Claritromicin

193739-2 FRONT 12.25" x 12.5" FOLD = 1.25" x 1.25" PRINTS BLACK 9/21/12 alternative, clinically feasible drugs, the test should be repeated. This category WARNINGS
Steady-State Clarithromycin Plasma
implies possible clinical applicability in body sites where the drug is physiolog- Use In Pregnancy
Concentration-Time Profiles
ically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN
clarithromycin extended-release: 2 x 500 mg q24h
technical factors from causing major discrepancies in interpretation. A report of CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPRO-
drugs, clarithromycin tablets should be used only to treat or prevent infections clarithromycin: 500 mg q12h
"Resistant" indicates that the pathogen is not likely to be inhibited if the antimi- PRIATE. IF PREGNANCY OCCURS WHILE TAKING THIS DRUG, THE PATIENT
that are proven or strongly suspected to be caused by bacteria.
crobial compound in the blood reaches the concentrations usually achievable; SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS.
CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY
DESCRIPTION
OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS,
Quality Control
Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6- 0 - MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17
methylerythromycin. The molecular formula is C H NO , and the molecular Standardized susceptibility test procedures require the use of laboratory control TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE
weight is 747.96. The structural formula is: bacteria to monitor and ensure the accuracy and precision of supplies and MAXIMUM RECOMMENDED HUMAN DOSES. (See PRECAUTIONS - Pregnancy.)
reagents in the assay, and the techniques of the individual performing the test.1,2 Hepatotoxicity
Standard clarithromycin powder should provide the following MIC ranges: Hepatic dysfunction, including increased liver enzymes, and hepatocellular QC Strain
MIC (mcg/mL)
and/or cholestatic hepatitis, with or without jaundice, has been reported withclarithromycin. 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. Discontinue clarithromycin immediately if signs and c ATCC is a registered trademark of the American Type Culture Collection.
d This quality control range is applicable only to S. pneumoniae ATCC 49619 QT Prolongation
Mean Plasma Concentration (mcg/mL)
tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been e This quality control range is applicable only to H. influenzae ATCC 49247 tested spontaneously reported during postmarketing surveillance in patients receiving by a microdilution procedure using HTM1.
clarithromycin. Fatalities have been reported. Clarithromycin should be avoided Time After Dosing (hours)
in patients with ongoing proarrhythmic conditions such as uncorrected In healthy human subjects, steady-state peak plasma clarithromycin concentra- Diffusion Techniques
hypokalemia or hypomagnesemia, clinically significant bradycardia (see tions of approximately 2 to 3 mcg/mL were achieved about 5 to 8 hours after Quantitative methods that require measurement of zone diameters also provide CONTRAINDICATIONS) and in patients receiving Class IA (quinidine,
oral administration of 2 x 500 mg clarithromycin extended-release tablets once reproducible estimates of the susceptibility of bacteria to antimicrobial procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of compounds. The zone size provides an estimate of the susceptibility of bacteria agents. Elderly patients may be more susceptible to drug-associated effects on Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, approximately 0.8 mcg/mL were attained about 6 to 9 hours after dosing.
to antimicrobial compounds. The zone size should be determined using a slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble Steady-state peak plasma clarithromycin concentrations of approximately 1 to standardized method.2,3 The procedure uses paper disks impregnated with 2 mcg/mL were achieved about 5 to 6 hours after oral administration of a single Drug Interactions
15-mcg of clarithromycin to test the susceptibility of bacteria. The disk diffusion 500 mg clarithromycin extended-release tablet once daily; for 14-OH Each orange oval film-coated clarithromycin extended-release tablet, for oral interpretive criteria are provided below.
Serious adverse reactions have been reported in patients taking clarithromycin clarithromycin, steady-state peak plasma concentrations of approximately administration, contains 500 mg of clarithromycin and the following inactive concomitantly with CYP3A4 substrates. These include colchicine toxicity with 0.6 mcg/mL were attained about 6 hours after dosing. Susceptibility Test Interpretive Criteria for Staphylococcus aureus
ingredients: compressible sugar, D&C yellow #10 Lake, FD&C yellow #6, colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and glycerol monostearate, polyethylene glycol 3000, polyvinyl alcohol, sodium Microbiology
Zone diameter (mm)
Interpretation
hypotension with calcium channel blockers metabolized by CYP3A4 (e.g., phosphate monobasic (anhydrous), talc and titanium dioxide. CONTRAINDICATIONS
Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal PRECAUTIONS – Drug Interactions).
