d maintain the effectiveness of clarithromycin extended-release tablets, usp and other antibacterial drugs, clarithromycin extended-release tablets, usp 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.

s of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. discontinue clarithromycin immediately if signs and symptoms of hepatitis occur. qt prolongation 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 postmarketing 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. drug interactions 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 disopyramide; 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). colchicine 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 coadministration 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). benzodiazepines increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam. quetiapine use quetiapine and clarithromycin concomitantly with caution. coadministration 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 coadministered 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. oral anticoagulants there is a risk of serious hemorrhage and significant elevations in inr and prothrombin time when clarithromycin is coadministered 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 extended-release tablets, 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.

uenzae 2 x 500 mg 7 m. catarrhalis 2 x 500 mg 7 s. pneumoniae 2 x 500 mg 7 community-acquired pneumonia due to h.influenzae 2 x 500 mg 7 h.parainfluenzae 2 x 500 mg 7 m.catarrhalis 2 x 500 mg 7 s. pneumoniae 2 x 500 mg 7 c.pneumoniae 2 x 500 mg 7 m.pneumoniae 2 x 500 mg 7

ubcutaneous 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 the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either clarithromycin tablets or clarithromycin extended-release tablets; however, patients taking clarithromycin extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking clarithromycin tablets. in addition, patients taking clarithromycin extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to clarithromycin tablets. in community-acquired pneumonia studies conducted in adults comparing clarithromycin to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs 32%; p < 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. postmarketing experience 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. there have been reports of clarithromycin extended-release tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened gi transit times. in several reports, tablet residues have occurred in the context of diarrhea. it is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibacterial 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). to report suspected adverse events, contact actavis at 1-800-272-5525 or fda at 1-800-fda-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

