DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
CLINICAL STUDIES
ANIMAL PHARMACOLOGY AND TOXICOLOGY
REFERENCES
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.
BIAXIN is available as tablets and granules for oral suspension.
Each yellow oval film-coated BIAXIN tablet contains 250 mg or 500 mg of clarithromycin and
the following inactive ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No.
10, FD&C
Blue No. l, magnesium stearate, povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan
monooleate, stearic acid, talc, titanium dioxide, and vanillin. The 250-mg tablet also conlains
pregelatinized starch.
After constitution each 5 mL of BIAXIN suspension contains 125 mg or 250 mg of
clarithromycin.
Each bottle of BIAXIN granules contains 1250 mg (50 mL size) 2500 mg (50 and 100 mL sizes)
or
5000 mg ( 100 mL size) of clarithromycin and the following inactive ingredients: carbomer, castor
oil, citric acid, hydroxypropyl methylcellulose phthalate, maltodextrin, potassium sorbate, povidone,
silicon
dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch favor.
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, BIAXIN 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 µg/mL with a 250-mg dose administered every 12 hours and 2 to 3 µg/mL with a
500-mg dose administered every 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 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the
recommended doses
of 250 mg and 500 mg administered every 12 hours. With a 250 mg every 12 hours dosing the
principal
metabolite 14-OH clarithromycin attains a peak steady-state concentration of about 0.6 µg/mL
and has
an elimination half-life of 5 to 6 hours. With a 500 mg every 12 hours dosing, the peak steady-
state concentration of 14-OH clarithromycin is slightly higher (up to 1 µg/mL), and its elimination
half-life is
about 7 hours. With either dose, 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 HlV-infected patients
taking 500- or 1000-mg doses
of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2-4
µg/mL and
5-10 µg/mL, respectively.
The steady-state concentrations of clarithromycin in subjects with impaired hepatic-function did
not
differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were
lower in the
hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least
partially
offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic
function
when compared to healthy subjects.
The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal
function. (See
PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and
fluids.
There are no data available on cerebrospinal fluid penetration. Because of high intracellular
concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue
and serum concentrations are presented below.
CONCENTRATION
(after 250 mg q 12 h)
Tissue Type Tissue Serum
(µg/g) (µg/mL)
Tonsil 1.6 0.8
Lung 8.8 1.7
When 250-mg doses of clarithromycin as BIAXIN 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 BIAXIN 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 q 12 h doses of
clarithromycin as
the suspension generally resulted in steady-state peak plasma concentrations of 3 to 7 µg/mL
for clarithromycin and 1 to 2 µg/mL for 14-OH clarithromycin.
In HIV-infected children taking 15 mg/kg every 12 hours, steady-state clarithromycin peak
concentrations generally ranged from 6-15 µg/mL.
Clarithromycin penetrates into the middle ear fluid of children with secretory otitis media.
CONCENTRATION
(after 7.5 mg /kg q 12 h for 5 doses)
Middle Ear Fluid Serum
Analyte (µg/mL) (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 (+ or – 0.4) µg/mL to 1.0 (+ or – 0.4) µg/mL and the
extent of
absorption from 7.2 (+ or – 2.5) hr·µg/mL to 6.5 (+ or – 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 (+ or – 1.5) µg/mL to 4.6 (+ or – 2.8) µg/mL and the extent of absorption from 10.0 (+ or – 5.5)
hr·µg/mL
to 14.2 (+ or – 9.4) hr·µg/mL.
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.
Against Haemophilus influenzae microorganisms, l4-OH clarithromycin is twice as active 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:
Gram-positive aerobes
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
Gram-negative aerobes
Haemophilus influenzas
Moraxella catarrhalis
Other aerobes
Mycoplasma pneumoniae
Mycobacteria
Mycobacterium avium complex (MAC) consisting of:
Beta-lactamase production should have no effect on clarithromycin activity.
NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to
clarithromycin.
The following in vitro data are available, but their clinical significance is unknown.
Clarithromycin
exhibits in vitro minimal inhibitory concentrations (MlC’s) of 2 µg/mL or less against most (> or = to 90%)
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.
