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Name:Clarithromycin
Manufacturer:Kaiser Foundation Hospitals
Category:Prescription Marketed Drugs


CLARITHROMYCIN  - clarithromycin tablet 
KAISER FOUNDATION HOSPITALS

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To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin and other antibacterial drugs, clarithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

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. The structural formula is:

Structure Image

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.

Clarithromycin is available as immediate-release tablets, extended-release tablets, and granules for oral suspension.

Each yellow oval film-coated immediate-release tablet of Clarithromycin Tablets, USP contains 250mg or 500mg of clarithromycin and the following inactive ingredients:

250mg tablets: hypromellose, hydroxypropyl cellulose, croscarmellose sodium, D and C Yellow No. 10, FD and C Blue No. 1, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide,and vanillin.

500 mg tablets: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose
sodium, D and C Yellow No. 10, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin.

Each yellow oval film-coated BIAXIN XL tablet (clarithromycin extended-release tablets) contains 500mg of clarithromycin and the following inactive ingredients: cellulosic polymers, D and C Yellow No. 10, lactose monohydrate, magnesium stearate, propylene glycol, sorbic acid, sorbitan monooleate, talc, titanium dioxide, and vanillin.

After constitution, each 5 mL of Clarithromycin for Oral Suspension, USP contains 125mg or 250mg of clarithromycin. Each bottle of Clarithromycin for Oral Suspension, USP contains 1250mg (50 mL size), 2500 mg (50 and 100 mL sizes) or 5000 mg (100 mL size) of clarithromycin and the following inactive ingredients: carbomer, castor oil, citric acid, hypromellose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch flavor.

CLINICAL PHARMACOLOGY

Pharmacokinetics


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 500mg 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 decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, Clarithromycin Tablets, USP 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 1 to 2 μg/mL with a 250 mg dose administered every 12 hours and 3 to 4 μg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 μg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 μg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as
clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125mg/5mL) suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. The renal clearance of clarithromycin is, however, relatively independent of the dose size and 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 either a 250 mg or a 500 mg tablet administered every 12 hours.

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following
administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500 or 1000mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 μg/mL and 5 to 10 μg/mL, respectively.

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.)

Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular
concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue and serum concentrations are presented below.

CONCENTRATION (after 250 mg q12h)
Tissue Type Tissue
(µg/g)
Serum
(µg/mL)
Tonsil 1.6 0.8
Lung 8.8 1.7

BIAXIN XL Filmtab (clarithromycin extended-release tablets) provide extended absorption of
clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal total daily dose of immediate-release clarithromycin tablets, BIAXIN XL tablets provide lower and later steadystate peak plasma concentrations but equivalent 24-hour AUC's for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of formation of 14-OH clarithromycin following administration of BIAXIN XL tablets (2 × 500 mg once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Therefore, BIAXIN XL tablets should be taken with food.

Steady-State Clarithromycin Plasma Concentration-Time Profiles


GRAPH

In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 to 3 μg/mL were achieved about 5 to 8 hours after oral administration of 2 × 500mg BIAXIN XL tablets once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.8 μg/mL were attained about 6 to 9 hours after dosing. Steady-state peak plasma clarithromycin concentrations of approximately 1 to 2 μg/mL were achieved about 5 to 6 hours after oral administration of a single 500 mg BIAXIN XL tablet once daily; for 14-OH clarithromycin, steadystate peak plasma concentrations of approximately 0.6μg/mL were attained about 6 hours after dosing.

When 250 mg doses of Clarithromycin for Oral Suspension, USP were administered to fasting healthy adult subjects, peak plasma concentrations were attained around 3 hours after dosing. Steady-state peak plasma concentrations were attained in 2 to 3 days and were approximately 2μg/mL for clarithromycin and 0.7 μg/mL for 14-OH clarithromycin when 250 mg doses of the clarithromycin suspension were administered every 12 hours. Elimination half-life of clarithromycin (3 to 4 hours) and that of 14-OH clarithromycin (5 to 7 hours) were similar to those observed at steady state following administration of equivalent doses of Clarithromycin Tablets, USP.

