1.1 Acute Bacterial Exacerbation of Chronic Bronchitis

Clarithromycin extended-release tablets are indicated in adults for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see Indications and Usage (1.9)].

1.2 Acute Maxillary Sinusitis

Clarithromycin extended-release tablets (in adults) are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see Indications and Usage (1.9)].

1.3 Community-Acquired Pneumonia

Clarithromycin extended-release tablets are indicated [see Indications and Usage (1.9)] for the treatment of mild to moderate infections caused by susceptible isolates due to:

•

Haemophilus influenzae (in adults)

•

Haemophilus parainfluenzae (in adults)

•

Moraxella catarrhalis (in adults)

•

Mycoplasma pneumoniae, Streptococcus pneumoniae, Chlamydophila pneumoniae (in adults).

1.9 Limitations of Use

Clarithromycin extended-release tablets are indicated only for acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia in adults. The efficacy and safety of clarithromycin extended-release tablets in treating other infections for which clarithromycin immediate-release tablets and clarithromycin granules are approved have not been established.

There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae and Staphylococcus aureus. Susceptibility testing should be performed when clinically indicated.

1.10 Usage

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.

2.1 Important Administration Instructions

Clarithromycin extended-release tablets should be taken with food. Swallow clarithromycin extended-release tablets whole; do not chew, break or crush clarithromycin extended-release tablets.

2.2 Adult Dosage

The recommended dosage of clarithromycin extended-release tablets for the treatment of mild to moderate infections in adults are listed in Table 1.

2.6 Dosage Adjustment in Patients with Renal Impairment

See Table 2 for dosage adjustment in patients with moderate or severe renal impairment with or without concomitant atazanavir or ritonavir-containing regimens [see Drug Interactions (7)].

2.7 Dosage Adjustment Due to Drug Interactions

Decrease the dose of clarithromycin by 50 % when coadministered with atazanavir [see Drug Interactions (7)]. Dosage adjustments for other drugs when coadministered with clarithromycin may be recommended due to drug interactions [see Drug Interactions (7)].

4.1 Hypersensitivity

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions (5.1)].

4.2 Cardiac Arrhythmias

Concomitant administration of clarithromycin with cisapride and pimozide is contraindicated [see Drug Interactions (7)].

There have been postmarketing reports of drug interactions when clarithromycin is coadministered with cisapride or pimozide, 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 clarithromycin. Fatalities have been reported.

4.3 Cholestatic Jaundice/Hepatic Dysfunction

Clarithromycin is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.

4.4 Colchicine

Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.

4.5 HMG-CoA Reductase Inhibitors

Do not use clarithromycin 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 and Precautions (5.4) and Drug Interactions (7)].

4.6 Ergot Alkaloids

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated [see Drug Interactions (7)].

4.7 Contraindications for Coadministered Drugs

For information about contraindications of other drugs indicated in combination with clarithromycin, refer to their full prescribing information (contraindications section).

5.1 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, discontinue clarithromycin therapy immediately and institute appropriate treatment.

5.2 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.

Avoid clarithromycin in the following patients:

•

patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes

•

patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2)]

•

patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia 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 [see Use in Specific Populations (8.5)].

5.3 Hepatotoxicity

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.

5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs

Drugs metabolized by CYP3A4: 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; 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. Use clarithromycin with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme. The use of clarithromycin with simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated [see Contraindications (4.5, 4.6) and Drug Interactions (7)].

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, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4.4) and Drug Interactions (7)].

HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated [see Contraindications (4.5)] 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.

Exercise caution when prescribing clarithromycin with atorvastatin or pravastatin. 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.

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 [see Drug Interactions (7)].

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 [see Drug Interactions (7)].

Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is coadministered with warfarin. Monitor INR and prothrombin times frequently while patients are receiving clarithromycin and oral anticoagulants concurrently [see Drug Interactions (7)].

Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam [see Drug Interactions (7)].

