To reduce the development of drug-resistant bacteria and maintain
the effectiveness of clarithromycin and other antibacterial drugs,
clarithromycin tablets should be used only to treat or prevent infections that
are proven or strongly suspected to be caused by bacteria. Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to
clarithromycin can be predicted using erythromycin.
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:
Clarithromycin is a white to off-white crystalline powder. It is soluble in
acetone, slightly soluble in methanol, ethanol, and acetonitrile, and
practically insoluble in water.
Each clarithromycin tablet intended for oral administration contains 250 mg
or 500 mg of clarithromycin. In addition, each clarithromycin tablet contains
the following inactive ingredients: croscarmellose sodium, hypromellose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate
80, povidone, talc, and titanium dioxide.
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 500 mg dose of
clarithromycin, food slightly delays the onset of clarithromycin absorption,
increasing the peak time from approximately 2 to 2.5 hours. Food also increases
the clarithromycin peak plasma concentration by about 24%, but does not affect
the extent of clarithromycin bioavailability. Food does not affect the onset of
formation of the antimicrobially active metabolite, 14-OH clarithromycin or its
peak plasma concentration but does slightly decrease the extent of metabolite
formation, indicated by an 11% decrease in area under the plasma
concentration-time curve (AUC). Therefore, clarithromycin tablets may be given
without regard to food.
In nonfasting healthy human subjects (males and females), peak plasma
concentrations were attained within 2 to 3 hours after oral dosing. Steady-state
peak plasma clarithromycin concentrations were attained within 3 days and were
approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3
to 4 mcg/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 mcg/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 mcg/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 (125 mg/5 mL)
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 mg or 1000 mg
doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 mcg/mL and 5 to 10 mcg/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
(mcg/g)
Serum
(mcg/mL)
Tonsil
1.6
0.8
Lung
8.8
1.7
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
(mcg/mL)/(mcg/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
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 USAGEsection. Helicobacter Helicobacter pylori
Pretreatment Resistance Clarithromycin pretreatment resistance rates were 3.5% (4/113) in
the omeprazole/clarithromycin dual-therapy studies (M93-067, M93-100) and 9.3%
(41/439) in the omeprazole/clarithromycin/amoxicillin triple-therapy studies
(126, 127, M96-446). Clarithromycin pretreatment resistance was 12.6% (44/348)
in the ranitidine bismuth citrate/clarithromycin b.i.d. versus t.i.d. clinical
study (H2BA3001). Clarithromycin pretreatment resistance rates were 9.5%
(91/960) by E-test and 11.3% (12/106) by agar dilution in the
lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials (M93-125,
M93-130, M93-131, M95-392, and M95-399).
Amoxicillin pretreatment susceptible isolates (<0.25 mcg/mL) were found in
99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin
clinical studies (126, 127, M96-446). Amoxicillin pretreatment minimum
inhibitory concentrations (MICs) >0.25 mcg/mL occurred in 0.7% (3/439) of the
patients, all of whom were in the clarithromycin/amoxicillin study arm.
Amoxicillin pretreatment susceptible isolates (<0.25 mcg/mL) occurred in
97.8% (936/957) and 98.0% (98/100) of the patients in the
lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials by E-test
and agar dilution, respectively. Twenty-one of the 957 patients (2.2%) by E-test
and 2 of 100 patients (2.0%) by agar dilution had amoxicillin pretreatment MICs
of >0.25 mcg/mL. Two patients had an unconfirmed pretreatment amoxicillin
minimum inhibitory concentration (MIC) of >256 mcg/mL by E-test.
Clarithromycin Susceptibility Test Results and Clinical/Bacteriological
Outcomes*
Ranitidine
bismuth citrate 400 mg b.i.d./clarithromycin 500 mg t.i.d. for 14 days followed
by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days
(H2BA3001)
Ranitidine
bismuth citrate 400 mg b.i.d./clarithromycin 500 mg b.i.d. for 14 days followed
by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days
(H2BA3001)
*Includes only patients with pretreatment clarithromycin susceptibility
tests†Susceptible (S) MIC <0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1 mcg/mL,
Resistant (R) MIC >2 mcg/mL
Patients not eradicated of H. pylori following
omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin,
omeprazole/clarithromycin/amoxicillin, or
lansoprazole/clarithromycin/amoxicillin therapy would likely have clarithromycin
resistant H. pylori isolates. Therefore, for patients
who fail therapy, clarithromycin susceptibility testing should be done, if
possible. Patients with clarithromycin resistant H. pylori
should not be treated with any of the following:
omeprazole/clarithromycin dual therapy; ranitidine bismuth
citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin
triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other
regimens which include clarithromycin as the sole antimicrobial agent.
