AZITHROMYCIN

Azithromycin for Injection, USP contains the active ingredient azithromycin, an azalide, a subclass of macrolide antibiotics, for intravenous injection. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R )-13-[(2,6-dideoxy-3- C -methyl-3- O -methyl-α- L - ribo -hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β- D-xylo -hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Azithromycin has the following structural formula: Azithromycin, as the monohydrate, is a white crystalline powder with a molecular formula of C 38 H 72 N 2 O 12 •H 2 O and a molecular weight of 767.00. Azithromycin for Injection, USP consists of azithromycin monohydrate and the following inactive ingredients: citric acid and sodium hydroxide. Azithromycin for Injection, USP is supplied in lyophilized form in a 10 mL vial equivalent to 500 mg of azithromycin for intravenous administration. Reconstitution, according to label directions, results in approximately 5 mL of azithromycin for intravenous injection with each mL containing azithromycin monohydrate equivalent to 100 mg of azithromycin. After reconstitution each mL contains: azithromycin monohydrate equivalent to 100 mg of azithromycin, 76.9 mg of citric acid, and sodium hydroxide for pH adjustment. structure

Azithromycin for Injection, USP is indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below. As recommended dosages, durations of therapy, and applicable patient populations vary among these infections, please see DOSAGE AND ADMINISTRATION for dosing recommendations. Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, or Streptococcus pneumoniae in patients who require initial intravenous therapy. Pelvic inflammatory disease due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma hominis in patients who require initial intravenous therapy. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin for Injection, USP. Azithromycin for Injection, USP should be followed by azithromycin by the oral route as required (see DOSAGE AND ADMINISTRATION ). Appropriate culture and susceptibility tests should be performed before treatment to determine the causative microorganism and its susceptibility to azithromycin. Therapy with azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Azithromycin for Injection, USP and other antibacterial drugs, Azithromycin for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

(See INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY .) The recommended dose of Azithromycin for Injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250 mg tablets to complete a 7 to 10 day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. The recommended dose of Azithromycin for Injection for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for one or two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg to complete a 7 day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin for Injection. Renal Insufficiency No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC 0-120 was similar in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment (see CLINICAL PHARMACOLOGY, Special Populations , Renal Insufficiency ). Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established. No dose adjustment recommendations can be made in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency ). No dosage adjustment is recommended based on age or gender (see CLINICAL PHARMACOLOGY, Special Populations ). The infusate concentration and rate of infusion for Azithromycin for Injection should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour. Azithromycin for Injection should not be given as a bolus or as an intramuscular injection. Preparation of the solution for intravenous administration is as follows: Reconstitution Prepare the initial solution of Azithromycin for Injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial and shaking the vial until all of the drug is dissolved. Since Azithromycin for Injection is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of Sterile Water is dispensed. Each mL of reconstituted solution contains 100 mg azithromycin. Reconstituted solution is stable for 24 hours when stored below 30°C (86°F). Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded. Dilute this solution further prior to administration as instructed below. Dilution To provide azithromycin over a concentration range of 1 to 2 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below: Normal Saline (0.9% sodium chloride) 1/2 Normal Saline (0.45% sodium chloride) 5% Dextrose in Water Lactated Ringer’s Solution 5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl 5% Dextrose in Lactated Ringer’s Solution 5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride) 5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) Normosol ® -M in 5% Dextrose Normosol ® -R in 5% Dextrose Final Infusion Solution Concentration (mg/mL) Amount of Diluent (mL) 1 mg/mL 500 mL 2 mg/mL 250 mL It is recommended that a 500 mg dose of Azithromycin for Injection, diluted as above, be infused over a period of not less than 60 minutes. Azithromycin for Injection should not be given as a bolus or as an intramuscular injection. Other intravenous substances, additives, or medications should not be added to Azithromycin for Injection or infused simultaneously through the same intravenous line. Storage Store the white to off-white lyophilized cake at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. When diluted according to the instructions (1 mg/mL to 2 mg/mL), Azithromycin for Injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F). Storage Store the white to off-white lyophilized cake at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. When diluted according to the instructions (1 mg/mL to 2 mg/mL), Azithromycin for Injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F).

Azithromycin for Injection is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic. Azithromycin for Injection is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

In clinical trials of intravenous azithromycin for community-acquired pneumonia, in which 2 to 5 IV doses were given, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. The majority of patients in these trials had one or more co-morbid diseases and were receiving concomitant medications. Approximately 1.2% of the patients discontinued intravenous azithromycin therapy, and a total of 2.4% discontinued azithromycin therapy by either the intravenous or oral route because of clinical or laboratory side effects. In clinical trials conducted in patients with pelvic inflammatory disease, in which 1 to 2 IV doses were given, 2% of women who received monotherapy with azithromycin and 4% who received azithromycin plus metronidazole discontinued therapy due to clinical side effects. Clinical side effects leading to discontinuations from these studies were most commonly gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), and rashes; laboratory side effects leading to discontinuation were increases in transaminase levels and/or alkaline phosphatase levels. Clinical Overall, the most common side effects associated with treatment in adult patients who received IV/PO azithromycin in studies of community-acquired pneumonia were related to the gastrointestinal system with diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%) being the most frequently reported. Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the injection site (6.5%) and local inflammation (3.1%). The most common side effects associated with treatment in adult women who received IV/PO azithromycin in studies of pelvic inflammatory disease were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most commonly reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was co-administered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%). No other side effects occurred in patients on the multiple-dose IV/PO regimen of azithromycin in these studies with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis. Nervous System: headache, somnolence. Allergic: bronchospasm. Special Senses: taste perversion. Post-Marketing Experience Adverse events reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: arthralgia, edema, urticaria and angioedema. Cardiovascular: arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and torsades de pointes. Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis and rare reports of tongue discoloration. General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal). Genitourinary: interstitial nephritis and acute renal failure and vaginitis. Hematopoietic: thrombocytopenia. Liver/Biliary: adverse reactions related to hepatic dysfunction have been reported in post-marketing experience with azithromycin (see WARNINGS , Hepatotoxicity ). Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Psychiatric: aggressive reaction and anxiety. Skin/Appendages: pruritus, rarely serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss. Laboratory Abnormalities Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of 4 to 6%, elevated ALT (SGPT), AST (SGOT), creatinine with an incidence of 1 to 3%, elevated LDH, bilirubin with an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 750 patients treated with azithromycin (IV/PO), less than 2% of patients discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities. Clinical Overall, the most common side effects associated with treatment in adult patients who received IV/PO azithromycin in studies of community-acquired pneumonia were related to the gastrointestinal system with diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%) being the most frequently reported. Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the injection site (6.5%) and local inflammation (3.1%). The most common side effects associated with treatment in adult women who received IV/PO azithromycin in studies of pelvic inflammatory disease were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most commonly reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was co-administered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%). No other side effects occurred in patients on the multiple-dose IV/PO regimen of azithromycin in these studies with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis. Nervous System: headache, somnolence. Allergic: bronchospasm. Special Senses: taste perversion. Post-Marketing Experience Adverse events reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: arthralgia, edema, urticaria and angioedema. Cardiovascular: arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and torsades de pointes. Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis and rare reports of tongue discoloration. General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal). Genitourinary: interstitial nephritis and acute renal failure and vaginitis. Hematopoietic: thrombocytopenia. Liver/Biliary: adverse reactions related to hepatic dysfunction have been reported in post-marketing experience with azithromycin (see WARNINGS , Hepatotoxicity ). Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Psychiatric: aggressive reaction and anxiety. Skin/Appendages: pruritus, rarely serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss. Laboratory Abnormalities Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of 4 to 6%, elevated ALT (SGPT), AST (SGOT), creatinine with an incidence of 1 to 3%, elevated LDH, bilirubin with an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 750 patients treated with azithromycin (IV/PO), less than 2% of patients discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities.