Biaxin

[clarithromycin]

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Steady-State Clarithromycin Plasma Concentration-Time Profiles

Time After Dosing (hours)

Text Continues Below

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Mean Plasma Concentration (mcg/mL)

Biaxin-XL: 2 x 500 mg q24h
Biaxin: 500 mg q12h

For information about other drugs indicated in combination with BIAXIN, refer to the CLINICAL PHARMACOLOGY section of their package inserts.

Microbiology:

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium aviumcomplex (MAC) microorganisms. Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than clarithromycin. The clinical significance of this activity against Mycobacterium aviumcomplex is unknown.

Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic Gram-positive microorganisms
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic Gram-negative microorganisms
Haemophilus influenzae
Haemophilus parainfluenzae
Moraxella catarrhalis
Other microorganisms
Mycoplasma pneumoniae
Chlamydia pneumoniae (TWAR)
Mycobacteria
Mycobacterium aviumcomplex (MAC) consisting of:
Mycobacterium avium
Mycobacterium intracellulare
Beta-lactamase production should have no effect on clarithromycin activity.

NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.
Omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; and lansoprazole/clarithromycin/amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitroand in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter
Helicobacter pylori
Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (M93-067, M93-100) and 9.3% (41/439) in the omeprazole/clarithromycin/amoxicillin triple therapy studies (126, 127, M96-446). Clarithromycin pretreatment resistance was 12.6% (44/348) in the ranitidine bismuth citrate/clarithromycin b.i.d. versus t.i.d. clinical study (H2BA3001). Clarithromycin pretreatment resistance rates were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (< 0.25 µg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin clinical studies (126, 127, M96-446). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin/amoxicillin study arm. Amoxicillin pretreatment susceptible isolates (< 0.25 µg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of the 957 patients (2.2%) by E-test and 2 of 100 patients (2.0%) by agar dilution had amoxicillin pretreatment MICs of > 0.25 µg/mL. Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 µg/mL by E-test.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a Clarithromycin Clarithromycin Post-treatment Results
Pretreatment Results
H. pylori H. pylori positive - not eradicated Post-treatment
negative susceptibility results
- eradicated Sb Ib Rb No MIC
Omeprazole 40 mg q.d./clarithromycin 500 mg t.i.d. for 14 days followed by omeprazole 20 mg q.d. for another 14 days
(M93-067, M93-100)
Susceptibleb 108 72 1 26 9
Intermediateb 11
Resistantb 44
Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg t.i.d. for 14 days followed by ranitidine bismuth
citrate 400 mg b.i.d. for another 14 days (H2BA3001)
Susceptibleb 124 98 4 14 8
Intermediateb 3 2 1
Resistantb 17 1 15 1
Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg b.i.d. for 14 days followed by ranitidine bismuth
citrate 400 mg b.i.d. for another 14 days (H2BA3001)
Susceptibleb 125 106 1 1 12 5
Intermediateb 22
Resistantb 20 1 19
Omeprazole 20 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (126, 127, M96-446)
Susceptibleb 171 153 7 3 8
Intermediateb
Resistantb 14 4 1 6 3
Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 14 days (M95-399, M93-131, M95-392)
Susceptibleb 112 105 7
Intermediateb 33
Resistantb 17 6 7 4
Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (M95-399)
Susceptibleb 42 40 1 1
Intermediateb
Resistantb 4 1 3

a Includes only patients with pretreatment clarithromycin susceptibility tests

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 omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin, omeprazole/clarithromycin/amoxicillin, or lansoprazole/clarithromycin/amoxicillin therapy would likely have clarithromycin resistant H. pylori isolates. Therefore, for patients who fail therapy, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the omeprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 84.9% (157/185) of the patients who had pretreatment amoxicillin susceptible MICs (< 0.25 µg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results, and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

In the lansoprazole/clarithromycin/amoxicillin 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 > 0.25 µg/mL, three of six had the H. pylori eradicated. 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. pyloriisolates.

The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive microorganisms
Streptococcus agalactiae
Streptococci (Groups C, F, G)
Viridans group streptococci
Aerobic Gram-negative microorganisms
Bordetella pertussis
Legionella pneumophila
Pasteurella multocida
Anaerobic Gram-positive microorganisms
Clostridium perfringens
Peptococcus niger
Propionibacterium acnes
Anaerobic Gram-negative microorganisms
Prevotella melaninogenica(formerly Bacteriodes melaninogenicus)

Susceptibility Testing Excluding Mycobacteria and Helicobacter:

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. The MIC values should be interpreted according to the following criteria:

For testing Staphylococcusspp.
MIC (µg/mL) Interpretation
2.0 Susceptible (S)
4.0 Intermediate (I)
8.0 Resistant (R)
For testing Streptococcusspp. including Streptococcus pneumoniaea
MIC (µg/mL) Interpretation
0.25 Susceptible (S)
0.5 Intermediate (I)
1.0 Resistant (R)

a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-
Hinton broth with 2-5% lysed horse blood.

For testing Haemophilusspp.b
MIC (µg/mL) Interpretation
8.0 Susceptible (S)
16.0 Intermediate (I)
32.0 Resistant (R)

b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using
Haemophilus Testing Medium (HTM).1

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.

A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated.

This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.

A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values:
Microorganism MIC (µg/mL)
S. aureus ATCC 29213 0.12 to 0.5
S. pneumoniaec ATCC 49619 0.03 to 0.12
Haemophilus influenzaed ATCC 49247 4 to 16

Note: When testing Streptococcus spp., including Streptococcus pneumoniae , susceptibility and resistance to clarithromycin can be predicted using erythromycin.

c This quality control range is applicable only to S. pneumoniaeATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

d This quality control range is applicable only to H. influenzaeATCC 49247 tested by a microdilution procedure using HTM 1.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg clarithromycin to test the susceptibility of microorganisms to clarithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-µg clarithromycin disk should be interpreted according to the following criteria:
For testing Staphylococcusspp.
Zone diameter (mm) Interpretation
18 Susceptible (S)
14 to 17 Intermediate (I)
13 Resistant (R)
For testing Streptococcusspp. including Streptococcus pneumoniaee
Zone diameter (mm) Interpretation
21 Susceptible (S)
17 to 20 Intermediate (I)
16 Resistant (R)
e These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep
blood incubated in 5% CO2.
For testing Haemophilusspp.f

Zone diameter (mm) Interpretation
13 Susceptible (S)
11 to 12 Intermediate (I)
10 Resistant (R)

f These zone diameter standards are applicable only to tests with Haemophilusspp. using HTM2.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for clarithromycin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-µg clarithromycin disk should provide the following zone diameters in this laboratory test quality control strain:
Microorganism Zone diameter (mm)
S. aureus ATCC 25923 26 to 32
S. pneumoniaeg ATCC 49619 25 to 31
Haemophilus influenzaeh ATCC 49247 11 to 17

g This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.

h This quality control limit applies to tests conducted with Haemophilus influenzaeATCC 49247 using HTM2.

In vitro Activity of Clarithromycin against Mycobacteria:

Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on M. aviumcomplex (MAC) isolates. Various in vitro methodologies employing broth or solid media at different pH’s, with and without oleic acid-albumin-dex-trose-catalase (OADC), have been used to determine clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5.0 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media.

Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a microdilution method with Middlebrook 7H9 broth. Results showed an MIC value of 4.0 µg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value 0.5 µg/mL. Clarithromycin was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Note: When testing Streptococcus spp., including Streptococcus pneumoniae , susceptibility and resistance to clarithromycin can be predicted using erythromycin.

Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 µg/mL. Clarithromycin inhibited all isolates at > 10.0 µg/mL.
Susceptibility Testing for Mycobacterium avium Complex (MAC):

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated.

Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to clarithromycin have not been established.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.3 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10 7 - 1 x 10 8 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)i Interpretation
< 0.25 Susceptible (S)
0.5 - 1.0 Intermediate (I)
> 2.0 Resistant (R)
Amoxicillin MIC (µg/mL)i,j Interpretation
< 0.25 Susceptible (S)

i These are tentative breakpoints for the agar dilution methodology, and they should not be used to interpret results obtained
using alternative methods.

j There were not enough organisms with MICs > 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)k
H. pylori ATCC 43504 Clarithromycin 0.015 - 0.12 µg/mL
H. pylori ATCC 43504 Amoxicillin 0.015 - 0.12 µg/mL

k These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.