For adult patients, the bioavailability of 10 mL of the 125mg/5 mL suspension or 10 mL of the 250mg/5 mL suspension is similar to a 250 mg or 500 mg tablet, respectively.

In children requiring antibiotic therapy, administration of 7.5 mg/kg q12h doses of clarithromycin as
the suspension generally resulted in steady-state peak plasma concentrations of 3 to 7 μg/mL for
clarithromycin and 1 to 2 μg/mL for 14-OH clarithromycin.

In HIV-infected children taking 15 mg/kg every 12 hours, steady-state clarithromycin peak
concentrations generally ranged from 6 to 15 μg/mL.

Clarithromycin penetrates into the middle ear fluid of children with secretory otitis media.


CONCENTRATION (after 7.5 mg/kg q12h for 5 doses)
Analyte Middle Ear Fluid
(µg/mL)
Serum
(µg/mL)
Clarithromycin 2.5 1.7
14-OH Clarithromycin 1.3 0.8

In adults given 250 mg clarithromycin as suspension (n = 22), food appeared to decrease mean peak plasma clarithromycin concentrations from 1.2 (± 0.4) μg/mL to 1.0 (± 0.4) μg/mL and the extent of absorption from 7.2 (± 2.5) hr• μg/mL to 6.5 (± 3.7) hr• μg/mL.

When children (n = 10) were administered a single oral dose of 7.5 mg/kg suspension, food increased mean peak plasma clarithromycin concentrations from 3.6 (± 1.5) μg/mL to 4.6 (± 2.8)μg/mL and the extent of absorption from 10.0 (± 5.5) hr•μg/mL to 14.2 (± 9.4) hr•μg/mL.

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to
healthy adult males. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were
increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.


Clarithromycin Tissue Concentrations 2 hours after Dose (µg/mL)/(µg/g)
Treatment N antrum fundus N mucus
Clarithromycin 5 10.48 ± 2.01 20.81 ± 7.64 4 4.15 ± 7.74
Clarithromycin + Omeprazole 5 19.96 ± 4.71 24.25 ± 6.37 4 39.29 ± 32.79

For information about other drugs indicated in combination with clarithromycin, 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 avium complex (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 avium complex 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 avium complex (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 vitro and 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 (less than 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) greater than 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 ( less than 0.25µg/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 greater than 0.25 µg/mL. Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 µg/mL by E-test.

Clarithromycin Table 1

a   Includes only patients with pretreatment clarithromycin susceptibility tests

b   Susceptible (S) MIC less than 0.25 μg/mL, Intermediate (I) MIC 0.5-1.0 μg/mL, Resistant (R)
MIC greater than 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 (less than 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 (less than 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 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.

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 method1 (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 Staphylococcus spp.
MIC (µg/mL) Interpretation
≤ 2.0 Susceptible (S)
4.0 Intermediate (I)
≥ 8.0 Resistant (R)

For testing Streptococcus spp. including Streptococcus pneumoniae a
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 Haemophilus spp.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

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

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
c   This quality control range is applicable only to S. pneumoniae ATCC 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. influenzae ATCC 49247 tested by a microdilution procedure using HTM1.


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 procedure2 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 Staphylococcus spp.
Zone diameter (mm) Interpretation
≥ 18 Susceptible (S)
14 to 17 Intermediate (I)
≤ 13 Resistant (R)
For testing Streptococcus spp. 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 Haemophilus spp.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 Haemophilus spp. using HTM2

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

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 influenzae ATCC 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. avium complex (MAC) isolates.

Various in vitro methodologies employing broth or solid media at different pH's, with and without oleic acid-albumin-dextrose-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 less than or equal to 4.0µg/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 less than or equal to 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.

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 greater than 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 107-1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (greater than  2-weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, theMICs 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
less than  0.25 Susceptible (S)
0.5-1.0 Intermediate (I)
greater than  2.0 Resistant (R)

Amoxicillin MIC (µg/mL) i,j Interpretation
less than 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 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)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.


INDICATIONS AND USAGE

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP are indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions as listed below:

Adults (Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP)

Pharyngitis/Tonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not available at present).

