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Prevacid

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Prevacid

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

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 4:

Table 4: Mean Antisecretory Effects After Single and Multiple Daily PREVACID Dosing

Parameter Baseline Value PREVACID
15 mg 30 mg
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 greater than 4 reflects a reduction in gastric acid by 99%.
*(p < 0.05) versus baseline only.
†(p < 0.05) versus baseline and lansoprazole 15 mg.

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.

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given daily, twice daily and three times daily (Table 5).

Table 5: Mean Antisecretory Effects After 5 Days of Twice Daily and Three Times Daily Dosing

Parameter PREVACID
30 mg daily 15 mg twice daily 30 mg twice daily 30 mg three times daily
% Time Gastric pH > 5 43 47 59* 77†
% Time Gastric pH > 6 20 23 28 45†
*(p < 0.05) versus PREVACID 30 mg daily
†(p < 0.05) versus PREVACID 30 mg daily, 15 mg twice daily and 30 mg twice daily.

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/kg/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. 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 [see Nonclinical Toxicology].

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/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rats.

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/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.

Microbiology

Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section [see INDICATIONS AND USAGE].

Helicobacter pylori Pretreatment Resistance

Clarithromycin pretreatment resistance ( ≥ 2.0 mcg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates ( ≤ 0.25 mcg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test, and 2 of 100 patients (2. 0%) by agar dilution, had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori (Table 6).

Table 6: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes*

Clarithromycin Pretreatment Results Clarithromycin Post-treatment Results
H. pylori negative -eradicated H. pylori positive – not eradicated
Post-treatment susceptibility results
S† I† R† No MIC
Triple Therapy 14-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399, M93-131, M95-392)
Susceptible† 112 105 7
Intermediate† 3 3
Resistant† 17 6 7 4
Triple Therapy 10-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399)
Susceptible† 42 40 1 1
Intermediate†
Resistant† 4 1 3
*Includes only patients with pretreatment clarithromycin susceptibility test results
†Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1.0 mcg/m L, Resistant (R) MIC ≥ 2 mcg/mL

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs ( ≤ 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily/amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.1 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 to 1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial-containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood ( ≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters.

After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria (Table 7):

Table 7

Clarithromycin MIC (mcg/mL)* Interpretation
≤ 0.25 Susceptible (S)
0.5-1.0 Intermediate (I)
≥ 2.0 Resistant (R)
Amoxicillin MIC (mcg/mL)*,† Interpretation
≤ 0.25 Susceptible (S)
*These are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods.
†There were not enough organisms with MICs greater than 0.25 mcg/mL to determine a resistance breakpoint.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values (Table 8):

Table 8

Microorganism Antimicrobial Agent MIC (mcg/mL)*
H. pylori ATCC 43504 Clarithromycin 0.015-0.12
H. pylori ATCC 43504 Amoxicillin 0.015-0.12
*These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.

Pharmacokinetics

PREVACID Delayed-Release Capsules and PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets 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 5.0 mcg/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.

Specific Populations

Pediatric Use

One to 17 years of age

The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 to 11 years, lansoprazole was dosed 15 mg daily for subjects weighing ≤ 30 kg and 30 mg daily for subjects we ighing greater than 30 kg. Mean Cmax and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg daily. Mean Cmax and AUC values of lansoprazole were not affected by body weight or age; and nearly dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetics in pediatric patients aged 1 to 17 years were similar to those observed in healthy adult subjects.

Neonate to less than one year of age

Refer to Section 8.4 for the pharmacokinetics of lansoprazole in pediatric patients with GERD aged less than 28 days and 1 to 11 months.

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. No dosage adjustment is necessary in the elderly [see Use In Specific Populations].

Renal Impairment

In patients with severe renal impairment, plasma protein binding decreased by 1.0% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment 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. No dosage adjustment is necessary in patients with renal impairment [see Use In Specific Populations].

Hepatic Impairment

In patients with various degrees of chronic hepatic impairment, 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. Consider dose reduction in patients with severe hepatic impairment [see Use In Specific Populations].

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 Use in Specific Populations].

Drug-Drug Interactions

PREVACID may interfere with the absorption of other drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, digoxin).

PREVACID is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that PREVACID 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.

Atazanavir

PREVACID causes long-lasting inhibition of gastric acid secretion. PREVACID substantially decreases the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, PREVACID, or other proton pump inhibitors, should not be co-administered with atazanavir.

Theophylline

When PREVACID 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 PREVACID is started or stopped to ensure clinically effective blood levels.

Warfarin

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 PREVACID, 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.

Methotrexate and 7-hydromethotrexate

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 twice daily and PREVACID 30 mg daily 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 reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted.

Amoxicillin

PREVACID has also been shown to have no clinically significant interaction with amoxicillin.

Sucralfate

In a single-dose crossover study examining PREVACID 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.

Clopidogrel

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with PREVACID 30 mg (n=40), for 9 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when PREVACID was coadministered compared to administration of clopidogrel alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day [40 times the recommended human dose (30 mg/day) based on body surface area (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.

Clinical Studies

Duodenal Ulcer

In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of PREVACID once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after two and four weeks was significantly higher with all doses of PREVACID than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with PREVACID 15 mg. Based on this study and the second study described below, the recommended dose of PREVACID in duodenal ulcer is 15 mg per day (Table 9).

Table 9: Duodenal Ulcer Healing Rates

Week PREVACID Placebo
(N=72)
15 mg daily
(N=68)
30 mg daily
(N=74)
60 mg daily
(N=70)
2 42.4%* 35.6%* 39.1%* 11.30%
4 89.4%* 91.7%* 89.9%* 46.10%
*(p ≤ 0.001) versus placebo.

PREVACID 15 mg was significantly more effective than placebo in relieving day and nighttime abdominal pain and in decreasing the amount of antacid taken per day.

In a second U.S. multicenter study, also double-blind, placebo-controlled, dose-comparison (15 and 30 mg of PREVACID once daily), and including a comparison with ranitidine, in 280 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after four weeks was significantly higher with both doses of PREVACID than with placebo. There was no evidence of a greater or earlier response with the higher dose of PREVACID. Although the 15 mg dose of PREVACID was superior to ranitidine at 4 weeks, the lack of significant difference at 2 weeks and the absence of a difference between 30 mg of PREVACID and ranitidine leaves the comparative effectiveness of the two agents undetermined (Table 10) [see INDICATIONS AND USAGE].

Table 10: Duodenal Ulcer Healing Rates

Week PREVACID Ranitidine 300 mg h.s.
(N=82)
Placebo
(N=41)
15 mg daily
(N=80)
30 mg daily
(N=77)
2 35.0% 44.2% 30.5% 34.2%
4 92.3%* 80.3%f 70.5%f 47.5%
*(p ≤ 0.05) versus placebo and ranitidine.
†(p ≤ 0.05) versus placebo.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of PREVACID in combination with amoxicillin capsules and clarithromycin tablets as triple 14day therapy or in combination with amoxicillin capsules as dual 14-day therapy for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established:

Triple therapy: PREVACID 30 mg twice daily/amoxicillin 1 g twice daily/clarithromyc n 500 mg twice daily

Dual therapy: PREVACID 30 mg three times daily/amoxicillin 1 g three times daily

All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of PREVACID triple therapy for 10 and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori (Tables 11 and 12) [see INDICATIONS AND USAGE].

Table 11 : H. pylori Eradication Rates – Triple Therapy (PREVACID/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of patients)

Study Duration Triple Therapy Evaluable Analysis* Triple Therapy Intent-to-Treat Analysis†
M93-131 14 days 92‡ [80.0-97.7] (N=48) 86‡ [73.3-93.5] (N=55)
M95-392 14 days 86§ [75.7-93.6] (N=66) 83§ [72.0-90.8] (N=70)
M95-399¶ 14 days 85 [77.0-91.0] (N=113) 82 [73.9-88.1] (N=126)
10 days 84 [76.0-89.8] (N=123) 81 [73.9-87.6] (N=135)
*Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.
†Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
‡(p < 0.05) versus PREVACID/amoxicillin and PREVACID/clarithromycin dual therapy.
§ (p < 0.05) versus clarithromycin/amoxicillin dual therapy.
¶ The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

Table 12 : H. pylori Eradication Rates – 14-Day Dual Therapy (PREVACID/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of patients)

Study Dual Therapy Evaluable Analysis* Dual Therapy Intent-to-Treat Analysis†
M93-131 77‡ [62.5-87.2] (N=51) 70‡ [56.8-81.2] (N=60)
M93-125 66§ [51.9-77.5] (N=58) 61§ [48.5-72.9] (N=67)
*Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
†Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
‡ (p < 0.05) versus PREVACID alone.
§ (p < 0.05) versus PREVACID alone or amoxicillin alone.

Long-Term Maintenance Treatment of Duodenal Ulcers

PREVACID has been shown to prevent the recurrence of duodenal ulcers. Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal ulcers. Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month period (Table 13) [see INDICATIONS AND USAGE].

Table 13: Endoscopic Remission Rates

Trial Drug No. of Pts. Percent in Endoscopic Remission
0-3 mo. 0-6 mo. 0-12 mo.
#1 PREVACID 15 mg daily 86 90%* 87%* 84%*
Placebo 83 49% 41% 39%
#2 PREVACID 30 mg daily 18 94%* 94%* 85%*
PREVACID 15 mg daily 15 87%* 79%* 70%*
Placebo 15 33% 0% 0%
%=Life Table Estimate
* (p ≤ 0.001) versus placebo.

In trial #2, no significant difference was noted between PREVACID 15 mg and 30 mg in maintaining remission.

Gastric Ulcer

In a U.S. multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher with PREVACID 15 mg and 30 mg once a day than with placebo (Table 14) [see INDICATIONS AND USAGE].

Table 14: Gastric Ulcer Healing Rates

Week PREVACID Placebo
(N=64)
15 mg daily
(N=65)
30 mg daily
(N=63)
60 mg daily
(N=61)
4 64.6%* 58.1%* 53.3%* 37.50%
8 92.2%* 96.8%* 93.2%* 76.70%
*(p ≤ 0.05) versus placebo.

Patients treated with any PREVACID dose reported significantly less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets used per day than the placebo group.

Independent substantiation of the effectiveness of PREVACID 30 mg was provided by a meta-analysis of published and unpublished data.

Healing of NSAID-Associated Gastric Ulcer

In two U.S. and Canadian multicenter, double-blind, active-controlled studies in patients with endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage of patients healed after 8 weeks was statistically significantly higher with 30 mg of PREVACID than with the active control. A total of 711 patients were enrolled in the study, and 701 patients were treated. Patients ranged in age from 18 to 88 years (median age 59 years), with 67% female patients and 33% male patients. Race was distributed as follows: 87% Caucasian, 8% Black, 5% Other. There was no statistically significant difference between PREVACID 30 mg daily and the active control on symptom relief (i.e., abdominal pain) (Table 15) [see INDICATIONS AND USAGE].

Table 15: NSAID-Associated Gastric Ulcer Healing Rates*

Study #1
  PREVACID 30 mg daily Active Control†
Week 4 60% (53/88) ‡ 28% (23/83)
Week 8 79% (62/79) ‡ 55% (41/74)
Study #2
  PREVACID 30 mg daily Active Control†
Week 4 53% (40/75) 38% (31/82)
Week 8 77% (47/61) ‡ 50% (33/66)
* Actual observed ulcer(s) healed at time points ± 2 days
†Dose for healing of gastric ulcer
‡ (p ≤ 0.05) versus the active control

Risk Reduction of NSAID-Associated Gastric Ulcer

In one large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) study in patients who required chronic use of an NSAID and who had a history of an endoscopically documented gastric ulcer, 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. 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. 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 16) [see INDICATIONS AND USAGE].

Table 16: Proportion of Patients Remaining Free of Gastric Ulcers*

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

Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD: In a U.S. multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated with GERD was observed with the administration of lansoprazole 15 mg once daily up to 8 weeks than with placebo. No significant additional benefit from lansoprazole 30 mg once daily was observed.

The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and night heartburn. Data for frequency and severity for the 8-week treatment period are presented in Table 17 and in Figures 1 and 2:

Table 17: Frequency of Heartburn

Variable Placebo
(n=43)
PREVACID 15 mg
(n=80)
PREVACID 30 mg
(n=86)
  Median
% of Days without Heartburn
Week 1 0% 71%* 46%*
Week 4 11% 81%* 76%*
Week 8 13% 84%* 82%*
% of Nights without Heartburn
Week 1 17% 86%* 57%*
Week 4 25% 89%* 73%*
Week 8 36% 92%* 80%*
*(p < 0.01) versus placebo.

Figure 1

Mean Severity of Day Heartburn  - Illustration

Figure 2

Mean Severity of Night Heartburn  - Illustration

In two U.S., multicenter double-blind, ranitidine-controlled studies of 925 total patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine 150 mg (twice daily) in decreasing the frequency and severity of day and night heartburn associated with GERD for the 8-week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was observed [see INDICATIONS AND USAGE].

Erosive Esophagitis

In a U.S. multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of 2 or more and grades 3 and 4 signifying erosive disease, the percentages of patients with healing are presented in Table 18:

Table 18: Erosive Esophagitis Healing Rates

Week PREVACID Placebo
(N=63)
15 mg daily
(N=69)
30 mg daily
(N=65)
60 mg daily
(N=72)
4 67.6%* 81.3% *† 80.6%*† 32.80%
6 87.7%* 95.4%* 94.3%* 52.50%
8 90.9%* 95.4%* 94.4%* 52.50%
*(p ≤ 0.001) versus placebo.
†(p ≤ 0.05) versus PREVACID 15 mg.

In this study, all PREVACID groups reported significantly greater relief of heartburn and less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the placebo group. Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg daily as the recommended dose.

PREVACID was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. PREVACID at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown below (Table 19).

Table 19: Erosive Esophagitis Healing Rates

Week PREVACID 30 mg daily
(N=115)
Ranitidine 150 mg twice daily
(N=127)
2 66.7%* 38.70%
4 82.5%* 52.00%
6 93.0%* 67.80%
8 92.1%* 69.90%
*(p ≤ 0.001) versus ranitidine.

In addition, patients treated with PREVACID reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg twice daily.

Although this study demonstrates effectiveness of PREVACID in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg four times daily, twice the dose used in this study.

In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, PREVACID produced healing rates similar to those shown above.

In a U.S. multicenter, double-blind, active-controlled study, 30 mg of PREVACID was compared with ranitidine 150 mg twice daily in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H2-receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day. PREVACID 30 mg was more effective than ranitidine 150 mg twice daily in healing reflux esophagitis, and the percentage of patients with healing were as follows. This study does not constitute a comparison of the effectiveness of histamine H2-receptor antagonists with PREVACID, as all patients had demonstrated unresponsiveness to the histamine H2-receptor antagonist mode of treatment. It does indicate, however, that PREVACID may be useful in patients failing on a histamine H2-receptor antagonist (Table 20) [see INDICATIONS AND USAGE].

Table 20: Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H2-Receptor Antagonist Therapy

Week PREVACID 30 mg daily (N=100) Ranitidine 150 mg twice daily (N=51)
4 74.7%* 42.60%
8 83.7%* 32.00%
*(p ≤ 0.001) versus ranitidine.

Long-Term Maintenance Treatment of Erosive Esophagitis

Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed esophagitis. Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month period (Table 21).

Table 21: Endoscopic Remission Rates

Trial Drug No. of Pts. Percent in Endoscopic Remission
0-3 mo. 0-6 mo. 0-12 mo.
#1 PREVACID 15 mg daily 59 83%* 81%* 79%*
PREVACID 30 mg daily 56 93%* 93%* 90%*
Placebo 55 31% 27% 24%
#2 PREVACID 15 mg daily 50 74%* 72%* 67%*
PREVACID 30 mg daily 49 75%* 72%* 55%*
Placebo 47 16% 13% 13%
%=Life Table Estimate
*(p ≤ 0.001) versus placebo.

Regardless of initial grade of erosive esophagitis, PREVACID 15 mg and 30 mg were similar in maintaining remission.

In a U.S., randomized, double-blind, study, PREVACID 15 mg daily (n = 100) was compared with ranitidine 150 mg twice daily (n = 106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12-month period. Treatment with PREVACID resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time than those treated with ranitidine (p < 0.001). In addition, PREVACID was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients treated with PREVACID remained asymptomatic for a significantly longer period of time than patients treated with ranitidine [see INDICATIONS AND USAGE].

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome (ZES) with or without multiple endocrine adenomas, PREVACID significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia and pain. Doses ranging from 15 mg every other day to 180 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients [see DOSAGE AND ADMINISTRATION]. PREVACID was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients). In most ZES patients, serum gastrin levels were not modified by PREVACID. However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy [see INDICATIONS AND USAGE].

REFERENCES

1. National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.

Last reviewed on RxList: 5/18/2012
This monograph has been modified to include the generic and brand name in many instances.

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