CLINICAL STUDIES

Mycobacterial Infections

Prophylaxis:

A randomized, double-blind study (561) compared clarithromycin 500 mg b.i.d. to placebo in patients with CDC-defined AIDS and CD 4 counts <100 cells/µL. This study accrued 682 patients from November 1992 to January 1994, with a median CD4 cell count at study entry of 30 cells/µL. Median duration of clarithromycin was 10.6 months vs. 8.2 months for placebo.

More patients in the placebo arm than the clarithromycin arm discontinued prematurely from the study (75.6% and 67.4%, respectively). However, if premature discontinuations due to MAC or death are excluded, approximately equal percentages of patients on each arm (54.8% on clarithromycin and 52.5% on placebo) discontinued study drug early for other reasons. The study was designed to evaluate the following endpoints:

1. MAC bacteremia, defined as at least one positive culture for M. avium complex bacteria from blood or another normally sterile site.

2. Survival.

3. Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including fever, night sweats, weight loss, anemia, or elevations in liver function tests.

MAC bacteremia:

In patients randomized to clarithromycin, the risk of MAC bacteremia was reduced by 69% compared to placebo. The difference between groups was statistically significant (p<0.001). On an intent-to-treat basis, the one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to clarithromycin and 19.4% for patients randomized to placebo. While only 19 of the 341 patients randomized to clarithromycin developed MAC, 11 of these cases were resistant to clarithromycin.

The patients with resistant MAC bacteremia had a median baseline CD 4 count of 10 cells/mm 3 (range 2 to 25 cells/mm 3). Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited. The 8 patients who received clarithromycin and developed susceptible MAC bacteremia had a median baseline CD 4 count of 25 cells/mm3 (range 10 to 80 cells/mm 3). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to clarithromycin. The median baseline CD 4 count was 15 cells/mm 3 (range 2 to 130 cells/mm 3) for placebo patients that developed MAC.

Survival:

A statistically significant survival benefit was observed.

Survival

All Randomized Patients

Mortality Reduction in
Placebo Clarithromycin Mortality on Clarithromycin

6 month 9.4% 6.5% 31%
12 month 29.7% 20.5% 31%
18 month 46.4% 37.5% 20%

Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated.

Clinically significant disseminated MAC disease:

In association with the decreased incidence of bacteremia, patients in the group randomized to clarithromycin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.

Safety:

In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the clarithromycin group and 8.2 months for the placebo group.

Treatment-related* Adverse Event Incidence Rates (%) in Immunocompromised Adult Patients
Receiving Prophylaxis Against M. aviumComplex
Clarithromycin Placebo

Body System‡ (n = 339) (n = 339)

Adverse Event % %
Body as a Whole

Abdominal pain 5.0% 3.5%
Headache 2.7% 0.9%
Digestive
Diarrhea 7.7% 4.1%
Dyspepsia 3.8% 2.7%
Flatulence 2.4% 0.9%
Nausea 11.2% 7.1%
Vomiting 5.9% 3.2%
Skin & Appendages
Rash 3.2% 3.5%
Special Senses
Taste Perversion 8.0% 0.3%

* Includes those events possibly or probably related to study drug and excludes concurrent conditions.
‡ > 2% Adverse Event Incidence Rates for either treatment group.

Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated group compared to the placebo-treated group. Discontinuation due to adverse events was required in 18% of patients receiving clarithromycin compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression and taste perversion.

Changes in Laboratory Values of Potential Clinical Importance:

In immunocompromised patients receiving prophylaxis against M. avium, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test.

1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

Days Since Randomization

0 100 200 400300 500 600 700

Proportion Surviving

Placebo
Clarithromycin

Percentage of Patients (a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M. aviumComplex
Clarithromycin
500 mg b.i.d. Placebo
Hemoglobin < 8 g/dL 4/118 3% 5/103 5%
Platelet Count < 50 x 109/L 11/249 4% 12/250 5%
WBC Count < 1 x 109/L 2/103 4% 0/95 0%
SGOT > 5 x ULNb 7/196 4% 5/208 2%
SGPT > 5 x ULNb 6/217 3% 4/232 2%
Alk. Phos. > 5 x ULNb 5/220 2% 5/218 2%
(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables).
(b) ULN = Upper Limit of Normal

Treatment:

