-3 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 1-2 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.
During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed 7 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.
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.
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.
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/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates.
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/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.
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/day, PREVACID 30 mg/day, misoprostol 200 micrograms QID, and placebo. Patients were allowed to take one or more NSAIDs and take concomitant low-dose aspirin (≤ 325 mg/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 gastrointestinal complication (such as bleeding, perforation, or obstruction). However, this study was not designed to demonstrate risk reduction of NSAID-associated serious gastrointestinal complications. Additionally, this study was not designed to demonstrate risk reduction of duodenal ulcers.
|15 mg QD||30 mg QD||200 µg QID|
|(p<0.001) PREVACID 15 mg QD versus placebo; PREVACID 30 mg QD versus placebo; and misoprostol 200 µg QID versus placebo.|
|(p<0.05) Misoprostol 200 µg QID versus PREVACID 15 mg QD; and misoprostol 200 µg QID versus PREVACID 30 mg QD|
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 < 750 mg, 750 to 1000 mg, and > 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.
|15 mg QD||30 mg QD||200 µg QID|
|(p<0.001) PREVACID 15 mg QD versus placebo; PREVACID 30 mg QD versus placebo; and misoprostol 200 µg QID versus placebo.|
NAPROSYN (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 bid (1500 mg/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 gastrointestinal 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 gastrointestinal 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 has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin.
The hepatic and renal tolerability of 6 months of naproxen administration was studied in two double blind clinical trials in rheumatoid arthritis patients. Patients received either 375 mg of naproxen BID or 750 mg of naproxen BID. Of the 586 patients studied, 98 (17%) patients were ≥ 65 years old. There were no differences in the occurrence of abnormal renal and hepatic laboratory tests in the geriatric patients, compared to younger patients.
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.
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 reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS – Aspirin-Sensitive Asthma).
PREVACID NapraPAC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
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 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, 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 with15 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 – 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.
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 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, and 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.
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.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the PREVACID NapraPAC Medication Guide that accompanies each prescription dispensed.
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.
NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE)-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
Patients who take aspirin and NAPROSYN are at higher risk of serious GI complications (including GI bleeding). Before prescribing aspirin and NAPROSYN together, consider the entire risk factor profile for NSAID-associated GI complications (e.g., increased age or prior history of peptic ulcer disease or GI bleed) and consider the risk/benefit ratio (see CLINICAL STUDIES, Risk Reduction of NSAID-Associated Gastric Ulcer(s)).
When NAPROSYN is administered with aspirin, its protein binding is reduced, although the clearance of free NAPROSYN is not altered. The clinical significance of this interaction is not known.
Clinical studies, as well as post-marketing observations, have shown that NAPROSYN can reduce the natriuretic effect of furosemide and thiazides. This response has been attributed to inhibition of renal prostaglandin synthesis. During coadministration of diuretics and NAPROSYN, patients should be observed closely for signs of acute renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
NSAIDs have produced an elevation of plasma lithium levels up to 15% and a reduction in renal lithium clearance by about 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by NSAIDs. Thus, when NSAIDs and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.
In an open-label, single-arm, eight-day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 to 15 mg of methotrexate given weekly), administration of 7 days of naproxen 500 mg BID and lansoprazole 30 mg QD had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse events were noted.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that concomitant use of both drugs increases the risk of serious GI bleeding compared to the use of either drug alone. Before prescribing warfarin and NAPROSYN together, consider the entire risk factor profile for NSAID-associated GI complications (e.g., increased age or prior history of peptic ulcer disease or GI bleeding) and consider the risk/benefit ratio.
No significant interactions have been observed in clinical studies with naproxen and warfarin-type anticoagulants. However, caution is advised since interactions have been seen with other NSAIDs of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function.
Naproxen is highly bound to plasma albumin; thus it has a theoretical potential for interaction with other albumin-bound drugs such as warfarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide, or sulphonylurea should be observed and dose adjustment should be considered if side effects occur.
Naproxen and other NSAIDs can reduce the antihypertensive effect of beta-blockers including propranolol.
Coadministration of NAPROSYN and probenecid increases naproxen anion plasma levels and extends its plasma half-life significantly.
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 and there was no evidence of a change in the efficacy of PREVACID.
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).
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 (5-HIAA).
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.
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole 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 (BSA)] 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 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
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.
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.
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.
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.
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.
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.
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.
The safety and effectiveness of PREVACID NapraPAC in pediatric patients have not been established.
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 – 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 the development 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.
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.
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.
Adverse reactions reported in 960 patients treated for rheumatoid arthritis or osteoarthritis in controlled NAPROSYN trials are listed below. In general, adverse reactions in patients treated chronically with NAPROSYN were reported 2 to 10 times more frequently than they were in short-term studies of 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal (GI) tract.
A clinical study found GI reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen (see CLINICAL PHARMACOLOGY).
In controlled clinical naproxen trials with about 80 pediatric patients and in well-monitored, open-label naproxen studies with about 400 pediatric, juvenile arthritis patients treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of GI and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults.
