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)
Clarithromycin Clarithromycin + Omeprazole
10.48 ± 2.01 19.96 ± 4.71
20.81 ± 7.64 24.25 ± 6.37
4.15 ± 7.74 39.29 ± 32.79
For information about other drugs indicated in combination with Clarithromycin, refer to the CLINICAL PHARMACOLOGY section of their package inserts.
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:
Chlamydophila pneumoniae (TWAR) [previously Chlamydia pneumonia ]
Mycobacterium avium complex (MAC) consisting of:
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.
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) 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 Outcomes *
Clarithromycin Pretreatment Results
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.
Streptococci (Groups C, F, G)
Viridans group streptococci
Gram-Negative Anaerobic Bacteria
Prevotella melaninogenica (formerly Bacteriodes melaninogenicus )
Susceptibility Testing Methods (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 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Clarithromycin powder. The MIC values should be interpreted according to the following criteria 2 :
Susceptibility Test Interpretive Criteria for Staphylococcus aureus
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.
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.
* ATCC is a registered trademark of the American Type Culture Collection. † 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. ‡ This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM 1.
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)
* These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO 2.
Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae *
Zone diameter (mm)
* These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM 2.
For testing Haemophilus spp. *
Zone diameter (mm)
Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae. susceptibility and resistance to Clarithromycin can be predicted using erythromycin.
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.
* This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood. † This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM 2.
Acceptable Quality Control Ranges for Clarithromycin
In vitro Activity of Clarithromycin Against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare. many studies only reported results on M. avium complex (MAC) isolates.
Various in vitro methodologies employing broth or solid media at different pH’s, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine Clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5 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 Mycobacterium avium Complex (MAC)
The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining Clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to Clarithromycin have not been established
Susceptibility Test for Helicobacter pylori
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 10 7 - 1 x 10 8 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:
* 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.
These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.
INDICATIONS AND USAGE
Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates of the designated bacteria in the conditions as listed below:
Adults (Clarithromycin Tablets)
Pharyngitis/Tonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of Clarithromycin in the subsequent prevention of rheumatic fever are not available at present.)
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis. or Streptococcus pneumoniae.
Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae. or Chlamydophila pneumoniae (TWAR).
Uncomplicated skin and skin structure infections due to Staphylococcus aureus. or Streptococcus pyogenes (Abscesses usually require surgical drainage).
Disseminated mycobacterial infections due to Mycobacterium avium. or Mycobacterium intracellulare.
Clarithromycin in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to eradicate H. pylori .
Clarithromycin in combination with PRILOSEC (omeprazole) capsules or TIRTEC (ranitidine bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. However, regimens which contain Clarithromycin as the single antimicrobial agent are more likely to be associated with the development of Clarithromycin resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in patients with known or suspected Clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting.
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 MICROBIOLOGY section.) The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.
Children (Clarithromycin Tablets)
Pharyngitis/Tonsillitis due to Streptococcus pyogenes.
Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae. or Chlamydophila pneumoniae (TWAR).
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis. or Streptococcus pneumoniae.
Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis. or Streptococcus pneumoniae.
Uncomplicated skin and skin structure infections due to Staphylococcus aureus. or Streptococcus pyogenes (Abscesses usually require surgical drainage).
Disseminated mycobacterial infections due to Mycobacterium avium. or Mycobacterium intracellulare.
Clarithromycin is indicated for the prevention of disseminated Mycobacterium avium 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 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 is contraindicated in patients with a known hypersensitivity to Clarithromycin or any of its excipients, erythromycin, or any of the macrolide antibiotics.
Clarithromycin is contraindicated in patients with a history of cholestatic jaundice/ hepatic dysfunction associated with prior use of Clarithromycin.
Concomitant administration of Clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine (see DRUG INTERACTIONS. ). There have been post-marketing reports of drug interactions when Clarithromycin and/or erythromycin are co-administered 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.
Concomitant administration of Clarithromycin and colchicine are contraindicated in patients with renal or hepatic impairment.
Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes .
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see WARNINGS ).
For information about contraindications of other drugs indicated in combination with Clarithromycin, refer to the CONTRAINDICATIONS section of their package inserts.
Use In Pregnancy
Clarithromycin SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. Clarithromycin HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS – Pregnancy ).
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with Clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue Clarithromycin immediately if signs and symptoms of hepatitis occur.
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving Clarithromycin. Fatalities have been reported. Clarithromycin should be avoided in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia (see CONTRAINDICATIONS ) and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Serious adverse reactions have been reported in patients taking Clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopramide; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e. g. verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older (see CONTRAINDICATIONS and PRECAUTIONS – Drug Interactions ). Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see PRECAUTIONS - Drug Interactions ).
Life-threatening and fatal drug interactions have been reported in patients treated with Clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of Clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of Clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and PRECAUTIONS – Drug Interactions ).
Increased sedation and prolongation of sedation have been reported with concomitant administration of Clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam.
Use of quetiapine and Clarithromycin concomitantly with caution. Co-administration could result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as Clarithromycin.
Oral Hypoglycemic Agents/Insulin
The concomitant use of Clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by Clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended.
There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when Clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving Clarithromycin and oral anticoagulants concurrently.
HMG-CoA Reductase Inhibitors (statins)
Concomitant use of Clarithromycin with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS ) as these statins are extensively metabolized by CYP3A4, and concomitant treatment with Clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking Clarithromycin concomitantly with these statins. If treatment with Clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing Clarithromycin with statins. In situations where the concomitant use of Clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e. g.fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile .
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile. and surgical evaluation should be instituted as clinically indicated.
Acute Hypersensitivity Reactions
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura Clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Combination Therapy with Other Drugs
For information about warnings of other drugs indicated in combination with Clarithromycin, refer to the WARNINGS section of their package inserts.
Prescribing Clarithromycin tablets 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 renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min (see DOSAGE AND ADMINISTRATION ).
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.
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 tablets, refer to the PRECAUTIONS section of their package inserts.
Information to Patients
Patients should be counseled that antibacterial drugs including Clarithromycin tablets should only be used to treat bacterial infections. They do not treat viral infections (e. g. the common cold). When Clarithromycin tablets are 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 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 tablets may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.
Clarithromycin tablets can be taken with or without food and can be taken with milk.
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 max. C min. and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.
Hypotension, brady arrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class.
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 co-administered, 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-OH-Clarithromycin were not significantly affected by co-administration of terfenadine once Clarithromycin reached steady-state conditions. Concomitant administration of Clarithromycin with terfenadine is contraindicated (see CONTRAINDICATIONS ).
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C max. AUC 0-24. and t 1/2 increases of 30%, 89%, and 34%, respectively), by the concomitant administration of Clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with Clarithromycin.
Co-administration of Clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-Clarithromycin plasma concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of Clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. 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 C max increased 100% whereas the AUC was unaffected (n=24). Administration of Clarithromycin and zidovudine should be separated by at least two hours. The impact of co-administration of Clarithromycin extended-release tablets and zidovudine has not been evaluated.
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 fluconazole 200 mg daily and Clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state Clarithromycin C min and AUC of 33% and 18%, respectively. Steady-state concentrations of 14-OH Clarithromycin were not significantly affected by concomitant administration of fluconazole. No dosage adjustment of Clarithromycin is necessary when co-administered with 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. Since concentrations of 14-OH Clarithromycin are significantly reduced when Clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex (see PRECAUTIONS – Drug Interactions ). Doses of Clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
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.
Digoxin is a substrate for P-glycoprotein (Pgp) and Clarithromycin is known to inhibit Pgp. When Clarithromycin and digoxin are co-administered, inhibition of Pgp by Clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving Clarithromycin and digoxin concomitantly have been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Co-administration of Clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.
Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e. g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme. 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.
The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible.
