Prevacid NapraPAC

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 Day1 Day 5
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*
NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%.
*(p<0.05) versus baselineand lansoprazole15 mg.
+(p<0.05) versus baseline only.

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 Ulcers1

Week PREVACID
15 mg daily
(N=121)
PREVACID
30 mg daily
(N=116)
Misoprostol
200 mcg QID
(N=106)
Placebo
(N=112)
4 90% 92% 96% 66%
8 86% 88% 95% 60%
12 80% 82% 93% 51%
1 % = Life Table Estimate

(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

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 Ulcers1

Week PREVACID
15 mg daily
(N=37)
PREVACID
30 mg daily
(N=24)
Misoprostol
200 mcg QID
(N=28)
Placebo
(N=30)
4 91% 83% 88% 52%
8 89% 83% 88% 52%
12 89% 83% 83% 33%
1 % = Life Table Estimate

(p < 0.001) PREVACID 15 mg daily versus placebo; PREVACID 30 mg daily versus placebo; and misoprostol 200 mcg QID versus placebo.

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.

Last reviewed on RxList: 12/19/2008
This monograph has been modified to include the generic and brand name in many instances.

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