CLARITHROMYCIN_- clarithromycin_tablet, film coated

Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12. 4) Absorption The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food. In non-fasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. 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. Tissue and Serum Concentrations of Clarithromycin CONCENTRATION (after 250 mg every 12 hours) Tissue Type Tissue (mcg/g) Serum (mcg/mL) Tonsil 1. 7 Metabolism and Elimination Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 mcg/mL to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 mcg/mL to 4 mcg/mL with a 500 mg dose administered every 8 hours to 12 hours. The elimination half-life of clarithromycin was about 3 hours to 4 hours with 250 mg administered every 12 hours but increased to 5 hours to 7 hours with 500 mg administered every 8 hours to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 hours 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 hours to 6 hours. With a 500 mg every 8 hours 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 hours to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 days 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. Specific Populations for Clarithromycin 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 C max 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) 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 C min Colchicine When a single dose of colchicine 0. 6 mg was administered with clarithromycin 250 mg BID for 7 days, the colchicine C max 0-infinity 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 C max max max 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 C max 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 (C max 0-24 ½ The plasma levels of clarithromycin and 14en dashOH clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean C max min 0-8 max min 0-8 Clarithromycin Tissue Concentrations 2 hours after Dose (mcg/mL)/(mcg/g) Treatment N antrum fundus N Mucus Clarithromycin 5 10. 74 Clarithromycin + Omeprazole 5 19. 79 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 C max min Midazolam When a single dose of midazolam was co-administered with clarithromycin tablets (500 mg twice daily for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600% after oral administration. For information about other drugs indicated in combination with clarithromycin, refer to their full prescribing information, CLINICAL PHARMACOLOGY section. 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. pylori Antimicrobial Activity Clarithromycin has been shown to be active against most of the isolates of the following microorganisms both in vitro [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 M. intracellulare Mycoplasma pneumoniae At least 90 percent of the microorganisms listed below exhibit in vitro 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 For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.

Clarithromycin tablets are a macrolide antimicrobial indicated for mild to moderate infections caused by designated, susceptible bacteria in the following: Acute Bacterial Exacerbation of Chronic Bronchitis in Adults ( 1. 1 Acute Maxillary Sinusitis ( 1. 2 Community-Acquired Pneumonia ( 1. 3 Pharyngitis/Tonsillitis ( 1. 4 Uncomplicated Skin and Skin Structure Infections ( 1. 5 Acute Otitis Media in Pediatric Patients ( 1. 6 Treatment and Prophylaxis of Disseminated Mycobacterial Infections ( 1. 7 Helicobacter pylori 1. 8 Limitations of Use 1. 9 Clarithromycin 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 Streptococcus pneumoniae [see Indications and Usage (1. 9) Clarithromycin tablets are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae Moraxella catarrhalis Streptococcus pneumoniae [see Indications and Usage (1. 9) Clarithromycin tablets are indicated [see Indications and Usage (1. 9) Haemophilus influenzae Mycoplasma pneumoniae Streptococcus pneumoniae Chlamydophila pneumoniae Clarithromycin tablets are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Streptococcus pyogenes Clarithromycin tablets are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Staphylococcus aureus Streptococcus pyogenes Clarithromycin tablets are indicated in pediatric patients for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae Moraxella catarrhalis Streptococcus pneumoniae [see Clinical Studies (14. 2) Clarithromycin tablets are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Mycobacterium avium Mycobacterium intracellulare [see Clinical Studies (14. 1) Clarithromycin tablets are given in combination with other drugs in adults as described below to eradicate H. pylori [see Clinical Studies (14. 3) Clarithromycin tablets in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment of patients with H. pylori Clarithromycin tablets in combination with PRILOSEC (omeprazole) capsules are indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae Staphylococcus aureus To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin tablets and other antibacterial drugs, clarithromycin tablets 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.

