Clarithromycin

1 INDICATIONS AND USAGE Clarithromycin is 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 ) Limitations of Use: 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 bacteria. ( 1.9 ) 1.1 Acute Bacterial Exacerbation of Chronic Bronchitis Clarithromycin is 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 is 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 is 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) • Mycoplasma pneumoniae , Streptococcus pneumoniae , Chlamydophila pneumoniae clarithromycin [in adults and pediatric patients] 1.4 Pharyngitis/Tonsillitis Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Streptococcus pyogenes as an alternative in individuals who cannot use first line therapy. 1.5 Uncomplicated Skin and Skin Structure Infections Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Staphylococcus aureus , or Streptococcus pyogenes . 1.6 Acute Otitis Media Clarithromycin is indicated in pediatric patients for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae , Moraxella catarrhalis , or Streptococcus pneumoniae [ see Clinical Studies ( 14.2 ) ]. 1.7 Treatment and Prophylaxis of Disseminated Mycobacterial Infections Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Mycobacterium avium or Mycobacterium intracellulare in patients with advanced HIV infection [ see Clinical Studies ( 14.1 ) ]. 1.9 Limitations of Use 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 DOSAGE AND ADMINISTRATION • Pediatric Patients: Clarithromycin 15 mg/kg/day divided every 12 hours for 10 days ( 2.4 ) • Mycobacterial Infections: Clarithromycin 500 mg every 12 hours; Clarithromycin 7.5 mg/kg up to 500 mg every 12 hours in pediatric patients ( 2.5 ) • Reduce dose in moderate renal impairment with concomitant atazanavir or ritonavir-containing regimens and in severe renal impairment ( 2.6 ) 2.1 Important Administration Instructions Clarithromycin for oral suspension may be given with or without food. 2.4 Pediatric Dosage 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 ) ]. 2.5 Dosage Regimens for Mycobacterial Infections For the treatment of disseminated infection due to Mycobacterium avium complex (MAC), clarithromycin is recommended as the primary agents. Clarithromycin should be used in combination with other antimycobacterial drugs (e.g. ethambutol) that have shown in vitro activity against MAC or clinical benefit in MAC treatment [ see Clinical Studies ( 14.1 ) ]. Adult Patients For treatment and prophylaxis of mycobacterial infections in adults, the recommended dose of clarithromycin 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 ) and Clinical Studies ( 14.1 ) ]. Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be discontinued when the patient is considered at low risk of disseminated infection. 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) ]. Table 2. Clarithromycin Dosage Adjustments in Patients with Renal Impairment Recommended ClarithromycinDosage Reduction Patients with severe renal impairment (CL cr of <30 mL/min) Reduce the dosage of Clarithromycin by 50% Patients with moderate renal impairment (CL cr of 30 to 60 mL/min) taking concomitant atazanavir or ritonavir-containing regimens Reduce the dosage of Clarithromycin by 50% Patients with severe renal impairment (CL cr of <30 mL/min) taking concomitant atazanavir or ritonavir-containing regimens Reduce the dosage of Clarithromycin by 75% 2.7 Dosage Adjustment Due to Drug Interactions Decrease the dose of clarithromycin by 50 % when co-administered with atazanavir [ see Drug Interactions ( 7 ) ]. Dosage adjustments for other drugs when co-administered with clarithromycin may be recommended due to drug interactions [ see Drug Interactions ( 7 ) ]. 2.8 Reconstitution of Clarithromycin for Oral Suspension The supplied clarithromycin granules must be reconstituted with water prior to administration of clarithromycin for oral suspension. Table 3 below indicates the volume of water to be added when reconstituting. To reconstitute: a. Add half the volume of water to the bottle containing the clarithromycin granules and shake vigorously. b. Add the remainder of water to the bottle and shake. Shake well before each use. After mixing, store at 15° to 30°C (59° to 86°F) and use within 14 days. Do not refrigerate. Table 3. Volume of Water to be Added When Reconstituting Clarithromycin Granules Total Volume After Reconstitution Clarithromycin Concentration After Reconstitution Amount of Water to be Added 50 mL 125 mg/5 mL 29.5 mL 100 mL 125 mg/5 mL 59 mL 50 mL 250 mg/5 mL 28.5 mL 100 mL 250 mg/5 mL 57 mL

5 WARNINGS AND PRECAUTIONS • Severe acute hypersensitivity reactions: Discontinue clarithromycin if occurs ( 5.1 ) • QT prolongation: Avoid clarithromycin in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmia ( torsades de pointes ), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics ( 5.2 ) • Hepatotoxicity: Discontinue if signs and symptoms of hepatitis occur ( 5.3 ) • Serious adverse reactions can occur due to drug interactions of clarithromycin with colchicine, some lipid-lowering agents, some calcium channel blockers, and other drugs ( 5.4 ) • Risk of all-cause mortality one year or more after the end of treatment in patients with coronary artery disease. Balance this potential risk with the treatment benefits when prescribing clarithromycin in these patients ( 5.5 ) • Clostridium difficile associated diarrhea (CDAD): Evaluate if diarrhea occurs ( 5.6 ) • Embryo-fetal Toxicity: Based on animal findings, clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate ( 5.7 ) • Exacerbation of myasthenia gravis has been reported in patients receiving clarithromycin therapy ( 5.8 ) 5.1 Severe 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), Henoch-Schonlein purpura, and acute generalized exanthematous pustulosis, 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 (e.g., quinidine, procainamide, disopyramide) or Class III (e.g., 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; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes ) 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 …

4 CONTRAINDICATIONS • 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 ) 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 Cisapride and Pimozide 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 co‑ administered 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 Lomitapide, Lovastatin, and Simvastatin Concomitant administration of clarithromycin with lomitapide is contraindicated due to potential for markedly increased transaminases [ see Warnings and Precautions ( 5.4 ) and Drug Interactions ( 7 ) ]. Concomitant administration of clarithromycin 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 ) and Drug Interactions ( 7 ) ]. 4.6 Ergot Alkaloids Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated [ see Drug Interactions ( 7 ) ]. 4.7 Lurasidone Concomitant administration of clarithromycin and lurasidone is contraindicated since it may result in an increase in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions ( 7 )]. 4.8 Contraindications for Co-administered Drugs For information about contraindications of other drugs indicated in combination with clarithromycin, refer to their full prescribing information (contraindications section).

7 DRUG INTERACTIONS 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.g., 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 Dofetilide Amiodarone Sotalol Procainamide Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [ see Warnings and Precautions ( 5.2 )]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co‑ administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range. Oral Anticoagulants Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [ see Warnings and Precautions ( 5.4 )]. Antiepileptics Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine. Antifungals Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole No Dose Adjustment Fluconazole: [ see Pharmacokinetics ( 12.3 ) ] Anti-Gout Agents Colc…

8.1 Pregnancy Risk Summary Based on findings from animal studies, clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions ( 5.7 )] . Limited data from a small number of published human studies with clarithromycin use during pregnancy are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of oral clarithromycin to pregnant mice, rats, rabbits, and monkeys during the period of organogenesis produced malformations in rats (cardiovascular anomalies) and mice (cleft palate) at clinically relevant doses based on body surface area comparison. Fetal effects in mice, rats, and monkeys (e.g., reduced fetal survival, body weight, body weight gain) and implantation losses in rabbits were generally considered to be secondary to maternal toxicity ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies were conducted in mice, rats, rabbits, and monkeys with oral and intravenously administered clarithromycin. In pregnant mice, clarithromycin was administered during organogenesis (gestation day [GD] 6 to 15) at oral doses of 15, 60, 250, 500, or 1000 mg/kg/day. Reduced body weight observed in dams at 1000 mg/kg/day (3 times the maximum recommended human dose [MRHD] based on body surface area comparison) resulted in reduced survival and body weight of the fetuses. At ≥500 mg/kg/day, increases in the incidence of post-implantation loss and cleft palate in the fetuses were observed. No adverse developmental effects were observed in mice at ≤250 mg/kg/day (≤1 times MRHD based on body surface area comparison). In pregnant Sprague Dawley rats, clarithromycin was administered during organogenesis (GD 6 to 15) at oral doses of 15, 50, or 150 mg/kg/day. Reductions in body weight and food consumption was observed in dams at 150 mg/kg/day. Increased resorptions and reduced body weight of the fetuses at this dose were considered secondary to maternal toxicity. Additionally, at 150 mg/kg/day (1 times MRHD based on body surface area comparison), a low incidence of cardiovascular anomalies (complete situs inversus, undivided truncus, IV septal defect) was observed in the fetuses. Clarithromycin did not cause adverse developmental effects in rats at 50 mg/kg/day (0.3 times MRHD based on body surface area comparison). Intravenous dosing of clarithromycin during organogenesis in rats (GD 6 to 15) at 15, 50, or 160 mg/kg/day was associated with maternal toxicity (reduced body weight, body-weight gain, and food consumption) at 160 mg/kg/day but no evidence of adverse developmental effects at any dose (≤1 times MRHD based on body surface area comparison). In pregnant Wistar rat, clarithromycin was administered during organogenesis (GD 7 to 17) at oral doses of 10, 40, or 160 mg/kg/day. Reduced body weight and food consumption were observed in dams at 160 mg/kg/day but there was no evidence of adverse developmental effects at any dose (≤1 times MRHD based on body surface area comparison). In pregnant rabbits, clarithromycin administered during organogenesis (GD 6 to 18) at oral doses of 10, 35, or 125 mg/kg/day resulted in reduced maternal food consumption and decreased body weight at the highest dose, with no evidence of any adverse developmental effects at any dose (≤ 2 times MRHD based on body surface area comparison). Intravenously administered cl…

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Acute Hypersensitivity Reactions [ see Warnings and Precautions ( 5.1 ) ] • QT Prolongation [ see Warnings and Precautions ( 5.2 ) ] • Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Serious Adverse Reactions Due to Concomitant Use with Other Drugs [ see Warnings andPrecautions ( 5.4 ) ] • Clostridium difficile Associated Diarrhea [ see Warnings and Precautions ( 5.6 ) ] • Exacerbation of Myasthenia Gravis [ 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 Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. The subsequent subsections list the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori infection. In general, these profiles are consistent with the pooled data described above. Prophylaxis of Mycobacterial Infections In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium , it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the clarithromycin group and 8.2 months for the placebo group. Table 4. Incidence Rates (%) of Selected Adverse Reactions* in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex Body System † 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% ‡ 0.3% 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 , evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test. Table 5. Percentage of Patients* Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex Clarithromycin 500 mg twice a day Placebo WBC Count <1 x 10 9 /L 2/103 (4%) 0/95 SGOT >5 x ULN † 7/196 (4%) 5/208 (2%) SGPT >5 x ULN † 6/217 (3%) 4/232 (2%) * Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables) † ULN= Upper Limit of Normal Treatment of Mycobacterial Infections The adverse reaction profiles for both the 500 mg and 1000 mg twice a day…