In patients taking NAPROSYN in clinical trials, the most frequently reported adverse experiences (approximately 1% to 10% of patients) were:
Gastrointestinal (GI) Experiences: heartburn1, abdominal pain1, nausea1, constipation1, diarrhea, dyspepsia, stomatitis
Central Nervous System: headache1, dizziness1, drowsiness1, lightheadedness, vertigo
Dermatologic: pruritus (itching)1, skin eruptions1, ecchymoses1, sweating, purpura
Special Senses: tinnitus1, visual disturbances, hearing disturbances
Cardiovascular: edema1, palpitations
General: dyspnea1, thirst
In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients:
Gastrointestinal Experiences: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes
The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through post-marketing reports. Those adverse reactions observed through post-marketing reports are italicized.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)
Cardiovascular: congestive heart failure, vasculitis
Gastrointestinal: GI bleeding and/or perforation, hematemesis, jaundice, pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic GI ulceration, ulcerative stomatitis
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction
Respiratory: eosinophilic pneumonitis
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.
Special Senses: hearing impairment
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis
In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients:
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death
Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, hepatitis, eructation, liver failure
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations
Respiratory: asthma, respiratory depression, pneumonia
Dermatologic: exfoliative dermatitis
Special Senses: blurred vision, conjunctivitis
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
Worldwide, over 10,000 patients have been treated with PREVACID in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. The adverse reaction profiles for PREVACID Delayed-Release Capsules and PREVACID for Delayed-Release Oral Suspension are similar. In general, PREVACID treatment has been well-tolerated in both short-term and long-term trials.
The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a greater rate in PREVACID-treated patients than placebo-treated patients in Table 4.
|Body System/Adverse Event||PREVACID
|Body as a Whole|
Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 mg and 30 mg of PREVACID, but higher in the patients who received 60 mg of PREVACID (2.9%, 1.4%, 4.2%, and 7.4%, respectively).
The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.
In the risk reduction study of PREVACID for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with PREVACID, misoprostol, and placebo was 5%, 22%, and 3%, respectively.
Additional adverse experiences occurring in <1% of patients or subjects who received PREVACID in domestic trials are shown below:
Body as a Whole– abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain; Cardiovascular System - angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation; Digestive System – abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, oral moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis; Endocrine System - diabetes mellitus, goiter, hypothyroidism; Hemic and Lymphatic System - anemia, hemolysis, lymphadenopathy; Metabolic and Nutritional Disorders - gout, dehydration, hyperglycemia /hypoglycemia, peripheral edema, weight gain/loss; Musculoskeletal System - arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, synovitis; Nervous System - abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased /increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo; Respiratory System - asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor; Skin and Appendages - acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria; Special Senses - abnormal vision, blurred vision, conjunctivitis, deafness, dry eyes, ear disorder, eye pain, otitis media, parosmia, photophobia, retinal degeneration, taste loss, taste perversion, tinnitus, visual field defect; Urogenital System - abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary tract infection, urinary urgency, urination impaired, vaginitis.
Additional adverse experiences have been reported since PREVACID has been marketed. The majority of these cases are foreign-sourced and a relationship to PREVACID has not been established. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system.
Body as a Whole - anaphylactic/anaphylactoid reactions; Digestive System - hepatotoxicity, pancreatitis, vomiting; Hemic and Lymphatic System - agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura; Musculoskeletal System– myositis; Skin and Appendages– severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal); Special Senses - speech disorder; Urogenital System –interstitial nephritis, urinary retention.
The following changes in laboratory parameters in patients who received PREVACID were reported as adverse events:
Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased /decreased/abnormal platelets, and increased gastrin levels. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.
In the placebo controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and PREVACID, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received PREVACID reported jaundice at any time during the study.
In case of PREVACID NapraPAC overdose, patients should contact a physician, poison control center, or emergency room. There are no data suggesting increased toxicity of the combination of NAPROSYN and PREVACID compared with the individual components.
Patients with a significant NAPROSYN overdose may have lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation, and/or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Seizures have been reported with NAPROSYN use, but it is not clear whether these cases were drug-related.
Following an NSAID overdose, patients should be managed by supportive care. There are no specific antidotes. Hemodialysis does not decrease the plasma naproxen concentration because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in symptomatic patients seen within 4 hours of ingestion or following a large overdose. Forced diuresis, alkalinization of urine, or hemoperfusion is not likely to be useful due to high protein binding.
To avoid exceeding the recommended doses of naproxen, do not use other naproxen-containing products (including NAPROSYN, ANAPROX/ANAPROX-DS, ALEVE, or naproxen sodium) with PREVACID NapraPAC. The oral LD50 (lethal dose 50 – the amount of drug which causes the death of 50% of a group of animals) of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
PREVACID is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of PREVACID with no adverse reaction.
Oral PREVACID doses up to 5000 mg/kg in rats (approximately 1300 times the 30 mg human dose based on BSA) and in mice (about 675.7 times the 30 mg human dose based on BSA) did not produce deaths or any clinical signs.
