Azithromycin monohydrate Injection, Powder, Lyophilized, For Solution

Azithromycin for injection is a macrolide antibacterial drug indicated for the treatment of the following infections caused by designated susceptible microorganisms: • Community-acquired pneumonia in adults (1.1)

• Pelvic inflammatory disease in adults (1.2)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.3) 1.1 Community-Acquired Pneumonia

Azithromycin for injection is indicated for the treatment of adult patients with community-acquired pneumonia due to the following susceptible microorganisms: Chlamydophila pneumoniae,

Haemophilus influenzae,

Legionella pneumophila,

Moraxella catarrhalis,

Mycoplasma pneumoniae,

Staphylococcus aureus, or

Streptococcus pneumoniae

in patients who require initial intravenous therapy. 1.2 Pelvic Inflammatory Disease

Azithromycin for injection is indicated for the treatment of adult patients with pelvic inflammatory disease due to the following susceptible microorganisms: 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. 1.3 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin 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.

• Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide antibacterial drug. (4.1)

• Patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. (4.2) 4.1 Hypersensitivity

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drugs. 4.2 Hepatic Dysfunction

Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

The following clinically significant adverse reactions are described elsewhere in labeling:

1. Hypersensitivity [see Warnings and Precautions (5.1)]
2. Hepatotoxicity [see Warnings and Precautions (5.2)]
3. Infantile Hypertrophic Pyloric Stenosis (IHPS) [see Warnings and Precautions (5.3)]
4. QT Prolongation [see Warnings and Precautions (5.4)]
5. Cardiovascular Death [see Warnings and Precautions (5.5)]
6. Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.6)]
7. Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.7)]

• Serious (including fatal) allergic and skin reactions. Discontinue azithromycin and initiate appropriate therapy if reaction occurs. (5.1)

• Hepatotoxicity: Severe and sometimes fatal, hepatoxicity has been reported. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. (5.2)

• Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. (5.3)

• Prolongation of QT interval and cases of torsades de pointes have been reported. This risk which can be fatal should be considered in patients with certain cardiovascular disorders including known QT prolongation or history torsades de pointes, those with proarrhythmic conditions, and with other drugs that prolong the QT interval. (5.4)

• Cardiovascular Death: Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. Consider balancing this potential risk with treatment benefits when prescribing azithromycin. (5.5)

• Clostridioides difficile

-Associated Diarrhea: Evaluate patients if diarrhea occurs. (5.6)

• Azithromycin may exacerbate muscle weakness in persons with myasthenia gravis. (5.7) 5.1 Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy.

[see

Contraindications (4.1)]

Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is unknown at present.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that the allergic symptoms may reappear after symptomatic therapy has been discontinued. 5.2 Hepatotoxicity

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. 5.3 Infantile Hypertrophic Pyloric Stenosis (IHPS)

Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. 5.4 QT Prolongation

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation, which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: • patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure

• patients on drugs known to prolong the QT interval

• patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval. 5.5 Cardiovascular Death

Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular mortality observed in these studies ranged from 20 to 400 per million azithromycin treatment courses. This potential risk was noted to be greater during the first five days of azithromycin use and does not appear to be limited to those patients with preexisting cardiovascular diseases. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. Consider balancing this potential risk with treatment benefits when prescribing azithromycin. 5.6

Clostridioides difficile

-Associated Diarrhea

Clostridioides difficile-

Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of

C. difficile.

C. difficile

produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of

C. difficile

cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against

C. difficile

may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of

C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.7 Exacerbation of Myasthenia Gravis

Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. 5.8 Infusion Site Reactions

Azithromycin for injection should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes.

[see

Dosage and Administration (2)]

Local IV site reactions have been reported with the intravenous administration of azithromycin. The incidence and severity of these reactions were the same when 500 mg azithromycin was given over 1 hour (2 mg/mL as 250 mL infusion) or over 3 hr (1 mg/mL as 500 mL infusion)

[see

Adverse Reactions (6)].

All volunteers who received infusate concentrations above 2 mg/mL experienced local IV site reactions and, therefore, higher concentrations should be avoided. 5.9 Development of Drug-Resistant Bacteria

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

The recommended dosage 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 . [see Indications and Usage (1.1) and Clinical Pharmacology (12.3)].

The recommended dosage 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.  [see Indications and Usage (1.2) and Clinical Pharmacology (12.3)].

Azithromycin for Injection, USP is supplied as white to off-white lyophilized powder in a single-dose vial equivalent to 500 mg of azithromycin for intravenous administration.

• Nelfinavir: Close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (7.1)

• Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time. (7.2) 7.1 Nelfinavir

Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted.

[see

Adverse Reactions (6)] 7.2 Warfarin

Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. 7.3 Potential Drug-Drug Interaction with Macrolides

Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.