|
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%.
Food slightly delays both the onset of clarithromycin
absorption and the formation of the antimicrobially active
metabolite, 14-OH clarithromycin, but does not affect
the extent of bioavailability. Therefore, clarithromycin
tablets may be given without regard to food.
In fasting healthy human subjects, peak serum concentrations
were attained within 2 hours after oral dosing. Steady-state
peak serum clarithromycin concentrations were attained
in 2 to 3 days and were approximately 1 mcg/ml with a
250-mg dose administered every 12 hours, 2 to 3 mcg/ml
with a 500 mg dose administered every 12 hours, and 3
to 4 mcg/ml with a 500-mg dose administered every 8 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
7-9 hours. With any of these dosing regimens, the steady-state
concentration of this metabolite is generally attained
within 2 to 3 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-
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 in TABLE 1.
| TABLE 1 Concentration
(after 250 mg q12h) |
| Tissue Type |
Tissue (µg/g) |
Serum (µg/ml) |
| Tonsil |
1.6 |
0.8 |
| Lung |
8.8 |
1.7 |
When 250-mg doses of clarithromycin suspension 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 2 µg/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.
For adult patients, the bioavailability of 10 ml of the
125-mg/5 ml suspension or 10 ml of the 250-mg/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 mcg/ml for clarithromycin and 1 to 2 mcg/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 mcg/ml.
Clarithromycin penetrates into the middle ear fluid of children
with secretory otitis media (see TABLE 2).
| TABLE 2
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 concentration from 3.6 (±1.5)
mcg/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
| TABLE
3 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 prescribing information.
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 INDICATIONS
AND USAGE.
Aerobic Gram-positive Microorganisms: Staphylococcus
aureus, Streptococcus pneumoniae, Streptococcus pyrogenes.
Aerobic Gram-negative Microorganisms: Haemophilus
influenzae, 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 INDICATIONS AND
USAGE.
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 bid versus tid 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
mg/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 mg/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 mg/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 mg/ml. Two patients had
an unconfirmed pretreatment amoxicillin minimum inhibitory
concentration (MIC) of >256 mg/ml by E-test.
| TABLE
4 Clarithromycin Susceptibility Test Results
and Clinical/Bacteriological Outcomes* |
|
Clarithromycin Pretreatment
Results |
Clarithromycin
Post-treatment Results |
| |
H.
pylori negative - eradicated |
H. pylori positive - not
eradicated Post-treatment susceptibility results |
| |
S† |
I† |
R† |
No
MIC |
| Omeprazole
40 mg qd/clarithromycin 500 mg tid for 14 days
followed by omeprazole 20 mg qd for another
14 days (M93-067, M93-100) |
| Susceptible† |
108 |
72 |
1 |
|
26 |
9 |
| Intermediate† |
1 |
|
|
|
1 |
|
| Resistant† |
4 |
|
|
|
4 |
|
| Ranitidine
bismuth citrate 400 mg bid/clarithromycin 500
mg tid for 14 days followed by ranitidine bismuth
citrate 400 mg bid for another 14 days (H2BA3001) |
| Susceptible† |
124 |
98 |
4 |
|
14 |
8 |
| Intermediate† |
3 |
2 |
|
|
|
1 |
| Resistantb |
17 |
1 |
|
|
15 |
1 |
| Rantidine
bismuth citrate 400 mg bid/clarithromycin 500
mg bid for 14 days followed by ranitidine bismuth
citrate 400 mg bid for another 14 days (H2BA3001) |
| Susceptible† |
125 |
106 |
1 |
1 |
12 |
5 |
| Intermediate† |
2 |
2 |
|
|
|
|
| Resistant† |
20 |
1 |
|
|
19 |
|
| Omeprazole
20 mg bid/clarithromycin 500 mg bid/amoxicillin
1 g bid for 10 days (126, 127, M96-446) |
| Susceptible† |
171 |
153 |
7 |
|
3 |
8 |
| Intermediate† |
|
|
|
|
|
|
| Resistant† |
14 |
4 |
1 |
|
6 |
3 |
| Lansoprazole
30 mg bid/clarithromycin 500 mg bid/amoxicillin
1 g bid for 14 days (M95-399, M93-131, M95-392) |
| Susceptible† |
112 |
105 |
|
|
|
7 |
| Intermediate† |
3 |
3 |
|
|
|
|
| Resistant† |
17 |
6 |
|
|
7 |
4 |
| Lansoprazole
30 mg bid/clarithromycin 500 mg bid/amoxicillin
1 g bid for 10 days (M95-399) |
| Susceptible† |
42 |
40 |
1 |
|
1 |
|
| Intermediate† |
|
|
|
|
|
|
| Resistant† |
4 |
1 |
|
|
3 |
|
| *
Includes only patients with pretreatment clarithromycin
susceptibility tests. |
| †
Susceptible (S) MIC <0.25 mg/ml,
Intermediate (I) MIC 0.5-1.0 mg/ml,
Resistant (R) MIC >2 mg/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
mg/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
mg/ml) were eradicated of H. pylori. Of those with pretreatment
amoxicillin MICs of >0.25 mg/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 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
criteria in TABLE 5.