5.5 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.6 Embryofetal Toxicity

Clarithromycin should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If clarithromycin is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development in monkeys, rats, mice, and rabbits at doses that produced plasma levels 2 times to 17 times the serum levels achieved in humans treated at the maximum recommended human doses [see Use in Specific Populations (8.1)].

5.7 Exacerbation of Myasthenia Gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

5.8 Development of Drug Resistant Bacteria

Prescribing clarithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash.

Gastrointestinal Adverse Reactions

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse reactions were reported by a similar proportion of patients taking either clarithromycin immediate-release tablets or clarithromycin extended-release tablets; however, patients taking clarithromycin extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking clarithromycin immediate-release tablets. In addition, patients taking clarithromycin extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse reactions compared to clarithromycin immediate-release tablets.

6.2 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: Thrombocytopenia, agranulocytosis

Cardiac: Ventricular arrhythmia, ventricular tachycardia, torsades de pointes

Ear and Labyrinth: Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal: 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: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin [see Warnings and Precautions (5.2)].

Infections and Infestations: Pseudomembranous colitis [see Warnings and Precautions (5.5)]

Immune System: Anaphylactic reactions, angioedema

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: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.

Musculoskeletal and Connective Tissue: Myopathy rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol [see Contraindications (4.5) and Warnings and Precautions (5.4)].

Nervous System: Parosmia, anosmia, ageusia, paresthesia and convulsions

Psychiatric: Abnormal behavior, confusional state, depersonalization, disorientation, hallucination, depression, manic behavior, abnormal dream, psychotic disorder. These disorders usually resolve upon discontinuation of the drug.

Renal and Urinary: Nephritis interstitial, renal failure

Skin and Subcutaneous Tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne

Vascular: Hemorrhage

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

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 [see Warnings and Precautions (5.6)].

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 twice the recommended maximum human dose based on mg/m2) 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 twice 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/m2, 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 produced fetal growth retardation at plasma levels that were twice the human serum levels.

8.3 Nursing Mothers

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.

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 antibacterial (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.

8.4 Pediatric Use

The safety and effectiveness of clarithromycin extended-release tablets in the treatment of pediatric patients has not been established.

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.

8.5 Geriatric Use

In a steady-state study in which healthy elderly subjects (65 years to 81 years of age) were given 500 mg of clarithromycin 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 reactions when compared to younger patients. Consider dosage adjustment 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 (5.3)].

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 and Precautions (5.4)].

Especially in elderly patients, there have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, some of which occurred in patients with renal insufficiency. Deaths have been reported in some patients [see Contraindications (4.4) and Warnings and Precautions (5.4)].

8.6 Renal and Hepatic Impairment

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 [see Dosage and Administration (2.6)].

12.1 Mechanism of Action

Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption

Clarithromycin Extended-Release Tablets

Clarithromycin extended-release tablets provide extended absorption of clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal total daily dose of immediate-release clarithromycin tablets, clarithromycin extended-release tablets provide lower and later steady-state peak plasma concentrations but equivalent 24-hour AUCs for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of formation of 14-OH clarithromycin following administration of clarithromycin extended-release tablets (2 x 500 mg tablets once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Therefore, clarithromycin extended-release tablets should be taken with food.

Figure 2: Steady-State Clarithromycin Plasma Concentration-Time Profiles

Distribution

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.

Metabolism and Elimination

Clarithromycin Extended-Release Tablets

In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 mcg/mL to 3 mcg/mL were achieved about 5 hours to 8 hours after oral administration of 1000 mg 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 hours to 9 hours after dosing. Steady-state peak plasma clarithromycin concentrations of approximately 1 mcg/mL to 2 mcg/mL were achieved about 5 hours to 6 hours after oral administration of a single 500 mg clarithromycin extended-release tablets once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.6 mcg/mL were attained about 6 hours after dosing.

Specific Populations for clarithromycin extended-release tablets

HIV Infection

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500-mg or 1000-mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 mcg/mL to 4 mcg/mL and 5 mcg/mL to 10 mcg/mL, respectively.

Hepatic Impairment

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.

Renal Impairment

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function [see Use in Specific Populations (8.6) and Dosage and Administration (2.6)].

Drug Interactions

Fluconazole

Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin Cmin and AUC increased 33% and 18%, respectively. Clarithromycin exposures were increased and steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole.

Colchicine

When a single dose of colchicine 0.6 mg was administered with clarithromycin 250 mg BID for 7 days, the colchicine Cmax increased 197% and the AUC0-∞ increased 239% compared to administration of colchicine alone.

Atazanavir

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%.

Ritonavir

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.

Saquinavir

Following administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers, the steady-state saquinavir AUC and Cmax increased 177% and 187% respectively compared to administration of saquinavir alone. Clarithromycin AUC and Cmax increased 45% and 39% respectively, whereas the 14–OH clarithromycin AUC and Cmax decreased 24% and 34% respectively, compared to administration with clarithromycin alone.

Didanosine

Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.

Zidovudine

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 Cmax increased 100% whereas the AUC was unaffected (n = 24).

Omeprazole

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin.

The plasma levels of clarithromycin and 14–OH clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14–OH clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Theophylline

In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.

Midazolam

When a single dose of midazolam was coadministered with clarithromycin tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600% after oral administration.

For information about other drugs indicated in combination with clarithromycin, refer to their full prescribing information, CLINICAL PHARMACOLOGY section.

12.4 Microbiology

Mechanism of Action

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis.

Resistance

The major routes of resistance are modification of the 23S rRNA in the 50S ribosomal subunit to insensitivity or drug efflux pumps. Beta-lactamase production should have no effect on clarithromycin activity.

Most isolates of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.

Antimicrobial Activity

Clarithromycin has been shown to be active against most of the isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-Positive Bacteria

•

Staphylococcus aureus

•

Streptococcus pneumoniae

•

Streptococcus pyogenes

Gram-Negative Bacteria

•

Haemophilus influenzae

•

Haemophilus parainfluenzae

•

Moraxella catarrhalis

Other Microorganisms

•

Chlamydophila pneumoniae

•

Helicobacter pylori

•

Mycobacterium avium complex (MAC) consisting of M. avium and M. intracellulare

•

Mycoplasma pneumoniae

At least 90 percent of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clarithromycin susceptible MIC breakpoint for organisms of similar type to those shown in Table 11. However, the efficacy of clarithromycin in treating clinical infections due to these microorganisms has 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

•

Legionella pneumophila

•

Pasteurella multocida

Anaerobic Bacteria

•

Clostridium perfringens

•

Peptococcus niger

•

Prevotella melaninogenica

•

Propionibacterium acnes

Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug for treatment.

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 test method1,2 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 11.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of bacteria to clarithromycin. The disk diffusion interpretive criteria are provided in Table 11.

Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

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.1-3 Standard clarithromycin powder should provide the following range of MIC values as noted in Table 12. For the diffusion technique using the 15 mcg disk, the criteria in Table 12 should be achieved.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The following in vitro mutagenicity tests have been conducted with clarithromycin:

•

Salmonella/Mammalian Microsomes Test

•

Bacterial Induced Mutation Frequency Test

•

In Vitro Chromosome Aberration Test

•

Rat Hepatocyte DNA Synthesis Assay

•

Mouse Lymphoma Assay

•

Mouse Dominant Lethal Study

•

Mouse Micronucleus Test

All tests had negative results except the in vitro chromosome aberration test which was positive in one test and negative in another. In addition, a bacterial reverse-mutation test (Ames test) has been performed on clarithromycin metabolites with negative results.

Impairment of Fertility

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/ to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were twice the human serum levels.

Testicular atrophy occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose (on a body surface area basis).

13.2 Animal Toxicology and/or Pharmacology

Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose (on a body surface area basis). Lymphoid depletion occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose (on a body surface area basis).

Clarithromycin Extended-Release Tablets USP 500 mg 60s Label Text

NDC 0093-7244-06

CLARITHROMYCIN

Extended-Release

Tablets USP

500 mg

Rx only

60 TABLETS

TEVA