Azithromycin Injection

Dosage Form: injection, powder, lyophilized, for solution
AZITHROMYCIN FOR INJECTION USP

For IV infusion only

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 bacteria.

Azithromycin Injection Description

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:

C38H72N2O12 M.W. 749

Azithromycin, as the monohydrate, is a white crystalline powder with a molecular formula of C38H72N2O12· H2O and a molecular weight of 767.

Azithromycin for injection USP consists of azithromycin monohydrate and the following inactive ingredients: citric acid, nitrogen, sodium hydroxide and water for injection. Azithromycin for injection USP is supplied in lyophilized form in a 14 mL vial equivalent to 500 mg of azithromycin for intravenous administration. Reconstitution, according to label directions, each mL contains azithromycin monohydrate equivalent to 100 mg of azithromycin, 76.9 mg of citric acid, and sodium hydroxide for pH adjustment.

Azithromycin Injection - Clinical Pharmacology

Pharmacokinetics

In patients hospitalized with community-acquired pneumonia receiving single daily one hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax ± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24 hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC24 was 9.60 ± 4.80 mcg·h/mL.

The mean Cmax, 24 hour trough and AUC24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ± 0.86 mcg·h/mL, respectively, in normal volunteers receiving a 3 hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3 hour dosage regimen for 2 to 5 days.

Plasma concentrations (mcg/mL ± S.D.) after the last daily intravenous infusion of 500 mg azithromycin

* = 500 mg (2 mg/mL) for 2 to 5 days in community-acquired pneumonia patients. † = 500 mg (1 mg/mL) for 5 days in healthy subjects.
Infusion Concentration, Duration	Time after starting the infusion (hr)
2 mg/mL, 1 hr*	0.5 2.98 ± 1.12	1 3.63 ± 1.73	2 0.60 ± 0.31	3 0.40 ± 0.23	4 0.33 ± 0.16	6 0.26 ± 0.14	8 0.27 ± 0.15	12 0.20 ± 0.12	24 0.20 ± 0.15
1 mg/mL, 3 hr†	0.91 ± 0.13	1.02 ± 0.11	1.14 ± 0.13	1.13 ± 0.16	0.32 ± 0.05	0.28 ± 0.04	0.27 ± 0.03	0.22 ± 0.02	0.18 ± 0.02

The average CLt and Vd values were 10.18 mL/min/kg and 33.3 L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000 mg doses given as 1 mg/mL over 2 hours.

Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels.

Following single oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, Cmax, trough level, and AUC24 were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·h/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500 mg I.V. 3 hour infusion (Cmax: 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5 mcg·h/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24 hour interval. The pharmacokinetic parameters on day 5 of azithromycin 250 mg capsules following a 500 mg oral loading dose to healthy young adults (age 18 to 40 years old) were as follows: Cmax: 0.24 mcg/mL, AUC24: 2.1 mcg·h/mL. Azithromycin 250 mg capsules are no longer commercially available. Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasting state.

Median azithromycin exposure (AUC0-288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following 1,500 mg of oral azithromycin, administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2 to 5) or 3 days (500 mg per day for days 1 to 3) to 12 healthy volunteers, was more than a 1000 fold and 800 fold greater than in serum, respectively.

Distribution

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL.

Tissue concentrations have not been obtained following intravenous infusions of azithromycin. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios following oral administration of azithromycin are shown in the following table:

AZITHROMYCIN CONCENTRATIONS FOLLOWING A 500 mg DOSE (TWO 250 mg CAPSULES) IN ADULTS

* High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity. † Sample was obtained 2 to 4 hours after the first dose. ‡ Sample was obtained 10 to 12 hours after the first dose. § Dosing regimen of 2 doses of 250 mg each, separated by 12 hours. ¶ Sample was obtained 19 hours after a single 500 mg dose.
TISSUE OR FLUID	TIME AFTER DOSE (h)	TISSUE OR FLUID CONCENTRATION (mcg/g or mcg/mL) *	CORRESPONDING PLASMA OR SERUM LEVEL (mcg/mL)	TISSUE (FLUID) PLASMA (SERUM) RATIO *
SKIN	72 to 96	0.4	0.012	35
LUNG	72 to 96	4	0.012	> 100
SPUTUM†	2 to 4	1	0.64	2
SPUTUM‡	10 to 12	2.9	0.1	30
TONSIL§	9 to 18	4.5	0.03	> 100
TONSIL§	180	0.9	0.006	> 100
CERVIX¶	19	2.8	0.04	70

Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients. Approximately 17 hours after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were less than 0.01 μg/mL in the presence of non-inflamed meninges.

Metabolism

In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.

Elimination

Plasma concentrations of azithromycin following single 500 mg oral and i.v. doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

In a multiple dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one hour intravenous dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hours was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.

Special Populations

Renal Insufficiency

Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min) (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency

The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.

Gender

There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.

Geriatric Patients

Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65 to 85 years old) were similar to those in younger volunteers (18 to 40 years old) for the 5 day therapeutic regimen.

Pediatric Patients

Pharmacokinetic studies with intravenous azithromycin have not been performed in children.

Drug-Drug Interactions

Drug interaction studies were performed with oral azithromycin and other drugs likely to be coadministered. The effects of coadministration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.

Coadministration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when coadministered with azithromycin.

Coadministration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2 (see PRECAUTIONS, Drug Interactions).

Table 1. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin

Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Mean Cmax	Mean AUC
Atorvastatin	10 mg/day × 8 days	500 mg/day PO on days 6 to 8	12	0.83 (0.63 to 1.08)	1.01 (0.81 to 1.25)
Carbamazepine	200 mg/day × 2 days, then 200 mg BID × 18 days	500 mg/day PO for days 16 to 18	7	0.97 (0.88 to 1.06)	0.96 (0.88 to 1.06)
Cetirizine	20 mg/day × 11 days	500 mg PO on day 7, then 250 mg/day on days 8 to 11	14	1.03 (0.93 to 1.14)	1.02 (0.92 to 1.13)
Didanosine	200 mg PO BID × 21 days	1,200 mg/day PO on days 8 to 21	6	1.44 (0.85 to 2.43)	1.14 (0.83 to 1.57)
Efavirenz	400 mg/day × 7 days	600 mg PO on day 7	14	1.04*	0.95*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	1.04 (0.98 to 1.11)	1.01 (0.97 to 1.05)
Indinavir	800 mg TID × 5 days	1,200 mg PO on day 5	18	0.96 (0.86 to 1.08)	0.90 (0.81 to 1.00)
Midazolam	15 mg PO on day 3	500 mg/day PO × 3 days	12	1.27 (0.89 to 1.81)	1.26 (1.01 to 1.56)
Nelfinavir	750 mg TID × 11 days	1,200 mg PO on day 9	14	0.90 (0.81 to 1.01)	0.85 (0.78 to 0.93)
Rifabutin	300 mg/day × 10 days	500 mg PO on day 1, then 250 mg/day on days 2 to 10	6	See footnote below	NA
Sildenafil	100 mg on days 1 and 4	500 mg/day PO × 3 days	12	1.16 (0.86 to 1.57)	0.92 (0.75 to 1.12)
Theophylline	4 mg/kg IV on days 1, 11, 25	500 mg PO on day 7, 250 mg/day on days 8 to 11	10	1.19 (1.02 to 1.40)	1.02 (0.86 to 1.22)
Theophylline	300 mg PO BID × 15 days	500 mg PO on day 6, then 250 mg/day on days 7 to 10	8	1.09 (0.92 to 1.29)	1.08 (0.89 to 1.31)
Triazolam	0.125 mg on day 2	500 mg PO on day 1, then 250 mg/day on day 2	12	1.06*	1.02*
Trimethoprim/ Sulfamethoxazole	160 mg/800 mg/day PO × 7 days	1,200 mg PO on day 7	12	0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03)	0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03)
Zidovudine	500 mg/day PO × 21 days	600 mg/day PO × 14 days	5	1.12 (0.42 to 3.02)	0.94 (0.52 to 1.70)
Zidovudine	500 mg/day PO × 21 days	1,200 mg/day PO × 14 days	4	1.31 (0.43 to 3.97)	1.30 (0.69 to 2.43)

NA – Not Available

* - 90% Confidence interval not reported

Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when coadministered with placebo.

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs (see PRECAUTIONS, Drug Interactions).

Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Mean Cmax	Mean AUC
Efavirenz	400 mg/day × 7 days	600 mg PO on day 7	14	1.22 (1.04 to 1.42)	0.92*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	0.82 (0.66 to 1.02)	1.07 (0.94 to 1.22)
Nelfinavir	750 mg TID × 11 days	1,200 mg PO on day 9	14	2.36 (1.77 to 3.15)	2.12 (1.80 to 2.50)
Rifabutin	300 mg/day × 10 days	500 mg PO on day 1, then 250 mg/day on days 2 to 10	6	See footnote below	NA

 NA – Not Available

* - 90% Confidence interval not reported

Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.

Microbiology: Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for azithromycin for injection.

Aerobic and facultative gram-positive microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

NOTE: Azithromycin demonstrates cross-resistance with erythromycin resistant gram- positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.

Aerobic and facultative gram-negative microorganisms

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

“Other” microorganisms

Chlamydia pneumoniae

Chlamydia trachomatis

Legionella pneumophila

Mycoplasma hominis

Mycoplasma pneumoniae

Beta-lactamase production should have no effect on azithromycin activity.

Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for azithromycin tablets and azithromycin for oral suspension.

Aerobic and facultative gram-positive microorganisms

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Aerobic and facultative gram-negative microorganisms

Haemophilus ducreyi

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

“Other” microorganisms

Chlamydia pneumoniae

Chlamydia trachomatis

Mycoplasma pneumoniae

Beta-lactamase production should have no effect on azithromycin activity.

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin.

However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic and facultative gram-positive microorganisms

Streptococci (Groups C, F, G)

Viridans group streptococci

Aerobic and facultative gram-negative microorganisms

Bordetella pertussis

Anaerobic microorganisms

Peptostreptococcus species

Prevotella bivia

“Other” microorganisms

Ureaplasma urealyticum

Beta-lactamase production should have no effect on azithromycin activity.

Susceptibility Testing Methods

When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mcg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 3.

Table 3. Susceptibility Interpretive Criteria for Azithromycin Susceptibility Test Result Interpretive Criteria

* The current absence of data on resistant strains precludes defining any category other than “susceptible”. If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. † Susceptibility of streptococci including, S. pneumoniae to azithromycin and other macrolides can be predicted by testing erythromycin. No interpretive criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested.
	Minimum Inhibitory				Disk Diffusion
	Concentrations (mcg/mL)				(zone diameters in mm)
Pathogen
	S	I	R *	S	I	R*
Haemophilus spp.	≤ 4	--	--	≥ 12	--	--
Staphylococcus aureus	≤ 2	4	≥ 8	≥ 18	14 to 17	≤ 13
Streptococci including
S. pneumoniae†	≤ 0.5	1	≥ 2	≥ 18	14 to 17	≤ 13

A report of “susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of “intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard azithromycin powder should provide the following range of values noted in Table 4. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.

Table 4. Acceptable Quality Control Ranges for Azithromycin

QC Strain	Minimum Inhibitory	Disk Diffusion
	Concentrations (mcg/mL)	(zone diameters in mm)
Haemophilus influenzae
ATCC 49247	1 to 4	13 to 21
Staphylococcus aureus
ATCC 29213	0.5 to 2
Staphylococcus aureus
ATCC 25923		21 to 26
Streptococcus pneumoniae
ATCC 49619	0.06 to 0.25	19 to 25

Indications and Usage for Azithromycin Injection

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.

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 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.

Contraindications

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.

Warnings

Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported (see CONTRAINDICATIONS). 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 reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

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.

Clostridium Difficile-associated diarrhea

Clostridium 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 antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General

Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycin is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR < 10 mL/min, caution should be exercised when prescribing azithromycin in these patients (see CLINICALPHARMACOLOGY, Special Populations and Renal Insufficiency).

Azithromycin for injection should be rec