hours after oral dosing. steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 mcg/ml with a 250 mg dose administered every 12 hours and 3 to 4 mcg/ml with a 500 mg dose administered every 8 to 12 hours. the elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. the nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. with a 250 mg every 12 hours dosing, the principal metabolite, 14-oh clarithromycin, attains a peak steady-state concentration of about 0.6 mcg/ml and has an elimination half-life of 5 to 6 hours. with a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-oh clarithromycin is slightly higher (up to 1 mcg/ml), and its elimination half-life is about 7 to 9 hours. with any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days. after a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. in comparison, after an oral dose of 250 mg (125 mg/5 ml) suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. the renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. the major metabolite found in urine is 14-oh clarithromycin, which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours. steady-state concentrations of clarithromycin and 14-oh clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with hiv infection were similar to those observed in healthy volunteers. in adult hiv-infected patients taking 500 or 1000 mg doses of clarithromycin every 12 hours, steady-state clarithromycin cmax values ranged from 2 to 4 mcg/ml and 5 to 10 mcg/ml, respectively. the steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-oh clarithromycin concentrations were lower in the hepatically impaired subjects. the decreased formation of 14-oh clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects. the pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function (see precautions and dosage and administration). clarithromycin and the 14-oh clarithromycin metabolite distribute readily into body tissues and fluids. there are no data available on cerebrospinal fluid penetration. because of high intracellular concentrations, tissue concentrations are higher than serum concentrations. examples of tissue and serum concentrations are presented below. concentration (after 250 mg q12h) tissue type tissue (mcg/g) serum (mcg/ml) tonsil 1.6 0.8 lung 8.8 1.7 clarithromycin extended-release tablets provide extended absorption of clarithromycin from the gastrointestinal tract after oral administration. relative to an equal total daily dose of immediate-release clarithromycin tablets, clarithromycin extended-release tablets provide lower and later steady-state peak plasma concentrations but equivalent 24-hour auc's for both clarithromycin and its microbiologically-active metabolite, 14-oh clarithromycin. while the extent of formation of 14-oh clarithromycin following administration of clarithromycin extended-release tablets (2 × 500 mg once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin auc relative to administration with food. therefore, clarithromycin extended-release tablets should be taken with food. [steady-state clarithromycin plasma concentration-time profiles] steady-state clarithromycin plasma concentration-time profiles in healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 to 3 mcg/ml were achieved about 5 to 8 hours after oral administration of 2 x 500 mg clarithromycin extended-release tablets once daily; for 14-oh clarithromycin, steady-state peak plasma concentrations of approximately 0.8 mcg/ml were attained about 6 to 9 hours after dosing. steady-state peak plasma clarithromycin concentrations of approximately 1 to 2 mcg/ml were achieved about 5 to 6 hours after oral administration of a single 500 mg clarithromycin extended-release tablet once daily; for 14-oh clarithromycin, steady-state peak plasma concentrations of approximately 0.6 mcg/ml were attained about 6 hours after dosing. microbiology clarithromycin exerts its antibacterial action by binding to the 50s ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis. clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative bacteria as well as most mycobacterium avium complex (mac) bacteria. additionally, the 14-oh clarithromycin metabolite also has clinically significant antimicrobial activity. the 14-oh clarithromycin is twice as active against haemophilus influenzae microorganisms as the parent compound. however, for mycobacterium avium complex (mac) isolates the 14-oh metabolite is 4 to 7 times less active than clarithromycin. the clinical significance of this activity against mycobacterium avium complex is unknown. clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the indications and usage section: gram-positive microorganisms staphylococcus aureus streptococcus pneumoniae streptococcus pyogenes gram-negative microorganisms haemophilus influenzae haemophilus parainfluenzae moraxella catarrhalis other microorganisms mycoplasma pneumoniae chlamydophila pneumoniae (twar) [previously chlamydia pneumoniae] the following in vitro data are available, but their clinical significance is unknown. clarithromycin exhibits in vitro activity against most isolates of the following bacteria; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. gram-positive bacteria streptococcus agalactiae streptococci (groups c, f, g) viridans group streptococci gram-negative bacteria bordetella pertussis legionella pneumophila pasteurella multocida gram-positive bacteria clostridium perfringens peptococcus niger propionibacterium acnes gram-negative anaerobic bacteria prevotella melaninogenica (formerly bacteriodes melaninogenicus) susceptibility testing methods dilution techniques quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (mics). these mics provide estimates of the susceptibility of bacteria to antimicrobial compounds. the mics should be determined using a standardized procedure. standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. the mic values should be interpreted according to the following criteria2: susceptibility test interpretive criteria for staphylococcus aureus mic (mcg/ml) interpretation ≤ 2.0 susceptible (s) 4.0 intermediate (i) ≥ 8.0 resistant (r) susceptibility test interpretive criteria for streptococcus pyogenes and streptococcus pneumoniaa a these interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted mueller-hinton broth with 2-5% lysed horse blood. mic (mcg/ml) interpretation ≤ 0.25 susceptible (s) 0.5 intermediate (i) ≥ 1.0 resistant (r) for testing haemophilusspp.b b these interpretive standards are applicable only to broth microdilution susceptibility tests with haemophilus spp. using haemophilus testing medium (htm).1 note: when testing streptococcus pyogenes and streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin. mic (mcg/ml) interpretation ≤ 8.0 susceptible (s) 16.0 intermediate (i) ≥ 32.0 resistant (r) a report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. a report of "intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. this category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. this category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. a report of "resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. quality control standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test.1,2 standard clarithromycin powder should provide the following mic ranges. catcc is a registered trademark of the american type culture collection. d this quality control range is applicable only to s. pneumoniae atcc 49619 tested by a microdilution procedure using cation-adjusted mueller-hinton broth with 2-5% lysed horse blood. e this quality control range is applicable only to h. influenzae atcc 49247 tested by a microdilution procedure using htm1. qc strain mic (mcg/ml) s. aureus atcc® 29213c 0.12 to 0.5 s. pneumoniaed atcc 49619 0.03 to 0.12 haemophilus influenzaee atcc 49247 4 to 16 diffusion techniques quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. the zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. the zone size should be determined using a standardized method.2,3 the procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of bacteria. the disk diffusion interpretive criteria are provided below. susceptibility test interpretive criteria for staphylococcus aureus zone diameter (mm) interpretation ≥ 18 susceptible (s) 14 to 17 intermediate (i) ≤ 13 resistant (r) susceptibility test interpretive criteria for streptococcus pyogenes and streptococcus pneumoniae f f these zone diameter standards only apply to tests performed using mueller-hinton agar supplemented with 5% sheep blood incubated in 5% co2. zone diameter (mm) interpretation ≥ 21 susceptible (s) 17 to 20 intermediate (i) ≤ 16 resistant (r) for testing haemophilus spp. g g these zone diameter standards are applicable only to tests with haemophilus spp. using htm2. note: when testing streptococcus pyogenes and streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin. zone diameter (mm) interpretation ≥ 13 susceptible (s) 11 to 12 intermediate (i) ≤ 10 resistant (r) quality control standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test.2,3 for the diffusion technique using the 15 mcg disk, the criteria in the following table should be achieved. acceptable quality control ranges for clarithromycin h this quality control range is applicable only to tests performed by disk diffusion using mueller-hinton agar supplemented with 5% defibrinated sheep blood. i this quality control limit applies to tests conducted with haemophilus influenzae atcc 49247 using htm2.