Three randomized studies (500, 577, and 521) compared different dosages of clarithromycin in patients with CDC-defined AIDS and CD4 counts <100 cells/µL. These studies accrued patients from May 1991 to March 1992. Study 500 was randomized, double-blind; Study 577 was open-label compassionate use. Both studies used 500 and 1000 mg b.i.d. doses; Study 500 also had a 2000 mg b.i.d. group. Study 521 was a pediatric study at 3.75, 7.5, and 15 mg/kg b.i.d. Study 500 enrolled 154 adult patients, Study 577 enrolled 469 adult patients, and Study 521 enrolled 25 patients between the ages of 1 to 20. The majority of patients had CD 4 cell counts <50/µL at study entry. The studies were designed to evaluate the following end points:

1. Change in MAC bacteremia or blood cultures negative for M. avium.

2. Change in clinical signs and symptoms of MAC infection including one or more of the following: fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly. The results for the 500 study are described below. The 577 study results were similar to the results of the 500 study. Results with the 7.5 mg/kg b.i.d. dose in the pediatric study were comparable to those for the 500 mg b.i.d. regimen in the adult studies.

Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection 4. This 24-week study enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive clarithromycin and ethambutol, and 51 patients randomized to receive clarithromycin, ethambutol, and clofazimine. Baseline characteristics between study arms were similar with the exception of median CFU counts being at least 1 log higher in the clarithromycin, ethambutol, and clofazimine arm.

Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol was well tolerated and extended the time to microbiologic relapse, largely through suppressing the emergence of clarithromycin resistant strains. However, the addition of clofazimine to the regimen added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher. The results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent.

MAC bacteremia:

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose groups. Mean reductions in colony forming units (CFU) are shown below. Included in the table are results from a separate study with a four drug regimen5 (ciprofloxacin, ethambutol, rifampicin, and clofazimine). Since patient populations and study procedures may vary between these two studies, comparisons between the clarithromycin results and the combination therapy results should be interpreted cautiously.

Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy)
500 mg b.i.d. 1000 mg b.i.d. 2000 mg b.i.d. Four Drug Regimen
(N=35) (N=32) (N=26) (N=24)
1.5 2.3 2.3 1.4

Although the 1000 mg and 2000 mg b.i.d. doses showed significantly better control of bacteremia during the first four weeks of therapy, no significant differences were seen beyond that point. The percent of patients whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was 61% (30/49) for the 500 mg b.i.d. group and 59% (29/49) and 52% (25/48) for the 1000 and 2000 mg b.i.d. groups, respectively.

The percent of patients who had 2 or more negative cultures during acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg b.i.d. groups and 8% (4/48) for the 2000 mg b.i.d. group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49), and 13% (6/48) of patients had relapsed in the 500, 1000, and 2000 mg b.i.d. dose groups, respectively. All of the isolates had an MIC < 8 µg/mL at pre-treatment.

Relapse was almost always accompanied by an increase in MIC. The median time to first negative culture was 54, 41, and 29 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively. The time to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg b.i.d. doses (median equal to 16 and 15 days, respectively) in comparison to the 500 mg b.i.d. group (median equal to 29 days). The median time to first positive culture or study discontinuation following the first negative culture was 43, 59 and 43 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively.

Clinically significant disseminated MAC Disease:

Among patients experiencing night sweats prior to therapy, 84% showed resolution or improvement at some point during the 12 weeks of clarithromycin at 500 to 2000 mg b.i.d. doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given below:

Resolution of Fever Resolution of Night Sweats
b.i.d. % b.i.d. %
dose % ever afebrile dose % ever resolving (mg) afebrile 6 weeks (mg) resolving 6 weeks
500 67% 23% 500 85% 42%
1000 67% 12% 1000 70% 33%
2000 62% 22% 2000 72% 36%

Weight Gain >3% Hemoglobin Increase >1 gm b.i.d. % b.i.d. %
dose % ever gaining dose % ever increasing
(mg) gaining 6 weeks (mg) increasing 6 weeks
500 33% 14% 500 58% 26%
1000 26% 17% 1000 37% 6%
2000 26% 12% 2000 62% 18%

The median duration of response, defined as improvement or resolution of clinical signs and symptoms, was 2 to 6 weeks. Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25 to 33% of patients who continued to show clinical response after 12 weeks.

Survival:

Median survival time from study entry (Study 500) was 249 days at the 500 mg b.i.d. dose compared to 215 days with the 1000 mg b.i.d. dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg b.i.d. group versus 13 deaths in 51 patients in the 1000 mg b.i.d. group. The reason for this apparent mortality difference is not known. Survival in the two groups was similar beyond 12 weeks. The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies.5

Median survival time from study entry in Study 577 was 199 days for the 500 mg b.i.d. dose and 179 days for the 1000 mg b.i.d. dose. During the first four weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg b.i.d. and 18 deaths in 214 patients taking 1000 mg b.i.d.

Safety:

The adverse event profiles showed that both the 500 and 1000 mg b.i.d. doses were well tolerated. The 2000 mg b.i.d. dose was poorly tolerated and resulted in a higher proportion of premature discontinuations. In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.

The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for Study 500 (randomized, double-blind) and Study 577 (open-label, compassionate use) and also combined. Adverse events were reported less frequently in Study 577, which may be due in part to differences in monitoring between the two studies. In adult patients receiving clarithromycin 500 mg b.i.d., the most frequently reported adverse events, considered possibly or probably related to study drug, with an incidence of 5% or greater, are listed below.

Most of these events were mild to moderate in severity, although 5% (Study 500: 8%; Study 577: 4%) of patients receiving 500 mg b.i.d. and 5% (Study 500: 4%; Study 577: 6%) of patients receiving 1000 mg b.i.d. reported severe adverse events. Excluding those patients who discontinued therapy or died due to complications of their underlying non-mycobacterial disease, approximately 8% (Study 500: 15%; Study 577: 7%) of the patients who received 500 mg b.i.d. and 12% (Study 500: 14%; Study 577: 12%)of the patients who received 1000 mg b.i.d. discontinued therapy due to drug-related events during the first 12 weeks of therapy. Overall, the 500 and 1000 mg b.i.d. doses had similar adverse event profiles.

Treatment-related* Adverse Event Incidence Rates (%) in Immunocompromised Adult Patients
During the First 12 Weeks of Therapy with 500 mg b.i.d. Clarithromycin Dose
Study Study
500 577 Combined
Adverse Event (n=53) (n=255) (n=308)
Abdominal Pain 7.5 2.4 3.2
Diarrhea 9.4 1.6 2.9
Flatulence 7.5 0.0 1.3
Headache 7.5 0.4 1.6
Nausea 28.3 9.0 12.3
Rash 9.4 2.0 3.2
Taste Perversion 18.9 0.4 3.6
Vomiting 24.5 3.9 7.5

* Includes those events possibly or probably related to study drug and excludes concurrent conditions. A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse events, excluding those due to the patient ’s concurrent condition, were consistent with those observed in adult patients.

Changes in Laboratory Values:

In immunocompromised patients treated with clarithromycin for mycobacterial infections, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal level (i.e., the extreme high or low limit) for the specified test.

Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits
During First 12 Weeks of Treatment 500 mg b.i.d. Dose (b)
Study 500 Study 577 Combined
BUN >50 mg/dL 0% <1% <1%
Platelet Count <50 x 10 9/L 0% <1% <1%
SGOT >5 x ULN c 0% 3% 2%
SGPT >5 x ULN c 0% 2% 1%
WBC <1 x 10 9/L 0% 1% 1%

(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables)
(b) (b) Includes all values within the first 12 weeks for patients who start on 500 mg b.i.d.
(c) ULN = Upper Limit of Normal
(d) Otitis Media

In a controlled clinical study of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral cephalosporin. In this study, very strict evaluability criteria were used to determine clinical response. For the 223 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the post-therapy visit was 88% for clarithromycin and 91% for the cephalosporin. In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained:

U.S. Acute Otitis Media Study Clarithromycin vs. Oral Cephalosporin

EFFICACY RESULTS

PATHOGEN OUTCOME

S. pneumoniae clarithromycin success rate, 13/15 (87%), control 4/5
H. influenzae* clarithromycin success rate, 10/14 (71%), control 3/4
M. catarrhalis clarithromycin success rate, 4/5, control 1/1
S. pyogenes clarithromycin success rate, 3/3, control 0/1
Overall clarithromycin success rate, 30/37 (81%), control 8/11 (73%)

* None of the H. influenzaeisolated pre-treatment was resistant to clarithromycin; 6% were resistant to the control agent.

Safety:

The incidence of adverse events in all patients treated, primarily diarrhea and vomiting, did not differ clinically or statistically for the two agents. In two other controlled clinical trials of acute otitis media performed in the United States, where significant rates of beta-la c-tamase producing organisms were found, clarithromycin was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. In these studies, very strict evaluability criteria were used to determine the clinical response s.

In the 233 patients who were evaluated for clinical efficacy, the combined clinical success rate (i.e., cure and improvement) at the post-therapy visit was 91% for both clarithromycin and the control. For the patients who had microbiologic determinations at the pre-treatment visit, the following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained:

Two U.S. Acute Otitis Media Studies Clarithromycin vs. Antimicrobial/Beta-lactamase Inhibitor

EFFICACY RESULTS

PATHOGEN OUTCOME

S. pneumoniae clarithromycin success rate, 43/51 (84%), control 55/56 (98%)
H. influenzae* clarithromycin success rate, 36/45 (80%), control 31/33 (94%)
M. catarrhalis clarithromycin success rate, 9/10 (90%), control 6/6

S. pyogenes clarithromycin success rate, 3/3, control 5/5

Overall clarithromycin success rate, 91/109 (83%), control 97/100 (97%) * Of the H. influenzaeisolated pre-treatment, 3% were resistant to clarithromycin and 10% were resistant to the control agent.

Safety:

The incidence of adverse events in all patients treated, primarily diarrhea (15% vs. 38%) and diaper rash (3% vs. 11%) in young children, was clinically and statistically lower in the clarithromycin arm versus the control arm. Duodenal Ulcer Associated with H. pyloriInfection Clarithromycin + Lansoprazole and Amoxicillin H. pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence:

Two U.S. randomized, double-blind clinical studies in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for eradication of H. pylori. Based on the results of these studies, the safety and efficacy of the following eradication regimen were established:

Triple therapy:

BIAXIN (clarithromycin) 500 mg b.i.d. + lansoprazole 30 mg b.i.d. + amoxicillin 1 gm b.i.d. Treatment was 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. The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradicating H. pylori.

Eradication of H. pylorihas 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 clarithromycin in combination with lansoprazole and amoxicillin as 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.

H. pylori Eradication Rates-Triple Therapy (BIAXIN/lansoprazole/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (number of patients)

Triple Therapy Triple Therapy

Study Duration Evaluable Analysis* Intent-to-Treat Analysis #
M93-131 14 days 92† [80.0 - 97.7] 86† [73.3 - 93.5]
(n = 48) (n=55)
M95-392 14 days 86‡ [75.7 - 93.6] 83‡ [72.0 - 90.8]
(n = 66) (n = 70)
M95-399¶ 14 days 85 [77.0 - 91.0] 82 [73.9 - 88.1]
(N = 113) (N = 126)
10 days 84 [76.0 - 89.8] 81 [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 (Delta West LTD., Bentley, Australia), histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients were dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as evaluable 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 BIAXIN/lansoprazole and lansoprazole/amoxicillin dual therapy.

‡ (p<0.05) versus BIAXIN/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.

Clarithromycin + Omeprazole and Amoxicillin Therapy
H. pylori Eradication for Reducing the Risk of Duodenal Ulcer

Recurrence:

Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus amoxicillin. Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer, and the third study (Study 446) was conducted in patients with a duodenal ulcer in the past 5 years, but without an ulcer present at the time of enrollment. The dosage regimen in the studies was clarithromycin 500 mg b.i.d. plus omeprazole 20 mg b.i.d. plus amoxicillin 1 gram b.i.d. for 10 days.

In Studies 126 and 127, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg q.d. End points studied were eradication of H. pylori and duodenal ulcer healing (studies 126 and 127 only). H. pylori status was determined by CLOtest ®, histology, and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive. The combination of clarithromycin plus omeprazole and amoxicillin was effective in eradicating H. pylori.

Per-Protocol and Intent-To-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]

Clarithromycin + omeprazole Clarithromycin + amoxicillin
+ amoxicillin

Per-Protocol† Intent-To-Treat‡ Per-Protocol† Intent-To-Treat‡
Study 126 *77 [64, 86] 69 [57, 79] 43 [31, 56] 37 [27, 48]
(n = 64) (n = 80) (n = 67) (n = 84)
Study 127 *78 [67, 88] 73 [61, 82] 41 [29, 54] 36 [26, 47]
(n = 65) (n = 77) (n = 68) (n = 84)
Study M96-446 *90 [80, 96] 83 [74, 91] 33 [24, 44] 32 [23, 42]
(n = 69) (n = 84) (n = 93) (n = 99)

† Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127; history of ulcer within 5 years, study M96-446) 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. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.

