S 015 LBL

PREVPAC Package Insert Page 1 of 24
(No. 3702)
TAPDN417-V2, Month Year
PREVPAC®
(lansoprazole 30-mg capsules, amoxicillin 500-mg capsules, USP, and clarithromycin 500-mg
tablets, USP)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of

PREVPAC and other antibacterial drugs, PREVPAC should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by bacteria.
THESE PRODUCTS ARE INTENDED ONLY FOR USE AS DESCRIBED. The individual
products contained in this package should not be used alone or in combination for other purposes.
The information described in this labeling concerns only the use of these products as indicated in
this daily administration pack. For information on use of the individual components when
dispensed as individual medications outside this combined use for treating Helicobacter pylori
(H. pylori), please see the package inserts for each individual product.
DESCRIPTION
PREVPAC consists of a daily administration pack containing two PREVACID 30-mg capsules,
four amoxicillin 500-mg capsules, USP, and two clarithromycin 500-mg tablets, USP, for oral
administration.
PREVACID® (lansoprazole) Delayed-Release Capsules

The active ingredient in PREVACID capsules is lansoprazole, a substituted benzimidazole, 2-
[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound
that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3O2S with a molecular
weight of 369.37. PREVACID has the following structure:
Lansoprazole is a white to brownish-white odorless crystalline powder which melts with

decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide;
soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate,
dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in
hexane and water.
Each delayed-release capsule contains enteric-coated granules consisting of 30 mg of
lansoprazole (active ingredient) and the following inactive ingredients: hydroxypropyl cellulose,
low substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium carbonate,
methacrylic acid copolymer, starch, talc, sugar sphere, sucrose, polyethylene glycol,
polysorbate 80, and titanium dioxide. Components of the gelatin capsule include gelatin, titanium
dioxide, D&C Red No. 28, FD&C Blue No. 1, and FD&C Red No. 40 (inactive ingredients).
Amoxicillin Capsules, USP

Amoxicillin, is a semisynthetic antibiotic, an analogue of ampicillin, with a broad spectrum of
bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically
it is (2S, 5R, 6R)-6-[(R)-(-)-2-amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-
1-aza-bicyclo[3.2.0] heptane-2-carboxylic acid trihydrate. Its empirical formula is C16H19N3O5S •
3H2O with a molecular weight of 419.45. Amoxicillin has the following structure:
Amoxicillin capsules are intended for oral administration. The yellow opaque capsules contain
amoxicillin trihydrate equivalent to 500 mg of amoxicillin.
Inactive ingredients: Capsule shells - yellow ferric oxide, titanium dioxide, gelatin, black ferric
oxide; Capsule contents – cellulose microcrystalline and magnesium stearate.
BIAXIN® Filmtab® (clarithromycin tablets, USP)

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-
methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96.
Clarithromycin has the following structure:
Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone,

slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. Each
yellow oval film-coated immediate-release tablet contains 500 mg of clarithromycin and the
following inactive ingredients: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide,
croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose,
povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin.
CLINICAL PHARMACOLOGY
Pharmacokinetics
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. The systemic pharmacokinetic information presented below is based
on studies in which each product was administered alone.
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. 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 50-70% 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 consistent 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.
Special Populations
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 1.0%-
1.5% after administration of 60 mg of lansoprazole. Patients with renal insufficiency had a
shortened elimination half-life and decreased total AUC (free and bound). The AUC for free
lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax
and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax
from subjects with normal renal function.
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 3.2-7.2 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 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.
Amoxicillin:
Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It
is rapidly absorbed after oral administration. It diffuses readily into most body tissues and fluids,
with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of
amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its
excretion can be delayed by concurrent administration of probenecid. In blood serum,
amoxicillin is approximately 20% protein-bound.
Orally administered doses of 500 mg amoxicillin capsules result in average peak blood
levels 1 to 2 hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.
Detectable serum levels are observed up to 8 hours after an orally administered dose of
amoxicillin. Approximately 60% of an orally administered dose of amoxicillin is excreted in the
urine within 6 to 8 hours.
Clarithromycin:
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 2 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
increase the extent of metabolite formation, indicated by an 11% decrease in area under the
plasma concentration-time curve (AUC). Therefore, BIAXIN tablets may be given without
regard to food.
In nonfasting healthy human subjects (males and females), peak plasma concentrations
were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin
concentrations were attained within 3 days and were approximately 3 to 4 µg/mL with a 500-mg
dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was 5 to
7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin
pharmacokinetics is slight at the recommended dose of 500 mg administered every 8 to 12 hours.
With a 500-mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH
clarithromycin is up to 1 µg/mL, and its elimination half-life is about 7 to 9 hours. The steady-
state concentration of this metabolite is generally attained within 3 to 4 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.
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.
The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal
function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Pharmacodynamics
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.
Helicobacter
Helicobacter pylori
Pretreatment Resistance
Clarithromycin pretreatment resistance (≥2.0 µg/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 µg/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 µg/mL. One patient on
the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum
inhibitory concentration (MIC) of greater than 256 µg/mL by E-test and the patient was
eradicated of H. pylori.
Table 1
Clarithromycin Susceptibility Test Results
and Clinical/Bacteriological Outcomesa
Clarithromycin Pretreatment Clarithromycin Post-treatment Results
Results
H. pylori negative H. pylori positive
–eradicated –not eradicated
Post-treatment susceptibility results
Sb Ib Rb No MIC
Triple Therapy 14-Day (lansoprazole 30 mg b.i.d./amoxicillin 1 gm b.i.d./clarithromycin
500 mg b.i.d.) (M95-399, M93-131, M95-392)
Susceptibleb 112 105 7
Intermediateb 3 3
Resistantb 17 6 7 4
Triple Therapy 10-Day (lansoprazole 30 mg b.i.d./amoxicillin 1 gm b.i.d./clarithromycin
500 mg b.i.d.) (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3
a
Includes only patients with pretreatment clarithromycin susceptibility test results
b
Susceptible (S) MIC ≤0.25 µg/mL, Intermediate (I) MIC 0.5 - 1.0 µg/mL, Resistant (R) MIC
≥2 µg/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 µg/mL) were eradicated of H. pylori. Of those with
pretreatment amoxicillin MICs of greater than 0.25 µg/mL, three of six had the H. pylori
eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg t.i.d./amoxicillin 1
gm t.i.d. 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 (≥ 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 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:
Clarithromycin MIC (µg/mL)a Interpretation

≤0.25 Susceptible (S)
0.5-1.0 Intermediate (I)
≥2.0 Resistant (R)
Amoxicillin MIC (µg/mL)b Interpretation
≤0.25 Susceptible (S)
a
These are tentative breakpoints for the agar dilution methodology and they should not be used
to interpret results obtained using alternative methods.
b
There were not enough organisms with MICs greater than 0.25 µg/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:
Microorganisms Antimicrobial Agent MIC (µg/mL)a
H. pylori ATCC 43504 Clarithromycin 0.015-0.12 µg/mL
H. pylori ATCC 43504 Amoxicillin 0.015-0.12 µg/mL
a
These are quality control ranges for the agar dilution methodology and they should not be
used to control test results obtained using alternative methods.
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 2.
Table 2: Mean Antisecretory Effects after Single and Multiple Daily PREVACID Dosing
PREVACID
Baseline 15 mg 30 mg
Parameter 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 greater than 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 30 mg of
lansoprazole and 2-3 hours with 15 mg of lansoprazole. After multiple daily dosing, increased
gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within 1-
2 hours post-dosing with 15 mg of lansoprazole.
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, b.i.d. and t.i.d.
Table 3: Mean Antisecretory Effects After 5 Days of b.i.d. and t.i.d. Dosing
PREVACID
Parameter 30 mg daily 15 mg b.i.d. 30 mg b.i.d. 30 mg t.i.d.
% 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 b.i.d. and 30 mg b.i.d.
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.
CLINICAL STUDIES
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 b.i.d. plus amoxicillin 1 gm b.i.d. plus clarithromycin
500 mg b.i.d.) 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
4 - 6 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 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.
Table 4
H. pylori Eradication Rates – Triple Therapy
(PREVACID/amoxicillin/clarithromycin)
Percent of Patients Cured
[95% Confidence Interval]
(Number of patients)
Triple Therapy Triple Therapy

Study Duration Evaluable Intent-to-Treat
Analysis* Analysis#
M93-131 14 days 92† 86†
[80.0-97.7] [73.3-93.5]
(N=48) (N=55)
M95-392 14 days 86‡ 83‡
[75.7-93.6] [72.0-90.8]
(N=66) (N=70)
M95-399+ 14 days 85 82
[77.0-91.0] [73.9-88.1]
(N=113) (N=126)
10 days 84 81
[76.0-89.8] [73.9-87.6]
(N=123) (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.
INDICATIONS AND USAGE

The components in PREVPAC (PREVACID, amoxicillin, and clarithromycin) are indicated for
the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year
history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to
reduce the risk of duodenal ulcer recurrence (see CLINICAL STUDIES and DOSAGE AND
ADMINISTRATION).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
PREVPAC and other antibacterial drugs, PREVPAC should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by susceptible bacteria. When
culture and susceptibility information are available, they should be considered in selecting or
modifying antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
PREVPAC is contraindicated in patients with known hypersensitivity to any component of the
formulation of PREVACID, any macrolide antibiotic, or any penicillin.
Concomitant administration of PREVPAC and any of the following drugs is
contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine.
There have been post-marketing reports of drug interactions when clarithromycin and/or
erythromycin are co-administered with cisapride, pimozide, astemizole, or terfenadine resulting in
cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and
torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin
and clarithromycin. Fatalities have been reported.
For information about contraindications of other drugs that may be used in combination
with amoxicillin or clarithromycin, refer to the CONTRAINDICATIONS section of their
package inserts.
Please refer to full prescribing information for amoxicillin and clarithromycin
before prescribing.
WARNINGS
Amoxicillin:
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC)
REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY.
ALTHOUGH ANAPHYLAXIS IS MORE FREQUENT FOLLOWING PARENTERAL
THERAPY, IT HAS OCCURRED IN PATIENTS ON ORAL PENICILLINS. THESE
REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF
PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO
MULTIPLE ALLERGENS.
THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF
PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS
WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH
AMOXICILLIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS
HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER
ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN SHOULD BE
DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED.
SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY
TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND
AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE
ADMINISTERED AS INDICATED.
Clarithromycin:
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN
CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS
APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN,
THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE
FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF
PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA
LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED
AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS -
Pregnancy).
There have been post-marketing reports of colchicine toxicity with concomitant use of
clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with
renal insufficiency. Deaths have been reported in some such patients (see PRECAUTIONS).
Amoxicillin and/or Clarithromycin:

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from
mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the
colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibiotic use. Careful medical
history is necessary since CDAD has been reported to occur over two months after the
administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile
may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted
as clinically indicated.
For information about warnings of other drugs that may be used in combination with amoxicillin
or clarithromycin, refer to the WARNINGS section of their package inserts.
PRECAUTIONS
Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be
administered without dosage adjustment to patients with hepatic impairment and normal renal
function. However, in the presence of severe renal impairment with or without coexisting hepatic
impairment, decreased dosage or prolonged dosing intervals may be appropriate.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in
mind during therapy. If superinfections occur, PREVPAC should be discontinued and
appropriate therapy instituted.
Symptomatic response to therapy with PREVACID does not preclude the presence of
gastric malignancy.
Prescribing PREVPAC in the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the
risk of the development of drug-resistant bacteria.
For information about precautions of other drugs that may be used in combination with
amoxicillin or clarithromycin, refer to the PRECAUTIONS section of their package inserts.
Information for Patients: Each dose of PREVPAC contains four pills: one pink and black
capsule (PREVACID), two opaque, yellow capsules (amoxicillin) and one yellow tablet
(clarithromycin). Each dose should be taken twice per day before eating. Patients should be
instructed to swallow each pill whole.
Biaxin may interact with some drugs; therefore patients should be advised to report to
their doctor the use of any other medications.
Patients should be counseled that antibacterial drugs including PREVPAC should only be
used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When
PREVPAC is prescribed to treat a bacterial infection, patients should be told that although it is
common to feel better early in the course of therapy, the medication should be taken exactly as
directed. Skipping doses or not completing the full course of therapy may (1) decrease the
effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop
resistance and will not be treatable by PREVPAC or other antibacterial drugs in the future.
Drug Interactions
PREVACID:
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.
It is theoretically possible that PREVACID may also 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.
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.
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.
PREVACID has also been shown to have no clinically significant interaction with
amoxicillin.
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.
Amoxicillin:
Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin
and probenecid may result in increased and prolonged blood levels of amoxicillin.
Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with
bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical
significance of this interaction is not well documented.
Clarithromycin:
Clarithromycin use in patients who are receiving theophylline may be associated with an increase
of serum theophylline concentrations. Monitoring of serum theophylline concentrations should
be considered for patients receiving high doses of theophylline or with baseline concentrations in
the upper therapeutic range. In two studies in which theophylline was administered with
clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or
12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of Cmax, Cmin,
and the area under the serum concentration time curve (AUC) of theophylline increased about
20%.
Concomitant administration of single doses of clarithromycin and carbamazepine has
been shown to result in increased plasma concentrations of carbamazepine. Blood level
monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations of the
active acid metabolite of terfenadine were threefold higher, on average, than the values observed
when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the
14-hydroxy-clarithromycin were not significantly affected by coadministration of terfenadine
once clarithromycin reached steady-state conditions. Concomitant administration of
clarithromycin with terfenadine is contraindicated (see CONTRAINDICATIONS).
Spontaneous reports in the post-marketing period suggest that concomitant administration
of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.
Prothrombin times should be carefully monitored while patients are receiving clarithromycin and
oral anticoagulants simultaneously.
Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin
concomitantly have also been reported in post-marketing surveillance. Some patients have shown
clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum
digoxin levels should be carefully monitored while patients are receiving digoxin and
clarithromycin simultaneously.
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein
(Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When
clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by
clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for
clinical symptoms of colchicine toxicity (see WARNINGS).
Erythromycin and clarithromycin are substrates and inhibitors of the 3A isoform
subfamily of the cytochrome P450 enzyme system (CYP3A). Coadministration of erythromycin
or clarithromycin and a drug primarily metabolized by CYP3A may be associated with elevations
in drug concentrations that could increase or prolong both the therapeutic and adverse effects of
the concomitant drug. Dosage adjustments may be considered, and when possible, serum
concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients

concurrently receiving clarithromycin or erythromycin.
The following are examples of some clinically significant CYP3A based drug
interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible.
Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine
were observed in clinical trials with clarithromycin.
The following CYP3A based drug interactions have been observed with erythromycin products
and/or with clarithromycin in post-marketing experience:
Antiarrhythmics: There have been post-marketing reports of torsades de pointes
occurring with concurrent use of clarithromycin and quinidine or disopyramide.
Electrocardiograms should be monitored for QTc prolongation during coadministration
of clarithromycin with these drugs. Serum levels of these medications should also be
monitored.
Ergotamine/dihydroergotamine: Post-marketing reports indicate that
coadministration of clarithromycin with ergotamine or dihydroergotamine has been
associated with acute ergot toxicity characterized by vasospasm and ischemia of the
extremities and other tissues including the central nervous system. Concomitant
administration of clarithromycin with ergotamine or dihydroergotamine is
contraindicated (see CONTRAINDICATIONS).
Triazolobenziodidiazepines (such as triazolam and alprazolam) and related
benzodiazepines (such as midazolam): Erythromycin has been reported to decrease the
clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect
of these benzodiazepines. There have been postmarketing reports of drug interactions
and CNS effects (e.g., somnolence and confusion) with the concomitant use of
clarithromycin and triazolam.
HMG-CoA Reductase Inhibitors: As with other macrolides, clarithromycin has
been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g.,
lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in
patients taking these drugs concomitantly.
Sildenafil (Viagra): Erythromycin has been reported to increase the systemic
exposure (AUC) of sildenafil. A similar interaction may occur with clarithromycin;
reduction of sildenafil dosage should be considered (see Viagra package insert).
There have been spontaneous or published reports of CYP3A based interactions of
erythromycin and/or clarithromycin with cyclosporine, carbamazepine, tacrolimus,
alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, and
bromocriptine.
Concomitant administration of clarithromycin with cisapride, pimozide,
astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS).
In addition, there have been reports of interactions of erythromycin or clarithromycin
with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin,
and valproate.
For information on interactions between clarithromycin in combination with other drugs
which may be administered to HIV-infected patients, see the BIAXIN package insert,
Drug Interactions, under the PRECAUTIONS section.
Drug/Laboratory Test Interactions

High urine concentrations of ampicillin may result in false-positive reactions when testing for the
presence of glucose in urine using Clinitest®, Benedict’s Solution or Fehling’s Solution. Since
this effect may also occur with amoxicillin, it is recommended that glucose tests based on
enzymatic glucose oxidase reactions (such as Clinistix®) be used. Following administration of

ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated
estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also
occur with amoxicillin.
Carcinogenesis, Mutagenesis, Impairment of Fertility

PREVACID:
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral
lansoprazole doses of 5 to 150 mg/kg/day - about 1 to 40 times the exposure on a body surface
(mg/m2) basis, of a 50-kg person of average height [1.46 m2 body surface area (BSA)] given the
recommended human dose of 30 mg/day (22.2 mg/m2). Lansoprazole produced dose-related
gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and
female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in
both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial
cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day
(4 to 40 times the recommended human dose based on BSA) exceeded the low background
incidence (range = 1.4 to 10%) for this strain of rat. In addition, in a one-year toxicity study,
testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg/kg/day of
lansoprazole (13 times the recommended human dose based on BSA).
In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole
doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on BSA.
Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also
produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The
tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the
recommended human dose based on BSA) and female mice treated with 150 to 600 mg/kg/day
(20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background
incidences in historical controls for this strain of mice. Lansoprazole treatment produced
adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the
recommended human dose based on BSA).
Lansoprazole was not genotoxic in the Ames test, the ex vivo rat hepatocyte unscheduled
DNA synthesis (UDS) test, the in vivo mouse micronucleus test, or the rat bone marrow cell
chromosomal aberration test. It was positive in in vitro human lymphocyte chromosomal
aberration assays.
Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose
based on BSA) was found to have no effect on fertility and reproductive performance of male and
female rats.
Amoxicillin:
Long-term studies in animals have not been performed to evaluate carcinogenic
potential. Studies to detect mutagenic potential of amoxicillin alone have not been
conducted.
Clarithromycin:
The following in vitro mutagenicity tests have been conducted with clarithromycin:
Salmonella/Mammalian Microsomes Test
Bacterial Induced Mutation Frequency Test
In Vitro Chromosome Aberration Test
Rat Hepatocyte DNA Synthesis Assay
Mouse Lymphoma Assay
Mouse Dominant Lethal Study
Mouse Micronucleus Test
All tests had negative results except the In Vitro Chromosome Aberration Test which was
weakly positive in one test and negative in another.
In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on
clarithromycin metabolites with negative results.
Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day
(1.3 times the recommended maximum human dose based on mg/m2) to male and female rats
caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of
offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.
In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum
levels. When given orally at 150 mg/kg/day (2.4 times the recommended maximum human dose
based on mg/m2), clarithromycin was shown to produce embryonic loss in monkeys. This effect
has been attributed to marked maternal toxicity of the drug at this high dose.
In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m2, which is
17 times less than the maximum proposed human oral daily dose of 618 mg/m2.
Long-term studies in animals have not been performed to evaluate the carcinogenic
potential of clarithromycin.
Pregnancy
Teratogenic Effects. Pregnancy Category C
Category C is based on the pregnancy category for clarithromycin.
Four teratogenicity studies in rats (three with oral doses and one with intravenous doses
up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at
oral doses up to 125 mg/kg/day (approximately 2 times the recommended maximum human dose
based on mg/m2) or intravenous doses of 30 mg/kg/day administered during gestation days 6 to
18 failed to demonstrate any teratogenicity from clarithromycin. Two additional oral studies in a
different rat strain at similar doses and similar conditions demonstrated a low incidence of
cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days 6 to 15.
Plasma levels after 150 mg/kg/day were 2 times the human serum levels. Four studies in mice
revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day (2 and
4 times the recommended maximum human dose based on mg/m2, respectively) during
gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day
exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of
70 mg/kg/day (an approximate equidose of the recommended maximum human dose based
on mg/m2) produced fetal growth retardation at plasma levels that were 2 times the human serum
levels.
There were no adequate and well-controlled studies of PREVPAC in pregnant women.

PREVPAC should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus (see WARNINGS).
Labor and Delivery

Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed
that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of
contractions, but moderately increased the height and duration of contractions. However, it is not
known whether use of these drugs in humans during labor or delivery has immediate or delayed
adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that
forceps delivery or other obstetrical intervention or resuscitation of the newborn will be
necessary.
Nursing Mothers
Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether
lansoprazole is excreted in human milk. Penicillins have been shown to be excreted in human
milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be
exercised when amoxicillin is administered to a nursing woman. It is not known whether
clarithromycin is excreted in human milk. It is known that clarithromycin is excreted in the milk
of lactating animals and that other drugs of this class are excreted in human milk.
Due to the potential for serious adverse reactions in nursing infants from PREVPAC, and
the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision
should be made whether to discontinue nursing or to discontinue PREVPAC, taking into account
the importance of the therapy to the mother.
Pediatric Use
Safety and effectiveness of PREVPAC in pediatric patients infected with H. pylori have not been
established (see CONTRAINDICATIONS and WARNINGS).
Use in Geriatric Patients

Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be
taken when administering PREVPAC to this patient population.
ADVERSE REACTIONS
The most common adverse reactions (≥3%) reported in clinical trials when all three components
of this therapy were given concomitantly for 14 days are listed in Table 5.
Table 5: Adverse Reactions Most Frequently

Reported in Clinical Trials (≥ 3%)
Triple Therapy
n=138
Adverse Reaction (%)
Diarrhea 7.0
Headache 6.0
Taste Perversion 5.0
The additional adverse reactions which were reported as possibly or probably related to treatment
(<3%) in clinical trials when all three components of this therapy were given concomitantly are
listed below and divided by body system:
Body as a Whole - abdominal pain; Digestive System - dark stools, dry mouth/thirst, glossitis,
rectal itching, nausea, oral moniliasis, stomatitis, tongue discoloration, tongue disorder, vomiting;
Musculoskeletal System - myalgia; Nervous System - confusion, dizziness; Respiratory System -
respiratory disorders; Skin and Appendages - skin reactions; Urogenital System - vaginitis,
vaginal moniliasis. There were no statistically significant differences in the frequency of reported
adverse events between the 10- and 14-day triple therapy regimens.
PREVACID:
The following adverse reactions from the labeling for PREVACID are provided for information.
Worldwide, over 10,000 patients have been treated with PREVACID in Phase 2 or Phase 3
clinical trials involving various dosages and durations of treatment. In general, PREVACID
treatment has been well-tolerated in both short-term and long-term trials.
Incidence in Clinical Trials

The following adverse events were reported by the treating physician to have a possible or
probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a
greater rate in PREVACID-treated patients than placebo-treated patients:
Table 6
Incidence of Possibly or Probably
Treatment-Related Adverse Events in Short-Term,
Placebo-Controlled PREVACID Studies
PREVACID Placebo
(N= 2768) (N= 1023)
Body System/Adverse Event % %
Body as a Whole
Abdominal Pain 2.1 1.2
Digestive System
Constipation 1.0 0.4
Diarrhea 3.8 2.3
Nausea 1.3 1.2
Headache was also seen at greater than 1% incidence but was more common on placebo. The
incidence of diarrhea was similar between patients who received placebo and patients who
received 15 mg and 30 mg of PREVACID, but higher in the patients who received 60 mg of
PREVACID (2.9%, 1.4%, 4.2%, and 7.4%, respectively).
The most commonly reported possibly or probably treatment-related adverse event during
maintenance therapy was diarrhea.
Additional adverse experiences occurring in less than 1% of patients or subjects who
received PREVACID in domestic trials are shown below.
Body as a Whole – abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis,
carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis,
infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain;
Cardiovascular System - angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral
infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock
(circulatory failure), syncope, tachycardia, vasodilation; Digestive System – abnormal stools,
anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis,
eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence,
gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly,
gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis,
increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea
and vomiting and diarrhea, oral moniliasis, rectal disorder, rectal hemorrhage, stomatitis,
tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis; Endocrine System -
diabetes mellitus, goiter, hypothyroidism; Hemic and Lymphatic System - anemia, hemolysis,
lymphadenopathy; Metabolic and Nutritional Disorders - gout, dehydration,
hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss; Musculoskeletal System -
arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia,
myasthenia, synovitis; Nervous System – abnormal dreams, agitation, amnesia, anxiety, apathy,
confusion, convulsion, depersonalization, depression, diplopia, dizziness, emotional lability,
hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia,
libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence,
thinking abnormality, tremor, vertigo; Respiratory System - asthma, bronchitis, cough increased,
dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, pharyngitis, pleural disorder,
pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis,
stridor; Skin and Appendages - acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair
disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder,
sweating, urticaria; Special Senses – abnormal vision, blurred vision, conjunctivitis, deafness,
dry eyes, ear disorder, eye pain, otitis media, parosmia, photophobia, retinal degeneration, taste
loss, taste perversion, tinnitus, visual field defect; Urogenital System - abnormal menses, breast
enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence,
kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder,
polyuria, testis disorder, urethral pain, urinary frequency, urinary tract infection, urinary urgency,
urination impaired, vaginitis.
Postmarketing
Additional adverse experiences have been reported since PREVACID has been marketed. The
majority of these cases are foreign-sourced and a relationship to PREVACID has not been
established. Because these events were reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events are listed below by COSTART body
system.
Body as a Whole – anaphylactic/anaphylactoid reactions; Digestive System – hepatotoxicity,
pancreatitis, vomiting; Hemic and Lymphatic System - agranulocytosis, aplastic anemia,
hemolytic anemia, leukopen0ia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic
thrombocytopenic purpura; Musculoskeletal System – myositis; Skin and Appendages – severe
dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic
epidermal necrolysis, (some-fatal); Special Senses – speech disorder; Urogenital System –
interstitial nephritis, urinary retention.
Laboratory Values
The following changes in laboratory parameters in patients who received PREVACID were
reported as adverse events:
Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased
creatinine, increased alkaline phosphatase, increased globulins, increased GGTP,
increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia,
eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol,
increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, and increased
gastrin levels. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also
reported. Additional isolated laboratory abnormalities were reported.
In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated,
0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and PREVACID, respectively,
had enzyme elevations greater than three times the upper limit of normal range at the final
treatment visit. None of these patients who received PREVACID reported jaundice at any time
during the study.
Amoxicillin:
The following adverse reactions from the labeling for amoxicillin are provided for information.
As with other penicillins, it may be expected that untoward reactions will be essentially limited to
sensitivity phenomena. They are more likely to occur in individuals who have previously
demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay
fever, or urticaria.
The following adverse reactions have been reported as associated with the use of penicillins:
Gastrointestinal - Nausea, vomiting, diarrhea, and hemorrhagic/pseudomembranous
colitis.
Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see
WARNINGS).
Hypersensitivity Reactions – Serum sickness like reactions, erythematous maculopapular

rashes, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal
necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria
have been reported.
Note: These hypersensitivity reactions may be controlled with antihistamines and, if necessary,
systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued
unless, in the opinion of the physician, the condition being treated is life-threatening and
amenable only to amoxicillin therapy.
Liver - A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the
significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice,
hepatic cholestasis and acute cytolytic hepatitis have been reported.
Renal – Crystalluria has also been reported (see OVERDOSAGE).
Hemic and Lymphatic Systems - Anemia, including hemolytic anemia, thrombocytopenia,
thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported
during therapy with penicillins. These reactions are usually reversible on discontinuation of
therapy and are believed to be hypersensitivity phenomena.
Central Nervous System – Reversible hyperactivity, agitation, anxiety, insomnia,
confusion, behavioral changes, and/or dizziness have been reported rarely.
Miscellaneous - Tooth discoloration (brown, yellow, or gray staining) has been rarely
reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated
with brushing or dental cleaning in most cases.
Clarithromycin:
The following adverse reactions from the labeling for clarithromycin are provided for
information.
The majority of side effects observed in clinical trials were of a mild and transient nature. Fewer
than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-
related side effects.
The most frequently reported events in adults were diarrhea (3%), nausea (3%), abnormal
taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). Most of these
events were described as mild or moderate in severity. Of the reported adverse events, only 1%
was described as severe.
Postmarketing Experience:
Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis,
Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Other spontaneously
reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting,
pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness.
There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth
discoloration is usually reversible with professional dental cleaning. There have been isolated
reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports
of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have
also been reported.
Transient CNS events including anxiety, behavioral changes, confusional states,
convulsions, depersonalization, disorientation, hallucinations, insomnia, manic behavior,
nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during postmarketing
surveillance. Events usually resolve with discontinuation of the drug.
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or
cholestatic hepatitis, with or without jaundice, has been infrequently reported with
clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare
instances, hepatic failure with fatal outcome has been reported and generally has been associated
with serious underlying diseases and/or concomitant medications.
There have been rare reports of hypoglycemia, some of which have occurred in patients
taking oral hypoglycemic agents or insulin.
As with other macrolides, clarithromycin has been associated with QT prolongation and
ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.
There have been reports of interstitial nephritis coincident with clarithromycin use.
There have been post-marketing reports of colchicine toxicity with concomitant use of
clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with
renal insufficiency. Deaths have been reported in some such patients (see WARNINGS and
PRECAUTIONS).
Changes in Laboratory Values: Changes in laboratory values with possible clinical significance
were as follows: Hepatic - elevated SGPT (ALT) less than 1%, SGOT (AST) less than 1%,
GGT less than 1%, alkaline phosphatase less than 1%, LDH less than 1%, total bilirubin less
than 1%; Hematologic - decreased WBC less than 1%, elevated prothrombin time 1%; Renal -
elevated BUN 4%, elevated serum creatinine less than 1%. GGT, alkaline phosphatase, and
prothrombin time data are from adult studies only.
OVERDOSAGE
In case of an overdose, patients should contact a physician, poison control center, or emergency
room. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the
combination compared to individual components.
PREVACID:
PREVACID is not removed from the circulation by hemodialysis. In one reported
overdose, a patient consumed 600 mg of PREVACID with no adverse reaction.
Oral PREVACID doses up to 5000 mg/kg in rats (approximately 1300 times the 30 mg human
dose based on BSA) and in mice (about 675.7 times the 30 mg human dose based on BSA) did
not produce deaths or any clinical signs.
Amoxicillin:
In case of overdosage, discontinue medication, treat symptomatically and institute supportive
measures as required. If the overdosage is very recent and there is no contraindication, an attempt
at emesis or other means of removal of drug from the stomach may be performed. A prospective
study of 51 pediatric patients at a poison-control center suggested that overdosages of less than
250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require
gastric emptying2.
Interstitial nephritis resulting in oliguric renal failure has been reported in a small number
of patients after overdosage with amoxicillin.
Crystalluria, in some cases leading to renal failure, has also been reported after
amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid
intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal
impairment appears to be reversible with cessation of drug administration. High blood levels
may occur more readily in patients with impaired renal function because of decreased renal
clearance of amoxicillin. Amoxicillin can be removed from circulation by hemodialysis.
Clarithromycin:
Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain,
vomiting, nausea, and diarrhea.
Adverse reactions accompanying overdosage should be treated by the prompt elimination
of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum
levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
DOSAGE AND ADMINISTRATION