Meets USP requirements for dissolution test 2.
subunit of susceptible bacteria resulting in inhibition of protein synthesis. Life-threatening and fatal drug interactions have been reported in patients CLINICAL PHARMACOLOGY
Clarithromycin is active in vitro against a variety of aerobic and anaerobic treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 Gram-positive and Gram-negative microorganisms as well as most Mycobac- Pharmacokinetics
Susceptibility Test Interpretive Criteria for Streptococcus
inhibitor and this interaction may occur while using both drugs at their terium avium complex (MAC) bacteria. pyogenes and Streptococcus pneumoniaef
recommended doses. If co-administration of clarithromycin and colchicine is Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral Additionally, the 14-OH clarithromycin metabolite also has clinically significant necessary in patients with normal renal and hepatic function, the dose of administration. The absolute bioavailability of 250 mg clarithromycin tablets Zone diameter (mm)
Interpretation
antimicrobial activity. The 14-OH clarithromycin is twice as active against colchicine should be reduced. Patients should be monitored for clinical was approximately 50%. For a single 500 mg dose of clarithromycin, food Haemophilus influenzae microorganisms as the parent compound. However, for symptoms of colchicine toxicity. Concomitant administration of clarithromycin slightly delays the onset of clarithromycin absorption, increasing the peak time Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 and colchicine is contraindicated in patients with renal or hepatic impairment from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak times less active than clarithromycin. The clinical significance of this activity (see CONTRAINDICATIONS and PRECAUTIONS – Drug Interactions).
plasma concentration by about 24%, but does not affect the extent of against Mycobacterium avium complex is unknown. clarithromycin bioavailability. Food does not affect the onset of formation of the These zone diameter standards only apply to tests performed using Mueller- Clostridium difficile Associated Diarrhea
antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma Clarithromycin has been shown to be active against most strains of the Hinton agar supplemented with 5% sheep blood incubated in 5% CO .
Clostridium difficile associated diarrhea (CDAD) has been reported with use of concentration but does slightly decrease the extent of metabolite formation, following microorganisms both in vitro and in clinical infections as described in For testing Haemophilus spp.g
nearly all antibacterial agents, including clarithromycin extended-release tablets, indicated by an 11% decrease in area under the plasma concentration-time the INDICATIONS AND USAGE section:
and may range in severity from mild diarrhea to fatal colitis. Treatment with curve (AUC). Therefore, clarithromycin tablets may be given without regard to Zone diameter (mm)
Interpretation
Gram-Positive Microorganisms
antibacterial agents alters the normal flora of the colon leading to overgrowth of In nonfasting healthy human subjects (males and females), peak plasma C. difficile produces toxins A and B which contribute to the development of concentrations were attained within 2 to 3 hours after oral dosing. Steady-state CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity peak plasma clarithromycin concentrations were attained within 3 days and g These zone diameter standards are applicable only to tests with Haemophilus and mortality, as these infections can be refractory to antimicrobial therapy and were approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 Gram-Negative Microorganisms
may require colectomy. CDAD must be considered in all patients who present hours and 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours.
with diarrhea following antibiotic use. Careful medical history is necessary since The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae,
CDAD has been reported to occur over two months after the administration of administered every 12 hours but increased to 5 to 7 hours with 500 mg susceptibility and resistance to clarithromycin can be predicted using administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmaco- kinetics is slight at the recommended doses of 250 mg and 500 mg If CDAD is suspected or confirmed, ongoing antibiotic use not directed against administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the Quality Control
Other Microorganisms
C. difficile may need to be discontinued. Appropriate fluid and electrolyte principal metabolite, 14-OH clarithromycin, attains a peak steady-state management, protein supplementation, antibiotic treatment of C. difficile, and Standardized susceptibility test procedures require the use of laboratory control concentration of about 0.6 mcg/mL and has an elimination half-life of 5 to 6 surgical evaluation should be instituted as clinically indicated.
bacteria to monitor and ensure the accuracy and precision of supplies and hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state reagents in the assay, and the techniques of the individual performing the test.2,3 For information about warnings of other drugs indicated in combination with concentration of 14-OH clarithromycin is slightly higher (up to 1 mcg/mL), and The following in vitro data are available, but their clinical significance is
For the diffusion technique using the 15 mcg disk, the criteria in the following clarithromycin, refer to the WARNINGS section of their package inserts.
its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, unknown. Clarithromycin exhibits in vitro activity against most isolates of the
the steady-state concentration of this metabolite is generally attained within 3 to following bacteria; however, the safety and effectiveness of clarithromycin in Acceptable Quality Control Ranges for Clarithromycin
treating clinical infections due to these bacteria have not been established in In the event of severe acute hypersensitivity reactions, such as anaphylaxis, After a 250 mg tablet every 12 hours, approximately 20% of the dose is adequate and well-controlled clinical trials. QC Strain
Zone diameter (mm)
Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with excreted in the urine as clarithromycin, while after a 500 mg tablet every eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura Gram-Positive Bacteria
12 hours, the urinary excretion of clarithromycin is somewhat greater, approxi- clarithromycin therapy should be discontinued immediately and appropriate mately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as This quality control range is applicable only to tests performed by disk clarithromycin. The renal clearance of clarithromycin is, however, relatively diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep independent of the dose size and approximates the normal glomerular filtration The concomitant use of clarithromycin and oral hypoglycemic agents and/or rate. The major metabolite found in urine is 14-OH clarithromycin, which insulin can result in significant hypoglycemia. With certain hypoglycemic drugs Gram-Negative Bacteria
accounts for an additional 10% to 15% of the dose with either a 250 mg or a such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of This quality control limit applies to tests conducted with Haemophilus 500 mg tablet administered every 12 hours. CYP3A enzyme by clarithromycin may be involved and could cause influenzae ATCC 49247 using HTM2.
hypolgycemia when used concomitantly. Careful monitoring of glucose is Steady-state concentrations of clarithromycin and 14-OH clarithromycin INDICATIONS AND USAGE
observed following administration of 500 mg doses of clarithromycin every 12 To reduce the development of drug-resistant bacteria and maintain the effective- hours to adult patients with HIV infection were similar to those observed in ness of clarithromycin extended-release tablets, USP and other antibacterial healthy volunteers. In adult HIV-infected patients taking 500 or 1000 mg doses Gram-Positive Bacteria
There is a risk of serious hemorrhage and significant elevations in INR and drugs, clarithromycin extended-release tablets, USP should be used only to treat of clarithromycin every 12 hours, steady-state clarithromycin C prothrombin time when clarithromycin is co-administered with warfarin. INR or prevent infections that are proven or strongly suspected to be caused by from 2 to 4 mcg/mL and 5 to 10 mcg/mL, respectively.
and prothrombin times should be frequently monitored while patients are susceptible bacteria. When culture and susceptibility information are available, The steady-state concentrations of clarithromycin in subjects with impaired receiving clarithromycin and oral anticoagulants concurrently. they should be considered in selecting or modifying antibacterial therapy. In the CLARITHROMYCIN
hepatic function did not differ from those in normal subjects; however, the absence of such data, local epidemiology and susceptibility patterns may EXTENDED-RELEASE
14-OH clarithromycin concentrations were lower in the hepatically impaired Gram-Negative Anaerobic Bacteria
contribute to the empiric selection of therapy. Concomitant use of clarithromycin with lovastatin or simvastatin is contraindi- TABLETS, USP
subjects. The decreased formation of 14-OH clarithromycin was at least Prevotella melaninogenica (formerly Bacteriodes melaninogenicus) Adults (Clarithromycin extended-release tablets, USP)
cated (see CONTRAINDICATIONS) as these statins are extensively metabolized
partially offset by an increase in renal clearance of clarithromycin in the subjects by CYP3A4, and concomitant treatment with clarithromycin increases their with impaired hepatic function when compared to healthy subjects. Susceptibility Testing
Clarithromycin extended-release tablets, USP are indicated for the treatment of plasma concentration, which increases the risk of myopathy, including adults with mild to moderate infection caused by susceptible strains of the The pharmacokinetics of clarithromycin was also altered in subjects with Dilution Techniques
rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking designated microorganisms in the conditions listed below: impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMIN-
clarithromycin concomitantly with these statins. If treatment with clarithromycin Quantitative methods are used to determine antimicrobial minimum inhibitory ISTRATION.)
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, cannot be avoided, therapy with lovastatin or simvastatin must be suspended concentrations (MICs). These MICs provide estimates of the susceptibility of Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into bacteria to antimicrobial compounds. The MICs should be determined using a body tissues and fluids. There are no data available on cerebrospinal fluid standardized procedure. Standardized procedures are based on a dilution Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Caution should be exercised when prescribing clarithromycin with statins. In penetration. Because of high intracellular concentrations, tissue concentrations method1 (broth or agar) or equivalent with standardized inoculum concentra- Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. situations where the concomitant use of clarithromycin with atorvastatin or are higher than serum concentrations. Examples of tissue and serum concentra- tions and standardized concentrations of clarithromycin powder. The MIC values pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily Community-Acquired Pneumonia due to Haemophilus influenzae, Haemophilus should be interpreted according to the following criteria2: and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not parainfluenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Chlamydia CONCENTRATION (after 250 mg q12h)
dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. It is Susceptibility Test Interpretive Criteria for Staphylococcus aureus
pneumoniae (TWAR), or Mycoplasma pneumoniae. recommended to prescribe the lowest registered dose if concomitant use Tissue Type
Tissue (mcg/g)
Serum (mcg/mL)
MIC (mcg/mL)
Interpretation
THE EFFICACY AND SAFETY OF CLARITHROMYCIN EXTENDED-RELEASE
TABLETS, USP IN TREATING OTHER INFECTIONS FOR WHICH OTHER
PRECAUTIONS
FORMULATIONS OF CLARITHROMYCIN ARE APPROVED HAVE NOT BEEN
ESTABLISHED.