Gram-positive aerobes
Listeria monocytogenes
Streptococcus agalactiae
Streptococci (Groups C, F, G)
Viridans group streptococci
Gram-negative aerobes
Bordetella pertussis
Campylobacter jejuni
Legionella pneumophila
Neisseria gonorrhoeae
Pasteurella multocida
Other aerobes
Chlamydia trachomatis
Gram-positive anaerobes
Clostridium perfringens
Peprococcus niger
Propionibacterium acnes
Gram-negative anaerobes
Prevotella melaninogenica (formerly Bacteriodes melaninogenicus)
Susceptibility Testing Excluding Mycobacteria:
Dilution Techniques:
Quantitative methods that are used to determine minimum inhibitory concentrations provide
reproducible
estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized
procedure
uses a standardized dilution method1 (broth, agar, or microdilution) or equivalent with
clarithromycin
powder. The MIC values obtained should be interpreted according to the following criteria:
MIC (µg/mL) Interpretation <= 2.0 (S) Susceptible 4.0 (I) Intermediate>= 8.0 (R) Resistant
A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually
achievable
concentrations of the antimicrobial compound in blood.
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 also provides a buffer zone that prevents small uncontrolled technical factors from
causing
major discrepancies in interpretation.
A report of “Resistant” indicates that usually achievable drug concentrations are unlikely to be
inhibitory, and that other therapy should be selected.
Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be
appropriate
to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further
information on drug concentrations achieved in infected body sites and other pharmacokinetic
properties of this
antimicrobial drug product.)
Standardized susceptibility test procedures require the use of laboratory control microorganisms.
Standard clarithromycin powder should provide the following MIC values:
Organism MIC (µg/mL) S. aureus ATCC 29213 0.12-0.5
Diffusion Techniques:
Quantitative methods that require measurement of zone diameters provide reproducible
estimates of the
susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 that
has been
recommended for use with disks to test the susceptibility of microorganisms to clarithromycin
uses the
15 µg clarithromycin disk. Interpretation involves the correlation of the diameter obtained in the
disk test
with the minimum inhibitory concentration (MIC) for clarithromycin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a
15-µg clarithromycin disk should be interpreted according to the following criteria:
Zone Diameter (mm) Interpretation >= 18 (S) Susceptible 14-17 (I) Intermediate <= 13 (R) Resistant
Interpretation should be as stated above for results using dilution techniques. However,
standardized diffusion methods for routine in vitro susceptibility testing, using the 15-µg 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, susceptibility test procedures require the use of
laboratory
control microorganisms. The 15-µg clarithromycin disk should give the following zone diameters
in this
laboratory test quality control strain:
Orgnaism Zone Diameter (mm) S. aureus ATCC 29523 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 Muelle-
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
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
MlC of 2.5 µg/mL. Clarithromycin inhibited all isolates at > 10.0 µg/mL.
Susceptibility Testing for Mycobacterium avium Complex (MAC):
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and
gram-negative bacteria should not be used for determining clarithromycin MIC values against
mycobacteria. In vitro
susceptibility testing methods and diagnostic products currently available for determining
minimum
inhibitory concentration (MlC) 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.
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the treatment
of mild
to moderate infections caused by susceptible strains of the designated microorganisms in the
conditions
listed 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, Moraxella
catarrhalis,
or Streptococcus pneumoniae
Pneumonia due to Mycoplasma pneumoniae, or Streptococcus pneumoniae
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
Children:
Pharyngitis/Tonsillitis due to Streptococcus pyogenes
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus
pneumoniae
Acute otitis media due to Haemophilus influenzas, 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:
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention
of
disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV
infection.
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.
Clarithromycin is contraindicated in patients receiving terfenadine therapy who have preexisting
cardiac abnormalities (arrhythmia, bradycardia, QT interval prolongation, ischemic heart disease,
congestive
heart failure, etc.) or electrolyte disturbances. (See PRECAUTIONS–Drug Interactions.)
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.)
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
clarithromycin,and may range in severity from mild to life threatening. Therefore, it is important
to
consider this diagnosis in patients who present with diarrhea subsequent to the administration of
antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit
overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficle is a primary cause of
“antibiotic-associated colitis”.