‡ Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.

* p < 0.05 versus clarithromycin plus amoxicillin.

Safety:

In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin, no adverse reactions peculiar to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with clarithromycin, omeprazole, or amoxicillin.

The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin (n=274) were

diarrhea (14%),
taste perversion (10%),
and headache (7%).

For information about adverse reactions with omeprazole or amoxicillin, refer to the ADVERSE REACTIONS section of their package inserts.

Clarithromycin + Omeprazole Therapy

Four randomized, double-blind, multi-center studies (067, 100, 812b, and 058) evaluated clarithromycin 500 mg t.i.d. plus omeprazole 40 mg q.d. for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or by omeprazole 40 mg q.d. (812b) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 067 and 100 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067 and 228 patients in Study 100.

These studies compared the combination regimenn to omeprazole and clarithromycin monotherapies. Studies 812b and 058 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b and 208 patients in Study 058. These studies compared the combination regimen to omeprazole monotherapy. The results for the efficacy analyses for these studies are described below.

Duodenal Ulcer Healing:

The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal ulcer.
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (n/N)
Clarithromycin +
Study Omeprazole Omeprazole Clarithromycin
U.S. Studies
Study 100 94% (58/62)† 88% (60/68) 71% (49/69)
Study 067 88% (56/64)† 85% (55/65) 64% (44/69)
Non-U.S. Studies
Study 058 99% (84/85) 95% (82/86) N/A
Study 812b1 100% (64/64) 99% (71/72) N/A
† p<0.05 for clarithromycin + omeprazole versus clarithromycin monotherapy.
1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28.
Eradication of H. pylori Associated with Duodenal Ulcer:
The combination of clarithromycin and omeprazole was effective in eradicating H. pylori.
H. pyloriEradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (n/N)
Clarithromycin +
Study Omeprazole Omeprazole Clarithromycin
U.S. Studies
Study 100 64% (39/61)†‡ 0% (0/59) 39% (17/44)
Study 067 74% (39/53)†‡ 0% (0/54) 31% (13/42)

Non-U.S. Studies
Study 058 74% (64/86)‡ 1% (1/90) N/A
Study 812b 83% (50/60)‡ 1% (1/74) N/A

† Statistically significantly higher than clarithromycin monotherapy (p<0.05).
‡ Statistically significantly higher than omeprazole monotherapy (p<0.05).
H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated.

In the per-protocol analysis, the following patients were excluded: dropouts, patients with major protocol violations, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication at 4 weeks after the end of treatment because they were found to have an unhealed ulcer at the end of treatment.

Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were healed post-treatment. Ulcer Recurrence at 6 months by H. pyloriStatus at 4-6 Weeks

H. pyloriNegative H. pyloriPositive
U.S. Studies
Study 100
Clarithromycin + Omeprazole 6% (2/34) 56% (9/16)
Omeprazole - (0/0) 71% (35/49)
Clarithromycin 12% (2/17) 32% (7/22)
Study 067
Clarithromycin + Omeprazole 38% (11/29) 50% (6/12)
Omeprazole - (0/0) 67% (31/46)
Clarithromycin 18% (2/11) 52% (14/27)
Non-U.S. Studies
Study 058
Clarithromycin + Omeprazole 6% (3/53) 24% (4/17)
Omeprazole 0% (0/3) 55% (39/71)
Study 812b*
Clarithromycin + Omeprazole 5% (2/42) 0% (0/7)
Omeprazole 0% (0/1) 54% (32/59)

*12-month recurrence rates:
Clarithromycin + Omeprazole 3% (1/40) 0% (0/6)
Omeprazole 0% (0/1) 67% (29/43)
Thus, in patients with duodenal ulcer associated with H. pylori infection, eradication of H. pylorireduced ulcer recurrence.

Safety:

The adverse event profiles for the four studies showed that the combination of clarithromycin 500 mg t.i.d. and omeprazole 40 m g q.d. for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or 40 mg q.d. (812b) for an additional 14 days was well tolerated. Of the 346 patients who received the combination, 12 (3.5%) patients discontinued study drug due to adverse events.

