Clarithromycin (clarithromycin 500 mg) Dailymed

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin and other antibacterial drugs, clarithromycin 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, USP 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 tablets, USP are available as immediate-release tablets.

Each white to off-white oval, film-coated tablet debossed “C250” or “C500” on one side and “G” on the other side contains 250 mg or 500 mg of clarithromycin and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch, stearic acid, titanium dioxide, triacetin, and vanillin.

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

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

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

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

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

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

CONCENTRATION (after 250 mg q12h)

Tissue Type	Tissue (mcg/g)	Serum (mcg/mL)
Tonsil	1.6	0.8
Lung	8.8	1.7

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult males. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean C_max was 10% greater, the mean C_min was 27% greater, and the mean AUC_0-8 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 C_max was 45% greater, the mean C_min was 57% greater, and the mean AUC_0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Clarithromycin Tissue Concentrations 2 hours after Dose (mcg/mL)/(mcg/g)

Treatment	N	antrum	fundus	N	mucus
Clarithromycin	5	10.48 ± 2.01	20.81 ± 7.64	4	4.15 ± 7.74
Clarithromycin + Omeprazole	5	19.96 ± 4.71	24.25 ± 6.37	4	39.29 ± 32.79

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

Microbiology

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

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

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:

Gram-positive Microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Microorganisms

Haemophilus influenzae

Haemophilus parainfluenzae

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 isolates of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.

Omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; and lansoprazole/clarithromycin/amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter Helicobacter pylori

Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (M93-067, M93-l00) and 9.3% (41/439) in the omeprazole/clarithromycin/amoxicillin triple-therapy studies (126, 127, M96-446). Clarithromycin pretreatment resistance was 12.6% (44/348) in the ranitidine bismuth citrate/clarithromycin b.i.d. versus t.i.d. clinical study (H2BA3001). Clarithromycin pretreatment resistance rates were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (< 0.25 mcg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin clinical studies (126, 127, M96-446). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 mcg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin/amoxicillin study arm. Amoxicillin pretreatment susceptible isolates (< 0.25 mcg/mL) occurred in 97.8% (936/957) and 98% (98/100) of the patients in the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of the 957 patients (2.2%) by E-test and 2 of 100 patients (2%) by agar dilution had amoxicillin pretreatment MICs of > 0.25 mcg/mL. Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/mL by E-test.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological OutcomesIncludes only patients with pretreatment clarithromycin susceptibility tests

Clarithromycin Pretreatment Results			Clarithromycin Post-treatment Results
		H. pylori negative - eradicated	H. pylori positive - not eradicated Post-treatment susceptibility results
		SBreakpoints for antimicrobial susceptibility testing at the time of studies were: Susceptible (S) MIC < 0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1 mcg/mL, Resistant (R) MIC > 2 mcg/mL. For current antimicrobial susceptibility testing guidelines see reference 4. For current susceptibility test interpretive criteria, see Susceptibility Test for Helicobacter pylori below.	I	R	No MIC
Omeprazole 40 mg q.d./clarithromycin 500 mg t.i.d. for 14 days followed by omeprazole 20 mg q.d. for another 14 days (M93-067, M93-100)
Susceptible	108	72	1		26	9
Intermediate	1				1
Resistant	4				4
Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg t.i.d. for 14 days followed by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days (H2BA3001)
Susceptible	124	98	4		14	8
Intermediate	3	2				1
Resistant	17	1			15	1
Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg b.i.d. for 14 days followed by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days (H2BA3001)
Susceptible	125	106	1	1	12	5
Intermediate	2	2
Resistant	20	1			19
Omeprazole 20 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (126, 127, M96-446)
Susceptible	171	153	7		3	8
Intermediate
Resistant	14	4	1		6	3
Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 14 days (M95-399, M93-131, M95-392)
Susceptible	112	105				7
Intermediate	3	3
Resistant	17	6			7	4
Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (M95-399)
Susceptible	42	40	1		1
Intermediate
Resistant	4	1			3

Patients not eradicated of H. pylori following omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin, omeprazole/clarithromycin/amoxicillin, or lansoprazole/clarithromycin/amoxicillin therapy would likely have clarithromycin resistant H. pylori isolates. Therefore, for patients who fail therapy, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the omeprazole/clarithromycin/amoxicillin triple therapy clinical trials, 84.9% (157/185) of the patients who had pretreatment amoxicillin susceptible MICs (< 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results, and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

In the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (< 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of > 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 12.8% (22/172) of the patients failed the 10 and 14 day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

The following in vitro data are available, but their clinical significance is unknown.