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae , Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.


Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR).


Uncomplicated skin and skin structure infections due to Staphylococcus aureus , or Streptococcus pyogenes (Abscesses usually require surgical drainage).


Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare


Clarithromycin Tablets, USP in combination with amoxicillin and PREVACID (lansoprazole) or
PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the
treatment of patients with H. pylori  infection and duodenal ulcer disease (active or five-year history of
duodenal ulcer) to eradicate H. pylori.

Clarithromycin Tablets, USP in combination with PRILOSEC (omeprazole) capsules or TRITEC
(ranitidine bismuth citrate) tablets are also indicated for the treatment of patients with an active
duodenal ulcer associated with H. pylori infection. However, regimens which contain clarithromycin as
the single antimicrobial agent are more likely to be associated with the development of clarithromycin
resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in
patients with known or suspected clarithromycin resistant isolates because the efficacy of treatment is
reduced in this setting.

In patients who fail therapy, susceptibility testing should be done if possible. If resistance to
clarithromycin is demonstrated, a non-clarithromycin-containing therapy is recommended. (For
information on development of resistance see Microbiology section.) The eradication of H. pylori has
been demonstrated to reduce the risk of duodenal ulcer recurrence.


Children (Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP)

Pharyngitis/Tonsillitis due to Streptococcus pyogenes

Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae, or
Chlamydia pneumoniae (TWAR)

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus
pneumoniae

Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis,or Streptococcus
pneumoniae

NOTE: For information on otitis media, see CLINICAL STUDIES - Otitis Media.

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus
pyogenes
(Abscesses usually require surgical drainage.)

Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare


Adults (BIAXIN XL Filmtab Tablets)

BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions listed below:

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Community-Acquired Pneumonia due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Chlamydia pneumoniae (TWAR), or Mycoplasma pneumoniae

THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN ESTABLISHED.


Prophylaxis

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP are indicated for the
prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced
HIV infection.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin
and other antibacterial drugs, clarithromycin 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

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin,
erythromycin, or any of the macrolide antibiotics.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated:
cisapride, pimozide, astemizole, terfenadine and ergotamine or dihydroergotamine (See Drug
Interactions
). There have been post-marketing reports of drug interactions when clarithromycin and/or
erythromycin are coadministered 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 indicated in combination with clarithromycin,
refer to the CONTRAINDICATIONS section of their package inserts.

WARNINGS

CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY
OCCURS WHILE TAKING THIS DRUG, 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.)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including clarithromycin, 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.

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.)

For information about warnings of other drugs indicated in combination with clarithromycin, refer to
the WARNINGS section of their package inserts.

PRECAUTIONS

General

Prescribing clarithromycin 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.

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.

Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients
with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION.)

Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a
history of acute porphyria.

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic
syndrome has been reported in patients receiving clarithromycin therapy.

For information about precautions of other drugs indicated in combination with clarithromycin, refer to
the PRECAUTIONS section of their package inserts.

Information For Patients

Patients should be counseled that antibacterial drugs including clarithromycin should only be used to
treat bacterial infections. They do not treat viral infections (e.g., the common cold). When
clarithromycin 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 clarithromycin or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.

Clarithromycin may interact with some drugs; therefore patients should be advised to report to their
doctor the use of any other medications.

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP can be taken with or
without food and can be taken with milk; however, BIAXIN XL (clarithromycin extended-release
tablets) should be taken with food. Do NOT refrigerate the suspension.

Drug Interactions

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%.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving
concurrent verapamil, belonging to the calcium channel blockers drug class.

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-OH-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.)

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to
healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax,
AUC0-24, and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of
clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered
alone and 5.7 when coadministered with clarithromycin.

Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant.

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult
patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin
appears to interfere with absorption of simultaneously administered oral zidovudine, this interaction
can be largely avoided by staggering the doses of clarithromycin and zidovudine. This interaction
does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with
zidovudine or dideoxyinosine. Similar interaction studies have not been conducted with clarithromycin
extended release and zidovudine.

Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients
resulted in no statistically significant change in didanosine pharmacokinetics.

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21
healthy volunteers led to increases in the mean steady-state clarithromycin Cmin and AUC of 33% and
18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affected
by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CLCR 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CLCR less than 30 mL/min, the dose of clarithromycin should be decreased by 75%.

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.

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is
known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by
clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in
patients receiving clarithromycin and digoxin concomitantly have also been reported in postmarketing
surveillance. Some patients have shown clinical signs consistent with digoxin toxicity,
including potentially fatal arrhythmias. Serum digoxin concentrations 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.)

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by
CYP3A may be associated with elevations in drug concentrations that could increase or prolong both
therapeutic and adverse effects of the concomitant drug.

Clarithromycin should be used with caution in patients receiving treatment with other drugs known to
be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g.,
carbamazepine) and/or the substrate is extensively metabolized by this enzyme. 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.

The following are examples of some clinically significant CYP3A based drug interactions. Interactions
with other drugs metabolized by the CYP3A isoform are also possible.

Carbamazepine and Terfenadine

Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were
observed in clinical trials with clarithromycin.


Efavirenz, Nevirapine, Rifampicin, Rifabutin and Rifapentine

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine,
rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower
the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that
is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired
during concomitant administration of clarithromycin and enzyme inducers.

Sildenafil, Tadalafil, and Vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A
may be inhibited by concomitantly administered clarithromycin.

Coadministration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased
phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should
be considered when these drugs are co-administered with clarithromycin.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6).
However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via
CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum
concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of
CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam
AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral
administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If
intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored
to allow dose adjustment.

The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A,
including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for
their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with
clarithromycin is unlikely. There have been post-marketing reports of drug interactions and central
nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of
clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is
suggested.


Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a
bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir
(400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in
exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir.

Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary
in patients with normal renal function. For patients with moderate renal function (creatinine clearance
30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with
creatinine clearance less than 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should
not be coadministered with protease inhibitors.

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional
drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while
itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and
clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or
prolonged pharmacologic effects.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a
bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg bid) and
saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state AUC
and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir
alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with
clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a
limited time at the doses/formulations studied. Observations from drug interaction studies using the
soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir
hard gelatin capsule. Observations from drug interactions studies performed with saquinavir alone
may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is
co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on
clarithromycin (see PRECAUTIONS – Drug Interactions).

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 concentrations 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 post-marketing
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, bromocriptine and vinblastine.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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 are no adequate and well-controlled studies in pregnant women. Clarithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)

Nursing Mothers

It is not known whether clarithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clarithromycin is administered to a nursing woman. 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. Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.

PEDIATRIC USE


Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been established. The safety of clarithromycin has not been studied in MAC patients under the age of 20 months. Neonatal and juvenile animals tolerated clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes but were less sensitive to toxicity in the liver, kidney, thymus, and genitalia.

Geriatric Use

In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. (See WARNINGS and PRECAUTIONS.)

ADVERSE REACTIONS

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 and fewer than 2% of pediatric patients without
mycobacterial infections discontinued therapy because of drug-related side effects. Fewer than 2% of
adult patients taking BIAXIN XL tablets discontinued therapy because of drug-related side effects.

The most frequently reported events in adults taking Clarithromycin Tablets, USP were diarrhea (3%),
nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache
(2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%),
abdominal pain (3%), rash (3%), 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.

The most frequently reported events in adults taking BIAXIN XL (clarithromycin extended-release
tablets) were diarrhea (6%), abnormal taste (7%), and nausea (3%). Most of these events were
described as mild or moderate in severity. Of the reported adverse events, less than 1% were
described as severe.

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall
gastrointestinal adverse events were reported by a similar proportion of patients taking either
Clarithromycin Tablets, USP or BIAXIN XL tablets; however, patients taking BIAXIN XL tablets
reported significantly less severe gastrointestinal symptoms compared to patients taking
Clarithromycin Tablets, USP. In addition, patients taking BIAXIN XL tablets had significantly fewer
premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events
compared to Clarithromycin Tablets, USP.