Adverse Events with an Incidence of 3% or Greater

Clarithromycin +
Omeprazole Omeprazole Clarithromycin
(N = 346) (N = 355) (N = 166)
Adverse Event % of Patients % of Patients % of Patients*

Taste Perversion 15% 1% 16%
Nausea 5% 1% 3%
Headache 5% 6% 9%
Diarrhea 4% 3% 7%
Vomiting 4% <1% 1%
Abdominal Pain 3% 2% 1%
Infection 3% 4% 2%
* Studies 067 and 100, only

Most of these events were mild to moderate in severity.

Changes in Laboratory Values:

Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole were as follows:
Hepatic - elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%.

Renal - elevated serum creatinine <1%.
For information on omeprazole, refer to the ADVERSE REACTIONS section of the PRILOSEC package insert.

Clarithromycin + Ranitidine Bismuth Citrate Therapy

In a U.S. double-blind, randomized, multicenter, dose-comparison trial, ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg b.i.d. for the first 2 weeks was found to have an equivalent H. pylori eradication rate (based on culture and histology) when compared to ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg t.i.d. for the first 2 weeks. The intent-to-treat H. pylorieradication rates are shown below:

H. pylori Eradication Rates in Study H2BA-3001
RBC 400 mg + RBC 400 mg + Clarithromycin Clarithromycin 95% CI Rate
Analysis 500 mg b.i.d. 500 mg t.i.d. Difference
ITT 65% (122/188) 63% (122/195) (-8%, 12%)
[58%, 72%] [55%, 69%]
Per-Protocol 72% (117/162) 71% (120/170) (-9%, 12%)
[65%, 79%] [63%, 77%]

H. pylori eradication was defined as no positive test at 4 weeks following the end of treatment. Patients must have had two tests performed, and these must have been negative to be considered eradicated of H. pylori. The following patients were excluded from the per-protocol analysis: patients not infected with H. pylori prestudy, dropouts, patients with major protocol violations, patients with missing H. pylori tests. Patients excluded from the intent-to-treat analysis included those not infected with H. pylori prestudy and those with missing H. pylori tests prestudy. Patients were assessed for H. pylori eradication (4 weeks following treatment) regardless of their healing status (at the end of treatment).

The relationship between H. pylori eradication and duodenal ulcer recurrence was assessed in a combined analysis of six U.S. randomized, double-blind, multicenter, placebo-controlled trials using ranitidine bismuth citrate with or without antibiotics. The re sults from approximately 650 U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two timesless likely in patients whose H. pyloriinfection was eradicated compared to patients in whom H. pyloriinfection was not eradicated.

Safety:

In clinical trials using combination therapy with clarithromycin plus ranitidine bismuth citrate, no adverse reactions peculiar to the combination of these drugs (using clarithromycin twice daily or three times a day) were observed. Adverse reactions that have occurred have been limited to those reported with clarithromycin or ranitidine bismuth citrate. (See ADVERSE REACTIONS section of the Tritec package insert.)

The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin (500 mg three times a day) with ranitidine bismuth citrate (n = 329) were taste disturbance (11%), diarrhea (5%), nausea and vomi ting (3%). The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin (500 mg t wice daily) with ranitidine bismuth citrate (n = 196) were taste disturbance (8%), nausea and vomiting (5%), and diarrhea (4%).

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Clarithromycin is rapidly and well-absorbed with dose-linear kinetics, low protein binding, and a high volume of distribution. Plasma half-life ranged from 1 to 6 hours and was species dependent. High tissue concentrations were achieved, but negligible accumulation was observed. Fecal clearance predominated. Hepatotoxicity occurred in all species tested (i.e., in rats and monkeys at doses 2 times greater than and in dogs at doses comparable to the maximum human daily dose, based on mg/m 2).

Renal tubular degeneration (calculated on a mg/m 2 basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose. Testicular atrophy (on a mg/m 2 basis) occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose.

Corneal opacity (on a mg/m2 basis) occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose. Lymphoid depletion (on a mg/m 2 basis) occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose. These adverse events were absent during clinical trials.

REFERENCES

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.

2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.

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

4. Chaisson RE, et al. Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of Bacteremic Mycobacterium aviumComplex Disease in Patients with HIV Infection. AIDS. 1997;11:311-317.

5. Kemper CA, et al. Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral Regimen. Ann Intern Med.1992;116:466-472.
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