Clarithromycin Information
Clarithromycin ()
Clarithromycin () Description
Clarithromycin () is a semi-synthetic macrolide antibiotic. Chemically, it is 6--methylerythromycin. The molecular formula is CHNO, and the molecular weight is 747.95. 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 granules for oral suspension.
After constitution, each 5 mL of Clarithromycin () for oral suspension, USP contains 125 mg or 250 mg of Clarithromycin () . Each bottle of Clarithromycin () granules for oral suspension contains 1250 mg (50 mL size), 2500 mg (50 and 100 mL sizes) or 5000 mg (100 mL size) of Clarithromycin () . In addition, each 5 mL of reconstituted Clarithromycin () for oral suspension USP contains the following inactive ingredients: citric acid (anhydrous), colloidal silicon dioxide, confectioner’s sugar, fruit punch flavor, glyceryl monostearate, hypromellose, maltodextrin, methacrylic acid copolymer dispersion, poloxamer, polyethylene glycol, polysorbate 80, potassium sorbate, povidone, titanium dioxide, triethyl citrate, and xanthan gum.
Clarithromycin () Clinical Pharmacology
Clarithromycin () is rapidly absorbed from the gastrointestinal tract after oraladministrationThe 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 mgadministered 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 about0.6 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/5mL) 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 every12 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 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 and ).
Clarithromycin () and the 14-OH Clarithromycin () metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid pen-etration. 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)
When 250 mg doses of Clarithromycin () as Clarithromycin () 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 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 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 Clarithromycin () 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 mcg/mL for Clarithromycin () and 1 to 2 mcg/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 mcg/mL.
Clarithromycin () penetrates into the middle ear fluid of children with secretoryotitis media.
CONCENTRATION
(after 7.5 mg/kg q12h for 5 doses)
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) hrmcg/mL to 6.5 (± 3.7) hrmcg/mL.
When children (n=10) were administered a single oral dose of 7.5 mg/kg 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) hrmcg/mL to 14.2 (± 9.4) hrmcg/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 C was 10% greater, the mean C was 27% greater, and the mean AUC 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 was 45% greater, the mean C was 57% greater, and the mean AUC 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)
For information about other drugs indicated in combination with Clarithromycin () , refer to the 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 against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most complex (MAC) microorganisms.
Additionally, the 14-OH Clarithromycin () metabolite also has clinically significant antimicrobial activity. The 14-OH Clarithromycin () is twice as active against microorganisms as the parent compound. However, for complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than Clarithromycin () . The clinical significance of this activity against complex is unknown.
Clarithromycin () has been shown to be active against most strains of the following microorganisms both and in clinical infections as described in the 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
Mycobacteria
Mycobacterium avium
Mycobacterium intracellulare
Beta-lactamase production should have no effect on Clarithromycin () activity.
NOTE:
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 and in clinical infections as described in the section.
Helicobacter
Helicobacter pylori
Pretreatment Resistance
Clarithromycin () pretreatment resistance rates were 3.5% (4/113) in the omeprazole/Clarithromycin () dual-therapy studies (M93-067, M93-100) 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 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. 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 Outcomes
Includes only patients with pretreatment Clarithromycin () susceptibility tests
Patients not eradicated of following omeprazole/Clarithromycin () , ranitidine bismuth citrate/Clarithromycin () , omeprzole/Clarithromycin () /amoxicillin, or lansoprazole/Clarithromycin () /amoxicillin therapy would likely have Clarithromycin () resistant isolates. Therefore, for patients who fail therapy, Clarithromycin () susceptibility testing should be done, if possible. Patients with Clarithromycin () resistant 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 (
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, three of six had the 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 isolates.
The following in vitro data are available, .
Clarithromycin () exhibits activity against most strains of the following micro-organisms; 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
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
Susceptibility Testing Excluding Mycobacteria and Helicobacter
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 (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 spp.
For testing spp. including
These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
For testing spp.
These interpretive standards are applicable only to broth microdilution susceptibility tests with . using Haemophilus Testing Medium (HTM).
Clarithromycin () has demonstrated activity against complex (MAC) microorganisms isolated from both AIDS and non-AID patients. While gene probe techniques may be used to distinguish species from , many studies only reported results on complex (MAC) isolates.
Various 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 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 complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model.
Clarithromycin () activity was evaluated against microorganisms. In one study utilizing the agar dilution method with Middlebroo 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 /mL. Clarithromycin () inhibited all isolates at > 10 mcg/mL.
The reference methodology for susceptibility testing of is agar dilution MICs. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 × 10 - 1 × 10 CFU/mL for ) 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 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:
These are tentative breakpoints for the agar dilution methodology, and they should not be used to interpret results obtained using alternative methods.
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Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard Clarithromycin () and amoxicillin powders should provide the following MIC values:
These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.
Clarithromycin () Indications And Usage
Clarithromycin () for oral suspension is indicated for the treatment of mild t moderate infections caused by susceptible strains of the designated microor-ganisms in the conditions as listed below:
Pharyngitis/Tonsillitis due to (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 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 or
Acute bacterial exacerbation of chronic bronchitis due to or
Community-Acquired Pneumonia due to or (TWAR).