Clarithromycin extended-release tablets provide extended absorption of CONTRAINDICATIONS
Prescribing clarithromycin extended-release tablets in the absence of a proven clarithromycin from the gastrointestinal tract after oral administration. Relative to Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and
or strongly suspected bacterial infection or a prophylactic indication is unlikely Clarithromycin is contraindicated in patients with a known hypersensitivity to an equal total daily dose of immediate-release clarithromycin tablets, Streptococcus pneumoniae a
to provide benefit to the patient and increases the risk of the development of clarithromycin or any of its excipients, erythromycin, or any of the macrolide clarithromycin extended-release tablets provide lower and later steady-state peak MIC (mcg/mL)
Interpretation
plasma concentrations but equivalent 24-hour AUC's for both clarithromycin and Clarithromycin is principally excreted via the liver and kidney.
its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of Clarithromycin is contraindicated in patients with a history of cholestatic formation of 14-OH clarithromycin following administration of clarithromycin jaundice/hepatic dysfunction associated with prior use of clarithromycin. Clarithromycin may be administered without dosage adjustment to patients with extended-release tablets (2 x 500 mg once daily) is not affected by food, hepatic impairment and normal renal function. However, in the presence of Concomitant administration of clarithromycin and any of the following drugs is administration under fasting conditions is associated with approximately 30% severe renal impairment with or without coexisting hepatic impairment, a These interpretive standards are applicable only to broth microdilution contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or lower clarithromycin AUC relative to administration with food. Therefore, decreased dosage or prolonged dosing intervals may be appropriate.
susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed dihydroergotamine (see Drug Interactions). There have been post-marketing
clarithromycin extended-release tablets should be taken with food.
reports of drug interactions when clarithromycin and/or erythromycin are Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of co-administered with cisapride, pimozide, astemizole, or terfenadine resulting myasthenic syndrome has been reported in patients receiving clarithromycin For testing Haemophilus spp.b
in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular MIC (mcg/mL)
Interpretation
fibrillation, and torsades de pointes) most likely due to inhibition of metabolism Information to Patients
of these drugs by erythromycin and clarithromycin. Fatalities have been reported.
Patients should be counseled that antibacterial drugs including clarithromycin Concomitant administration of clarithromycin and colchicine is contraindicated in extended-release tablets should only be used to treat bacterial infections. They patients with renal or hepatic impairment. do not treat viral infections (e.g., the common cold). When clarithromycin b These interpretive standards are applicable only to broth microdilution suscep- Clarithromycin should not be given to patients with history of QT prolongation or extended-release tablets are prescribed to treat a bacterial infection, patients tibility tests with Haemophilus spp. using Haemophilus Testing Medium (HTM).1 ventricular cardiac arrhythmia, including torsades de pointes. should be told that although it is common to feel better early in the course oftherapy, the medication should be taken exactly as directed. Skipping doses or Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae,
Clarithromycin should not be used concomitantly with HMG-CoA reductase not completing the full course of therapy may (1) decrease the effectiveness of susceptibility and resistance to clarithromycin can be predicted using inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or the immediate treatment and (2) increase the likelihood that bacteria will simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.
develop resistance and will not be treatable by clarithromycin extended-release (see WARNINGS).
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the tablets or other antibacterial drugs in the future.
antimicrobial compound in the blood reaches the concentrations usually For information about contraindications of other drugs indicated in combination Diarrhea is a common problem caused by antibiotics which usually ends when achievable. A report of "Intermediate" indicates that the result should be with clarithromycin, refer to the CONTRAINDICATIONS section of their package
the antibiotic is discontinued. Sometimes after starting treatment with considered equivocal, and, if the microorganism is not fully susceptible to antibiotics, patients can develop watery and bloody stools (with or without This electronic proof, for your written approval, is provided for purposes of indicating Barcode(s) provided on this proof is (are) for purposes of indicating encodation color break and image placement only, and not as a representation of color fidelity.
only and not to be used for grading according to ANSI standards.
stomach cramps and fever) even as late as two or more months after having may be necessary and possible prolongation and intensity of effect should be gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The DOSAGE AND ADMINISTRATION
taken the last dose of the antibiotic. If this occurs, patients should contact their anticipated. Caution and appropriate dose adjustments should be considered 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum Clarithromycin extended-release tablets should be taken with food. when triazolam or alprazolam is co-administered with clarithromycin. For levels. In monkeys, an oral dose of 70 mg/kg/day (an approximate equidose of Clarithromycin extended-release tablets should be swallowed whole and not benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, the recommended maximum human dose based on mg/m2) produced fetal Clarithromycin may interact with some drugs, therefore patients should be nitrazepam, lorazepam), a clinically important interaction with clarithromycin is growth retardation at plasma levels that were 2 times the human serum levels. advised to report to their doctor the use of any other medications. Clarithromycin Clarithromycin may be administered without dosage adjustment in the presence extended-release tablets should be taken with food.