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures
should be
initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug
alone.
In moderate to severe cases consideration should he given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficle colitis.
General: 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.
Information to Patients: BIAXIN tablets and oral suspension can be taken with or without food
and can
be taken with milk. Do NOT refrigerate the suspension.
Drug Interactions: Clarithromycin use in patients who are receiving theophylline may be
associated with
an increase of serum theophylline concentrations. Monitoring of serum theophylline
concentrations
should be considered for patients receiving high doses of theophylline or with baseline
concentrations in
the upper therapeutic range. In two studies in which theophylline was administered with
clarithromycin
(a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together
with
250 or 500 mg ql2h clarithromycin), the steady-state levels of Cmax Cmin and the area under the
serum
concentration lime 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. The increase in the QT interval seen in association with the elevated
terfenadine acid
metabolite level is unlikely to be of clinical significance in healthy individuals. Clarithromycin
should not
be given to patients receiving terfenadine therapy who have preexisting cardiac abnormalities
(arrhythmia, bradycardia, QT interval prolongation, ischemic heart disease ,congestive heart failure,
etc.) or electrolyte disturbances. (See CONTRAINDICATIONS.)
Simultaneous oral administration of BIAXIN tablets and zidovudine to HlV-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
Biaxin 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 BIAXIN tablets and didanosine to 12 HlV-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.
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 arrhythmias. Serum digoxin levels should be carefully
monitored
while patients are receiving digoxin and clarithromycin simultaneously.
The following drug interactions, other than increased serum concentrations of carbamazepine
and
active acid metabolite of terfenadine, have not been reported in clinical trials with clarithromycin;
however, they have been observed with erythromycin products and/or with clarithromycin in
post-marketing
experience.
Concurrent use of erythromycin or clarithromycin and ergotamine or dihydroergotamine has
been associated in some patients with acute ergot toxicity characterized by severe peripheral
vasospasm and
dysesthesia.
Erythromycin has been reported to decrease the clearance of triazolam and, thus, may increase
the
pharmacologic effect of triazolam. 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.
The use of erythromycin and clarithromycin in patients concurrently taking drugs metabolized
by the cytochrome P450 system may be associated with elevations in serum levels of these
other drugs. There
have been reports of interactions of erythromycin and/or clarithromycin with carbamazepine,
cyclosporine, hexobarbital, phenytoin, alfentanil, disopyramide, lovastatin, bromocriptine,
valproate,
terfenadine, cisapride, pimozide, and astemizole. Serum concentrations of drugs metabolized by
the
cytochrome P450 system should be monitored closely in patients concurrently receiving these
drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
The following in vitro mutagenicity tests have been conducted with clarithromycin:
Salmonella/Mammalian Microsomes Test
Bacterial Induced Mutation Frequency Test
In vitro Chromosome Aberration Test
Rat Hepatocyte DNA Synthesis Assay
Mouse Lymphoma Assay
Mouse Dominant Lethal Study
Mouse Micronucleus Test
All tests had negative results except the In Vitro Chromosome Aberration Test which was
weakly positive in one test and negative in another.
In addition, a Bacterial Reverse-Mutation
Test (Ames Test) has been performed on clarithromycin
metabolites with negative results.
Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3
times the
recommended maximum human dose based on mg/m2) to male and female rats caused no
adverse effects
on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in
rats after
150 mg/kg/day were 2 times the human serum levels.
In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels.
When given
orally at 150 mg/kg/day (2.4 times the recommended maximum human dose based on mg/m2),
clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed
to marked
maternal toxicity of the drug at this high dose.
In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m2, which is 17 times
less than
the maximum proposed human oral daily dose of 618 mg/m2.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential
of clarithromycin.
Pregnancy: Teratogenic Effects. Pregnancy Category C.
Four teratogenicity studies in rats (three with oral doses and one with intravenous doses up to
160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral
doses
up to 125 mg/kg/day (approximately 2 times the recommended maximum human dose based on
mg/m2)
or intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18 failed to
demonstrate
any teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at
similar
doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses
of
150 mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day
were
2 times the human serum levels. Four studies in mice revealed a variable incidence of cleft
palate following oral doses of 1000 mg/kg/day (2 and 4 times the recommended maximum human dose
based on
mg/m2, respectively) during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day.
The
1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In
monkeys, an oral
dose of 70 mg/kg/day (an approximate equidose of the recommended maximum human dose
based on
mg/m2) produced fetal growth retardation at plasma levels that were 2 times the human serum
levels.
There are no adequate and well-controlled studies in pregnant women. Clarithromycin should
be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See
WARNINGS.)
Nursing Mothers: it is not known whether clarithromycin is excreted in human milk. Because
many drugs
are excreted in human milk, caution should be exercised when clarithromycin is administered to
a nursing
woman. It is known that clarithromycin is excreted in the milk of lactating animals and that other
drugs of
this class are excreted in human milk. Preweaned rats, exposed indirectly via consumption of
milk from
dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data
indicating higher
drug levels in milk than in plasma.
Pediatric Use: Safety and effectiveness of clarithromycin in children 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.
Generic 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.
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 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 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-trealed 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 and
Stevens-Johnson syndrome have occurred. Other spontaneously reported adverse events
include glossitis
stomatitis, oral moniliasis, vomiting and dizziness. 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 have also been reported.
Transient CNS events including behavioral changes, confusional states, depersonalization,
disorientation, hallucinations, insomnia, nightmares, tinnitus and vertigo have been reported
during post-marketing
surveillance. Events usually resolve quickly 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.
Rarely, erythromycin and clarithromycin have been associated with ventricular arrhythmias,
including
ventricular tachycardia and torsades de pointes, in individuals with prolonged QTc intervals.
Changes in Laboratoly Values: Changes in laboratory values with possible clinical significance
were as
follows:
Hepatic – elevated SGPT (ALT) <1 %; SGOT (AST) < 1 %; GGT < 1 %; alkaline phosphatase <1 %; LDH < 1 %; total bilirubin < l%
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.
BIAXIN® Filmtab® (clarithromycin tablets) and BIAXIN® Granules (clarithromycin for oral
suspension) may be given with or without food.
ADULT DOSAGE GUIDELINES
Infection Dosage Normal Duration
(q 12 h) (days)
Pharyngitis/Tonsillitis 250 mg 10
Acute maxillary sinusitis 500 mg 14
Acute exacerbation of
chronic bronchitis due to:
S. pneumoniae 250 mg 7-14
M. caterrhalis 250 mg 7-14
H. influenzae 500 mg 7-14
Pneumonia due to:
S. pneumoniae 250 mg 7-14
M. pneumoniae 250 mg 7-14
Uncomplicated skin 250 mg 7-14
and skin structure
Children- The usual recommended daily dosage is 15 mg/kg/day divided q 12 h for 10 days.
PEDIATRIC DOSAGE GUIDELINES
Based on Body Weight
Dosing Calculated on 7.5 mg/kg/ q12h
Weight Dose 125 mg/ 250 mg/
Kg lbs (q12h) 5 mL 5 mL
9 20 62.5 mg 2.5 mL q12h 1.25 mL q12h
17 37 125 mg 5 mL q12h 2.5 mL q12h
25 55 187.5 mg 7.5 mL q12h 3.75 mL q12h
33 73 250 mg 10 mL q12h 5 mL q12h
Clarithromycin may be administered without dosage adjustment in the presence of hepatic
impairment
if there is normal renal function. However, in the presence of severe renal impairment (CRCL
<30 mL/min), with or without coexisting hepatic impairment, the dose should be halved or the dosing interval doubled.
Mycobacterial infections:
Prophylaxis: The recommended dose of BIAXIN 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, including ethambutol,
clofazimine, and rifampin. Although no controlled clinical trial information is available for combination
therapy with clarithromycin, the U.S. Public Health Service Task Force has provided
recommendations for
the treatment of MAC.3 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.
Constituting Instructions
The table below indicates the volume of water to be added when constituting:
Clarithromycin Amount of
Total volume concentration after water to
after constitution constitution be added*
50 mL 125 mg/5 mL 27 mL
100 mL 125 mg/5 mL 55 mL
50 mL 250 mg/5 mL 27 mL
100 mL 250 mg/5 mL 55 mL
* see instructions below.
Add half the volume of water to the bottle and shake vigorously. Add the remainder of water to the
bottle and shake.
Shake well before each use. Oversize bottle provides shake space. Keep tightly closed.
Do not refrigerate. After mixing, store at 15° to 30°C (59° to 86°F) and use within 14 days.
BIAXIN® Filmtab®(clarithromycin tablets) are supplied as yellow oval film-coated tablets
imprinted (on
one side) in blue with the Abbott logo and a two-letter Abbo-Code designation, KT for the 250 mg
tabl
and KL for the 500 mg tablet, in the following packaging sizes:
250 mg tablets:
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-
3368-11)
500 mg tablets:
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-
2586- 11)
BIAXIN® Granules (clarithromycin for oral suspension) is supplied in the following strengths and
sizes:
Total Clarithromycin Clarithromycin
volume after concentration after contents per
constitution constitution bottle NDC
50 mL 125 mg/5 mL 1250 mg 0074-3163-50
100 mL 125 mg/5 mL 2500 mg 0074-3163-13
50 mL 250 mg/5 mL 2500 mg 0074-3188-13
100 mL 250 mg/5 mL 5000 mg 0074-3188-13
Store tablets and granules for oral suspension at controlled room temperature 15° to 30°C (59° to
86°F) in
a well-closed container. Protect from light. Do not refrigerate BIAXIN suspension.
Mycobacterial Infections
Prophylaxis:
A randomized, double-blind study (561) compared clarithromycin 500 mg b.i.d. to placebo in
patients
with CDC-defined AIDS and CD4 counts <100 cells/uL. This study accrued 682 patients from November 1992 to January 1994, with a median CD4 cell count at study entry of 30 cells/uL. 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). Howeever, 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.
Mortality Reduction in
Placebo Clarithromycin Mortality on Clarithromycin
6 month 9.4% 6.5% 31%
12 month 29.7% 20.5% 31%
18 month 46.4% 37.5% 20%
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival
benefit of
clarithromycin may be underestimated.
Clinically significant disseminated MAC disease:
In association with the decreased incidence of bacteremia, patients in the group randomized to
clarithromycin showed reductions in the signs and symptoms of disseminated MAC disease,
including fever,
night sweats, weight loss, and anemia.
Safety:
In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium,
it was often difficult to distinguish adverse events possibly associated with clarithromycin
administration
from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6
months for
the clarithromycin group and 8.2 months for the placebo group.
Treatment-related* Adverse Event Incidence Rates
(%) in Immunocompromised Adult Patients Receiving
Prophylaxis Against M. avium Complex
Clarithromycin Placebo
Body Systemt (n = 339) (n = 339)
Adverse Event % %
Body as a Whole
Abdominal pain 5.0% 3.5%
Headache 2.7% 0.9%
Digestive
Diarrhea 7.7% 4.1%
Dyspepsia 3.8% 2.7%
Flatulence 2.4% 0.9%
Nausia 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.
t > or = to 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.
Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients
Receiving Prophylaxis Against M. avium Complex
Clarithromycin
500 mg b.i.d. Placebo
Hemoglobin <8 g/dL 4/118 3% 5/103 5% Platelet Count < 50 x 109/L 11/249 4% 12/250 5%
WBC Count <1 x 109/L 2/103 4% 0/95 0%
SGOT > 5 x ULNb 7/196 4% 5/208 2%
SGPT > 5 x ULNb 6/217 3% 4/232 2%
Alk. Phos. > 5 x ULNb 5/220 2% 5/218 2%
(a) Includes only patients with baseline values within the normal range or borderline high
(hematology
variables) and within the normal range or borderline low (chemistry variables).
(b) ULN = Upper Limit of Normal
Treatment:
Three randomized studies (500, 577, and 521) compared different dosages of clarithromycin in
patients
with CDC-defined AIDS and CD4 counts <100 cells/uL. 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 1-20. The majority of patients had CD4 cell counts < 50/uL at study entry. The studies were designed to evaluate the following end points:
1.Change in MAC bacteremia or blood cultures negative for M. avium.
2.Change in clinical signs and symptoms of MAC infection including one or more of the
following:
fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly.
The results for the 500 study are described below. The 577 study results were similar to the
results of the
500 study. Results with the 7.5 mg/kg b.i.d. dose in the pediatric study were comparable to those
for the
500 mg b.i.d. regimen in the adult studies.
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 regimen4 (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. 100 mg b.i.d. 2000 mg b.i.d. Four Drug Regimen
(n = 35) (n = 32) (n = 26) (n = 24)
1.5 2.3 2.3 1.4
Although the 1000 mg and 2000 mg b.i.d. doses showed significantly better control of
bacteremia during the first four weeks of therapy, no significant differences were seen beyond that point. The
percent of
patients whose blood was sterilized as shown by one or more negative cultures at any time
during acute
therapy was 61% (30/49) for the 500 mg b.i.d. group and 59% (29/49) and 52% (25/48) for the
1000 and
2000 mg b.i.d. groups, respectively. The percent of patients who had 2 or more negative cultures
during
acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and
1000 mg
b.i.d. groups and 8% (4/48) for the 2000 mg b.i.d. group. By Day 84, 23% (11/49), 37% (18/49),
and
56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49),
and 13%
(6/48) of patients had relapsed in the 500, 1000, and 2000 mg b.i.d. dose groups, respectively.
All of the
isolates had an MIC <8 µg/mL at pretreatment. 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 500-2000 mg b.i.d. doses. Similarly, 77% of
patients reported resolution or improvement in fevers at some point. Response rates for clinical
signs of
MAC are given below:
Resolution of Fever Resolution of Night Sweats
b.i.d. % b.i.d. %
dose % ever afebrile dose % ever resolving
(mg) afebrile > or = to 6 weeks (mg) resolving > or = to 6 weeks
500 67% 23% 500 85% 42%
1000 67% 12% 1000 70% 33%
2000 62% 22% 2000 72% 36%
Weight Gain > 3% Hemoglobin Increase > 1 gm
b.i.d. % b.i.d. %
dose % ever afebrile dose % ever resolving
(mg) afebrile > or = to 6 weeks (mg) resolving > or = to 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 2-6 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 25-33% 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.4
Median survival time from study entry in Study 577 was 199 days for the 500 mg b.i.d. dose
and
179 days for the 1000 mg b.i.d. dose. During the first four weeks of therapy, while patients were
maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg
b.i.d. and
18 deaths in 214 patients taking 1000 mg b.i.d.
Safety:
The adverse event profiles showed that both the 500 and 1000 mg b.i.d. doses were well
tolerated. The
2000 mg b.i.d. dose was poorly tolerated and resulted in a higher proportion of premature
discontinuations.
In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to
distinguish
adverse events possibly associated with clarithromycin administration from underlying signs of
HIV disease or intercurrent illness.
The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for Study 500 (randomized, double-blind) and Study
577 (open-label, compassionate use) and also combined. Adverse events were reported less frequently in
Study 577,
which may be due in part to differences in monitoring between the two studies. In adult patients
receiving clarithromycin 500 mg b.i.d., the most frequently reported adverse events, considered
possibly or
probably related to study drug, with an incidence of 5% or greater, are listed below. Most of these
events
were mild to moderate in severity, although 5% (Study 500: 8%; Study 577: 4%) of patients
receiving
500 mg b.i.d. and 5% (Study 500: 4%; Study 577: 6%) of patients receiving 1000 mg b.i.d.
reported
severe adverse events. Excluding those patients who discontinued therapy or died due to
complications
of their underlying non-mycobacterial disease, approximately 8% (Study 500: 15%; Study 577:
7%) of
the patients who received 500 mg b.i.d. and 12% (Study 500: 14%; Study 577: 12%) of the
patients who
received 1000 mg b.i.d. discontinued therapy due to drug-related events during the first 12
weeks of therapy. Overall, the 500 and 1000 mg b.i.d. doses had similar adverse event profiles.