Uncomplicated skin and skin structure infections due to or (Abscesses usually require surgical drainage.)
Disseminated mycobacterial infections due to or
In patients who fail therapy, susceptibility testing should be done if possible. If resistance to Clarithromycin () is demonstrated, a non-Clarithromycin () -containing therapy is recommended. (For information on development of resistance see section.) The eradication of has been demonstrated to reduce the risk of duodenal ulcer recurrence.
Pharyngitis/Tonsillitis due to
Community-Acquired Pneumonia due to or (TWAR)
Acute maxillary sinusitis due to or
Acute otitis media due to or
Uncomplicated skin and skin structure infections due to or (Abscesses usually require surgical drainage.)
Disseminated mycobacterial infections due to or
Clarithromycin () for oral suspension is indicated for the prevention of disseminated complex (MAC) disease in patients with advanced HIV infection.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Clarithromycin () and other antibacterial drugs, Clarithromycin () for oral suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Clarithromycin () Contraindications
Clarithromycin () is contraindicated in patients with a known hypersensitivity to Clarithromycin () , erythromycin, or any of the macrolide antibiotics.
Concomitant administration of Clarithromycin () and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine and ergotamine or dihydroergotamine (see ). There have been post-marketing reports of drug interactions when Clarithromycin () and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin and Clarithromycin () . Fatalities have been reported.
For information about contraindications of other drugs indicated in combination with Clarithromycin () , refer to the section of their package inserts.
Clarithromycin () Warnings
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of and surgical evaluation should be instituted as clinically indicated.
There have been post-marketing reports of colchicine toxicity with concomitant use of Clarithromycin () and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. (See .)
For information about warnings of other drugs indicated in combination with Clarithromycin () , refer to the section of their package inserts.
Clarithromycin () Precautions
Prescribing Clarithromycin () in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
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 renalimpairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.
Clarithromycin () in combination with ranitidine bismuth citrate therapy is notrecommended in patients with creatinine clearance less than 25 mL/min. (See
Clarithromycin () in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving Clarithromycin () therapy.
For information about precautions of other drugs indicated in combination with Clarithromycin () , refer to the section of their package inserts.
Patients should be counseled that antibacterial drugs including Clarithromycin () for oral suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Clarithromycin () is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Clarithromycin () for oral suspension or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Clarithromycin () may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.
Clarithromycin () for oral suspension can be taken with or without food and can be taken with milk. Do refrigerate the suspension.
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 C, C, 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 .)
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 (C, AUC, and T 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 coadministered with Clarithromycin () .
Coadministration 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 Clarithromycin () 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 Clarithromycin () tablets were administered two to four hours prior to oral zidovudine, the steady-state zidovudine C was increased by approximately 2-fold, whereas the AUC was unaffected.
Simultaneous administration of Clarithromycin () 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 () C and AUC of 33% and 18%, respectively. Steady-state concentrations of 14-OH Clarithromycin () were not significantly affected by concomitant administration of fluconazole.
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 () . Clarithromycin () may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CL30 to 60 mL/min, the dose of Clarithromycin () should be reduced by 50%. For patients with CL
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 potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and Clarithromycin () simultaneously.
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin () and other macrolides are known to inhibit CYP3 A and Pgp. When Clarithromycin () and colchicine are administered together, inhibition of Pgp and/or CYP3A by Clarithromycin () may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity. (See .)
Erythromycin and Clarithromycin () are substrates and inhibitors of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Coadministration of erythromycin or Clarithromycin () and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving Clarithromycin () or erythromycin.
The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were observed in clinical trials with Clarithromycin () .
The following CYP3A based drug interactions have been observed with erythromycin products and/or with Clarithromycin () in post-marketing experience:
Antiarrhythmics:
Triazolobenziodidiazepines (Such as Triazolam and Aalprazolam) and Related Benzodiazepines (such as Midazolam):
HMG-CoA Reductase Inhibitors:
Sildenafil (Viagra):
There have been spontaneous or published reports of CYP3A based interactions of erythromycin and/or Clarithromycin () with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, and bromocriptine.
Concomitant administration of Clarithromycin () with cisapride, pimozide, astemi-zole, or terfenadine is contraindicated (see ).
In addition, there have been reports of interactions of erythromycin or Clarithromycin () with drugs not thought to be metabolized by CYP3A including hexobarbital, phenytoin, and valproate.
The following mutagenicity tests have been conducted with Clarithromycin () :
All tests had negative results except the 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) 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), 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, fetal loss occurred at an intravenous dose of 33 mg/m, which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Clarithromycin () .
Clarithromycin () 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 taking Clarithromycin () tablets 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% wasdescribed as severe.
In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either Clarithromycin () immediate-release tablets or Clarithromycin () extended-release tablets; however, patients taking Clarithromycin () extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking Clarithromycin () immediate-release tablets. In addition, patients taking claritromycin extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to Clarithromycin () immediate-release tablets.
In community-acquired 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
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
Clarithromycin () Overdosage
Overdosage of Clarithromycin () can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.
Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, Clarithromycin () serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
Clarithromycin () Dosage And Administration
Clarithromycin () for oral suspension may be given with or without food.
Triple therapy: Clarithromycin () /lansoprazole/amoxicillin
The recommended adult dose is 500 mg Clarithromycin () , 30 mg lansoprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 or 14 days. (See and sections.)
Triple therapy: Clarithromycin () /omeprazole/amoxicillin
The recommended adult dose is 500 mg Clarithromycin () , 20 mg omeprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 days. (See and sections.) In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.
Dual therapy: Clarithromycin () /omeprazole
The recommended adult dose is 500 mg Clarithromycin () given three times daily (q8h) and 40 mg omeprazole given once daily (qAM) for 14 days. (See and sections.) An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.
Dual therapy: Clarithromycin () /ranitidine bismuth citrate
The recommended adult dose is 500 mg Clarithromycin () given twice daily (q12h) or three times daily (q8h) and 400 mg ranitidine bismuth citrate given twice daily (q12h) for 14 days. An additional 14 days of 400 mg twice daily is recommended for ulcer healing and symptom relief. Clarithromycin () and ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See and sections.)
Children - The usual recommended daily dosage is 15 mg/kg/day divided q12h for 10 days.
Clarithromycin () may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. However, in the presence of severe renal impairment (CR
Clarithromycin () How Supplied
Clarithromycin () for oral suspension is supplied in the following strengths and sizes:
Store Clarithromycin () granules for oral suspension at 20°- 25°C (68°- 77°F) [See USP Controlled Room Temperature.] in a well-closed container. Do not refrigerate Clarithromycin () suspension.
Clarithromycin () Clinical Studies
A randomized, double-blind study (561) compared Clarithromycin () 500 mg b.i.d. to placebo in patients with CDC-defined AIDS and CD counts
MAC bacteremia
In patients randomized to Clarithromycin () , the risk of MAC bacteremia was reduced by 69% compared to placebo. The difference between groups was statistically significant (p
Survival
A statistically significant survival benefit was observed.
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of Clarithromycin () may be underestimated.
In association with the decreased incidence of bacteremia, patients in the group randomized to Clarithromycin () showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.
In AIDS patients treated with Clarithromycin () over long periods of time for prophylaxis against , it was often difficult to distinguish adverse events possibly associated with Clarithromycin () administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the Clarithromycin () group and 8.2 months for the placebo group.
* Includes those events possibly or probably related to study drug and excludes concurrent conditions.
Among these events, taste perversion was the only event that had significantly higher incidence in the Clarithromycin () -treated group compared to the placebo-treated group.
Discontinuation due to adverse events was required in 18% of patients receiving Clarithromycin () compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in Clarithromycin () treated patients include headache, nausea, vomiting, depression and taste perversion.
Changes in Laboratory Values of Potential Clinical Importance
In immunocompromised patients receiving prophylaxis against evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test.
Clarithromycin () Animal Pharmacology And Toxicology
Clarithromycin () is rapidly and well-absorbed with dose-linear kinetics, low protein binding, and a high volume of distribution. Plasma half-life ranged from 1 to 6 hours and was species dependent. High tissue concentrations were achieved, but negligible accumulation was observed. Fecal clearance predominated. Hepatotoxicity occurred in all species tested (i.e., in rats and monkeys at doses 2 times greater than and in dogs at doses comparable to the maximum human daily dose, based on mg/m). Renal tubular degeneration (calculated on a mg/m basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose. Testicular atrophy (on a mg/m basis) occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose. Corneal opacity (on a mg/m basis) occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose. Lymphoid depletion (on a mg/m basis) occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose. These adverse events were absent during clinical trials.
Clarithromycin () References
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.
3. National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL. January 11-13, 1998.
4. Chaisson RE, et al. Clarithromycin () and Ethambutol with or without Clofazimine for the Treatment of Bacteremic Complex Disease in Patients with HIV Infection. . 1997;11:311-317.
5. Kemper CA, et al. Treatment of Complex Bacteremia in AIDS with a Four-Drug Oral Regimen. 1992;116:466-472.
6. Tritec is a registered trademark of GlaxoSmithKline
Manufactured in Romania by Sandoz SRL
For Sandoz Inc., Princeton, NJ 08540
Rev. October 2010
Clarithromycin () Principal Display Panel
Clarithromycin () for Oral Suspension, USP
125 mg* per 5 mL
when reconstituted
*When mixed as directed, each teaspoonful (5 mL) contains 125 mg of Clarithromycin () in a fruit punch flavored, aqueous vehicle.
Rx only
50 mL ( when mixed)
Clarithromycin () Principal Display Panel
Clarithromycin () for Oral Suspension, USP
250 mg* per 5 mL
when reconstituted
*When mixed as directed, each teaspoonful (5 mL) contains 250 mg of Clarithromycin () in a fruit punch flavored, aqueous vehicle.
Rx only
50 mL (when mixed)