Clarithromycin exhibits in vitro activity against most isolates of the following bacteria; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these bacteria have not been established in adequate and well controlled clinical trials.

Gram-positive Bacteria:

Streptococcus agalactiae

Streptococci (Groups C, F, G)

Viridans group streptococci

Gram-negative Bacteria:

Bordetella pertussis

Legionella pneumophila

Pasteurella multocida

Gram-positive Bacteria:

Clostridium perfringens

Peptococcus niger

Propionibacterium acnes

Gram-negative Anaerobic Bacteria:

Prevotella melaninogenica (formerly Bacteriodes melaninogenicus)

Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)

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 method¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. The MIC values should be interpreted according to the following criteria²:

Susceptibility Test Interpretive Criteria for Staphylococcus aureus

MIC (mcg/mL)	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae^a

MIC (mcg/mL)	Interpretation
≤ 0.25	Susceptible (S)
0.5	Intermediate (I)
≥ 1	Resistant (R)

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

For testing Haemophilus spp.^b

MIC (mcg/mL)	Interpretation
≤ 8	Susceptible (S)
16	Intermediate (I)
≥ 32	Resistant (R)

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

Boxed Warning section

Note: When testing Streptococcus pyogenes and 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.

Quality Control: Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay and the techniques of the individual performing the test.^1,2 Standard clarithromycin powder should provide the following MIC ranges:

QC Strain		MIC (mcg/mL)
S. aureus	ATCC®29213ATCC is a registered trademark of the American Type Culture Collection.	0.12 to 0.5
S. pneumoniae 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.	ATCC 49619	0.03 to 0.12
Haemophilus influenzae This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1.	ATCC 49247	4 to 16

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method.^2,3 The procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of bacteria. The disk diffusion interpretive criteria are provided below.

Susceptibility Test Interpretive Criteria for Staphylococcus aureus

Zone diameter (mm)	Interpretation
≥ 18	Susceptible (S)
14 to 17	Intermediate (I)
≤ 13	Resistant (R)

Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae^f

Zone diameter (mm)	Interpretation
≥ 21	Susceptible (S)
17 to 20	Intermediate (I)
≤ 16	Resistant (R)

^fThese zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO₂.

For testing Haemophilus spp.^g

Zone diameter (mm)	Interpretation
≥ 13	Susceptible (S)
11 to 12	Intermediate (I)
≤ 10	Resistant (R)

 ^gThese zone diameter standards are applicable only to tests with Haemophilus spp. using HTM².

Boxed Warning section

Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

Quality Control: Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay and the techniques of the individual performing the test.^2,3 For the diffusion technique using the 15 mcg disk, the criteria in the following table should be achieved.

Acceptable Quality Control Ranges for Clarithromycin

QC Strain		Zone diameter (mm)
S. aureus	ATCC 25923	26 to 32
S. pneumoniae This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.	ATCC 49619	25 to 31
Haemophilus influenzae This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM 2 .	ATCC 49247	11 to 17

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 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 mcg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value ≤ 0.5 mcg/mL. Clarithromycin was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Clarithromycin inhibited all isolates at > 10 mcg/mL.

Susceptibility Testing for Complex (MAC)

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to clarithromycin have not been established.

Susceptibility Test for

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.⁴ One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10⁷ to 1 x 10⁸ CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (> 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Susceptibility Test Interpretive Criteria for H. pylori

Clarithromycin MIC (mcg/mL)*	Interpretation
≤ 0.25	Susceptible (S)
0.5	Intermediate (I)
≥ 1	Resistant (R)

Susceptibility Test Interpretive Criteria for H. pylori

Amoxicillin MIC (mcg/mL) These are tentative breakpoints for the agar dilution methodology and should not be used to interpret results obtained using alternative methods. , There were not enough organisms with MICs > 0.25 mcg/mL to determine a resistance breakpoint.	Interpretation
< 0.25	Susceptible (S)

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay and the techniques of the individual performing the test. Standard clarithromycin or amoxicillin powder should provide the following MIC ranges:

Acceptable Quality Control Ranges		Antimicrobial Agent	MIC (mcg/mL) 1
H. pylori	ATCC 43504	Clarithromycin	0.015 to 0.12 mcg/mL
H. pylori	ATCC 43504	Amoxicillin	0.015 to 0.12 mcg/mL

¹These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods.