Biaxin and Biaxin XL - Scientific Information
|Condition:||Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bronchitis, Dental Abscess, Helicobacter Pylori Infection, Legionella Pneumonia, Mycoplasma Pneumonia, Mycobacterium avium-intracellulare, Treatment, Mycobacterium avium-intracellulare, Prophylaxis, Nongonococcal Urethritis, Otitis Media, Pertussis, Pertussis Prophylaxis, Pharyngitis, Pneumonia, Sinusitis, Skin and Structure Infection, Skin or Soft Tissue Infection, Strep Throat (Streptococcal Pharyngitis), Toxoplasmosis, Tonsillitis/Pharyngitis, Upper Respiratory Tract Infection|
|Ingredients:||Сlarithromycin, croscarmellose sodium, d&amp;c yellow no. 10, fd&amp;c blue no. 1, magnesium stearate, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, vanillin, hypromelloses, povidones, hydroxypropyl cellulose (type h), carbomer homopolymer type b (allyl pentaerythritol crosslinked).|
Clarithromycin is a semi-synthetic macrolide antimicrobial for oral use. Chemically, it is 6-0 -methylerythromycin. The molecular formula is C38 H69 NO13 , and the molecular weight is 747.96. The structural formula is:
Figure 1: Structure of Clarithromycin
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 immediate-release tablets, extended-release tablets, and granules for oral suspension.
Each yellow oval film-coated immediate-release Biaxin Filmtab tablet (clarithromycin tablets, USP) contains 250 mg or 500 mg of clarithromycin and the following inactive ingredients:
- 250 mg tablets: hypromellose, hydroxypropyl cellulose, croscarmellose sodium, D&C Yellow No. 10, FD&C Blue No. 1, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, and vanillin.
- 500 mg tablets: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin.
Each yellow oval film-coated Biaxin XL Filmtab tablet (clarithromycin extended-release tablets) contains 500 mg of clarithromycin and the following inactive ingredients: cellulosic polymers, D&C Yellow No. 10, lactose monohydrate, magnesium stearate, propylene glycol, sorbic acid, sorbitan monooleate, talc, titanium dioxide, and vanillin.
Each 5 mL of Biaxin reconstituted suspension (clarithromycin for oral suspension, USP) 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, hypromellose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch flavor.
Mechanism of Action
Clarithromycin is a macrolide antimicrobial drug [see Microbiology].
Biaxin Filmtab Immediate-Release Tablets
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 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, Biaxin Filmtab 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.
Biaxin XL Filmtab Extended-Release Tablets
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 AUCs for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of formation of 14-OH clarithromycin following administration of Biaxin XL Filmtab (2 x 500 mg tablets 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, Biaxin XL Filmtab should be taken with food.
Figure 2: Steady-State Clarithromycin Plasma Concentration-Time Profiles
Biaxin Granules For Oral Suspension
When 250 mg doses of clarithromycin as Biaxin as an oral suspension were administered to fasting healthy adult subjects, peak plasma concentrations were attained around 3 hours after dosing.
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 adults given 250 mg clarithromycin as suspension (n = 22), food appeared to decrease mean peak plasma clarithromycin concentrations from 1.2 (± 0.4) mcg/mL to 1.0 (± 0.4) mcg/mL and the extent of absorption from 7.2 (± 2.5) hr•mcg/mL to 6.5 (± 3.7) hr•mcg/mL.
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 every 12 hours)|
Metabolism and Elimination
Biaxin Filmtab Immediate-Release Tablets
Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 mcg/mL to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 mcg/mL to 4 mcg/mL with a 500 mg dose administered every 8 hours to 12 hours. The elimination half-life of clarithromycin was about 3 hours to 4 hours with 250 mg administered every 12 hours but increased to 5 hours to 7 hours with 500 mg administered every 8 hours to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 hours 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 hours to 6 hours. With a 500 mg every 8 hours 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 hours to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 days 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.
Biaxin XL Filmtab Extended-Release Tablets
In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 mcg/mL to 3 mcg/mL were achieved about 5 hours to 8 hours after oral administration of 1000 mg Biaxin XL Filmtab once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.8 mcg/mL were attained about 6 hours to 9 hours after dosing. Steady-state peak plasma clarithromycin concentrations of approximately 1 mcg/mL to 2 mcg/mL were achieved about 5 hours to 6 hours after oral administration of a single 500 mg Biaxin XL Filmtab once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.6 mcg/mL were attained about 6 hours after dosing.
Steady-state peak plasma concentrations were attained in 2 days to 3 days and were approximately 2 mcg/mL for clarithromycin and 0.7 mcg/mL for 14-OH clarithromycin when 250-mg doses of the clarithromycin suspension were administered every 12 hours. Elimination half-life of clarithromycin (3 hours to 4 hours) and that of 14-OH clarithromycin (5 hours to 7 hours) were similar to those observed at steady state following administration of equivalent doses of Biaxin Filmtab.
Specific Populations for Biaxin Filmtab, Biaxin XL Filmtab, and Biaxin Granules Formulations
Biaxin Granules For Oral Suspension in Pediatric Patients
Clarithromycin penetrates into the middle ear fluid of pediatric patients with secretory otitis media.
|CONCENTRATION (after 7.5 mg/kg every 12 hours for 5 doses|
|Analyte||Middle Ear Fluid|
When pediatric patients (n = 10) were administered a single oral dose of 7.5 mg/kg Biaxin as an oral suspension, food increased mean peak plasma clarithromycin concentrations from 3.6 (± 1.5) mcg/mL to 4.6 (± 2.8) mcg/mL and the extent of absorption from 10.0 (± 5.5) hr•mcg/mL to 14.2 (± 9.4) hr•mcg/mL.
In pediatric patients requiring antibacterial therapy, administration of 7.5 mg/kg every 12 hours of Biaxin as an oral suspension generally resulted in steady-state peak plasma concentrations of 3 mcg/mL to 7 mcg/mL for clarithromycin and 1 mcg/mL to 2 mcg/mL for 14-OH clarithromycin.
In HIV-infected pediatric patients taking 15 mg/kg of Biaxin as an oral suspension every 12 hours, steady-state clarithromycin peak concentrations generally ranged from 6 mcg/mL to 15 mcg/mL.
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 Cmax values ranged from 2 mcg/mL to 4 mcg/mL and 5 mcg/mL 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 Use in Specific Populationsand Dosage and Administration].
Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin Cmin and AUC increased 33% and 18%, respectively. Clarithromycin exposures were increased and steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole.
When a single dose of colchicine 0.6 mg was administered with clarithromycin 250 mg BID for 7 days, the colchicine Cmax increased 197% and the AUC0-∞ increased 239% compared to administration of colchicine alone.
Following administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), the clarithromycin AUC increased 94%, the 14-OH clarithromycin AUC decreased 70% and the atazanavir AUC increased 28%.
Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin.
Following administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers, the steady-state saquinavir AUC and Cmax increased 177% and 187% respectively compared to administration of saquinavir alone. Clarithromycin AUC and Cmax increased 45% and 39% respectively, whereas the 14–OH clarithromycin AUC and Cmax decreased 24% and 34% respectively, compared to administration with clarithromycin alone.
Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.
Following administration of clarithromycin 500 mg tablets twice daily with zidovudine 100 mg every 4 hours, the steady-state zidovudine AUC decreased 12% compared to administration of zidovudine alone (n=4). Individual values ranged from a decrease of 34% to an increase of 14%. When clarithromycin tablets were administered two to four hours prior to zidovudine, the steady-state zidovudine Cmaxincreased 100% whereas the AUC was unaffected (n=24).
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 t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin.
The plasma levels of clarithromycin and 14–OH 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–OH clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8was 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)|
|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|
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%.
When a single dose of midazolam was co-administered with clarithromycin tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600% after oral administration.
For information about other drugs indicated in combination with Biaxin, refer to their full prescribing information, CLINICAL PHARMACOLOGY section.
Mechanism of Action
Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis.
The major routes of resistance are modification of the 23S rRNA in the 50S ribosomal subunit to insensitivity or drug efflux pumps. Beta-lactamase production should have no effect on clarithromycin activity.
Most isolates of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.
If H. pylori is not eradicated after treatment with clarithromycin-containing combination regimens, patients may develop clarithromycin resistance in 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; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antibacterial agent.
Clarithromycin has been shown to be active against most of the isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage].
- Staphylococcus aureus
- Streptococcus pneumoniae
- Streptococcus pyogenes
- Haemophilus influenzae
- Haemophilus parainfluenzae
- Moraxella catarrhalis
- Chlamydophila pneumoniae
- Helicobacter pylori
- Mycobacterium avium complex (MAC) consisting of M. avium and M. intracellulare
- Mycoplasma pneumoniae
At least 90 percent of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clarithromycin susceptible MIC breakpoint for organisms of similar type to those shown in Table 3. However, the efficacy of clarithromycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.
- Streptococcus agalactiae
- Streptococci (Groups C, F, G)
- Viridans group streptococci
- Legionella pneumophila
- Pasteurella multocida
- Clostridium perfringens
- Peptococcus niger
- Prevotella melaninogenica
- Propionibacterium acnes
Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug for treatment.
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 test method1,2 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 3.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of bacteria to clarithromycin. The disk diffusion interpretive criteria are provided in Table 3.
Susceptibility Testing for Mycobacterium avium Complex (MAC)
The reference methodology for susceptibility testing of Mycobacterium avium complex (MAC) is broth dilution (either microdilution or macrodilution method).4 For broth microdilution testing, cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with 5% OADC is recommended. Transparent colonies should be used for the inoculum, if present. Susceptibility testing at either pH 6.8 or pH 7.4 is acceptable, provided that interpretation is done based on the culture conditions employed. Microdilution trays are incubated at 35 ºC to 37 ºC in ambient air and examined after seven days. Trays should be incubated and read again at 10 to 14 days, if growth is poor on initial inspection.
Susceptibility Testing for Helicobacter pylori
The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.5 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 -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 MIC values should be interpreted according to the criteria in Table 3.
(zone diameters in mm)
|Staphylococcus aureus||≤ 2||4||≥ 8||≥ 18||14--17||≤ 13|
|Streptococcus pyogenes and Streptococcus pneumoniae||≤ 0.25a||0.5a||≥ 1a||≥ 21b||17--20b||≤ 16b|
|Haemophilus influenzae||≤ 8c||16c||≥ 32c||≥ 13d||11--12d||≤ 10d|
|Helicobacter pylorie||≤ 0.25||0.5||≥ 1||--||--||--|
a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation adjusted Mueller Hinton broth with 2-5% lysed horse blood2.
b These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO22.
c These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Testing Medium (HTM)2.
d These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM2.
e These are tentative breakpoints for clarithromycin for the agar dilution methodology and should not be used to interpret results obtained using alternative methods5. Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae , susceptibility and resistance to clarithromycin can be predicted using erythromycin.
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) 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 (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.
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.1-5 Standard clarithromycin powder should provide the following range of MIC values as noted in Table 4. For the diffusion technique using the 15 mcg disk, the criteria in Table 4 should be achieved.
|QC Strain||MIC (mcg/mL)||Zone diameter (mm)|
|Staphylococcus aureus ATCC 29213a||0.12 – 0.5||--|
|Staphylococcus aureus ATCC 25923||--||26 – 32|
|Streptococcus pneumoniae ATCC 49619||0.03 – 0.12b||25 – 31c|
|Haemophilus influenzae ATCC 49247||4 – 16d||11 – 17e|
|Helicobacter pylori ATCC 43504||0.015 – 0.12f||--|
|M. avium ATCC 700898||1 – 4g||--|
a ATCC is a registered trademark of the American Type Culture Collection.
b This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation adjusted Mueller Hinton broth with 2-5% lysed horse blood.1,2
c This quality control range is applicable only to S. pneumoniae ATCC 49619 for tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.2,3
d This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1,2.
e This quality control limit applies to disk diffusion tests conducted with Haemophilus influenzae ATCC 49247 using HTM2,3.
f These are quality control ranges for the agar dilution methodology5 and should not be used to control test results obtained using alternative methods.
g When tested at pH 6.8 (if tested at pH 5.0 to 7.4 at 7.4, the acceptable range is 0.5 mcg/mL to 2 mcg/mL)4.
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 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.
Impairment of Fertility
Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/ 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 twice the human serum levels.
Testicular atrophy 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 (on a body surface area basis).
Animal Toxicology and/or Pharmacology
Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose (on a body surface area basis). Lymphoid depletion occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose (on a body surface area basis).
Prophylaxis of Mycobacterial Infections
A randomized, double-blind clinical trial (trial 3) compared clarithromycin 500 mg twice a day to placebo in patients with CDC-defined AIDS and CD4counts less than 100 cells/µL. This trial accrued 682 patients from November 1992 to January 1994, with a median CD4 cell count at entry of 30 cells/mcL. Median duration of Biaxin was 10.6 months vs. 8.2 months for placebo. More patients in the placebo arm than the Biaxin arm discontinued prematurely from the trial (75.6% and 67.4%, respectively). However, if premature discontinuations due to Mycobacterium avium complex (MAC) or death are excluded, approximately equal percentages of patients on each arm (54.8%) on Biaxin and 52.5% on placebo) discontinued study drug early for other reasons. The trial was designed to evaluate the following endpoints:
- MAC bacteremia, defined as at least one positive culture for Mycobacterium avium complex bacteria from blood or another normally sterile site
- 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
In patients randomized to Biaxin, 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 Biaxin and 19.4% for patients randomized to placebo. While only 19 of the 341 patients randomized to Biaxin developed MAC, 11 of these cases were resistant to Biaxin. The patients with resistant MAC bacteremia had a median baseline CD4 count of 10 cells/mm3 (range 2 cells/mm3 to 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 Biaxin and developed susceptible MAC bacteremia had a median baseline CD4 count of 25 cells/mm3 (range 10 cells/mm3 to 80 cells/mm3). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to Biaxin. The median baseline CD4 count was 15 cells/mm3(range 2 cells/mm3 to 130 cells/mm3) for placebo patients that developed MAC.
A statistically significant survival benefit of Biaxin compared to placebo was observed (see Figure 3 and Table 5). Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of Biaxin may be underestimated.
Figure 3. Survival of All Randomized AIDS Patients Over Time in Trial 3
|Mortality Rates||Reduction in Mortality Rates on|
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of MAC bacteremia, patients in the group randomized to Biaxin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.
Treatment of Mycobacterial Infections
Dose-Ranging Monotherapy Trials in Adult AIDS Patients with MAC
Two randomized clinical trials (Trials 1 and 2) compared different dosages of Biaxin in patients with CDC-defined AIDS and CD4 counts less than100 cells/mcL. These trials accrued patients from May 1991 to March 1992. Trial 500 was a randomized, double-blind trial; trial 577 was an open-label compassionate use trial. Both trials used 500 mg and 1000 mg twice daily dosing of Biaxin; trial 1 also had a 2000 mg twice daily Biaxin group. Trial 1 enrolled 154 adult patients and trial 2 enrolled 469 adult patients. The majority of patients had CD4 cell counts less than 50 cells/mcL at study entry. The trials were designed to evaluate the following end points:
- Change in MAC bacteremia or blood cultures negative for M. avium.
- 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 trial 1 are described below. The trial 2 results were similar to the results of trial 1.
Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all Biaxin dosage groups. The mean reductions in MAC colony forming units (CFU) from baseline after 4 weeks of therapy in the 1000 mg (n=32) twice daily and 2000 mg (n=26) twice daily regimen was 2.3 Log CFU compared to 1.5 Log CFU in the Biaxin 500 mg twice daily (n=35) regimen. A separate trial with a four drug regimen6 (ciprofloxacin, ethambutol, rifampicin, and clofazimine) had a mean reduction of 1.4 Log CFU.
Clinical outcomes evaluated with the different dosing regimens of clarithromycin monotherapy are shown in Table 6. The 1000 mg and 2000 mg twice daily doses showed significantly better control of bacteremia during the first four weeks of therapy. No significant differences were seen beyond that point. All of the isolates had MIC less than 8 mcg/mL at pre-treatment. Relapse was almost always accompanied by an increase in MIC.
|One or more negative blood cultures at any time during acute therapy||61% (30/49)||59% (29/49)||52% (25/48)|
|Two or more negative blood cultures during acute therapy sustained through study day 84||25% (12/49)||25% (12/49)||8% (4/48)|
|Death or discontinuation by day 84||23% (11/49)||37% (18/49)||56% (27/48)|
|Relapse by day 84||14% (7/49)||12% (6/49)||13% (6/48)|
|Median time to first negative culture (in days)||54||41||29|
|Median time to first decrease of at least 1 log CFU (in days)||29||16||15|
|Median time to first positive culture or study discontinuation following the first negative culture (in days)||43||59||43|
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 Biaxin at 500 mg to 2000 mg twice daily doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given in Table 7 below.
The median duration of response, defined as improvement or resolution of clinical signs and symptoms, was 2 weeks to 6 weeks.
Since the trial was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25% to 33% of patients who continued to show clinical response after 12 weeks.
|Resolution of Fever||Resolution of Night Sweats|
6 weeks or
6 weeks or
|Weight Gain Greater Than 3%||Hemoglobin Increase Greater Than 1 gm|
6 weeks or
6 weeks or
Median survival time from trial entry (trial 1) was 249 days at the 500 mg twice daily dose compared to 215 days with the 1000 mg twice daily dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg twice daily group versus 13 deaths in 51 patients in the 1000 mg twice daily 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.6
Median survival time from entry in trial 2 was 199 days for the 500 mg twice a day dose and 179 days for the 1000 mg twice a day 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 twice daily and 18 deaths in 214 patients taking 1000 mg twice daily.
Dosage-Ranging Monotherapy Trials in Pediatric AIDS Patients with MAC
Trial 4 was a pediatric trial of 3.75 mg/kg, 7.5 mg/kg, and 15 mg/kg of Biaxin twice daily in patients with CDC-defined AIDS and CD4 counts less than 100 cells/mcL. The trial enrolled 25 patients between the ages of 1 to 20. The trial evaluated the same endpoints as in the adult trials 1 and 2. Results with the 7.5 mg/kg twice daily dose in the pediatric trial were comparable to those for the 500 mg twice daily regimen in the adult trials.
Combination Therapy in AIDS Patients with Disseminated MAC
Trial 5 compared the safety and efficacy of Biaxin in combination with ethambutol versus Biaxin in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection. This 24-week trial enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive Biaxin and ethambutol, and 51 patients randomized to receive clarithromycin, ethambutol, and clofazime. Baseline characteristics between treatment arms were similar with the exception of median CFU counts being at least 1 log higher in the Biaxin, ethambutol, and clofazime arm.
Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol extended the time to microbiologic relapse, largely through suppressing the emergence of clarithromycin resistant strains. However, the addition of clofazimine to the regimen added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher. The results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent.
Otitis Media Trial of Biaxin vs. Oral Cephalosporin
In a controlled clinical trial of pediatric patients with acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, Biaxin was compared to an oral cephalosporin. In this trial, 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 Biaxin and 91% for the cephalosporin.
In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 8.
|Pathogen||Clinical Success Rates|
|S. pneumoniae||13/15 (87%)||4/5|
|H. influenzaea||10/14 (71%)||3/4|
|All Pathogens Combined||30/37 (81%)||8/11 (73%)|
a None of the H. influenzae isolated pre-treatment was resistant to Biaxin; 6% were resistant to the control agent.
Otitis Media Trials of Biaxin vs. Antimicrobial/Beta-lactamase Inhibitor
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, Biaxin was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. In these trials, 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 Biaxin and the control.
For the patients who had microbiologic determinations at the pre-treatment visit, the presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 9.
|Clinical Success Rates|
|S. pneumoniae||43/51 (84%)||55/56 (98%)|
|H. influenzaea||36/45 (80%)||31/33 (94%)|
|M. catarrhalis||9/10 (90%)||6/6|
|All Pathogens Combined||91/109 (83%)||97/100 (97%)|
a Of the H. influenzae isolated pre-treatment, 3% were resistant to Biaxin and 10% were resistant to the control agent.
H. pylori Eradication to Decrease the Risk of Duodenal Ulcer Recurrence
Biaxin + Lansoprazole and Amoxicillin
Two U.S. randomized, double-blind clinical trials (trial 6 and trial 7) in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of Biaxin 500 mg twice daily in combination with lansoprazole 30 mg twice daily and amoxicillin 1 gm twice daily as 14-day triple therapy for eradication of H. pylori.
H. pylori eradication was defined as two negative tests (culture and histology) at 4 weeks to 6 weeks following the end of treatment.
The combination of Biaxin plus lansoprazole and amoxicillin as triple therapy was effective in eradication of H. pylori (see results in Table 10). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
A randomized, double-blind clinical trial (trial 8) performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of Biaxin in combination with lansoprazole and amoxicillin as triple therapy for 10 days and 14 days. This trial established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori (see results in Table 10).
|Trial 6||14 days||92c [80-97.7]|
(n = 48)
(n = 55)
|Trial 7||14 days||86d [75.7-93.6]|
(n = 66)
(n = 70)
|Trial 8e||14 days||85 [77-91]|
(N = 113)
(N = 126)
|10 days||84 [76-89.8]|
(N = 123)
(N = 135)
a Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pyloriinfection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD., Bentley, Australia), histology, and/or culture. Patients were included in the analysis if they completed the trial. Additionally, if patients were dropped out of the trial due to an adverse reaction related to the drug, they were included in the analysis as evaluable failures of therapy.
b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
c (p < 0.05) versus Biaxin/lansoprazole and lansoprazole/amoxicillin dual therapy.
d (p < 0.05) versus Biaxin/amoxicillin dual therapy.
e The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day, is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.
Biaxin + Omeprazole and Amoxicillin Therapy
Three U.S., randomized, double-blind clinical trials in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared Biaxin plus omeprazole and amoxicillin to Biaxin plus amoxicillin. Two trials (trials 9 and 10) were conducted in patients with an active duodenal ulcer, and the third trial (trial 11) was conducted in patients with a duodenal ulcer in the past 5 years, but without an ulcer present at the time of enrollment. The dosage regimen in the trials was Biaxin 500 mg twice a day plus omeprazole 20 mg twice a day plus amoxicillin 1 gram twice a day for 10 days. In trials 9 and 10, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once a day. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (trials 9 and 10 only). H. pylori status was determined by CLOtest® , histology, and culture in all three trials. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive. The combination of Biaxin plus omeprazole and amoxicillin was effective in eradicating H. pylori (see results in Table 11).
|Biaxin + omeprazole + amoxicillin||Biaxin + amoxicillin|
|Trial 9||c77 [64, 86] (n = 64)||69 [57, 79] (n = 80)||43 [31, 56] (n = 67)||37 [27, 48] (n = 84)|
|Trial 10||c78 [67, 88] (n = 65)||73 [61, 82] (n = 77)||41 [29, 54] (n = 68)||36 [26, 47] (n = 84)|
|Trial 11||c90 [80, 96] (n = 69)||83 [74, 91] (n = 84)||33 [24, 44] (n = 93)||32 [23, 42] (n = 99)|
a Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer trials 9 and 10; history of ulcer within 5 years, trial 11) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest® , histology, and/or culture. Patients were included in the analysis if they completed the trial. Additionally, if patients dropped out of the trial due to an adverse reaction related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.
b Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.
c p < 0.05 versus Biaxin plus amoxicillin.