Amoxicillin Susceptibility Test Results and
Clinical/Bacteriological Outcomes In the omeprazole/clarithromycin/amoxicillin triple-therapy
clinical trials, 84.9% (157/185) of the patients who had pretreatment
amoxicillin susceptible MICs (<0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment susceptibility test
results, and 17 had post-treatment H. pylori isolates
with amoxicillin susceptible MICs. Eleven of the patients who failed triple
therapy also had post-treatment H. pylori isolates
with clarithromycin resistant MICs.
In the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical
trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin
susceptible MICs (<0.25 mcg/mL) were eradicated of H.
pylori. Of those with pretreatment amoxicillin MICs of >0.25 mcg/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
Propionibacterium acnes
Anaerobic Gram-negative Microorganisms Prevotella melaninogenica (formerly
Bacteriodes melaninogenicus) Susceptibility Testing Excluding Mycobacteria and
HelicobacterDilution 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
(mcg/mL)
Interpretation
≤2.0
Susceptible (S)
4.0
Intermediate (I)
≥8.0
Resistant
(R)
For testing Streptococcus spp. including Streptococcus pneumoniae*
MIC
(mcg/mL)
Interpretation
≤0.25
Susceptible (S)
0.5
Intermediate (I)
≥1.0
Resistant
(R)
*These interpretive standards are applicable only to broth microdilution
susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 to 5%
lysed horse blood.
*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:
*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 to 5% lysed horse blood.†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 mcg 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 mcg 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 pneumoniae*
Zone diameter
(mm)
Interpretation
>21
Susceptible (S)
17 to 20
Intermediate (I)
<16
Resistant
(R)
*These zone diameter standards only apply to tests performed using
Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
*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 mcg clarithromycin disk should
provide the following zone diameters in this laboratory test quality control
strain:
*This quality control range is applicable only to tests performed by disk
diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep
blood.†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 micro-dilution method
with Middlebrook 7H9 broth. Results showed an MIC value of <4.0 mcg/mL in 81%
and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of
the non-AIDS isolates had an MIC value <0.5 mcg/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 mcg/mL. Clarithromycin inhibited all isolates at
>10.0 mcg/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 MICs3 One
to three micro-liters of an inoculum equivalent to a No. 2 McFarland standard (1
x 107-1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared
antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated
sheep blood (>2-weeks old). The agar dilution plates are incubated at 35°C in
a microaerobic environment produced by a gas generating system suitable for
Campylobacter species. After 3 days of incubation,
the MICs are recorded as the lowest concentration of antimicrobial agent
required to inhibit growth of the organism. The clarithromycin and amoxicillin
MIC values should be interpreted according to the following criteria:
*These are tentative breakpoints for the agar dilution methodology, and they
should not be used to interpret results obtained using alternative methods.†There were not enough organisms with MICs >0.25 mcg/mL to determine a
resistance breakpoint.
Standardized susceptibility test procedures require the use of laboratory
control microorganisms to control the technical aspects of the laboratory
procedures. Standard clarithromycin and amoxicillin powders should provide the
following MIC values:
*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 are indicated for the treatment of mild to
moderate infections caused by susceptible strains of the designated
microorganisms in the conditions as uled below: Adults 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 in combination with amoxicillin and lansoprazole or
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 in combination with omeprazole capsules or 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 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
Prophylaxis Clarithromycin tablets 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 tablets and other antibacterial drugs,
clarithromycin tablets 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 co-administered with
cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias
(QT prolongation, ventricular tachycardia, ventricular fibrillation, and
torsades de pointes) most likely due to inhibition of metabolism of these drugs
by erythromycin and clarithromycin. Fatalities have been reported.
For information about contraindications of other drugs 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 tablets 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 tablets may interact with some drugs; therefore patients
should be advised to report to their doctor the use of any other
medications.
Clarithromycin tablets can be taken with or without food and can be taken
with milk. 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%.
Concomitant administration of single doses of clarithromycin and
carbamazepine has been shown to result in increased plasma concentrations of
carbamazepine. Blood level monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma
concentrations of the active acid metabolite of terfenadine were threefold
higher, on average, than the values observed when terfenadine was administered
alone. The pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin
were not significantly affected by coadministration of terfenadine once
clarithromycin reached steady-state conditions. Concomitant administration of
clarithromycin with terfenadine is contraindicated. (See CONTRAINDICATIONS.)
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 T1/2 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 co-administered with clarithromycin.
Co-administration 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 resulted in decreased steady-state zidovudine
concentrations. When 500 mg of clarithromycin were administered twice daily,
steady-state zidovudine AUC was reduced by a mean of 12% (n=4). Individual
values ranged from a decrease of 34% to an increase of 14%. Based on limited
data in 24 patients, when clarithromycin tablets were administered two to four
hours prior to oral zidovudine, the steady-state zidovudine Cmax was increased by approximately 2-fold, whereas the AUC was
unaffected.
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.
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 CLCR30 to 60 mL/min, the dose of
clarithromycin should be reduced by 50%. For patients with CLCR <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.
Elevated digoxin serum concentrations in patients receiving clarithromycin
and digoxin concomitantly have also been reported in post-marketing
surveillance. Some patients have shown clinical signs consistent with digoxin
toxicity, including potentially fatal arrhythmias. Serum digoxin 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.)
Erythromycin and clarithromycin are substrates and inhibitors of the 3A
isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Coadministration
of erythromycin or clarithromycin and a drug primarily metabolized by CYP3A may
be associated with elevations in drug concentrations that could increase or
prolong both the therapeutic and adverse effects of the concomitant drug. Dosage
adjustments may be considered, and when possible, serum concentrations of drugs
primarily metabolized by CYP3A should be monitored closely in patients
concurrently receiving clarithromycin or erythromycin.
The following are examples of some clinically significant CYP3A based drug
interactions. Interactions with other drugs metabolized by the CYP3A isoform are
also possible. Increased serum concentrations of carbamazepine and the active
acid metabolite of terfenadine were observed in clinical trials with
clarithromycin.
The following CYP3A based drug interactions have been observed with
erythromycin products and/or with clarithromycin in postmarketing
experience: Antiarrhythmics There have been postmarketing 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, and bromocriptine.
Concomitant administration of clarithromycin with cisapride, pimozide,
astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS).
In addition, there have been reports of interactions of erythromycin or
clarithromycin with drugs not thought to be metabolized by CYP3A including
hexobarbital, phenytoin, and valproate. 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. PregnancyTeratogenic EffectsPregnancy 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.
The most frequently reported events in adults taking clarithromycin tablets
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.
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 or clarithromycin
extended-release tablets; however, patients taking clarithromycin
extended-release tablets reported significantly less severe gastrointestinal
symptoms compared to patients taking clarithromycin tablets. In addition,
patients taking clarithromycin extended-release tablets had significantly fewer
premature discontinuations for drug-related gastrointestinal or abnormal taste
adverse events compared to clarithromycin tablets.
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<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<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, usually in conjunction with taste perversion or taste
loss have also been reported.
Transient CNS events including anxiety, behavioral changes, confusional
states, convulsions, depersonalization, disorientation, hallucinations,
insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo
have been reported during 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.
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:
Hematologic – decreased WBC <1%; elevated prothrombin time 1%
Renal – elevated BUN 4%; elevated serum creatinine <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 may be given with or without
food.
ADULT DOSAGE GUIDELINES
Infection
Clarithromycin Tablets
Dosage (q12h)
Duration (days)
Pharyngitis/Tonsillitis due to S.
pyogenes
250 mg
10
Acute maxillary sinusitis due to
H. influenzae
M. catarrhalis
S.
pneumoniae
500 mg
14
Acute exacerbation of chronic bronchitis due to
H. influenzae
H. parainfluenzae
M. catarrhalis
S.
pneumoniae
500 mg
500 mg
250 mg 250 mg
7-14
7
7-14 7-14
Community-Acquired Pneumonia due to
H. influenzae
H. parainfluenza
M. catarrhalis
S. pneumoniae
C. pneumoniae
M.
pneumoniae
250mg
--
--
250 mg
250 mg 250 mg
7
--
--
7-14
7-14 7-14
Uncomplicated skin and skin structure
S. aureus
S.
pyogenes
250 mg
7-14
H.
pylori
Eradication to Reduce the Risk of Duodenal Ulcer
RecurrenceTriple 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
(q12h)
kg
lbs
9
20
62.5 mg
17
37
125 mg
25
55
187.5 mg
33
73
250 mg
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 <30 mL/min),
with or without coexisting hepatic impairment, the dose should be halved or the
dosing interval doubled. Mycobacterial InfectionsProphylaxis 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 500 mg are white, oval-shaped, film-coated tablets,
debossed GG C9 on one side and plain on the reverse side, and are supplied as
follows:
Bottles of 15
NDC 54868-5430-0
Bottles of 20
NDC 54868-5430-1
Bottles of 30
NDC 54868-5430-2
Bottles of 60
NDC 54868-5430-3
Store at 20°-25°C (68°-77°F) (see USP Controlled Room
Temperature).
Dispense in a tight container as described in the USP. Protect from
light.
Clinical Studies
Mycobacterial InfectionsProphylaxis A randomized, double-blind study (561) compared clarithromycin
500 mg b.i.d. to placebo in patients with CDC-defined AIDS and CD4 counts <100 cells/µL. This study accrued 682 patients from
November 1992 to January 1994, with a median CD4 cell
count at study entry of 30 cells/µL. Median duration of clarithromycin was 10.6
months vs. 8.2 months for placebo. More patients in the placebo arm than the
clarithromycin arm discontinued prematurely from the study (75.6% and 67.4%,
respectively). However, if premature discontinuations due to MAC or death are
excluded, approximately equal percentages of patients on each arm (54.8% on
clarithromycin and 52.5% on placebo) discontinued study drug early for other
reasons. The study was designed to evaluate the following endpoints:
MAC bacteremia, defined as at least one positive culture for M. avium complex bacteria from blood or another normally
sterile site.
Survival
Clinically significant disseminated MAC disease, defined as MAC bacteremia
accompanied by signs or symptoms of serious MAC infection, including fever,
night sweats, weight loss, anemia, or elevations in liver function
tests.
MAC Bacteremia In patients randomized to clarithromycin, the risk of MAC
bacteremia was reduced by 69% compared to placebo. The difference between groups
was statistically significant (p<0.001). On an intent-to-treat basis, the
one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized
to clarithromycin and 19.4% for patients randomized to placebo. While only 19 of
the 341 patients randomized to clarithromycin developed MAC, 11 of these cases
were resistant to clarithromycin. The patients with resistant MAC bacteremia had
a median baseline 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
Mortality
Reduction in
Mortality on Clarithromycin
Placebo
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
*Includes those events possibly or probably related to study drug and
excludes concurrent conditions.†>2% Adverse Event Incidence Rates for either treatment group.
Among these events, taste perversion was the only event that had
significantly higher incidence in the clarithromycin-treated group compared to
the placebo-treated group.
Discontinuation due to adverse events was required in 18% of patients
receiving clarithromycin compared to 17% of patients receiving placebo in this
trial. Primary reasons for discontinuation in clarithromycin treated patients
include headache, nausea, vomiting, depression and taste perversion. Changes in Laboratory Values of Potential Clinical
Importance In immuno-compromised 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* Exceeding Extreme Laboratory Value in Patients
Receiving Prophylaxis Against M. avium Complex
*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).†ULN = Upper Limit of Normal
Treatment Three randomized studies (500, 577, and 521) compared different
dosages of clarithromycin in patients with CDC-defined AIDS and CD4 counts <100 cells/mcL. 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
<50/mcL at study entry. The studies were designed to evaluate the following
end points:
Change in MAC bacteremia or blood cultures negative for M. avium.
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) infection4. 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 <8 mcg/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 uled below. Most of these events were
mild to moderate in severity, although 5% (Study 500: 8%; Study 577: 4%) of
patients receiving 500 mg b.i.d. and 5% (Study 500: 4%; Study 577: 6%) of
patients receiving 1000 mg b.i.d. reported severe adverse events. Excluding
those patients who discontinued therapy or died due to complications of their
underlying non-mycobacterial disease, approximately 8% (Study 500: 15%; Study
577: 7%) of the patients who received 500 mg b.i.d. and 12% (Study 500: 14%;
Study 577: 12%) of the patients who received 1000 mg b.i.d. discontinued therapy
due to drug-related events during the first 12 weeks of therapy. Overall, the
500 and 1000 mg b.i.d. doses had similar adverse event profiles.
Treatment-related* Adverse Event Incidence Rates (%) in
Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500
mg b.i.d. Clarithromycin Dose
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* Exceeding Extreme Laboratory Value Limits
During First 12 Weeks of Treatment 500 mg b.i.d. Doseâ€
*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)†Includes all values within the first 12 weeks for patients who start on 500
mg b.i.d.‡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
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 control
agent.
Safety The incidence of adverse events in all patients treated,
primarily diarrhea and vomiting, did not differ clinically or statistically for
the two agents.