| TABLE 5 |
| MIC (mcg/ml) |
Interpretation |
| £2.0 |
Susceptible (S) |
| 4.0 |
Intermediate (I) |
| ³8.0 |
Resistant (R) |
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 MIC
values found in TABLE 6.
| TABLE 6 |
| Microorganism |
|
MIC (µg/ml) |
| S. aureus |
ATCC 29213 |
0.12 to 0.5 |
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 criteria found in TABLE 7.
| TABLE 7 |
| Zone Diameter (mm) |
Interpretation |
| ³18 |
Susceptible (S) |
| 14-17 |
Intermediate (I) |
| £13 |
Resistant (R) |
Interpretation should be as stated in TABLE 7 for results
using dilution techniques. Interpretation involves correlation
of the diameter obtained in the disk test with the MIC
for clarithromycin. However, standardized diffusion methods
for routine in vitro susceptibility testing, using the
15-mcg clarithromycin disk, do not measure the additive
antimicrobial activity of the 14-OH metabolite and, thus,
may underestimate the drug's potential activity against
Haemophilus influenzae. Haemophilus influenzae isolates
falling into the "Intermediate" category often
respond to treatment.
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 zone diameters in the laboratory
test quality control strain found in TABLE 8.
| TABLE 8 |
| Organism |
|
Zone Diameter (mm) |
| S. aureus |
ATCC 25923 |
26-32 |
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 £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 MICs.3 One to three microliters
of an inoculum equivalent to a No. 2 McFarland standard
(1 ´ 107 - 1 ´ 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 criteria shown in TABLE 9.
|
TABLE 9
|
|
Clarithromycin MIC (mg/ml)*
|
Interpretation |
|
<0.25
|
Susceptible
(S) |
|
0.5-1.0
|
Intermediate
(I) |
|
>2.0
|
Resistant (R) |
| *
These are tentative breakpoints for the agar dilution
methodology, and they should not be used to interpret
results obtained using alternative methods. |
|
TABLE 10
|
|
Amoxicillin MIC (mg/ml)*†
|
Interpretation |
|
<0.25
|
Susceptible
(S) |
| *
These are tentative breakpoints for the agar dilution
methodology, and they should not be used to interpret
results obtained using alternative methods. |
| †
There were not enough organisms with MICs > 0.25
mg/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
MIC values shown in TABLE 11.
|
TABLE 11
|
|
Microorganisms
|
Antimicrobial Agent
|
MIC (mg/ml)*
|
| H. pylori ATCC
43504 |
Clarithromycin |
0.015-0.12 mg/ml |
| H. pylori ATCC
43504 |
Amoxicillin |
0.015-0.12 mg/ml |
| *
These are quality control ranges for the agar dilution
methodology and they should not be used to control
test results obtained using alternative methods. |
CLINICAL STUDIES
Mycobacterial Infections Prophylaxis
A randomized, double-blind study (561) compared clarithromycin
500 mg bid to placebo in patients with CDC-defined AIDS
and CD4 counts <100 cells/mcl. This study accrued 682
patients from November 1992 to January 1994, with a median
CD4 cell count at study entry of 30 cells/mcl. Median
duration of clarithromycin was 10.6 months vs. 8.2 months
for placebo. More patients in the placebo arm than the
clarithromycin arm discontinued prematurely from the study
(75.6% and 67.4%, respectively). However, if premature
discontinuations due to MAC or death are excluded, approximately
equal percentages of patients on each arm (54.8% on clarithromycin
and 52.5% on placebo) discontinued study drug early for
other reasons. The study was designed to evaluate the
following endpoints:
1. MAC bacteremia, defined as at least
one positive culture for M. avium complex bacteria from
blood or another normally sterile site.
2. Survival.
3. Clinically significant disseminated
MAC disease, defined as MAC bacteremia accompanied by signs
or symptoms of serious MAC infection, including fever, night
sweats, weight loss, anemia, or elevations in liver function
tests.