Biaxin + Omeprazole Therapy
Four randomized, double-blind, multi-center trials (trials 12, 13, 14, and 15) evaluated Biaxin 500 mg three times a day plus omeprazole 40 mg once a day for 14 days, followed by omeprazole 20 mg once a day (trials 12, 13, and 15) or by omeprazole 40 mg once a day (trial 14) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Trials 12 and 13 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in trial 12 and 228 patients in trial 13. These trials compared the combination regimen to omeprazole and Biaxin monotherapies. Trials 14 and 15were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in trial 14 and 208 patients in trial 15. These trials compared the combination regimen to omeprazole monotherapy. The results for the efficacy analyses for these trials are described in Tables 20, 21, and 22.
Duodenal Ulcer Healing
The combination of Biaxin and omeprazole was as effective as omeprazole alone for healing duodenal ulcer (see Table 12).
|Trial 13||94% (58/62)a||88% (60/68)||71% (49/69)|
|Trial 12||88% (56/64)a||85% (55/65)||64% (44/69)|
|Trial 15||99% (84/85)||95% (82/86)||N/A|
|Trial 14b||100% (64/64)||99% (71/72)||N/A|
a p < 0.05 for Biaxin + omeprazole versus Biaxin monotherapy.
b In trial 14 patients received omeprazole 40 mg daily for days 15 to 28.
Eradication of H. pylori Associated with Duodenal Ulcer
The combination of Biaxin and omeprazole was effective in eradicating H. pylori (see Table 13). H. pylorieradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated. In the per-protocol analysis, the following patients were excluded: dropouts, patients with major protocol violations, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication at 4 weeks after the end of treatment because they were found to have an unhealed ulcer at the end of treatment.
|Trial 13||64% (39/61)a,b||0% (0/59)||39% (17/44)|
|Trial 12||74% (39/53)a,b||0% (0/54)||31% (13/42)|
|Trial 15||74% (64/86)b||1% (1/90)||N/A|
|Trial 14||83% (50/60)b||1% (1/74)||N/A|
a Statistically significantly higher than Biaxin monotherapy (p < 0.05).
b Statistically significantly higher than omeprazole monotherapy (p < 0.05).
Duodenal Ulcer Recurrence
Ulcer recurrence at 6-months and at 12 months following the end of treatment was assessed for patients in whom ulcers were healed post-treatment (see the results in Table 14). Thus, in patients with duodenal ulcer associated with H. pylori infection, eradication of H. pylori reduced ulcer recurrence.
|H. pylori Negative at 4-6|
|H. pylori Positive at 4-6|
Recurrence at 6 Months
|Biaxin + Omeprazole||6% (2/34)||56% (9/16)|
|Biaxin||12% (2/17)||32% (7/22)|
|Biaxin + Omeprazole||38% (11/29)||50% (6/12)|
|Biaxin||18% (2/11)||52% (14/27)|
Recurrence at 6 Months
|Biaxin + Omeprazole||6% (3/53)||24% (4/17)|
|Omeprazole||0% (0/3)||55% (39/71)|
|Biaxin + Omeprazole||5% (2/42)||0% (0/7)|
|Omeprazole||0% (0/1)||54% (32/59)|
Recurrence at 12-Months in Trial 14
|Biaxin + Omeprazole||3% (1/40)||0% (0/6)|
|Omeprazole||0% (0/1)||67% (29/43)|