CLINICAL PHARMACOLOGY
PHARMACOKINETICS
NAPROSYN
Absorption
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.
Distribution
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 (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen). However, the concentration of unbound naproxen continues to increase proportionally to dose.
Metabolism
Naproxen is extensively metabolized to 6-O-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Elimination
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 (less than 1%), 6-O-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. In patients with renal failure metabolites may accumulate.
Special Populations
Pediatric Use
The combination of naproxen and lansoprazole has not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY, PREVACID Special Populations - Pediatric Use.)
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 to accumulate in the presence of renal insufficiency. (See CLINICAL PHARMACOLOGY, PREVACID Special Populations - Renal Insufficiency.)
PREVACID
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. Peak plasma concentrations of lansoprazole (Cmax) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single-dose oral administration. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing. Absorption
The absorption of lansoprazole is rapid, with mean Cmax occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both Cmax and AUC are diminished by about 50-70% if the drug is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the drug is given before meals. Distribution
Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is consistent over the concentration range of 0.05 to 5.0 µg/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 (H+,K+)-ATPase within the parietal cell canaliculus, but are not present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. 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 of14 C-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 metabolites of lansoprazole.
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, 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 1.0%-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). AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment, and Cmax and Tmax were not different from subjects with healthy kidneys. (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 the drug was prolonged from 1.5 hours to 3.2-7.2 hours. An increase in mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose re-duction in patients with severe hepatic disease should be considered. Race
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 are approximately twice that seen in pooled U.S. data; however, the inter-individual variability is high. The Cmax values are comparable.
PHARMACODYNAMICS
NAPROSYN
Naproxen is an NSAID with analgesic and antipyretic properties. The naproxen anion inhibits prostaglandin synthesis but beyond this its mode of action is unknown.
PREVACID
MECHANISM OF ACTION
Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but 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.
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 >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.
In a crossover study that included lansoprazole 15 and 30 mg for five days, the following effects on intragastric pH were noted:
Table 1 Mean Antisecretory Effects After Single and Multiple Daily Dosing
|
|
PREVACID
|
|
Parameter
|
Baseline
|
15 mg
|
30 mg
|
|
Value
|
Day 1
|
Day 5
|
Day 1
|
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 >4 reflects a reduction in gastric acid by 99%.
*(p<0.05) versus baseline and lansoprazole 15 mg.
|
| +(p<0.05) versus baseline only. |
|
After the initial dose in this study, increased gastric pH was seen within 1-2 hours with lansoprazole 30 mg and 2-3 hours with lansoprazole 15 mg. After multiple daily dosing, increased gastric pH was seen within the first hour postdosing with lansoprazole 30 mg and within 1-2 hours postdosing with lansoprazole 15 mg.
The inhibition of gastric acid secretion as measured by intragastric pH returns gradually to normal over two to four days after multiple doses. There is no indication of rebound gastric acidity.
ENTEROCHROMAFFIN-LIKE (ECL) CELL EFFECTS
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.
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 lansoprazole given orally in doses of 15 mg to 60 mg. 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 dosages up to 150 mg/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. No visual toxicity was observed among 56 patients who had extensive baseline eye evaluations, were treated with up to 180 mg/day of lansoprazole and were observed for up to 58 months. Other rat-specific findings after lifetime exposure included focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy.
CLINICAL STUDIES
PREVACID®NAPRAPAC™ (375 OR 500)
RISK REDUCTION OF NSAID-ASSOCIATED GASTRIC ULCER
A large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) study was conducted in patients who required chronic use of an NSAID and had a history of an endoscopically documented gastric ulcer. Patients took one or more NSAIDs during the study. Concomitant aspirin use (</= 325 mg) was allowed. The proportion of patients remaining free from gastric ulcer at 4, 8, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo (see Table 2). 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, 4% other. Concomitant aspirin was used in 20% of the patients. The 30 mg dose of PREVACID demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose.
Table 2 NSAID-Associated Gastric Ulcer Risk Reduction Rates
|
% of Patients Remaining Gastric Ulcer-Free 1 |
|
Week
|
PREVACID
15 mg QD
(N=121) |
PREVACID
30 mg QD
(N=116) |
Misoprostol
200 µg 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 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
|
|
A retrospective subset analysis of 119 patients whose NSAID was naproxen only or naproxen and aspirin only, was performed. Again, the proportion of patients remaining free from gastric ulcer at 4, 8, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo (see Table 3). 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, 4% other. Concomitant aspirin was used in 15% of the patients. The 30 mg dose of PREVACID demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose.
Table 3 Gastric Ulcer Risk Reduction Rates in Patients whose NSAID was Naproxen Only or Naproxen and Aspirin Only
|
% of Patients Remaining Gastric Ulcer-Free 1 |
|
Week
|
PREVACID
15 mg QD
(N=37) |
PREVACID
30 mg QD
(N=24) |
Misoprostol
200 µg 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 QD versus placebo; PREVACID 30 mg QD versus placebo; and misoprostol 200 µg QID versus placebo.
|
|
For patients who received PREVACID the highest total daily dose of naproxen was as follows: 5 patients took < 750 mg/daily, 54 patients took 750 - 1000 mg daily. Only 2 patients who received PREVACID took greater than 1000 mg of naproxen.
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 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.
In51 Cr 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.
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