3 Pediatric Patients: 2. 4 Mycobacterial Infections: 2. 5 Reduce dose in moderate renal impairment with concomitant atazanavir or ritonavir-containing regimens and in severe renal impairment ( 2. 6 Clarithromycin tablets may be given with or without food. The recommended dosages of clarithromycin tablets for the treatment of mild to moderate infections in adults are listed in Table 1. Adult Dosage Guidelines Clarithromycin Tablets Infection Dosage (every 12 hours) Duration (days) Acute bacterial exacerbation of chronic bronchitis 250 to 500 mg a 7 b Acute maxillary sinusitis 500 mg 14 Community-acquired pneumonia 250 mg 7 d Pharyngitis/Tonsillitis 250 mg 10 Uncomplicated skin and skin structure infections 250 mg 7 to 14 Treatment and prophylaxis of disseminated Mycobacterium avium [see Dosage and Administration (2. 5) 500 mg e - H. pylori [see Dosage and Administration (2. 3) 500 mg 10 to 14 H. 3) 500 mg every 8 hours 14 a M. catarrhalis S. pneumoniae H. influenzae H. parainfluenzae b H. parainfluenzae d H. influenzae e Triple therapy: Clarithromycin tablets/lansoprazole/amoxicillin The recommended adult dosage is 500 mg clarithromycin tablets, 30 mg lansoprazole, and 1 gram amoxicillin, all given every 12 hours for 10 or 14 days [see Indications and Usage (1. 8) Clinical Studies (14. 3) Triple therapy: Clarithromycin tablets/omeprazole/amoxicillin The recommended adult dosage is 500 mg clarithromycin tablets, 20 mg omeprazole, and 1 gram amoxicillin; all given every 12 hours for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief [see Indications and Usage (1. 3) Dual therapy: Clarithromycin tablets/omeprazole The recommended adult dosage is 500 mg clarithromycin tablets given every 8 hours and 40 mg omeprazole given once every morning for 14 days. An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief [see Indications and Usage (1. 3) The recommended daily dosage is 15 mg/kg/day divided every 12 hours for 10 days (up to the adult dose). Refer to dosage regimens for mycobacterial infections in pediatric patients for additional dosage information [see Dosage and Administration (2. 5) For the treatment of disseminated infection due to Mycobacterium avium in vitro [see Clinical Studies (14. 1) Adult Patients For treatment and prophylaxis of mycobacterial infections in adults, the recommended dose of clarithromycin tablets is 500 mg every 12 hours. Pediatric Patients For treatment and prophylaxis of mycobacterial infections in pediatric patients, the recommended dose is 7. 5 mg/kg every 12 hours up to 500 mg every 12 hours. [See Use in Specific Populations (8. 4) Clinical Studies (14. 1) Clarithromycin tablets therapy should continue if clinical response is observed. Clarithromycin tablets can be discontinued when the patient is considered at low risk of disseminated infection. 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) Table 2. Clarithromycin Tablets Dosage Adjustments in Patients with Renal Impairment Recommended Clarithromycin Tablets Dosage Reduction Patients with severe renal impairment (CL cr Reduce the dosage of clarithromycin tablets by 50% Patients with moderate renal impairment (CL cr Reduce the dosage of clarithromycin tablets by 50% Patients with severe renal impairment (CL cr Reduce the dosage of clarithromycin tablets by 75% Decrease the dose of clarithromycin tablets by 50 % when co-administered with atazanavir [see Drug Interactions (7) [see Drug Interactions (7).

The following serious adverse reactions are described below and elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) Clostridium difficile [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 8) Most frequent adverse reactions for both adult and pediatric populations in clinical trials: abdominal pain, diarrhea, nausea, vomiting, dysgeusia ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. The subsequent subsections list the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori Prophylaxis of Mycobacterial Infections In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium Table 4. Incidence Rates (%) of Selected Adverse Reactions a M. avium Body System b Adverse Reaction Clarithromycin (n=339) % Placebo (n=339) % Body as a Whole Abdominal pain 5% 4% Headache 3% 1% Digestive Diarrhea 8% 4% Dyspepsia 4% 3% Flatulence 2% 1% Nausea 11% 7% Vomiting 6% 3% Skin & Appendages Rash 3% 4% Special Senses Taste Perversion 8% c 0. 3% a b c Discontinuation due to adverse reactions occurred in 18% of patients receiving clarithromycin compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression, and taste perversion. Changes in Laboratory Values Selected laboratory adverse experiences that were reported during therapy in greater than 2 % of adult patients treated with clarithromycin in a randomized double-blind clinical trial involving 682 patients are presented in Table 5. In immunocompromised patients receiving prophylaxis against M. avium Table 5. Percentage of Patients a M. avium Clarithromycin 500 mg twice a day Placebo WBC Count <1 x 10 9 2/103 (4%) 0/95 SGOT >5 x ULN b 7/196 (4%) 5/208 (2%) SGPT >5 x ULN b 6/217 (3%) 4/232 (2%) a b Treatment of Mycobacterial Infections The adverse reaction profiles for both the 500 mg and 1000 mg twice a day dose regimens were similar. In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness. The following analysis summarizes experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for trial 1 (randomized, double-blind) and trial 2 (open-labeled, compassionate use) and also combined. Adverse reactions were reported less frequently in trial 2, which may be due in part to differences in monitoring between the two studies. In adult patients receiving clarithromycin 500 mg twice a day, the most frequently reported adverse reactions, considered possibly or possibly related to study drug, with an incidence of 5% or greater, are listed below (Table 6). Approximately 8% of the patients who received 500 mg twice a day and 12% of the patients who received 1000 mg twice a day discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy; adverse reactions leading to discontinuation in at least 2 patients included nausea, vomiting, abdominal pain, diarrhea, rash, and asthenia. Selected Treatment-Related a Adverse Reaction Trial 1 (n=53) Trial 2 (n=255) Combined (n=308) Abdominal Pain 8 2 3 Diarrhea 9 2 3 Flatulence 8 0 1 Headache 8 0 2 Nausea 28 9 12 Rash 9 2 3 Taste Perversion 19 0 4 Vomiting 25 4 8 a A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse reactions excluding those due to the patient’s concurrent conditions were consistent with those observed in adult patients. Changes in Laboratory Values In the first 12 weeks of starting on clarithromycin 500 mg twice a day, 3% of patients has SGOT increases and 2% of patients has SGPT increases > 5 times the upper limit of normal in trial 2 (469 enrolled adult patients) while trial 1 (154 enrolled patients) had no elevation of transaminases. This includes only patients with baseline values within the normal range or borderline low. Duodenal ulcer associated with H. pylori In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin, no adverse reactions specific to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with clarithromycin, omeprazole or amoxicillin. The adverse reaction profiles are shown below (Table 7) for four randomized double-blind clinical trials in which patients received the combination of clarithromycin 500 mg three times a day, and omeprazole 40 mg daily for 14 days, followed by omeprazole 20 mg once a day, (three studies) or 40 mg once a day (one study) for an additional 14 days. Of the 346 patients who received the combination, 3. 5% of patients discontinued drug due to adverse reactions. Adverse Reactions with an Incidence of 3% or Greater Adverse Reaction Clarithromycin + Omeprazole (n=346) % of Patients Omeprazole (n=355) % of Patients Clarithromycin (n=166) % of Patients a Taste Perversion 15 1 16 Nausea 5 1 3 Headache 5 6 9 Diarrhea 4 3 7 Vomiting 4 <1 1 Abdominal Pain 3 2 1 Infection 3 4 2 a Changes in Laboratory Values Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole in four randomized double-blind trials in 945 patients are as follows: Hepatic: elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%, Renal: elevated serum creatinine <1%. Less Frequent Adverse Reactions Observed During Clinical Trials of Clarithromycin Based on pooled data across all indications, the following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%: Blood and Lymphatic System Disorders: Cardiac Disorders: Ear and Labyrinth Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: Immune System Disorders: Infections and Infestations: Investigations: dehydrogenase increased, albumin globulin ratio abnormal Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Psychiatric Disorders: Renal and Urinary Disorders: Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: 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 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 reactions compared to clarithromycin tablets. All-Cause Mortality in Patients with Coronary Artery Disease 1 to 10 Years Following Clarithromycin Exposure In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality was observed in patients randomized to clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. Patients were treated with clarithromycin or placebo for 14 days and observed for primary outcome events (e. , all-cause mortality or non-fatal cardiac events) for several years. 1 The cause of the difference in all-cause mortality has not been established. Other epidemiologic studies evaluating this risk have shown variable results [see Warnings and Precautions (5. 5) 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: Cardiac: torsades de pointes Ear and Labyrinth: Gastrointestinal: [see Warnings and Precautions (5. 2) Infections and Infestations: [see Warnings and Precautions (5. 6) Immune System: Investigations: Metabolism and Nutrition: Musculoskeletal and Connective Tissue: [see Contraindications (4. 5) Warnings and Precautions (5. 4) Nervous System: Psychiatric Renal and Urinary: Skin and Subcutaneous Tissue: Vascular:.

Hypersensitivity to clarithromycin or any macrolide drug ( 4. 1 Cisapride and pimozide ( 4. 2 History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin ( 4. 3 Colchicine in renal or hepatic impairment ( 4. 4 Lomitapide, lovastatin, and simvastatin ( 4. 5 Ergot alkaloids (ergotamine or dihydroergotamine) ( 4. 6 Lurasidone ( 4. 7 Clarithromycin tablets are contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions (5. 1) Concomitant administration of clarithromycin tablets with cisapride and pimozide is contraindicated [see Drug Interactions (7) There have been postmarketing reports of drug interactions when clarithromycin is co-administered with cisapride or pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes Clarithromycin tablets are contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin. Concomitant administration of clarithromycin tablets and colchicine is contraindicated in patients with renal or hepatic impairment. Concomitant administration of clarithromycin tablets with lomitapide is contraindicated due to potential for markedly increased transaminases [see Warnings and Precautions (5. 4) Drug Interactions (7) Concomitant administration of clarithromycin tablets with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) is contraindicated, due to the increased risk of myopathy, including rhabdomyolysis [see Warnings and Precautions (5. 4) Drug Interactions (7) Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated [see Drug Interactions (7) Concomitant administration of [see Drug Interactions (7) For information about contraindications of other drugs indicated in combination with clarithromycin tablets, refer to their full prescribing information (contraindications section).

Geriatric: torsades de pointes 8. 5 Risk Summary [see Warnings and Precautions (5. 7) Risk Summary Males [see Nonclinical Toxicology (13. 1) The safety and effectiveness of clarithromycin tablets have been established for the treatment of the following conditions or diseases in pediatric patients 6 months and older. Use in these indications is based on clinical trials in pediatric patients or adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients: Pharyngitis/Tonsillitis Community-Acquired Pneumonia Acute maxillary sinusitis Acute otitis media [see Clinical Studies (14. 2) Uncomplicated skin and skin structure infections The safety and effectiveness of clarithromycin tablets have been established for the prevention of disseminated Mycobacterium avium 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. 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 [see Warnings and Precautions (5. 3) Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e. , 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) Warnings and Precautions (5. 4) 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.

Co-administration of clarithromycin is known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e. , carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Adjust dosage when appropriate and monitor serum concentrations of drugs primarily metabolized by CYP3A closely in patients concurrently receiving clarithromycin. Table 8: Clinically Significant Drug Interactions with Clarithromycin Drugs That Are Affected By Clarithromycin Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments Antiarrhythmics: Disopyramide, Quinidine torsades de pointes [see Warnings and Precautions (5. 2) Digoxin Oral Anticoagulants: Oral anticoagulants: [see Warnings and Precautions (5. 4) Antiepileptics: Carbamazepine Antifungals: Itraconazole: Fluconazole: [see Pharmacokinetics (12. 3) Anti-Gout Agents: Colchicine [see Contraindications (4. 4) Warnings and Precautions (5. 4) Antipsychotics: Pimozide: [See Contraindications (4. 2) Quetiapine Lurasidone [See Contraindications (4. 7) Antispasmodics: Tolterodine Antivirals: Atazanavir [see Pharmacokinetics (12. 3) Saquinavir [see Pharmacokinetics (12. 3) Ritonavir, Etravirine: [see Pharmacokinetics (12. 3) Maraviroc registered Boceprevir: registered Zidovudine: [see Pharmacokinetics (12. 3) Calcium Channel Blockers: Verapamil [see Warnings and Precautions (5. 4) Amlodipine, Diltiazem [See Warnings and Precautions (5. 4) Nifedipine [see Warnings and Precautions (5. 4) Ergot Alkaloids: Ergotamine, Dihydroergotamine [see Contraindications (4. 6) Gastroprokinetic Agents: Cisapride [See Contraindications (4. 2) Lipid-lowering agents: Lomitapide, Lovastatin, Simvastatin: [see Contraindications (4. 5) Warnings and Precautions (5. 4) [See Warnings and Precautions (5. 4) Hypoglycemic Agents: Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone [See Warnings and Precautions (5. 4) Adverse Reactions (6. 2) Insulin [See Warnings and Precautions (5. 2) Immunosuppressants: Cyclosporine Tacrolimus Phosphodiesterase inhibitors: Sildenafil, Tadalafil, Vardenafil Proton Pump Inhibitors: Omeprazole [see Pharmacokinetics (12. 3) Xanthine Derivatives: Theophylline [see Pharmacokinetics (12. 3) Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam [see Warnings and Precautions (5. 4) Pharmacokinetics (12. 3) Triazolam, Alprazolam Temazepam, Nitrazepam, Lorazepam Cytochrome P450 Inducers: Rifabutin Other Drugs Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Drugs that Affect Clarithromycin Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments Antifungals: Itraconazole Antivirals: Atazanavir: [see Clinical Pharmacology (12. 3) Mycobacterium avium Ritonavir Mycobacterium avium [see Pharmacokinetics (12. 3) Etravirine: Mycobacterium avium Proton Pump Inhibitors: Omeprazole [see Pharmacokinetics (12. 3) Miscellaneous Cytochrome P450 Inducers: Co-administration of clarithromycin can alter the concentrations of other drugs. The potential for drug-drug interactions must be considered prior to and during therapy.

OVERDOSAGE
Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea. Treat adverse reactions accompanying overdosage by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
NONCLINICAL TOXICOLOGY
Mutagenesis in vitro Salmonella Bacterial Induced Mutation Frequency Test In Vitro Rat Hepatocyte DNA Synthesis Assay Mouse Lymphoma Assay Mouse Dominant Lethal Study Mouse Micronucleus Test All tests had negative results except the in vitro Impairment of Fertility Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day 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). 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).
CLINICAL STUDIES
Prophylaxis of Mycobacterial Infections A randomized, double-blind clinical trial (trial 3) compared clarithromycin 500 mg twice a day to placebo in patients with CDC-defined AIDS and CD 4 4 Mycobacterium avium 1. MAC bacteremia, defined as at least one positive culture for Mycobacterium avium 2. Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including fever, night sweats, weight loss, anemia, or elevations in liver function tests MAC Bacteremia In patients randomized to clarithromycin, the risk of MAC bacteremia was reduced by 69% compared to placebo. The difference between groups was statistically significant (p < 0. On an intent-to-treat basis, the one-year cumulative incidence of MAC bacteremia was 5. 0% for patients randomized to clarithromycin and 19. 4% for patients randomized to placebo. While only 19 of the 341 patients randomized to clarithromycin developed MAC, 11 of these cases were resistant to clarithromycin. The patients with resistant MAC bacteremia had a median baseline CD 4 3 3 3 4 3 3 3 4 3 3 3 Survival A statistically significant survival benefit of clarithromycin compared to placebo was observed (see Figure 3 and Table 13). Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated. Survival of All Randomized AIDS Patients Over Time in Trial 3 Table 13. Mortality Rates at 18 months in Trial 3 Mortality Rates Reduction in Mortality Rates on Clarithromycin Placebo Clarithromycin 6 month 9. 5% 31% 12 month 29. 5% 31% 18 month 46. 5% 20% Clinically Significant Disseminated MAC Disease In association with the decreased incidence of MAC bacteremia, patients in the group randomized to clarithromycin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia. Treatment of Mycobacterial Infections Dose-Ranging Monotherapy Trials in Adult AIDS Patients with MAC Two randomized clinical trials (Trials 1 and 2) compared different dosages of clarithromycin in patients with CDC-defined AIDS and CD 4 4 1. Change in MAC bacteremia or blood cultures negative for M. Change in clinical signs and symptoms of MAC infection including one or more of the following: fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly. The results for trial 1 are described below. The trial 2 results were similar to the results of trial 1. MAC Bacteremia Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all clarithromycin dosage groups. The mean reductions in MAC colony forming units (CFU) from baseline after 4 weeks of therapy in the 1000 mg (n=32) twice daily and 2000 mg (n=26) twice daily regimen was 2. 3 Log CFU compared to 1. 5 Log CFU in the clarithromycin 500 mg twice daily (n=35) regimen. A separate trial with a four-drug regimen 2 Clinical outcomes evaluated with the different dosing regimens of clarithromycin monotherapy are shown in Table 14. The 1000 mg and 2000 mg twice daily doses showed significantly better control of bacteremia during the first four weeks of therapy. No significant differences were seen beyond that point. All of the isolates had MIC less than 8 mcg/mL at pre-treatment. Relapse was almost always accompanied by an increase in MIC. Outcome with the Different Dosing Regimens of Clarithromycin Outcome Clarithromycin 500 mg twice daily Clarithromycin 1000 mg twice daily Clarithromycin 2000 mg twice daily One or more negative blood cultures at any time during acute therapy 61% (30/49) 59% (29/49) 52% (25/48) Two or more negative blood cultures during acute therapy sustained through study day 84 25% (12/49) 25% (12/49) 8% (4/48) Death or discontinuation by day 84 23% (11/49) 37% (18/49) 56% (27/48) Relapse by day 84 14% (7/49) 12% (6/49) 13% (6/48) Median time to first negative culture (in days) 54 41 29 Median time to first decrease of at least 1 log CFU (in days) 29 16 15 Median time to first positive culture or study discontinuation following the first negative culture (in days) 43 59 43 Clinically Significant Disseminated MAC Disease Among patients experiencing night sweats prior to therapy, 84% showed resolution or improvement at some point during the 12 weeks of clarithromycin at 500 mg to 2000 mg twice daily doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given in Table 15 below. The median duration of