CLARITHROMYCIN
DESCRIPTION:
Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-
methylerythromycin. The molecular formula is C38H69NO13, and the molecular
weight is 747.96.
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.
CLARIBID is available as tablets and granules for oral suspension.
Each yellow oval film-coated CLARIBID 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. 1, magnesium stearate,
povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate,
stearic acid, talc, titanium dioxide, and vanillin. The 250-mg tablet also
contains pregelatinized starch.
ACTIONS/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,
CLARIBID 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 Mu-g/mL
with a 250-mg dose administered every 12 hours, 2 to 3 Mu-g/mL with a 500-mg
dose administered every 12 hours, and 3 to 4 Mu-g/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 Mu-g/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 Mu- g/mL), and
its elimination half-life is about 7 to 9 hours. With any of these dosing
regimens, the steady-state concentration of this metabolite is generally
attained within 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 Mu-g/mL and 5 to 10 Mu-g/mL, respectively.
The steady-state concentrations of clarithromycin in subjects with impaired
hepatic function did not differ from those in normal subjects; however, the 14-
OH clarithromycin concentrations were lower in the hepatically impaired
subjects. The decreased formation of 14-OH clarithromycin was at least partially
offset by an increase in renal clearance of clarithromycin in the subjects with
impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was also altered in subjects with
impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION).)
Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into
body tissues and fluids. There are no data available on cerebrospinal fluid
penetration. Because of high intracellular concentrations, tissue concentrations
are higher than serum concentrations. Examples of tissue and serum
concentrations are presented below.
CONCENTRATION
(after 250 mg q12h)
TISSUE SERUM
TISSUE TYPE (Mcgm/g) (Mcgm/mL)
Tonsil 1.6 0.8
Lung 8.8 1.7
When 250-mg doses of clarithromycin as CLARIBID 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 Mcgm/mL for clarithromycin and 0.7 Mcgm/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 CLARIBID
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 Mu-g/mL for clarithromycin and 1 to 2 Mu-g/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 Mu- g/mL.
Clarithromycin penetrates into the middle ear fluid of children with secretory
otitis media.
CONCENTRATION
(after 7.5 mg/kg q12h for 5 doses)
------------------------------------------------------------------------------
MIDDLE EAR FLUID SERUM
ANALYTE (Mcgm/mL) (Mcgm/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)
Mcgm/mL to 1.0 (+/- 0.4) Mcgm/mL and the extent of absorption from 7.2 (+/-2.5)
hr*Mcgm/mL to 6.5 (+/- 3.7) hr*Mcgm/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) Mcgm/mL to 4.6 (+/- 2.8) Mcgm/mL and the extent of absorption from
10.0 (+/- 5.5) hr*Mcgm/mL to 14.2 (+/- 9.4) hr*Mcgm/mL.
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40
mg daily to healthy adult males. The plasma levels of clarithromycin and 14-
hydroxy-clarithromycin were increased by the concomitant administration of
omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was
27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was
administered with omeprazole than when clarithromycin was administered alone.
Similar results were seen for 14-hydroxy- clarithromycin, the mean Cmax was 45%
greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater.
Clarithromycin concentrations in the gastric tissue and mucus were also
increased by concomitant administration of omeprazole.
CLARITHROMYCIN TISSUE CONCENTRATIONS
2 HOURS AFTER DOSE (MCGM/ML)/(MCGM/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 on omeprazole, refer to the ACTIONS/CLINICAL PHARMACOLOGY
section of the PRILOSEC package insert.
For Information on ranitidine bismuth citrate, refer to the ACTIONS/CLINICAL
PHARMACOLOGY) section of the TRITEC package insert.
MICROBIOLOGY:
Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal
subunit of susceptible microorganisms resulting in inhibition of protein
synthesis.
Clarithromycin is active IN VITRO against a variety of aerobic and anaerobic
gram-positive and gram-negative microorganisms as well as most MYCOBACTERIUM
AVIUM complex (MAC) microorganisms.
Additionally, the 14-OH clarithromycin metabolite also has clinically
significant antimicrobial activity. The 14-OH clarithromycin is twice as active
against HAEMOPHILUS INFLUENZAE microorganisms as the parent compound. However,
for MYCOBACTERIUM AVIUM complex (MAC) isolates the 14-OH metabolite is 4 to 7
times less active than clarithromycin. The clinical significance of this
activity against MYCOBACTERIUM AVIUM complex is unknown.