In two other controlled clinical trials of acute otitis media performed in
the United States, where significant rates of beta-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%)
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
InfectionClarithromycin + Lansoprazole and AmoxicillinH.
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
(Clarithromycin/Lansoprazole/Amoxicillin) Percent of Patients Cured [95%
Confidence Interval] (number of patients)
*Based on evaluable patients with confirmed duodenal ulcer (active or within
one year) and H. pylori infection at baseline defined
as at least two of three positive endoscopic tests from CLOtest® (Delta West
LTD., Bentley, Australia), histology, and/or culture. Patients were included in
the analysis if they completed the study. Additionally, if patients were dropped
out of the study due to an adverse event related to the study drug, they were
included in the analysis as evaluable failures of therapy.†Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a
confirmed duodenal ulcer (active or within one year). All dropouts were included
as failures of therapy.‡(p<0.05) versus clarithromycin/lansoprazole and lansoprazole/amoxicillin
dual therapy.§(p<0.05) versus clarithromycin/amoxicillin dual therapy.¶The 95% confidence interval for the difference in eradication rates, 10-day
minus 14-day, is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1)in the
intent-to-treat analysis.
Clarithromycin + Omeprazole and Amoxicillin
TherapyH.
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]
*Patients were included in the analysis if they had confirmed duodenal ulcer
disease (active ulcer studies 126 and 127; history of ulcer within 5 years,
study M96-446) and H. pylori infection at baseline
defined as at least two of three positive endoscopic tests from CLOtest®,
histology, and/or culture. Patients were included in the analysis if they
completed the study. Additionally, if patients dropped out of the study due to
an adverse event related to the study drug, they were included in the analysis
as failures of therapy. The impact of eradication on ulcer recurrence has not
been assessed in patients with a past history of ulcer.†Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal
ulcer disease. All dropouts were included as failures of therapy.‡p<0.05 versus clarithromycin plus amoxicillin.
Safety In clinical trials using combination therapy with clarithromycin
plus omeprazole and amoxicillin, no adverse reactions peculiar to the
combination of these drugs have been observed. Adverse reactions that have
occurred have been limited to those that have been previously reported with
clarithromycin, omeprazole, or amoxicillin.
The most frequent adverse experiences observed in clinical trials using
combination therapy with clarithromycin plus omeprazole and amoxicillin (n=274)
were diarrhea (14%), taste perversion (10%), and headache (7%).
For information about adverse reactions with omeprazole or amoxicillin, refer
to the ADVERSE REACTIONS
section of their package inserts.
Clarithromycin + Omeprazole Therapy Four randomized, double-blind, multi-center studies (067, 100,
812b, and 058) evaluated clarithromycin 500 mg t.i.d. plus omeprazole 40 mg q.d.
for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or by
omeprazole 40 mg q.d. (812b) for an additional 14 days in patients with active
duodenal ulcer associated with H. pylori. Studies 067
and 100 were conducted in the U.S. and Canada and enrolled 242 and 256 patients,
respectively. H. pylori infection and duodenal ulcer
were confirmed in 219 patients in Study 067 and 228 patients in Study 100. These
studies compared the combination 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)
*p<0.05 for clarithromycin + omeprazole versus clarithromycin monotherapy.†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)
*Statistically significantly higher than clarithromycin monotherapy
(p<0.05)†Statistically significantly higher than omeprazole monotherapy
(p<0.05). H. pylori eradication was defined as no positive
test (culture or histology) at 4 weeks following the end of treatment, and two
negative tests were required to be considered eradicated. In the per-protocol
analysis, the following patients were excluded: dropouts, patients with major
protocol violations, patients with missing H. pylori
tests post-treatment, and patients that were not assessed for H. pylori eradication at 4 weeks after the end of treatment
because they were found to have an unhealed ulcer at the end of treatment.
Ulcer recurrence at 6-months following the end of treatment was assessed for
patients in whom ulcers were healed post-treatment.
Ulcer Recurrence at 6 months by H. pylori Status at 4 to 6
Weeks
*See 12-Month Recurrence Rates.
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.
*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:
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
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.
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.
National Committee for Clinical Laboratory Standards. Summary Minutes,
Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL. January 11-13,
1998.
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.
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.
07-2008M
7291
Sandoz Inc.
Princeton, NJ 08540 Relabeling and Repackaging by:
Physicians Total Care, Inc.Tulsa, OKÂ Â Â Â Â Â 74146
Principal Display Panel
clarithromycin (Clarithromycin) tabletÂ
500 mg
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