response, defined as improvement or resolution of clinical signs and symptoms, was 2 weeks to 6 weeks. Since the trial was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25% to 33% of patients who continued to show clinical response after 12 weeks. Response Rates for Clinical Signs of MAC During 6 Weeks to 12 Weeks of Treatment Resolution of Fever Resolution of Night Sweats Clarithromycin twice daily dose (mg) % ever afebrile % afebrile Clarithromycin twice daily dose (mg) % ever resolving % resolving 500 67% 23% 500 85% 42% 1000 67% 12% 1000 70% 33% 2000 62% 22% 2000 72% 36% Weight Gain Greater Than 3% Hemoglobin Increase Greater Than 1 gm Clarithromycin twice daily dose (mg) % ever gaining % gaining Clarithromycin twice daily dose (mg) % ever increasing % increasing 500 33% 14% 500 58% 26% 1000 26% 17% 1000 37% 6% 2000 26% 12% 2000 62% 18% Survival Median survival time from trial entry (trial 1) was 249 days at the 500 mg twice daily dose compared to 215 days with the 1000 mg twice daily dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg twice daily group versus 13 deaths in 51 patients in the 1000 mg twice daily group. The reason for this apparent mortality difference is not known. Survival in the two groups was similar beyond 12 weeks. The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies. 2 Median survival time from entry in trial 2 was 199 days for the 500 mg twice a day dose and 179 days for the 1000 mg twice a day dose. During the first four weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg twice daily and 18 deaths in 214 patients taking 1000 mg twice daily. Dosage-Ranging Monotherapy Trials in Pediatric AIDS Patients with MAC Trial 4 was a pediatric trial of 3. 75 mg/kg, 7. 5 mg/kg, and 15 mg/kg of clarithromycin twice daily in patients with CDC-defined AIDS and CD 4 Combination Therapy in AIDS Patients with Disseminated MAC Trial 5 compared the safety and efficacy of clarithromycin in combination with ethambutol versus clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection. This 24-week trial enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive clarithromycin and ethambutol, and 51 patients randomized to receive clarithromycin, ethambutol, and clofazime. Baseline characteristics between treatment arms were similar with the exception of median CFU counts being at least 1 log higher in the clarithromycin, ethambutol, and clofazime arm. Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol extended the time to microbiologic relapse, largely through suppressing the emergence of clarithromycin resistant strains. However, the addition of clofazimine to the regimen added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher. The results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent. Figure 1 Otitis Media Trial of Clarithromycin vs. Oral Cephalosporin In a controlled clinical trial of pediatric patients with acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral cephalosporin. In this trial, strict evaluability criteria were used to determine clinical response. For the 223 patients who were evaluated for clinical efficacy, the clinical success rate (i. , cure plus improvement) at the post-therapy visit was 88% for clarithromycin and 91% for the cephalosporin. In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The presumptive bacterial eradication/clinical cure outcomes (i. , clinical success) are shown in Table 16. Clinical Success Rates of Otitis Media Treatment by Pathogen Pathogen Clinical Success Rates Clarithromycin Oral Cephalosporin S. pneumoniae 13/15 (87%) 4/5 H. influenzae a 10/14 (71%) 3/4 M. catarrhalis 4/5 1/1 S. pyogenes 3/3 0/1 All Pathogens Combined 30/37 (81%) 8/11 (73%) a H. influenzae Otitis Media Trials of Clarithromycin vs. Antimicrobial/Beta-lactamase Inhibitor In two other controlled clinical trials of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. In these trials, strict evaluability criteria were used to determine the clinical responses. In the 233 patients who were evaluated for clinical efficacy, the combined clinical success rate (i. , cure and improvement) at the post-therapy visit was 91% for both clarithromycin and the control. For the patients who had