Clarithromycin has been shown to be active against most strains of the following
microorganisms both IN VITRO and in clinical infections as described in the
INDICATIONS AND USAGE section:
AEROBIC GRAM-POSITIVE MICROORGANISMS
STAPHYLOCOCCUS AUREUS
STREPTOCOCCUS PNEUMONIAE
STREPTOCOCCUS PYOGENES
AEROBIC GRAM-NEGATIVE MICROORGANISMS
HAEMOPHILUS INFLUENZAE
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.
Clarithromycin has been shown to be active against most strains of HELICOBACTER
PYLORI IN VITRO and in clinical infections when combined with omeprazole or
ranitidine bismuth citrate as described in the INDICATIONS AND USAGE section.
HELICOBACTER
HELICOBACTER PYLORI
Some HELICOBACTER PYLORI isolates obtained from patients treated with
clarithromycin plus omeprazole demonstrated an increase in clarithromycin MIC's
over time, indicating decreasing susceptibility and increasing resistance. In
the two U.S. clarithromycin plus omeprazole clinical trials, 104 patients had H.
PYLORI isolated and clarithromycin MIC's determined pre-treatment. Of these, 4
patients had resistant strains, 2 patients had strains with intermediate
susceptibility, and 98 patients had susceptible strains. Of the patients with
susceptible H. PYLORI pre-treatment, 72 patients were eradicated of the H.
PYLORI and 26 patients had H. PYLORI present post-treatment. Isolates from 25 of
these 26 patients became resistant to clarithromycin. The six patients with
resistant or intermediate H. PYLORI strains pre-treatment had resistant strains
isolated post-treatment.
Emerging clarithromycin resistance was not assessed for the ranitidine bismuth
citrate plus clarithromycin regimen because there were no patients that had H.
PYLORI isolates with both pre-treatment and post-treatment susceptibility tests.
No adequate data were collected during clinical trials or IN VITRO studies to
indicate that ranitidine bismuth citrate can either decrease or increase
emerging clarithromycin resistance.
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
LISTERIA MONOCYTOGENES
STREPTOCOCCUS AGALACTIAE
STREPTOCOCCI (GROUPS C, F, G)
Viridans group streptococci
AEROBIC GRAM-NEGATIVE MICROORGANISMS
BORDETELLA PERTUSSIS
CAMPYLOBACTER JEJUNI
LEGIONELLA PNEUMOPHILA
NEISSERIA GONORRHOEAE
PASTEURELLA MULTOCIDA
OTHER MICROORGANISMS
CHLAMYDIA TRACHOMATIS
ANAEROBIC GRAM-POSITIVE MICROORGANISMS
CLOSTRIDIUM PERFRINGENS
PEPTOCOCCUS NIGER
PROPIONIBACTERIUM ACNES
ANAEROBIC GRAM-NEGATIVE MICROORGANISMS
PREVOTELLA MELANINOGENICA (formerly BACTERIODES MELANINOGENICUS)
SUSCEPTIBILITY TESTING EXCLUDING MYCOBACTERIA AND HELICOBACTER:
DILUTION TECHNIQUES:
Quantitative methods are used to determine antimicrobial minimal inhibitory
concentrations (MIC's). These MIC's provide estimates of the susceptibility of
bacteria to antimicrobial compounds. The MIC's should be determined using a
standardized procedure. Standardized procedures are based on a dilution method
(REF.1) (broth or agar) or equivalent with standardized inoculum concentrations
and standardized concentrations of clarithromycin powder. The MIC values should
be interpreted according to the following criteria:
MIC (MU-G/ML) INTERPRETATION
(=)2.0 Susceptible (S)
4.0 Intermediate (I)
(>/=)8.0 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 following MIC
values:
MICROORGANISM MIC (MU-G/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 procedure (REF. 2) requires the use of
standardized inoculum concentrations. This procedure uses paper disks
impregnated with 15-Mcgm-g 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-Mcgm-g clarithromycin disk should be interpreted
according to the following criteria:
ZONE DIAMETER (MM) INTERPRETATION
(>/=) 18 Susceptible (S)
14 to 17 Intermediate (I)
(=) 13 Resistant (R)
Interpretation should be as stated above for results using dilution techniques.