There are no adequate and well-controlled studies in pregnant women. of hepatic impairment if there is normal renal function. In patients with severe There have been post-marketing reports of drug interactions and central Clarithromycin should be used during pregnancy only if the potential benefit Drug Interactions
renal impairment (CLCR <30 mL/min), the dose of clarithromycin should be nervous system (CNS) effects (e.g., somnolence and confusion) with the justifies the potential risk to the fetus. (See WARNINGS.)
reduced by 50%. However, when patients with moderate or severe renal Clarithromycin use in patients who are receiving theophylline may be associated concomitant use of clarithromycin and triazolam. Monitoring the patient for Nursing Mothers
impairment are taking clarithromycin concomitantly with atazanavir or ritonavir, with an increase of serum theophylline concentrations. Monitoring of serum increased CNS pharmacological effects is suggested. the dose of clarithromycin should be reduced by 50% or 75% for patients with theophylline concentrations should be considered for patients receiving high It is not known whether clarithromycin is excreted in human milk. Because many Atazanavir
CLCR of 30 to 60 mL/min or <30 mL/min, respectively. doses of theophylline or with baseline concentrations in the upper therapeutic drugs are excreted in human milk, caution should be exercised when range. In two studies in which theophylline was administered with Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and clarithromycin is administered to a nursing woman. It is known that ADULT DOSAGE GUIDELINES
clarithromycin (a theophylline sustained-release formulation was dosed at either there is evidence of a bidirectional drug interaction. Following administration of clarithromycin is excreted in the milk of lactating animals and that other drugs Clarithromycin Extended-release Tablets
6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), the of this class are excreted in human milk. Preweaned rats, exposed indirectly via , and the area under the serum concentration clarithromycin AUC increased 94%, the 14-OH clarithromycin AUC decreased consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were Infection
Duration
time curve (AUC) of theophylline increased about 20%.
70% and the atazanavir AUC increased 28%. When clarithromycin is not adversely affected, despite data indicating higher drug levels in milk than in co-administered with atazanavir, the dose of clarithromycin should be decreased Hypotension, bradyarrhythmias, and lactic acidosis have been observed in by 50%. Since concentrations of 14-OH clarithromycin are significantly reduced patients receiving concurrent verapamil, belonging to the calcium channel Pediatric Use
when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Safety and effectiveness of clarithromycin in pediatric patients under 6 months Concomitant administration of single doses of clarithromycin and carbamazepine has Mycobacterium avium complex (see PRECAUTIONS – Drug Interactions).
of age have not been established. The safety of clarithromycin has not been been shown to result in increased plasma concentrations of carbamazepine. Blood Doses of clarithromycin greater than 1000 mg per day should not be studied in MAC patients under the age of 20 months. Neonatal and juvenile level monitoring of carbamazepine may be considered.
co-administered with protease inhibitors. animals tolerated clarithromycin in a manner similar to adult animals. Younganimals were slightly more intolerant to acute overdosage and to subtle Acute exacerbation of chronic bronchitis due to: When clarithromycin and terfenadine were coadministered, plasma concentra- Itraconazole
reductions in erythrocytes, platelets and leukocytes but were less sensitive to tions of the active acid metabolite of terfenadine were threefold higher, on Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, toxicity in the liver, kidney, thymus, and genitalia. average, than the values observed when terfenadine was administered alone.
potentially leading to a bidirectional drug interaction when administered The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not Geriatric Use
concomitantly. Clarithromycin may increase the plasma concentrations of significantly affected by coadministration of terfenadine once clarithromycin itraconazole, while itraconazole may increase the plasma concentrations of In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) reached steady-state conditions. Concomitant administration of clarithromycin clarithromycin. Patients taking itraconazole and clarithromycin concomitantly were given 500 mg every 12 hours, the maximum serum concentrations and with terfenadine is contraindicated. (See CONTRAINDICATIONS.)
should be monitored closely for signs or symptoms of increased or prolonged area under the curves of clarithromycin and 14-OH clarithromycin were Simultaneous oral administration of clarithromycin tablets and zidovudine to increased compared to those achieved in healthy young adults. These changes HIV-infected adult patients may result in decreased steady-state zidovudine in pharmacokinetics parallel known age-related decreases in renal function. In Saquinavir
concentrations. Following administration of clarithromycin 500 mg tablets twice clinical trials, elderly patients did not have an increased incidence of adverse daily with zidovudine 100 mg every 4 hours, the steady-state zidovudine AUC Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and events when compared to younger patients. Dosage adjustment should be decreased 12% compared to administration of zidovudine alone (n=4). Individual there is evidence of a bidirectional drug interaction. Following administration of considered in elderly patients with severe renal impairment. Elderly patients may values ranged from a decrease of 34% to an increase of 14%. When clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) be more susceptible to development of torsades de pointes arrhythmias than clarithromycin tablets were administered two to four hours prior to zidovudine, to 12 healthy volunteers, the steady-state saquinavir AUC and C younger patients (See WARNINGS and PRECAUTIONS.)
177% and 187% respectively compared to administration of saquinavir alone.