Carefully consider the potential benefits and risks of PREVACID NapraPAC and other treatment options before deciding to use PREVACID NapraPAC. Use the lowest effective NAPROSYN dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
The recommended PREVACID NapraPAC doses for the risk reduction of NSAID-associated gastric ulcers – in adult patients with a history of a documented gastric ulcer who require the use of an NSAID – for the treatment of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and/or ankylosing spondylitis are the following:
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. PREVACID Delayed-Release Capsules should be swallowed whole; they should not be chewed or crushed.
After observing the response to initial therapy with PREVACID NapraPAC, the NAPROSYN dose and frequency should be adjusted to suit an individual patient's needs. Controlled studies of PREVACID NapraPAC did not extend beyond 12 weeks.
Renal insufficiency patients and geriatric patients do not require adjustment of the 15 mg PREVACID component of PREVACID NapraPAC. However, dose adjustment for the NAPROSYN component of PREVACID NapraPAC should be considered for geriatric patients and patients with liver disease. NAPROSYN-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30 mL/minute). (See WARNINGS, Renal Effects; PRECAUTIONS, Hepatic Effects; and PRECAUTIONS, Geriatric Use.)
PREVACID NapraPAC 250 is supplied as a weekly blister card packaged as a monthly (28 days) course of therapy. Each weekly blister card contains:
PREVACID NapraPAC 375 is supplied as a weekly blister card packaged as a monthly (28 days) course of therapy. Each weekly blister card contains:
PREVACID NapraPAC 500 is supplied as a weekly blister card packaged as a monthly (28 days) course of therapy. Each weekly blister card contains:
NDC 0300-1548-07 Weekly Blister Card, 250 mg
NDC 0300-1545-07 Weekly Blister Card, 375 mg
NDC 0300-1546-07 Weekly Blister Card, 500 mg
NDC 0300-1548-30 One Month Administration Pack, 250 mg
NDC 0300-1545-30 One Month Administration Pack, 375 mg
NDC 0300-1546-30 One Month Administration Pack, 500 mg
Protect from light and moisture.
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]
Store and dispense in original container.
U.S. Patent No. 6,047,829
Distributed by TAP Pharmaceuticals Inc.
Lake Forest, Illinois 60045, U.S.A
ALEVE® is a registered trademark of Bayer-Roche L.L.C.
ANAPROX®/ANAPROX DS®, EC-NAPROSYN®, NAPROSYN®, and NAPROSYN® SUSPENSION are registered trademarks of and NAPRAPAC™ is a trademark of Syntex Pharmaceuticals International Limited, A Bermuda Corporation.
PREVACID® is a registered trademark of TAP Pharmaceuticals Inc.
11292-R4, Rev. August 2006
©2003-2006 TAP Pharmaceutical Products Inc.
(No. 1545, 1546, 1548)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
Tell your healthcare provider:
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
|Serious side effects include:||Other side effects include:|
Get emergency help right away if you have any of the following symptoms:
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
NSAID medicines that need a prescription
|Generic Name||Requires Prescription|
||Cataflam, Voltaren, Arthrotec (combined with misoprostol)|
|Etodolac||Lodine, Lodine XL|
|Fenoprofen||Nalfon, Nalfon 200|
|Ibuprofen||Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone)|
|Indomethacin||Indocin, Indocin SR, Indo-Lemmon, Indomethagan|
|Naproxen||Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, PREVACID NapraPAC (PREVACID copackaged with NAPROSYN)|
|Tolmetin||Tolectin, Tolectin DS, Tolectin 600|
PREVACID® NapraPAC™ (prĕv ă sĭd napră pak)
(lansoprazole delayed release capsules and naproxen tablets kit)
What is PREVACID® NapraPAC™?
PREVACID NapraPAC contains two medicines:
PREVACID NapraPAC is used to lower the chance of getting another stomach ulcer in adult patients who have had stomach ulcers and who need to take an NSAID to treat the signs and symptoms of rheumatoid arthritis, osteoarthritis, and/or ankylosing spondylitis.
It is not known if PREVACID NapraPAC lowers the risk of ulcers of the intestines or if PREVACID NapraPAC reduces the risk of bleeding from stomach ulcers and ulcers of the intestines.
PREVACID NapraPAC comes in three dose strengths:
The lowest possible dose for the shortest time possible should be prescribed to treat your condition.
PREVACID NapraPAC has not been studied in children.
Can I take other medicines with PREVACID NapraPAC?
Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Both of the medicines in PREVACID NapraPAC can affect other medicines you take and sometimes cause serious side effects. Especially, tell your doctor if you take:
How should I take PREVACID NapraPAC?
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Rev. August 2006
|PREVACID NapraPAC 250 (lansoprazole and naproxen)|
|PREVACID NapraPAC 375 (lansoprazole and naproxen)|
|PREVACID NapraPAC 500 (lansoprazole and naproxen)|
Data are from FDA and U.S. National Library of Medicine.