MAC Bacteremia
In patients randomized to clarithromycin, the risk of MAC
bacteremia was reduced by 69% compared to placebo. The difference
between groups was statistically significant (p<0.001).
On an intent-to-treat basis, the one-year cumulative incidence
of MAC bacteremia was 5.0% for patients randomized to clarithromycin
and 19.4% for patients randomized to placebo. While only
19 of the 341 patients randomized to clarithromycin developed
MAC, 11 of these cases were resistant to clarithromycin.
The patients with resistant MAC bacteremia had a median
baseline CD4 count of 10 cells/mm3 (range 2-25 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 10-80 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 2-130 cells/mm3) for placebo
patients that developed MAC.
Survival
A statistically significant survival benefit was observed.
(See TABLE 12.)
| TABLE 12 |
| |
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.
| TABLE 13
Treatment-related* Adverse Event Incidence Rates
(%) in Immunocompromised Adult Patients Receiving
Prophylaxis Against M. Avium Complex |
| |
Clarithromycin |
Placebo |
| |
(n=339) |
(n=339) |
| Body System†/ Adverse
Event |
% |
% |
| Body
as a Whole |
| Abdominal
pain |
5.0% |
3.5% |
| Headache |
2.7% |
0.9% |
| Digestive |
| Diarrhea |
7.7% |
4.1% |
| Dyspepsia |
3.8% |
2.7% |
| Flatulence |
2.4% |
0.9% |
| Nausea |
11.2% |
7.1% |
| Vomiting |
5.9% |
3.2% |
| Skin
& Appendages |
| Rash |
3.2% |
3.5% |
| Special
Senses |
| Taste
Perversion |
8.0% |
0.3% |
| *
Includes those events possibly or probably related
to study drug and excludes concurrent conditions. |
| †
>2% Adverse Event Incidence Rates for either
treatment group. |
Among these events, taste perversion was the only event
that had significantly higher incidence in the clarithromycin-treated
group compared to the placebo-treated group. Discontinuation due to adverse events was
required in 18% of patients receiving clarithromycin compared
to 17% of patients receiving placebo in this trial. Primary
reasons for discontinuation in clarithromycin treated
patients include headache, nausea, vomiting, depression
and taste perversion.
Changes in Laboratory Values
of Potential Clinical Importance
In immunocompromised patients receiving
prophylaxis against M. avium, evaluations of laboratory
values were made by analyzing those values outside the
seriously abnormal value (i.e., the extreme high or low
limit) for the specified test.
| TABLE 14
Percentage of Patients* Exceeding Extreme Laboratory
Value in Patients Receiving Prophylaxis Against
M. avium Complex |
| |
|
Clarithromycin
500 mg bid |
Placebo |
| Hemoglobin |
< 8g/dl |
4/118 |
3% |
5/103 |
5% |
| Platelet Count |
< 50 ´
109/L |
11/249 |
4% |
12/250 |
5% |
| WBC Count |
<1´109/L |
2/103 |
4% |
0/95 |
0% |
| SGOT |
>5´ULN† |
7/196 |
4% |
5/208 |
2% |
| SGPT |
>5´ULN† |
6/217 |
3% |
4/232 |
2% |
| Alk. Phos. |
>5´ULN† |
5/220 |
2% |
5/218 |
2% |
| * Includes
only patients with baseline values within the normal
range or borderine 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 bid doses; Study 500 also had a 2000 mg bid
group. Study 521 was a pediatric study at 3.75, 7.5, and
15 mg/kg bid. 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:
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, nightsweats, weight loss, diarrhea, splenomegaly,
and hepatomegaly.
The results for the 500 study are described in Survival.
The 577 study results were similar to the results of the
500 study. Results with the 7.5 mg/kg bid dose in the
pediatric study were comparable to those for the 500 mg
bid 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 clofazamine 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 in TABLE 15. 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.
| TABLE 15
Mean Reductions in Log CFU from Baseline (After
4 Weeks of Therapy) |
| 500 mg bid (N=35) |
1000 mg bid (N=32) |
2000 mg bid (N=26) |
Four Drug Regimen (N=24) |
| 1.5 |
2.3 |
2.3 |
1.4 |
Although the 1000 mg and 2000 mg bid 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 bid
group and 59% (29/49) and 52% (25/48) for the 1000 and
2000 mg bid 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 bid groups and 8% (4/48) for
the 2000 mg bid 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
bid 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 bid groups, respectively. The
time to first decrease of at least 1 log in CFU count
was significantly shorter with the 1000 and 2000 mg bid
doses (median equal to 16 and 15 days, respectively) in
comparison to the 500 mg bid 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 bid
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
500-2000 mg bid doses. Similarly, 77% of patients reported
resolution or improvement in fevers at some point.
Response rates for clinical signs of MAC are given in
TABLE 16 and TABLE 17.
| TABLE 16 |
| Resolution
of Fever |
Resolution
of Night Sweats |
bid
dose
(mg) |
% ever
afebrile |
% afebrile
³6 weeks |
bid
dose
(mg) |
% ever
resolving |
% resolving
³6 weeks |
| 500 |
67% |
23% |
500 |
85% |
42% |
| 1000 |
67% |
12% |
1000 |
70% |
33% |
| 2000 |
62% |
22% |
2000 |
72% |
36% |
| TABLE 17 |
| Weight Gain
>3% |
Hemoglobin
Increase >1 gm |
bid
dose
(mg) |
% ever
gaining |
% ever
gaining
³6 weeks |
bid
dose
(mg) |
% ever
increasing |
% ever
increasing
³6 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 2-6
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 wshow clinical response after 12 weeks.
Survival
Median survival time from study entry (Study
500) was 249 days at the 500 mg bid dose compared to 215
days with the 1000 mg bid dose. However, during the first
12 weeks of therapy, there were 2 deaths in 53 patients
in the 500 mg bid group versus 13 deaths in 51 patients
in the 1000 mg bid 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 bid dose and 179 days for the
1000 mg bid 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 bid and 18 deaths in 214 patients taking 1000 mg bid.
Safety
The adverse event profiles showed that both
the 500 and 1000 mg bid doses were well tolerated. The
2000 mg bid 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 analyses in TABLE 18 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 party to differences
in monitoring between the two studies. In adult patients
receiving clarithromycin 500 mg bid, 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 bid and 5% (Study 500: 4%;
Study 577: 6%) of patients receiving 1000 mg bid 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
bid and 12% (Study 500: 14%; Study 577: 12%) of the patients
who received 1000 mg bid discontinued therapy due to drug-related
events during the first 12 weeks of therapy. Overall,
the 500 and 1000 mg bid doses had similar adverse event
profiles (see TABLE 18).
| TABLE 18
Treatment-related* Adverse Event Incidence Rates
(%) in Immunocompromised Adult Patients During the
First 12 Weeks of Therapy with 500 mg bid Clarithromycin
Dose |
| |
Study |
Study |
|
| |
500 |
577 |
Combined |
| Adverse Event |
(n=53) |
(n=255) |
(n=308) |
| Abdominal Pain |
7.5 |
2.4 |
3.2 |
| Diarrhea |
9.4 |
1.6 |
2.9 |
| Flatulence |
7.5 |
0.0 |
1.3 |
| Headache |
7.5 |
0.4 |
1.6 |
| Nausea |
28.3 |
9.0 |
12.3 |
| Rash |
9.4 |
2.0 |
3.2 |
| Taste Perversion |
18.9 |
0.4 |
3.6 |
| Vomiting |
24.5 |
3.9 |
7.5 |
| * Includes
those events possibly or probably related to study
drug and excludes concurrent conditions. |
A limited number of pediatric AIDS patients have been
treated with clarithromycin suspension for mycobacterial
infections. The most frequently reported adverse events,
excluding those due to the patient's concurrent condition,
were consistent with those observed in adult patients.
Changes in Laboratory Values
In immunocompromised patients treated with
clarithromycin for mycobacterial infections, evaluations
of laboratory values were made by analyzing those values
outside the seriously abnormal level (i.e., the extreme
high or low limit) for the specified test (see TABLE 19).
| TABLE 19
Percentage of Patients* Exceeding Extreme Laboratory
Value Limits During First 12 Weeks of Treatment
500 mg bid Dose† |
| |
|
Study 500 |
Study 577 |
Combined |
| BUN |
>50 mg/dl |
0% |
<1% |
<1% |
| Platelet Count |
<50 ´
109/L |
0% |
<1% |
<1% |
| SGOT |
>5 ´
ULN‡ |
0% |
3% |
2% |
| SGPT |
>5 ULN‡ |
0% |
2% |
1% |
| WBC |
<1 ´
109/L |
0% |
1% |
1% |
| * Includes
only patients with baseline values within the normal
range or borderline high (hematology variables)
and within normal range
or borderline low (chemistry variables). |
| † Includes
all values within first 12 weeks for patients who
start on 500 mg twice a day. |
| ‡ 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 presumptive
bacterial eradication/clinical cure outcomes (i.e., clinical
success) were obtained and are found in TABLE 20.
| TABLE 20
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. pyrogenes |
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
|