Carbamazepine and Terfenadine
Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were observed in clinical trials with Clarithromycin.
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When a single dose of colchicine 0.6 mg was administered with Clarithromycin 250 mg BID for 7 days, the colchicine C max increased 197% and the AUC 0-∞ increased 239% compared to administration of colchicine alone. The dose of colchicine should be reduced when co-administered with Clarithromycin in patients with normal renal and hepatic function. Concomitant use of Clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see WARNINGS ).
Efavirenz, Nevirapine, Rifampicin, Rifabutin, and Rifapentine
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of Clarithromycin, thus decreasing plasma concentrations of Clarithromycin, while increasing those of 14-OH-Clarithromycin. Since the microbiological activities of Clarithromycin and 14-OH-Clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of Clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Concomitant administration of rifabutin and Clarithromycin resulted in an increase in rifabutin, and decrease in Clarithromycin serum levels together with an increased risk of uveitis.
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-Clarithromycin, were increased. Because 14-OH-Clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to Clarithromycin should be considered for the treatment of MAC.
Sildenafil, Tadalafil, and Vardenafil
Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of Clarithromycin. Co-administration of Clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with Clarithromycin is not recommended.
The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with Clarithromycin.
Triazolobenzodiazepines (e. g. alprazolam, midazolam, triazolam)
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. When oral midazolam is co-administered with Clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated. Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with Clarithromycin. For benzodiazepines which are not metabolized by CYP3A (e. g. temazepam, nitrazepam, lorazepam), a clinically important interaction with Clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e. g. somnolence and confusion) with the concomitant use of Clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
Both Clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. 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%. When Clarithromycin is co-administered with atazanavir, the dose of Clarithromycin should be decreased by 50%. Since concentrations of 14-OH Clarithromycin are significantly reduced when Clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex (see PRECAUTIONS – Drug Interactions ). Doses of Clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Both Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly. Clarithromycin may increase the plasma concentrations of itraconazole, while itraconazole may increase the plasma concentrations of Clarithromycin. Patients taking itraconazole and Clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Both Clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction. 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 C max increased 177% and 187% respectively compared to administration of saquinavir alone. Clarithromycin AUC and C max increased 45% and 39% respectively, whereas the 14-OH Clarithromycin AUC and C max decreased 24% and 34% respectively, compared to administration with Clarithromycin alone. No dose adjustment of Clarithromycin is necessary when Clarithromycin is co-administered with saquinavir in patients with normal renal function. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on Clarithromycin (refer to interaction between Clarithromycin and ritonavir) (see PRECAUTIONS — Drug Interactions ).
The following CYP3A based drug interactions have been observed with erythromycin products and/or with Clarithromycin in post-marketing experience:
There have been post-marketing reports of torsades de pointes occurring with concurrent use of Clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of Clarithromycin with these drugs. Serum concentrations of these medications should also be monitored. There have been postmarketing reports of hypoglycemia with concomitant administration of Clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of Clarithromycin and disopyramide.
Postmarketing reports indicate that co-administration of Clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of Clarithromycin with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS ).
Triazolobenzodiazepines (Such as Triazolam and Alprazolam) and Related Benzodiazepines (Such as Midazolam)
Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. There have been post-marketing reports of drug interactions and CNS effects (e. g. somnolence and confusion) with the concomitant use of Clarithromycin and triazolam.
Quetiapine is a substrate for CYP3A4, which is inhibited by Clarithromycin. Co-administration with Clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as Clarithromycin.
Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. A similar interaction may occur with Clarithromycin; reduction of sildenafil dosage should be considered. (See Viagra package insert.)
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, bromocriptine, vinblastine, phenobarbital and St. John’s Wort.
Concomitant administration of Clarithromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS ).
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The following in vitro mutagenicity tests have been conducted with Clarithromycin:
Salmonella /Mammalian Microsomes Test
Bacterial Induced Mutation Frequency Test
In Vitro Chromosome Aberration Test
Rat Hepatocyte DNA Synthesis Assay
Mouse Lymphoma Assay
Mouse Dominant Lethal Study
Mouse Micronucleus Test
All tests had negative results except the In Vitro Chromosome Aberration Test which was weakly positive in one test and negative in another.
In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on Clarithromycin metabolites with negative results.
Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m 2 ) 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 2 ), Clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.
In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m 2. which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m 2 .
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Clarithromycin.
Pregnancy Category C :Four teratogenicity studies in rats (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approximately 2 times the recommended maximum human dose based on mg/m 2 ) or intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18 failed to demonstrate any teratogenicity from Clarithromycin. Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day were 2 times the human serum levels. Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day (2 and 4 times the recommended maximum human dose based on mg/m 2. respectively) during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day (an approximate equidose of the recommended maximum human dose based on mg/m 2 ) produced fetal growth retardation at plasma levels that were 2 times the human serum levels.
There are no adequate and well-controlled studies in pregnant women. Clarithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see WARNINGS ).
Clarithromycin and its active metabolite 14-hydroxy Clarithromycin are excreted in human milk. Serum and milk samples were obtained after 3 days of treatment, at steady state, from one published study of 12 lactating women who were taking Clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk fed infant would receive an estimated average of 136 mcg/kg/day of Clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than 6 months of age.
A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (6 were exposed to Clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.
Caution should be exercised when Clarithromycin is administered to nursing women. The development and health benefits of human milk feeding should be considered along with the mother’s clinical need for Clarithromycin and any potential adverse effects on the human milk fed child from the drug or from the underlying maternal condition.
Safety and effectiveness of Clarithromycin in pediatric patients under 6 months of age have not been established. The safety of Clarithromycin has not been studied in MAC patients under the age of 20 months. Neonatal and juvenile animals tolerated Clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes but were less sensitive to toxicity in the liver, kidney, thymus, and genitalia.
In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum serum concentrations and area under the curves of Clarithromycin and 14-OH Clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients (see WARNINGS and PRECAUTIONS ).
Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e. g. verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older (see WARNINGS ).
The most frequent and common adverse reactions related to Clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. These adverse reactions are consistent with the known safety profile of macrolide antibiotics.
There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.
Adverse Reactions Observed During Clinical Trials of Clarithromycin
The following adverse reactions were observed in clinical trials with Clarithromycin at a rate greater than or equal to 1%:
Gastrointestinal Disorders: Diarrhea, vomiting, dyspepsia, nausea, abdominal pain
Hepatobiliary Disorders: Liver function test abnormal
Immune System Disorders: Anaphylactoid reaction
Infection and Infestations: Candidiasis
Nervous System Disorders: Dysgeusia, headache
Psychiatric Disorders: Insomnia
Skin and Subcutaneous Tissue Disorders: Rash
Other Adverse Reactions Observed During Clinical Trials of Clarithromycin
The following adverse reactions were observed in clinical trials with Clarithromycin at a rate less than 1%:
Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocythemia, eosinophilia
Cardiac Disorders: Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations
Ear and Labyrinth Disorders: Vertigo, tinnitus, hearing impaired
Gastrointestinal Disorders: Stomatitis, glossitis, esophagitis, gastrooesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence
General Disorders and Administration Site Conditions: Malaise, pyrexia, asthenia, chest pain, chills, fatigue
Hepatobiliary Disorders: Cholestasis, hepatitis
Immune System Disorders: Hypersensitivity
Infections and Infestations: Cellulitis, gastroenteritis, infection, vaginal infection
Investigations: Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal
Metabolism and Nutrition Disorders: Anorexia, decreased appetite
Musculoskeletal and Connective Tissue Disorders: Myalgia, muscle spasms, nuchal rigidity
Nervous System Disorders: Dizziness, tremor, loss of consciousness, dyskinesia, somnolence
Psychiatric Disorders: Anxiety, nervousness
Renal and Urinary Disorders: Blood creatinine increased, blood urea increased
Respiratory, Thoracic and Mediastinal Disorders: Asthma, epistaxis, pulmonary embolism
Skin and Subcutaneous Tissue Disorders: Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular
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 < 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of Clarithromycin-treated patients.
In two U. S. studies of acute otitis media comparing Clarithromycin to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in Clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21% vs. 40%, p < 0.001). One-third as many Clarithromycin-treated patients reported diarrhea as did amoxicillin/potassium clavulanate-treated patients.
The following adverse reactions have been identified during post approval use of Clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Thrombocytopenia, agranulocytosis
Cardiac Disorders: Torsades de pointes. ventricular tachycardia, ventricular arrhythmia
Ear and Labyrinth Disorders: Deafness was reported chiefly in elderly women and was usually reversible.
Gastrointestinal Disorders: Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug.
Hepatobiliary Disorders: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with Clarithromycin (see WARNINGS - Hepatotoxicity ).
Immune System Disorders: Anaphylactic reaction, angioedema
Infections and Infestations: Pseudomembranous colitis
Investigations: Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure.
Metabolism and Nutrition Disorders: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.
Musculoskeletal and Connective Tissue Disorders: Myopathy, rhabdomyolysis was reported and in some of the reports, Clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see CONTRAINDICATIONS and WARNINGS ).
Nervous System Disorders: Convulsion, ageusia, parosmia, anosmia, paraesthesia
Psychiatric Disorders: Psychotic disorder, confusional state, depersonalization, depression, disorientation, manic behavior, hallucination, abnormal behavior, abnormal dreams. These disorders usually resolve upon discontinuation of the drug.
There are no data on the effect of Clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.
Renal and Urinary Disorders: Nephritis interstitial, renal failure
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne
Vascular Disorders: Hemorrhage
There have been 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 WARNINGS and PRECAUTIONS ).
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.
DOSAGE AND ADMINISTRATION
Clarithromycin can be given with or without food.
Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. In patients with severe renal impairment (CL CR < 30 mL/min), the dose of Clarithromycin should be reduced by 50%. However, when patients with moderate or severe renal impairment are taking Clarithromycin concomitantly with atazanavir or ritonavir, the dose of Clarithromycin should be reduced by 50% or 75% for patients with CL CR of 30 to 60 mL/min or < 30 mL/min, respectively.
ADULT DOSAGE GUIDELINES
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
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 INDICATIONS AND USAGE and CLINICAL STUDIES 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 INDICATIONS AND USAGE and CLINICAL STUDIES 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 INDICATIONS AND USAGE and CLINICAL STUDIES 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 INDICATIONS AND USAGE and CLINICAL STUDIES sections).
The usual recommended daily dosage is 15 mg/kg/day divided q12h for 10 days.
PEDIATRIC DOSAGE GUIDELINES
The recommended dose of Clarithromycin for the prevention of disseminated Mycobacterium avium disease is 500 mg b. i.d. In children, the recommended dose is 7.5 mg/kg b. i.d. up to 500 mg b. i.d. No studies of Clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC treatment studies in children. Dosing recommendations for children are in the table above.
Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to Mycobacterium avium complex. Clarithromycin should be used in combination with other antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (see CLINICAL STUDIES ). The recommended dose for mycobacterial infections in adults is 500 mg b. i.d. In children, the recommended dose is 7.5 mg/kg b. i.d. up to 500 mg b. i.d. Dosing recommendations for children are in the table above.
Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be discontinued when the patient is considered at low risk of disseminated infection.
Clarithromycin Tablets USP
250 mg tablets are supplied as a round, white, film coated beveled edged, standard biconvex tablet, debossed with product identification “54 271” on one side and plain on the other side.
NDC 0054-0036-21: Bottle of 60 Tablets
500 mg tablets are supplied as a white, film coated, standard biconvex, capsule shaped tablet, debossed with product identification “54 312” on one side and plain on the other side.
NDC 0054-0037-21: Bottle of 60 Tablets
Store at 20° to 25