Treatment-related* Adverse Event Incidence Rates (%) in
Immunocompromised Adult Patients During the First
12 Weeks of Therapy with 500 mg b.i.d. Clarithromycin Dose
Study Study
500 577 Combined
Adverse Event (n = 53) (n = 225) (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
Nausia 28.3 9.0 12.3
Rash 9.4 2.0 3.2
Taste Perversion 18.9 0.4 3.6
Vomiting 24.5 3.9 7.5
* Includes those events possibly or probably related to study drug and excludes concurrent
conditions.
A limited number of pediatric AIDS patients have been treated with clarithromycin suspension
for
mycobacterial infections. The most frequently reported adverse events, excluding those due to
the
patient’s concurrent condition, were consistent with those observed in adult patients.
Changes in laboratory Values:
In immunocompromised patients treated with clarithromycin for mycobacterial infections,
evaluations of
laboratory values were made by analyzing those values outside the seriously abnormal level
(i.e., the
extreme high or low limit) for the specified test.
Percentage of Patients(a) Eceeding Extreme Laboratory Value Limits
During First 12 Weeks of Treatment
500 mg b.i.d. Dose(b)
Study 500 Study 577 Combined
BUN > 50 mg/dL 0% <1% < 1% Platelet Count < 50 x 109/L 0% <1% < 1% SGOT> 5 x UNLc 0% 3% 2%
SGPT > 5 x ULNc 0% 2% 1%
WBC <1 x 109/L 0% 1% 1%
(a) Includes only patients with baseline values within the normal range or borderline high
(hematology
variables) and within the normal range or borderline low (chemistry variables)
(b) Includes all values within first 12 weeks for patients who start on 500 mg b.i.d.
(c) ULN = Upper Limit of Normal
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States, where
significant rates
of beta-lactamase producing organisms were found, clarithromycin was compared to an oral
cephalosporin. In this study, very strict evaluability criteria were used to determine clinical
response. For
the 223 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus
improvement) at the post-therapy visit was 88% for clarithromycin and 91% for the
cephalosporin.
In a smaller number of patients, microbiologic determinations were made at the pre-treatment
visit. The
following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were
obtained:
U.S. Acute Otitis Media Study
Clarithromycin vs. Oral Cephalosporin
EFFICACY RESULTS
PATHOGEN OUTCOME
S. pneumoniae clarithromycin success rate, 13/15 (87%),
control 4/5
H. influenzae* clarithromycin success rate, 10/14 (71%),
control 3/4
M. catarrhalis clarithromycin success rate, 4/5,
control 1/1
S. pyogenes clarithromycin success rate, 3/3,
control 0/1
Overall clarithromycin success rate, 30/37, (81%),
control 8/11 (73%)
* None of the H. influenzae isolaled pre-treatment was resistant to clarithromycin; 69% 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%)
H. influenzae* clarithromycin success rate, 36/45 (80%),
control 31/33 (94%)
M. catarrhalis clarithromycin success rate, 9/10 (90%),
control 6/6
S. pyogenes clarithromycin success rate, 3/3,
control 5/5
Overall clarithromycin success rate, 91/109 (83%),
control 97/100 (97%)
* Of the H. influenzae isolated pre-treatment, 3% were resistant to clarithromycin and 10% were
resistant to the control agent.
Safety:
The incidence of adverse events in all patients treated, primarily diarrhea (15% vs. 38%) and
diaper rash
(3% vs. 11%) in young children, was clinically and statistically lower in the clarithromycin arm
versus
the control arm.
Clarithromycin is rapidly and well-absorbed with dose-linear kinetics, low protein binding, and a
high
volume of distribution. Plasma half-life ranged from 1-6 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.
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria that Grow Aerobically – Third Edition. Approved Standard
NCCLS Document
M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December, 1993.
2. National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Disk
Susceptibility Tests – Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No.
24,
NCCLS, Villanova, PA, December, 1993.
3. Public Health Service Task Force on Prophylaxis and Therapy for Disseminated
Mycobacterium avium
complex. Recommendations on Prophylaxis and Therapy for Mycobacterium avium Complex
Disease
in Patients Infected With The Human Immunodeficiency Virus. NEJM. 1993;329:898-904.
4. 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.
Filmtab – Film-sealed tablets, Abbott
Revised: October 1995