ADVERSE REACTIONS
unaffected (n=24). Administration of clarithromycin and zidovudine should be increased 45% and 39% respectively, whereas the separated by at least two hours. The impact of co-administration of The majority of side effects observed in clinical trials were of a mild and clarithromycin extended-release tablets and zidovudine has not been evaluated.
compared to administration with clarithromycin alone. No dose adjustment of transient nature. Fewer than 3% of adult patients without mycobacterial clarithromycin is necessary when clarithromycin is co-administered with infections and fewer than 2% of pediatric patients without mycobacterial Simultaneous administration of clarithromycin tablets and didanosine to 12 HOW SUPPLIED
saquinavir in patients with normal renal function. When saquinavir is infections discontinued therapy because of drug-related side effects. Fewer than HIV-infected adult patients resulted in no statistically significant change in co-administered with ritonavir, consideration should be given to the potential 2% of adult patients taking clarithromycin extended-release tablets Clarithromycin extended-release tablets, USP are supplied as orange, film effects of ritonavir on clarithromycin (refer to interaction between clarithromycin discontinued therapy because of drug-related side effects. coated, oval shaped tablets debossed with and “777” on one side.
Following administration of fluconazole 200 mg daily and clarithromycin and ritonavir) (see PRECAUTIONS – Drug Interactions).
The most frequently reported events in adults taking clarithromycin tablets were Bottles of 60 (NDC 62037-777-60), bottles of 500 (NDC 62037-777-05), bottles 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin Cmin The following CYP3A based drug interactions have been observed with diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal of 1000 (NDC 62037-777-10) and clarithromycin extended-release tablets, USP and AUC increased 33% and 18%, respectively. Steady-state concentrations of erythromycin products and/or with clarithromycin in post-marketing experience: pain/discomfort (2%), and headache (2%). In pediatric patients, the most carton of 4 blister packages 14 tablets each (NDC 62037-777-14). 14-OH clarithromycin were not significantly affected by concomitant adminis- frequently reported events were diarrhea (6%), vomiting (6%), abdominal pain tration of fluconazole. No dosage adjustment of clarithromycin is necessary Antiarrhythmics
Store clarithromycin extended-release tablets, USP at 20° to 25°C (68° to 77°F).
(3%), rash (3%), and headache (2%). Most of these events were described as There have been post-marketing reports of torsades de pointes occurring with mild or moderate in severity. Of the reported adverse events, only 1% was Ritonavir
concurrent use of clarithromycin and quinidine or disopyramide. ANIMAL PHARMACOLOGY AND TOXICOLOGY
Electrocardiograms should be monitored for QTc prolongation during Concomitant administration of clarithromycin and ritonavir (n=22) resulted in a The most frequently reported events in adults taking clarithromycin extended- Clarithromycin is rapidly and well-absorbed with dose-linear kinetics, low coadministration of clarithromycin with these drugs. Serum concentrations of 77% increase in clarithromycin AUC and a 100% decrease in the AUC of release tablets were diarrhea (6%), abnormal taste (7%), and nausea (3%).
protein binding, and a high volume of distribution. Plasma half-life ranged from these medications should also be monitored.
14-OH clarithromycin. Clarithromycin may be administered without dosage Most of these events were described as mild or moderate in severity. Of the 1 to 6 hours and was species dependent. High tissue concentrations were adjustment to patients with normal renal function taking ritonavir. Since Ergotamine/Dihydroergotamine
reported adverse events, less than 1% were described as severe. achieved, but negligible accumulation was observed. Fecal clearance predomi- concentrations of 14-OH clarithromycin are significantly reduced when nated. Hepatotoxicity occurred in all species tested (i.e., in rats and monkeys at Post-marketing reports indicate that coadministration of clarithromycin with In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis clarithromycin is co-administered with ritonavir, alternative antibacterial doses 2 times greater than and in dogs at doses comparable to the maximum ergotamine or dihydroergotamine has been associated with acute ergot toxicity studies overall gastrointestinal adverse events were reported by a similar therapy should be considered for indications other than infections due to human daily dose, based on mg/m2 ). Renal tubular degeneration (calculated on characterized by vasospasm and ischemia of the extremities and other tissues proportion of patients taking either clarithromycin tablets or clarithromycin Mycobacterium avium complex (see PRECAUTIONS – Drug Interactions).
a mg/m2 basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, including the central nervous system. Concomitant administration of extended-release tablets; however, patients taking clarithromycin extended- Doses of clarithromycin greater than 1000 mg per day should not be and in dogs at doses 12 times greater than the maximum human daily dose. clarithromycin with ergotamine or dihydroergotamine is contraindicated (see release tablets reported significantly less severe gastrointestinal symptoms co-administered with protease inhibitors. Testicular atrophy (on a mg/m2 basis) occurred in rats at doses 7 times, in dogs CONTRAINDICATIONS).