microbiologic determinations at the pre-treatment visit, the presumptive bacterial eradication/clinical cure outcomes (i. , clinical success) are shown in Table 17. Clinical Success Rates of Acute Otitis Media Treatment by Pathogen Clinical Success Rates PATHOGEN Clarithromycin Antimicrobial/Beta-lactamase Inhibitor S. pneumoniae 43/51 (84%) 55/56 (98%) H. influenzae a 36/45 (80%) 31/33 (94%) M. catarrhalis 9/10 (90%) 6/6 S. pyogenes 3/3 5/5 All Pathogens Combined 91/109 (83%) 97/100 (97%) a H. influenzae Clarithromycin + Lansoprazole and Amoxicillin Two U. randomized, double-blind clinical trials (trial 6 and trial 7) in patients with H. pylori The combination of clarithromycin plus lansoprazole and amoxicillin as triple therapy was effective in eradication of H. pylori A randomized, double-blind clinical trial (trial 8) performed in the U. in patients with H. pylori Table 18. pylori Trial Duration Triple Therapy Evaluable Analysis a Triple Therapy Intent-to-Treat Analysis b Trial 6 14 days 92 c 86 c Trial 7 14 days 86 d 83 d Trial 8 e 14 days 85 [77 to 91] 82 [73. 1] 10 days 84 [76 to 89. pylori c d e Clarithromycin + Omeprazole and Amoxicillin Therapy Three U. , randomized, double-blind clinical trials in patients with H. pylori registered H. pylori Table 19. pylori Clarithromycin + omeprazole + amoxicillin Clarithromycin + amoxicillin Per-Protocol a Intent-to-Treat b Per-Protocol a Intent-to-Treat b Trial 9 c 69 [57, 79] 43 [31, 56] 37 [27, 48] Trial 10 c 73 [61, 82] 41 [29, 54] 36 [26, 47] Trial 11 c 83 [74, 91] 33 [24, 44] 32 [23, 42] a H. pylori registered b H. pylori c Clarithromycin + Omeprazole Therapy Four randomized, double-blind, multi-center trials (trials 12, 13, 14, and 15) evaluated clarithromycin 500 mg three times a day plus omeprazole 40 mg once a day for 14 days, followed by omeprazole 20 mg once a day (trials 12, 13, and 15) or by omeprazole 40 mg once a day (trial 14) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori Duodenal Ulcer Healing The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal ulcer (see Table 20). End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (n/N) Trial Clarithromycin + Omeprazole Omeprazole Clarithromycin U. Trials Trial 13 94% (58/62) a 88% (60/68) 71% (49/69) Trial 12 88% (56/64) a 85% (55/65) 64% (44/69) Non-U. Trials Trial 15 99% (84/85) 95% (82/86) N/A Trial 14 b 100% (64/64) 99% (71/72) N/A a b Eradication of H. pylori Associated with Duodenal Ulcer The combination of clarithromycin and omeprazole was effective in eradicating H. pylori Table 21. pylori Trial Clarithromycin + Omeprazole Omeprazole Clarithromycin U. Trials Trial 13 64% (39/61) a,b 0% (0/59) 39% (17/44) Trial 12 74% (39/53) a,b 0% (0/54) 31% (13/42) Non-U. Trials Trial 15 74% (64/86) b 1% (1/90) N/A Trial 14 83% (50/60) b 1% (1/74) N/A a b Duodenal Ulcer Recurrence Ulcer recurrence at 6-months and at 12 months following the end of treatment was assessed for patients in whom ulcers were healed post-treatment (see the results in Table 22). Thus, in patients with duodenal ulcer associated with H. pylori Table 22. Duodenal Ulcer Recurrence at 6 months and 12 months in Patients with Healed Ulcers H. pylori Negative at 4 to 6 Weeks H. pylori Positive at 4 to 6 Weeks U. Trials Recurrence at 6 Months Trial 100 Clarithromycin + Omeprazole 6% (2/34) 56% (9/16) Omeprazole (0/0) 71% (35/49) Clarithromycin 12% (2/17) 32% (7/22) Trial 067 Clarithromycin + Omeprazole 38% (11/29) 50% (6/12) Omeprazole (0/0) 67% (31/46) Clarithromycin 18% (2/11) 52% (14/27) Non-U. Trials Recurrence at 6 Months Trial 058 Clarithromycin + Omeprazole 6% (3/53) 24% (4/17) Omeprazole 0% (0/3) 55% (39/71) Trial 812b Clarithromycin + Omeprazole 5% (2/42) 0% (0/7) Omeprazole 0% (0/1) 54% (32/59) Non-U. Trials Recurrence at 12 Months in Trial 14 Clarithromycin + Omeprazole 3% (1/40) 0% (0/6) Omeprazole 0% (0/1) 67% (29/43).
REFERENCES
Winkel P, Hilden J, Hansen JF, Kastrup J, Kolmos HJ, Kjøller E, et al. Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10 years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol 2015;182:459-65. Kemper CA, et al. Treatment of Mycobacterium avium Ann Intern Med

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