In community-acquired pneumonia studies conducted in adults comparing clarithromycin to
erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive
system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs. 32%;
p less than 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse
events compared to 4% of clarithromycin-treated patients.

In two U.S. studies of acute otitis media comparing clarithromycin to amoxicillin/potassium
clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in
clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21%
vs. 40%, p less than 0.001). One-third as many clarithromycin-treated patients reported diarrhea as did
amoxicillin/potassium clavulanate-treated patients.

Post-Marketing 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
including smell loss, 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, depression, manic behavior, nightmares,
psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing 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.

There have been post-marketing reports of BIAXIN XL tablets in the stool, many of which have
occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal
disorders with shortened GI transit times.

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

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
concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP may be given with or
without food. BIAXIN XL Filmtab (clarithromycin extended-release tablets) should be taken with food.
BIAXIN XL tablets should be swallowed whole and not chewed, broken or crushed.

ADULT DOSAGE GUIDELINES

BIAXIN Tablets BIAXIN XL Tablets
Infection Dosage
(q12h)
Duration
(days)
Dosage
(q24h)
Duration
(days)
Pharyngitis/Tonsillitis due to



     S. pyogenes 250 mg 10 - -
Acute maxillary sinusitis due to 500 mg 14 2 x 500 mg 14
     H. influenzae



     M. catarrhalis



     S. pneumoniae



Acute exacerbation of chronic bronchitis due to



     H. influenzae 500 mg 7-14 2 x 500 mg 7
     H. parainfluenzae 500 mg 7 2 x 500 mg 7
     M. catarrhalis 250 mg 7-14 2 x 500 mg 7
     S. pneumoniae 250 mg 7-14 2 x 500 mg 7
Community-Acquired Pneumonia due to



     H. influenzae 250 mg 7 2 x 500 mg 7
     H. parainfluenzae - - 2 x 500 mg 7
     M. catarrhalis - - 2 x 500 mg 7
     S. pneumoniae 250 mg 7-14 2 x 500 mg 7
     C. pneumoniae 250 mg 7-14 2 x 500 mg 7
     M. pneumoniae 250 mg 7-14 2 x 500 mg 7
Uncomplicated skin and skin structure 250 mg 7-14 - -
     S. aureus



     S. pyogenes



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

Triple therapy: clarithromycin/lansoprazole/amoxicillin

The recommended adult dose is 500 mg clarithromycin, 30 mg lansoprazole, and 1 gram amoxicillin,
all given twice daily (q12h) for 10 or 14 days. (See INDICATIONS AND USAGE and CLINICAL STUDIES sections.)

Triple Therapy: clarithromycin/omeprazole/amoxicillin

The recommended adult dose is 500 mg clarithromycin, 20 mg omeprazole, and 1 gram amoxicillin,
all given twice daily (q12h) for 10 days. (See INDICATIONS AND USAGE and CLINICAL STUDIES
sections.) In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of
omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy: clarithromycin/omeprazole

The recommended adult dose is 500 mg clarithromycin given three times daily (q8h) and 40 mg
omeprazole given once daily (qAM) for 14 days. (See INDICATIONS AND USAGE and CLINICAL
STUDIES
sections.) An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer
healing and symptom relief.

Dual Therapy: clarithromycin/ranitidine bismuth citrate

The recommended adult dose is 500 mg clarithromycin given twice daily (q12h) or three times daily
(q8h) and 400 mg ranitidine bismuth citrate given twice daily (q12h) for 14 days. An additional 14
days of 400 mg twice daily is recommended for ulcer healing and symptom relief. Clarithromycin and
ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine
clearance less than 25 mL/min. (See INDICATIONS AND USAGE and CLINICAL STUDIES
sections.)

Children

The usual recommended daily dosage is 15 mg/kg/day divided q12h for 10 days.


PEDIATRIC DOSAGE GUIDELINES
Based on Body Weight
Dosing Calculated on 7.5 mg/kg q12h
Weight Dose
Kg lbs (q12h) 125 mg/5 mL 250 mg/5 mL
9
17
25
33
20
37
55
73
62.5 mg
125 mg
187.5 mg
250 mg
2.5 mL q12h
5 mL q12h
7.5 mL q12h
10 mL q12h
1.25 mL q12h
2.5 mL q12h
3.75 mL q12h
5 mL q12h

Clarithromycin may be administered without dosage adjustment in the presence of hepatic
impairment if there is normal renal function. However, in the presence of severe renal impairment
(CRCL less than 30 mL/min), with or without coexisting hepatic impairment, the dose should be halved or the dosing interval doubled.

Mycobacterial Infections

Prophylaxis

The recommended dose of clarithromycin for the prevention of disseminated Mycobacterium avium
disease is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. No
studies of clarithromycin for MAC prophylaxis have been performed in pediatric populations and the
doses recommended for prophylaxis are derived from MAC treatment studies in children. Dosing
recommendations for children are in the table above.

Treatment

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due
to Mycobacterium avium complex. Clarithromycin should be used in combination with other
antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC
treatment. (See CLINICAL STUDIES.) The recommended dose for mycobacterial infections in adults
is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. Dosing
recommendations for children are in the table above.

Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are
observed.

HOW SUPPLIED

Clarithromycin Tablets, USP are supplied as yellow oval film-coated tablets in the following packaging
sizes:

500 mg tablets: (debossed with DV on one side, and D on the opposite side)

Bottles of 720 (NDC 0179-0021-88)

Store 500 mg Clarithromycin Tablets, USP at controlled room temperature 20° to 25°C (68° to 77°F)
in a well-closed container.

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 CD4 counts less than 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 less than 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 CD4 count of 10 cells/mm3 (range 2 to 25 cells/mm3). 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 CD4 count of 25 cells/mm3 (range 10 to 80 cells/mm3). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to clarithromycin. The median baseline CD4 count was 15 cells/mm3 (range 2 to 130 cells/mm3) for placebo patients that developed MAC.


Survival
A statistically significant survival benefit was observed.

Survival All Randomized Patients

Survival All Randomized Patients Graph


                Mortality

Placebo Clarithromycin Reduction in 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. avium Complex
Body System
Adverse Event
Clarithromycin
(n = 339)
%
Placebo
(n = 339)
%

*   Includes those events possibly or probably related to study drug and excludes concurrent conditions.

‡   > 2% Adverse Event Incidence Rates for either treatment group.

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%

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.

Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M. avium Complex
Clarithromycin
500 mg b.i.d.
Placebo

(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

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 ULN(b) 7/196 4% 5/208 2%
SGPT > 5 x ULN(b) 6/217 3% 4/232 2%
Alk. Phos. > 5 x ULN(b) 5/220 2% 5/218 2%

Treatment


Three randomized studies (500, 577, and 521) compared different dosages of clarithromycin in patients with CDC-defined AIDS and CD4 counts less than 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 CD4 cell counts less than 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.
(N = 35)
1000 mg b.i.d.
(N = 32)
2000 mg b.i.d.
(N = 26)
Four Drug Regimen
(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 less than 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.
dose
(mg)
% ever
afebrile
%
afebrile
≥ 6 weeks
b.i.d.
dose
(mg)
% ever
resolving
%
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.
dose
(mg)
% ever
gaining
%
gaining
≥ 6 weeks
b.i.d.
dose
(mg)
% ever
increasing
%
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 drugrelated 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
Adverse Event Study 500
(n = 53)
Study 577
(n = 255)
Combined
(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 greater than 50 mg/dL 0% less than 1% less than 1%
Platelet Count less than 50 x 109/L 0% less than 1% less than 1%
SGOT greater than 5 x ULN(c) 0% 3% 2%
SGPT greater than 5 x ULN(c) 0% 2% 1%
WBC less than 1 x 109/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) Includes all values within the first 12 weeks for patients who start on 500 mg b.i.d.
(c) ULN = Upper Limit of Normal

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. influenzae isolated pre-treatment was resistant to clarithromycin; 6% were resistant to the controlagent.


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-lactamase 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 responses. 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. influenzae isolated 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. pylori Infection

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: 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 clarithromycin plus lansoprazole and amoxicillin 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 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)
Study Duration Triple Therapy
Evaluable Analysis*
Triple Therapy
Intent-to-Treat Analysis#
M93-131 14 days 92 [80.0-97.7]
(n = 48)
86 [73.3-93.5]
(n = 55)
M95-392 14 days 86 [75.7-93.6]
(n = 66)
83 [72.0-90.8]
(n = 70)
M95-399¶ 14 days 85 [77.0-91.0]
(N = 113)
82 [73.9-88.1]
(N = 126)

10 days 84 [76.0-89.8]
(N = 123)
81 [73.9-87.6]
(N = 135)
*   Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (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 less than 0.05) versus BIAXIN/lansoprazole and lansoprazole/amoxicillin dual therapy.

‡   (p less than 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. Endpoints 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 + amoxicillin Clarithromycin + amoxicillin

Per-Protocol Intent-to-Treat Per-Protocol Intent-to-Treat
Study 126 *77 [64, 86]
(n = 64)
69 [57, 79]
(n = 80)
43 [31, 56]
(n = 67)
37 [27, 48]
(n = 84)
Study 127 *78 [67, 88]
(n = 65)
73 [61, 82]
(n = 77)
41 [29, 54]
(n = 68)
36 [26, 47]
(n = 84)
Study M96-446 *90 [80, 96]
(n = 69)
83 [74, 91]
(n = 84)
33 [24, 44]
(n = 93)
32 [23, 42]
(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 less than 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 regimen 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)
Study Clarithromycin + 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 less than 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. pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (n/N)
Study Clarithromycin + 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 less than 0.05).

‡  Statistically significantly higher than omeprazole monotherapy (p less than 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. pylori Status at 4-6 Weeks

H. pylori Negative H. pylori Positive
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. pylori reduced 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 mg 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
Adverse Event Clarithromycin + Omeprazole
(N = 346)
% of Patients
Omeprazole
(N = 355)
% of Patients
Clarithromycin
(N = 166)
% of Patients*
Taste Perversion 15% 1% 16%
Nausea 5% 1% 3%
Headache 5% 6% 9%
Diarrhea 4% 3% 7%
Vomiting 4% less than 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 less than 1%; GGT less than 1%; SGOT (AST) less than 1%; SGPT (ALT) less than 1%.

Renal - elevated serum creatinine less than 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. pylori eradication rates are shown below:

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

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 results from approximately 650 U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylori infection was eradicated compared to patients in whom H. pylori infection 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 vomiting (3%). The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin (500 mg twice 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/m2). Renal tubular degeneration (calculated on a mg/m2 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/m2 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/m2 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 avium Complex 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.

Clarithromycin Tablets, USP,  500 mg
Manufactured By: Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
Manufactured For: DAVA Pharmaceuticals, Inc., Fort Lee, NJ 07024
Repackaged by Kaiser Foundation Hospitals, Livermore, CA 94551

Principal Package Label Clarithromycin 500mg


CLARITHROMYCIN 
clarithromycin tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0179-0021(NDC:68774-122)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CLARITHROMYCIN (CLARITHROMYCIN) CLARITHROMYCIN 500 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE  
HYDROXYPROPYL CELLULOSE  
CROSCARMELLOSE SODIUM  
D&C YELLOW NO. 10  
MAGNESIUM STEARATE  
POVIDONE  
PROPYLENE GLYCOL  
SORBIC ACID  
SORBITAN MONOOLEATE  
TITANIUM DIOXIDE  
VANILLIN  
Product Characteristics
Color yellow Score no score
Shape OVAL Size 18mm
Flavor Imprint Code DV;D
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0179-0021-88 720 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA050662 10/01/2009

Labeler - KAISER FOUNDATION HOSPITALS (053052619)
Establishment
Name Address ID/FEI Operations
KAISER FOUNDATION HOSPITALS 053052619 repack
Establishment
Name Address ID/FEI Operations
Abbott Pharmaceuticals PR, Ltd. (DBA) 780357856 manufacture

Revised: 10/2009 KAISER FOUNDATION HOSPITALS



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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