compared to patients taking clarithromycin tablets. In addition, patients taking at doses 3 times, and in monkeys at doses 8 times greater than the maximum Spontaneous reports in the post-marketing period suggest that concomitant clarithromycin extended-release tablets had significantly fewer premature Triazolobenziodidiazepines (Such as Triazolam and Alprazolam) and Related
human daily dose. Corneal opacity (on a mg/m2 basis) occurred in dogs at administration of clarithromycin and oral anticoagulants may potentiate the discontinuations for drug-related gastrointestinal or abnormal taste adverse Benzodiazepines (Such as Midazolam)
doses 12 times and in monkeys at doses 8 times greater than the maximum effects of the oral anticoagulants. Prothrombin times should be carefully events compared to clarithromycin tablets. human daily dose. Lymphoid depletion (on a mg/m2 basis) occurred in dogs at monitored while patients are receiving clarithromycin and oral anticoagulants Erythromycin has been reported to decrease the clearance of triazolam and In community-acquired pneumonia studies conducted in adults comparing doses 3 times greater than and in monkeys at doses 2 times greater than the midazolam, and thus, may increase the pharmacologic effect of these clarithromycin to erythromycin base or erythromycin stearate, there were fewer maximum human daily dose. These adverse events were absent during clinical benzodiazepines. There have been post-marketing reports of drug interactions Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to adverse events involving the digestive system in clarithromycin-treated patients and CNS effects (e.g., somnolence and confusion) with the concomitant use of inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of compared to erythromycin-treated patients (13% vs 32%; p<0.01). Twenty REFERENCES
Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated percent of erythromycin-treated patients discontinued therapy due to adverse digoxin serum concentrations in patients receiving clarithromycin and digoxin Sildenafil (Viagra)
events compared to 4% of clarithromycin-treated patients. 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution concomitantly have been reported in post-marketing surveillance. Some Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - 9th Erythromycin has been reported to increase the systemic exposure (AUC) of Post-Marketing Experience
patients have shown clinical signs consistent with digoxin toxicity, including edition. Approved Standard. CLSI Document M07-A9, CLSI. 950 West Valley Rd, sildenafil. A similar interaction may occur with clarithromycin; reduction of potentially fatal arrhythmias. Monitoring of serum digoxin concentrations Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of sildenafil dosage should be considered. (See Viagra package insert.) should be considered, especially for patients with digoxin concentrations in the anaphylaxis, Stevens-Johnson syndrome, drug rash with eosinophilia and 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing, 22nd There have been spontaneous or published reports of CYP3A based interactions systemic symptoms (DRESS), Henoch-Schonlein Purpura and toxic epidermal Informational Supplement, CLSI Document M100-S22, 2012.
of erythromycin and/or clarithromycin with cyclosporine, carbamazepine, necrolysis have occurred. Other spontaneously reported adverse events include Co-administration of clarithromycin, known to inhibit CYP3A, and a drug tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue 3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests, 11th primarily metabolized by CYP3A may be associated with elevations in drug cilostazol, bromocriptine and vinblastine.
discoloration, thrombocytopenia, leukopenia, neutropenia, dizziness, myalgia edition. Approved Standard CLSI Document M02-A11, 2012. concentrations that could increase or prolong both therapeutic and adverse and hemorrhage. There have been reports of tooth discoloration in patients Concomitant administration of clarithromycin with cisapride, pimozide, treated with clarithromycin. Tooth discoloration is usually reversible with astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS.)
Watson Laboratories, Inc.
Clarithromycin should be used with caution in patients receiving treatment with professional dental cleaning. There have been isolated reports of hearing loss, other drugs known to be CYP3A enzyme substrates, especially if the CYP3A In addition, there have been reports of interactions of erythromycin or which is usually reversible, occurring chiefly in elderly women. Reports of substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate clarithromycin with drugs not thought to be metabolized by CYP3A, including alterations of the sense of smell including smell loss, usually in conjunction with Watson Pharma, Inc.
is extensively metabolized by this enzyme. Dosage adjustments may be hexobarbital, phenytoin, and valproate.
taste perversion or taste, loss have also been reported. considered, and when possible, serum concentrations of drugs primarily Carcinogenesis, Mutagenesis, Impairment of Fertility
Transient CNS events including anxiety, behavioral changes, confusional states, metabolized by CYP3A should be monitored closely in patients concurrently convulsions, depersonalization, disorientation, hallucinations, insomnia, The following in vitro mutagenicity tests have been conducted with depression, manic behavior, nightmares, psychosis, tinnitus, tremor, and The following are examples of some clinically significant CYP3A based drug vertigo have been reported during post-marketing surveillance. Events usually interactions. Interactions with other drugs metabolized by the CYP3A isoform Salmonella /Mammalian Microsomes Test resolve with discontinuation of the drug. Bacterial Induced Mutation Frequency Test Adverse reactions related to hepatic dysfunction have been reported in postmar- Carbamazepine and Terfenadine
In Vitro Chromosome Aberration Test keting experience with clarithromycin (See WARNINGS – Hepatotoxicity).
Increased serum concentrations of carbamazepine and the active acid There have been rare reports of hypoglycemia, some of which have occurred in metabolite of terfenadine were observed in clinical trials with clarithromycin.
patients taking oral hypoglycemic agents or insulin. Colchicine
There have been postmarketing reports of Clarithromycin extended-release tablets in the stool, many of which have occurred in patients with anatomic Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycopro- (including ileostomy or colostomy) or functional gastrointestinal disorders with tein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When a single dose of colchicine 0.6 mg was administered with All tests had negative results except the In Vitro Chromosome Aberration Test clarithromycin 250 mg BID for 7 days, the colchicine Cmax increased 197% and which was weakly positive in one test and negative in another. As with other macrolides, clarithromycin has been associated with QT the AUC0-∞ increased 239% compared to administration of colchicine alone. The prolongation and ventricular arrhythmias, including ventricular tachycardia and dose of colchicine should be reduced when co-administered with clarithromycin In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed in patients with normal renal and hepatic function. Concomitant use of on clarithromycin metabolites with negative results. There have been reports of interstitial nephritis coincident with clarithromycin clarithromycin and colchicine is contraindicated in patients with renal or Fertility and reproduction studies have shown that daily doses of up to hepatic impairment (See WARNINGS).
160 mg/kg/day (1.3 times the recommended maximum human dose based on There have been post-marketing reports of colchicine toxicity with concomitant Efavirenz, Nevirapine, Rifampicin, Rifabutin, and Rifapentine
mg/m2) 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 use of clarithromycin and colchicine, especially in the elderly, some of which Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, after 150 mg/kg/day were 2 times the human serum levels. occurred in patients with renal insufficiency. Deaths have been reported in some and rifapentine will increase the metabolism of clarithromycin, thus decreasing such patients. (See WARNINGS and PRECAUTIONS.)
plasma concentrations of clarithromycin, while increasing those of 14-OH- In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human There have been cases of rhabdomyolysis reported with clarithromycin use. In clarithromycin. Since the microbiological activities of clarithromycin and 14-OH- serum levels. When given orally at 150 mg/kg/day (2.4 times the recommended some cases, clarithromycin was administered concomitantly with other drugs clarithromycin are different for different bacteria, the intended therapeutic effect maximum human dose based on mg/m2), clarithromycin was shown to produce known to be associated with rhabdomyolysis (such as statins, fibrates, could be impaired during concomitant administration of clarithromycin and embryonic loss in monkeys. This effect has been attributed to marked maternal enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. In rabbits, in utero fetal loss occurred at an intravenous dose of Changes in Laboratory Values
Sildenafil, Tadalafil, and Vardenafil
33 mg/m2, which is 17 times less than the maximum proposed human oral daily Changes in laboratory values with possible clinical significance were as follows: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin.
Long-term studies in animals have not been performed to evaluate the carcino- Elevated SGPT (ALT) <1%; SGOT (AST) <1%; GGT <1%; alkaline phosphatase Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will <1%; LDH <1%; total bilirubin <1% result in increased exposure of these phosphodiesterase inhibitors. Coadminis- Pregnancy
tration of these phosphodiesterase inhibitors with clarithromycin is not Hematologic
Teratogenic Effects
Decreased WBC <1%; elevated prothrombin time 1% Tolterodine
Pregnancy Category C
The primary route of metabolism for tolterodine is via CYP2D6. However, in a Four teratogenicity studies in rats (three with oral doses and one with Elevated BUN 4%; elevated serum creatinine <1% subset of the population devoid of CYP2D6, the identified pathway of intravenous doses up to 160 mg/kg/day administered during the period of major metabolism is via CYP3A. In this population subset, inhibition of CYP3A results organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approxi- GGT, alkaline phosphatase, and prothrombin time data are from adult studies only. in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg mately 2 times the recommended maximum human dose based on mg/m2) or OVERDOSAGE
twice daily is recommended in patients deficient in CYP2D6 activity (poor intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18 metabolizers) when co-administered with clarithromycin.
failed to demonstrate any teratogenicity from clarithromycin. Two additional oral Overdosage of clarithromycin can cause gastrointestinal symptoms such as studies in a different rat strain at similar doses and similar conditions demon- abdominal pain, vomiting, nausea, and diarrhea.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
strated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day Adverse reactions accompanying overdosage should be treated by the prompt When a single dose of midazolam was co-administered with clarithromycin administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day elimination of unabsorbed drug and supportive measures. As with other tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after were 2 times the human serum levels. Four studies in mice revealed a variable macrolides, clarithromycin serum concentrations are not expected to be intravenous administration of midazolam and 600% after oral administration.
incidence of cleft palate following oral doses of 1000 mg/kg/day (2 and 4 times appreciably affected by hemodialysis or peritoneal dialysis.
When oral midazolam is co-administered with clarithromycin, dose adjustments the recommended maximum human dose based on mg/m2, respectively) during This electronic proof, for your written approval, is provided for purposes of indicating Barcode(s) provided on this proof is (are) for purposes of indicating encodation color break and image placement only, and not as a representation of color fidelity.
only and not to be used for grading according to ANSI standards.

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