"The U.S. Food and Drug Administration today approved the Gastric Emptying Breath Test (GEBT), a new non-invasive test to aid in the diagnosis of delayed gastric emptying, known as gastroparesis.
Current tests used to diagnose gastroparesis "...
Pharmacokinetics when all three of the PREVPAC components (PREVACID capsules, amoxicillin capsules, clarithromycin tablets) were coadministered has not been studied. Studies have shown no clinically significant interactions of PREVACID and amoxicillin or PREVACID and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of PREVACID, amoxicillin and clarithromycin after administration of these agents concomitantly. Thesystemic pharmacokinetic information presented below is based on studies in which each product was administered alone.
Absorption: PREVACID capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. 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%. 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. 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.
Absorption: Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It is rapidly absorbed after oral administration. Orally administered doses of 500 mg amoxicillin capsules result in average peak blood levels one to two hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.
Distribution: Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound.
Metabolism/Elimination: The elimination half-life of amoxicillin is 61.3 minutes. Detectable serum levels are observed up to eight hours after an orally administered dose of amoxicillin. Approximately 60% of the orally administered dose of amoxicillin is excreted unchanged in the urine within six to eight hours post-dose; its excretion can be delayed by concurrent administration of probenecid.
Absorption: Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately two to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.
In nonfasting, healthy human subjects (males and females), peak plasma concentrations were attained within two to three hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within three days and were approximately 3 to 4 mcg/mL with a 500 mg dose administered every eight to 12 hours.
Metabolism/Elimination: The elimination half-life of clarithromycin was five to seven hours with 500 mg administered every eight to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended dose of 500 mg administered every eight to 12 hours. With a 500 mg every eight to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is up to 1 mcg/mL, and its elimination half-life is about seven to nine hours. The steady-state concentration of this metabolite is generally attained within three to four days.
After a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with a 500 mg tablet administered every 12 hours.
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500-mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 mcg/mL.
The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.
Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intercellular concentrations, tissue concentrations are higher than serum concentrations.
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.
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 (see DOSAGE AND ADMINISTRATION).
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 reduction of PREVACID dosage in patients with severe hepatic impairment.
Gender: In a study comparing 12 male and six female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results.
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 were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.
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.
Helicobacter pylori Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 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 M95399).
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 two 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: 1 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|
|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)|
|Triple Therapy 10-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily /clarithromycin 500 mg twice daily) (M95-399)|
|*Includes only patients with pretreatment clarithromycin
susceptibility test results
†Breakpoints for antimicrobial susceptibility testing at the time of the studies were: Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1.0 mcg/mL, Resistant (R) MIC ≥ 2 mcg/mL. For current performance standards for antimicrobial susceptibility testing, see section below title, Susceptibility Test for Helicobacter pylori.
Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done if possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or other 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 per 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 107-1 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 (greater than 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After three 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:
Susceptibility Test Interpretive Criteria for H.
|Clarithromycin MIC (mcg/mL)*||Interpretation|
|≤ 0.25||Susceptible (S)|
|≥ 1.0||Resistant (R)|
Interpretive Criteria for H. pylori
|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
† 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 bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test. Standard clarithromycin or amoxicillin powder should provide the following MIC ranges.
|Acceptable Quality Control Ranges||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.|
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 three and greater than four. 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 2.
Table 2: Mean Antisecretory Effects After Single and
Multiple Daily PREVACID Dosing
|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 Hour 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 one to two hours with 30 mg of lansoprazole and two to three 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 one to two 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 five and six was evaluated in a crossover study of PREVACID given daily, twice daily and three times daily.
Table 3: Mean Antisecretory Effects After 5 Days of
Twice Daily and Three Times Daily Dosing
|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.
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 PREVPAC as triple 14-day therapy for the eradication of H. pylori. The triple therapy regimen (PREVACID 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) produced statistically significantly higher eradication rates than PREVACID plus amoxicillin, PREVACID plus clarithromycin, and amoxicillin plus clarithromycin dual therapies.
H. pylori eradication was defined as two negative tests (culture and histology) at four to six weeks following the end of treatment.
Triple therapy was shown to be more effective than all possible dual therapy combinations. The combination of PREVACID plus amoxicillin and clarithromycin as triple therapy was effective in eradicating H. pylori. 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 ten and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori.
Table 4 : 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.
1. CLSI. Methods for Antimicrobial Dilution and Disk Diffusion Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria – 2nd edition. CLSI document M45-A2, 2010.
Last reviewed on RxList: 1/14/2014
This monograph has been modified to include the generic and brand name in many instances.
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