The recommended adult oral dose is 30 mg PREVACID, 1 g amoxicillin, and 500 mg
clarithromycin administered together twice daily (morning and evening) for 10 or 14 days (see
INDICATIONS AND USAGE).
PREVPAC is not recommended in patients with creatinine clearance less than
30 mL/min.
HOW SUPPLIED
PREVPAC is supplied as an individual daily administration pack, each containing:
PREVACID:
– Two opaque, hard gelatin, black and pink PREVACID 30-mg capsules, with the TAP logo and
“PREVACID 30” imprinted on the capsules.
Amoxicillin Capsules, USP:

− Four yellow, opaque, hard gelatin amoxicillin 500-mg capsules, USP, imprinted AMOX 500
on one side and GG 849 on the other side.
BIAXIN Filmtab:
– Two yellow oval film-coated clarithromycin 500-mg tablets, USP, debossed with the Abbott
logo on one side and “KL” on the other side of the tablets.
NDC 0300-3702-01 Daily administration pack

NDC 0300-3702-11 Daily administration card
Store at a controlled room temperature between 20°C and 25°C (68°F and 77°F). Protect from
light and moisture.
Rx only
REFERENCE
1. National Committee for Clinical Laboratory Standards. Summary Minutes,
Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.
2. Swanson Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and
cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;
30:66-67.
U.S. Patent No. 5,013,743

PREVPAC is distributed by TAP Pharmaceuticals Inc.
PREVACID® (lansoprazole) Delayed-Release Capsules

Distributed by TAP Pharmaceuticals Inc.
Lake Forest, IL 60045, U.S.A.
Amoxicillin Capsules, USP

Manufactured by Sandoz GmbH, Kundl, Austria
for Sandoz Inc., Broomfield, CO 80020, U.S.A.
BIAXIN® Filmtab® (clarithromycin tablets, USP)

Manufactured by Abbott Laboratories
North Chicago, IL 60064, U.S.A.
TAPDN417-V2, Month Year

©1997-YEAR TAP Pharmaceutical Products Inc.

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PREVPAC Package Insert Page 1 of 24

To reduce the development of drug-resistant bacteria and maintain the effectiveness of

PREVACID® (lansoprazole) Delayed-Release Capsules

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with

Amoxicillin Capsules, USP

BIAXIN® Filmtab® (clarithromycin tablets, USP)

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone,

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

Susceptibility Test for Helicobacter pylori

Clarithromycin MIC (µg/mL)a Interpretation

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned

Triple Therapy Triple Therapy

INDICATIONS AND USAGE

Amoxicillin and/or Clarithromycin:

concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients

Drug/Laboratory Test Interactions

enzymatic glucose oxidase reactions (such as Clinistix®) be used. Following administration of

Carcinogenesis, Mutagenesis, Impairment of Fertility

There were no adequate and well-controlled studies of PREVPAC in pregnant women.

Labor and Delivery

Use in Geriatric Patients

Table 5: Adverse Reactions Most Frequently

Incidence in Clinical Trials

Hypersensitivity Reactions – Serum sickness like reactions, erythematous maculopapular

DOSAGE AND ADMINISTRATION

Amoxicillin Capsules, USP:

NDC 0300-3702-01 Daily administration pack

U.S. Patent No. 5,013,743

PREVPAC is distributed by TAP Pharmaceuticals Inc.

PREVACID® (lansoprazole) Delayed-Release Capsules

Amoxicillin Capsules, USP

BIAXIN® Filmtab® (clarithromycin tablets, USP)

TAPDN417-V2, Month Year

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