DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Clarithromycin (Clarithromycin) - Description and Clinical Pharmacology

 
 



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

DESCRIPTION

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6- 0 -methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. The structural formula is:

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water.

Clarithromycin is available as extended-release tablets.

Each yellow oval-shaped film-coated clarithromycin extended-release tablet for oral administration contains 1 gram clarithromycin, USP and the following inactive ingredients: ammonium hydroxide, colloidal silicon dioxide, D&C yellow no. 10 aluminum lake, hydroxypropyl cellulose, hypromellose, iron oxide black, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate, povidone, propylene glycol, shellac, sodium stearyl fumarate, talc, titanium dioxide.

Meets USP Dissolution Test 3.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.

In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 mcg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 mcg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours.

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

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

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

CONCENTRATION (after 250 mg q12h)
Tissue Type Tissue (mcg/g) Serum (mcg/mL)
Tonsil1.60.8
Lung8.81.7

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

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

The following pharmacokinetic data is from Ranbaxy’s study of clarithromycin extended-release tablets 1000 mg and clarithromycin extended-release tablets 500 mg. Clarithromycin extended-release tablets 1000 mg produced blood levels similar to those achieved with the two doses of clarithromycin extended-release tablets 500 mg. Orally administered doses of clarithromycin extended-release tablets 1000 mg result in average peak blood levels of clarithromycin in 10.985 hours and for clarithromycin extended-release tablets 500 mg in 9.588 hours after administration in fasting conditions.

Oral administration of single doses of clarithromycin extended-release tablets 1000 mg and two doses of clarithromycin extended-release tablets 500 mg to 34 adult volunteers yielded the following comparable pharmacokinetic data under fasting conditions.

Doseln AUC0-t (ng.h/mL)Cmax (ng/mL)
1000 mg (clarithromycin extended-release)(one tablet)36645.02482188.4419
2 x 500 mg (clarithromycin extended-release)(two tablets)37615.91512206.2014

Dosing was following an overnight fast.

Orally administered single doses of clarithromycin extended-release tablets 1000 mg result in average peak blood levels in 6.118 hours and two doses of clarithromycin extended-release tablets 500 mg in 6.235 hours after administration under fed conditions. Oral administration of single doses of clarithromycin extended-release tablets 1000 mg and two doses of clarithromycin extended-release tablets 500 mg to 34 adult volunteers yielded the following comparable pharmacokinetic data under fed conditions.

Dose*ln AUC0-t (ng.h/mL)Cmax (ng/mL)
1000 mg (clarithromycin extended-release)(one tablet)58485.50533957.2018
2 x 500 mg (clarithromycin extended-release)(two tablets)60796.11853478.3286

* Dosing was following a high fat high calorie breakfast.

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

Microbiology

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms.

Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown.

Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic Gram-positive microorganisms

Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes

Aerobic Gram-negative Microorganisms

Haemophilus influenzae
Haemophilus parainfluenzae
Moraxella catarrhalis

Other Microorganisms

Mycoplasma pneumoniae
Chlamydia pneumoniae
(TWAR)

The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive Microorganisms

Streptococcus agalactiae
Streptococci
(Groups C, F, G)Viridans group streptococci

Aerobic Gram-negative Microorganisms

Bordetella pertussis Legionella pneumophila Pasteurella multocida

Anaerobic Gram-positive Microorganisms

Clostridium perfringens Peptococcus niger Propionibacterium acnes

Anaerobic Gram-negative Microorganisms

Prevotella melaninogenica (formerly Bacteriodes melaninogenicus)

Susceptibility Testing:

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 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:

For testing Staphylococcus spp.
MIC (mcg/mL) Interpretation
≤ 2Susceptible (S)
4Intermediate (I)
≥ 8Resistant (R)
For testing Streptococcus spp. including Streptococcus pneumoniae a
MIC (mcg/mL) Interpretation

a   These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

≤ 0.25Susceptible (S)
0.5Intermediate (I)
≥ 1Resistant (R)
For testing Haemophilus spp.b
MIC (mcg/mL) Interpretation

b   These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Testing Medium (HTM). 1

≤ 8Susceptible (S)
16Intermediate (I)
≥ 32Resistant (R)
Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values:

Microorganism MIC (mcg/mL)

c   This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

d   This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1.

S. aureus ATCC 292130.12 to 0.5
S. pneumoniae cATCC 496190.03 to 0.12
Haemophilus influenzae dATCC 492474 to 16

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 2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mcg clarithromycin to test the susceptibility of microorganisms to clarithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mcg clarithromycin disk should be interpreted according to the following criteria:

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

e   These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO 2.

≥ 21Susceptible (S)
17 to 20Intermediate (I)
≤ 16Resistant (R)
For testing Haemophilus spp.f
Zone diameter (mm) Interpretation

f   These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM2.

≥ 13Susceptible (S)
11 to 12Intermediate (I)
≤ 10Resistant (R)
Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for clarithromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 mcg clarithromycin disk should provide the following zone diameters in this laboratory test quality control strain:

Microorganism Zone diameter (mm)

g   This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.

h   This quality control limit applies to tests conducted with H. influenzae ATCC 49247 using HTM2.

S. aureus ATCC 2592326 to 32
S. pneumoniae gATCC 4961925 to 31
Haemophilus influenzae hATCC 4924711 to 17

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2014