Interpretation involves correlation of the diameter obtained in the disk test
with the MIC for clarithromycin. However, standardized diffusion methods for
routine IN VITRO susceptibility testing, using the 15-Mu-g 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-Mu-g
clarithromycin disk should provide the following zone diameters in this
laboratory test quality control strain:
MICROORGANISM ZONE DIAMETER (MM)
S. AUREUS ATCC 25923 26 to 32
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 Mu-g/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 Mu-g/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 Mcgm/mL. Clarithromycin
inhibited all isolates at > 10.0 Mcgm/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.
IN VITRO ACTIVITY OF CLARITHROMYCIN AGAINST HELICOBACTER PYLORI:
Clarithromycin has demonstrated IN VITRO activity against HELICOBACTER PYLORI
isolated from patients with duodenal ulcers. IN VITRO susceptibility testing
methods (broth microdilution, agar dilution, E-test, and disk diffusion) and
diagnostic products currently available for determining minimum inhibitory
concentrations (MIC's) and zone sizes have not been standardized, validated, or
approved for testing H. PYLORI. The clarithromycin MIC values and zone sizes
will vary depending on the susceptibility testing methodology employed, media,
growth additives, pH, inoculum concentration tested, growth phase, incubation
atmosphere, and time.
SUSCEPTIBILITY TEST FOR HELICOBACTER PYLORI:
IN VITRO susceptibility testing methods and diagnostic products currently
available for determining minimum inhibitory concentrations (MIC's) and zone
sizes have not been standardized, validated, or approved for testing H. PYLORI
microorganisms. MIC values for H. PYLORI isolates collected during the two U.S.
clinical trials evaluating clarithromycin plus omeprazole, were determined by
broth microdilution MIC methodology(raised to the power of 3). Results obtained
during the clarithromycin plus omeprazole clinical trials fell into a distinct
bimodal distribution of susceptible and resistant clarithromycin MIC's.
If the broth microdilution MIC methodology published in Hachem, et. al.(raised
to the power of 3) is used and the following tentative breakpoints are employed,
there should be reasonable correlation between MIC results and clinical and
microbiological outcomes for patients treated with clarithromycin plus
omeprazole.
MIC (MU-G/ML) INTERPRETATION
(=)0.06 Susceptible (S)
0.12 to 2.0 Intermediate (I)
(>/=)4 Resistant (R)
These breakpoints should not be used to interpret results obtained using
alternative methods.
INDICATIONS AND USAGE:
CLARIBID Filmtab tablets and CLARIBID 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, STREPTOCOCCUS PNEUMONIAE, or CHLAMYDIA
PNEUMONIAE (TWAR)
Uncomplicated skin and skin structure infections due to STAPHYLOCOCCUS AUREUS,
or STREPTOCOCCUS PYOGENES (Abscesses usually require surgical drainage.)
Disseminated mycobacterial infections due to MYCOBACTERIUM AVIUM, or
MYCOBACTERIUM INTRACELLULARE
CLARIBID (clarithromycin) Filmtab tablets in combination with PRILOSEC
(omeprazole) capsules or TRITEC (ranitidine bismuth citrate) tablets is
indicated for the treatment of patients with an active duodenal ulcer associated
with H. PYLORI infection. The eradication of H. PYLORI has been demonstrated to
reduce the risk of duodenal ulcer recurrence.
In patients who fail therapy, susceptibility testing should be done if possible.
If resistance is demonstrated, alternative therapy is recommended. (For
information on development of resistance see MICROBIOLOGY section.
CHILDREN:
Pharyngitis/Tonsillitis due to STREPTOCOCCUS PYOGENES
Pneumonia due to MYCOPLASMA PNEUMONIAE, STREPTOCOCCUS PNEUMONIAE, or CHLAMYDIA
PNEUMONIAE (TWAR)
Acute maxillary sinusitis due to HAEMOPHILUS INFLUENZAE, MORAXELLA CATARRHALIS,
or STREPTOCOCCUS PNEUMONIAE
Acute otitis media due to HAEMOPHILUS INFLUENZAE, MORAXELLA CATARRHALIS, or
STREPTOCOCCUS PNEUMONIAE
NOTE: For information on otitis media, see CLINICAL STUDIES: OTITIS MEDIA.
Uncomplicated skin and skin structure infections due to STAPHYLOCOCCUS AUREUS,
or STREPTOCOCCUS PYOGENES (Abscesses usually require surgical drainage.)
Disseminated mycobacterial infections due to MYCOBACTERIUM AVIUM, or
MYCOBACTERIUM INTRACELLULARE
PROPHYLAXIS:
CLARIBID Filmtab tablets and CLARIBID Granules for oral suspension are indicated for
the prevention of disseminated MYCOBACTERIUM AVIUM complex (MAC) disease in
patients with advanced HIV infection.
CONTRAINDICATIONS:
Clarithromycin is contraindicated in patients with a known hypersensitivity to
clarithromycin, erythromycin, or any of the macrolide antibiotics.
Concomitant administration of clarithromycin with cisapride, pimozide, or
terfenadine is contraindicated. There have been post-marketing reports of drug
interactions when clarithromycin and/or erythromycin are co-administered with
cisapride, pimozide, or terfenadine resulting in cardiac arrhythmias (QT
prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de
pointes) most likely due to inhibition of hepatic metabolism of these drugs by
erythromycin and clarithromycin. Fatalities have been reported.
For information on omeprazole, refer to the CONTRAINDICATIONS section of the
PRILOSEC package insert.
For information on ranitidine bismuth citrate, refer to the CONTRAINDICATIONS
section of the TRITEC package insert.
WARNINGS:
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS
WHILE TAKING THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD
TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY
OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT
DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN
HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES. SEE PRECAUTIONS
PREGNANCY.
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 DIFFICILE 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 be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically
effective against CLOSTRIDIUM DIFFICILE colitis.
For information on omeprazole, refer to the WARNINGS section of the PRILOSEC
package insert.
For information on ranitidine bismuth citrate, refer to the WARNINGS section of
the TRITEC package insert.
PRECAUTIONS:
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.
Clarithromycin in combination with ranitidine bismuth citrate therapy is not
recommended in patients with creatinine clearance less than 25 mL/min. (See
DOSAGE AND ADMINISTRATION.)
Clarithromycin in combination with ranitidine bismuth citrate should not be used
in patients with a history of acute porphyria.
For information on omeprazole, refer to the PRECAUTIONS section of the PRILOSEC
package insert.
For information on ranitidine bismuth citrate, refer to the PRECAUTIONS section
of the TRITEC package insert.
INFORMATION TO PATIENTS:
CLARIBID 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 q12h clarithromycin), the steady-state
levels of Cmax, Cmin, and the area under the serum concentration time curve
(AUC) of theophylline increased about 20%.
Concomitant administration of single doses of clarithromycin and carbamazepine
has been shown to result in increased plasma concentrations of carbamazepine.
Blood level monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations
of the active acid metabolite of terfenadine were threefold higher, on average,
than the values observed when terfenadine was administered alone. The
pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin
reached steady-state conditions. Concomitant administration of clarithromycin
with terfenadine is contraindicated. (See CONTRAINDICATIONS.)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40
mg daily to healthy adult subjects. The steady-state plasma concentrations of
omeprazole were increased (Cmax, AUC0-24, and T 1/)2 increases of 30%, 89%, and
34%, respectively), by the concomitant administration of clarithromycin. The
mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and
5.7 when co- administered with clarithromycin.
Co-administration of clarithromycin with ranitidine bismuth citrate resulted in
increased plasma ranitidine concentrations (57%), increased plasma bismuth
trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma
concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of CLARIBID tablets and zidovudine to HIV-
infected adult patients resulted in decreased steady-state zidovudine
concentrations. When 500 mg of clarithromycin were administered twice daily,
steady-state zidovudine AUC was reduced by a mean of 12% (n=4). Individual
values ranged from a decrease of 34% to an increase of 14%. Based on limited
data in 24 patients, when CLARIBID 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 CLARIBID tablets and didanosine to 12 HIV-infected
adult patients resulted in no statistically significant change in didanosine
pharmacokinetics.
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg
twice daily to 21 healthy volunteers led to increases in the mean steady-state
clarithromycin Cmin and AUC of 33% and 18%, respectively. Steady-state
concentrations of 14-OH clarithromycin were not significantly affected by
concomitant administration of fluconazole.
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.
There have been reports of an interaction between erythromycin and astemizole
resulting in QT prolongation and torsades de pointes. Concomitant administration
of erythromycin and astemizole is contraindicated. Because clarithromycin is
also metabolized by cytochrome P450, concomitant administration of
clarithromycin with astemizole is not recommended.
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, tacrolimus,
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/m(squared))
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/m(squared)), 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/m(squared), which is 17 times less than the maximum proposed human oral daily
dose of 618 mg/m(squared).
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/m(squared)) 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/m(squared), 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/m(squared)) 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.
GERIATRIC USE:
In a steady-state study in which healthy elderly subjects (age 65 to 81 years
old) were given 500 mg every 12 hours, the maximum serum concentrations and area
under the curves of clarithromycin and 14-OH clarithromycin were increased
compared to those achieved in healthy young adults. These changes in
pharmacokinetics parallel known age-related decreases in renal function. In
clinical trials, elderly patients did not have an increased incidence of adverse
events when compared to younger patients. Dosage adjustment should be considered
in elderly patients with severe renal impairment.
DRUG INTERACTIONS:
Clarithromycin use in patients who are receiving theophylline may be associated
with an increase of serum theophylline concentrations. Monitoring of serum
theophylline concentrations should be considered for patients receiving high
doses of theophylline or with baseline concentrations in the upper therapeutic
range. In two studies in which theophylline was administered with clarithromycin
(a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or
12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state
levels of Cmax, Cmin, and the area under the serum concentration time curve
(AUC) of theophylline increased about 20%.
Concomitant administration of single doses of clarithromycin and carbamazepine
has been shown to result in increased plasma concentrations of carbamazepine.
Blood level monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations
of the active acid metabolite of terfenadine were threefold higher, on average,
than the values observed when terfenadine was administered alone. The
pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin were not
significantly affected by coadministration of terfenadine once clarithromycin
reached steady-state conditions. Concomitant administration of clarithromycin
with terfenadine is contraindicated. (See CONTRAINDICATIONS.)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40
mg daily to healthy adult subjects. The steady-state plasma concentrations of
omeprazole were increased (Cmax, AUC0-24, and T 1/)2 increases of 30%, 89%, and
34%, respectively), by the concomitant administration of clarithromycin. The
mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and
5.7 when co- administered with clarithromycin.
Co-administration of clarithromycin with ranitidine bismuth citrate resulted in
increased plasma ranitidine concentrations (57%), increased plasma bismuth
trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma
concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of CLARIBID tablets and zidovudine to HIV-
infected adult patients resulted in decreased steady-state zidovudine
concentrations. When 500 mg of clarithromycin were administered twice daily,
steady-state zidovudine AUC was reduced by a mean of 12% (n=4). Individual
values ranged from a decrease of 34% to an increase of 14%. Based on limited
data in 24 patients, when CLARIBID 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 CLARIBID tablets and didanosine to 12 HIV-infected
adult patients resulted in no statistically significant change in didanosine
pharmacokinetics.
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg
twice daily to 21 healthy volunteers led to increases in the mean steady-state
clarithromycin Cmin and AUC of 33% and 18%, respectively. Steady-state
concentrations of 14-OH clarithromycin were not significantly affected by
concomitant administration of fluconazole.
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.
There have been reports of an interaction between erythromycin and astemizole
resulting in QT prolongation and torsades de pointes. Concomitant administration
of erythromycin and astemizole is contraindicated. Because clarithromycin is
also metabolized by cytochrome P450, concomitant administration of
clarithromycin with astemizole is not recommended.
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, tacrolimus,
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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The majority of side effects observed in clinical trials were of a mild and
transient nature. Fewer than 3% of adult patients without mycobacterial
infections and fewer than 2% of pediatric patients without mycobacterial
infections discontinued therapy because of drug-related side effects.
The most frequently reported events in adults 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-treated patients reported diarrhea as
did amoxicillin/potassium clavulanate-treated patients.