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ZITHROMAX® TABLET, SUSPENSION Clinical Pharmacology (azithromycin dihydrate TABLET, SUSPENSION)


12.1 Mechanism of Action

Azithromycin is a macrolide antibacterial drug. [see Microbiology (12.4)]

12.2 Pharmacodynamics

Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

12.3 Pharmacokinetics

Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0–72=4.3 (1.2) mcg∙hr/mL; Cmax=0.5 (0.2) mcg/mL; Tmax=2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.

In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1500 mg of 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 2–5) or 3 days (500 mg per day for days 1–3). Due to limited serum samples on day 2 (3-day regimen) and days 2–4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC0–∞ for the fitted concentration profile was comparable between the 5-day and 3-day regimens.

3-Day Regimen5-Day Regimen
Total AUC for the entire 3-day and 5-day regimens.
Pharmacokinetic Parameter [mean (SD)]Day 1Day 3Day 1Day 5
Cmax (serum, mcg/mL)0.44 (0.22)0.54 (0.25)0.43 (0.20)0.24 (0.06)
Serum AUC0–∞ (mcg∙hr/mL)17.4 (6.2)*14.9 (3.1)*
Serum T1/271.8 hr68.9 hr


The absolute bioavailability of azithromycin 250 mg capsules is 38%.

In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.

When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.


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.

The antibacterial 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.

Azithromycin has been shown to penetrate into human tissues, including skin, lung, tonsil, and cervix. Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical significance of these tissue concentration data is unknown.

Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of noninflamed meninges.


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


Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Specific Populations

Patients with Renal Impairment

Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 × 250 mg capsules), 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).

Patients with Hepatic Impairment

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

Male and Female Patients

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 parameters in older volunteers (65 to 85 years old) were similar to those in young adults (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen. [see Geriatric Use (8.5)]

Pediatric Patients

In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 in two groups of pediatric patients (aged 1–5 years and 5–15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax=0.216 mcg/mL, Tmax=1.9 hr, and AUC0–24=1.822 mcg∙hr/mL for the 1 to 5-year-old group and were Cmax=0.383 mcg/mL, Tmax=2.4 hr, and AUC0–24=3.109 mcg∙hr/mL for the 5 to 15-year-old group.

In another study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days, of whom 31 patients were evaluated for azithromycin pharmacokinetics following a low fat breakfast. In this study, azithromycin concentrations were determined over a 24 hr period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. Seventeen patients (weighing 41.7 kg or less) received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg.

Pharmacokinetic Parameter
[mean (SD)]
5-Day Regimen
(12 mg/kg for 5 days)
Cmax (mcg/mL)0.5 (0.4)
Tmax (hr)2.2 (0.8)
AUC0–24(mcg∙hr/mL)3.9 (1.9)

Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2)]

Drug Interaction Studies

Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration 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.

Co-administration 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 co-administered with azithromycin.

Co-administration 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 Drug Interactions (7.3)]

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin
Co-administered DrugDose of Co-administered DrugDose of AzithromycinnRatio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean CmaxMean AUC
- 90% Confidence interval not reported
Atorvastatin10 mg/day for 8 days500 mg/day orally on days 6–8120.83
(0.63 to 1.08)
(0.81 to 1.25)
Carbamazepine200 mg/day for 2 days, then 200 mg twice a day for 18 days500 mg/day orally for days 16–1870.97
(0.88 to 1.06)
(0.88 to 1.06)
Cetirizine20 mg/day for 11 days500 mg orally on day 7, then 250 mg/day on days 8–11141.03
(0.93 to 1.14)
(0.92 to 1.13)
Didanosine200 mg orally twice a day for 21 days1200 mg/day orally on days 8–2161.44
(0.85 to 2.43)
(0.83 to 1.57)
Efavirenz400 mg/day for 7 days600 mg orally on day 7141.04*0.95*
Fluconazole200 mg orally single dose1200 mg orally single dose181.04
(0.98 to 1.11)
(0.97 to 1.05)
Indinavir800 mg three times a day for 5 days1200 mg orally on day 5180.96
(0.86 to 1.08)
(0.81 to 1.00)
Midazolam15 mg orally on day 3500 mg/day orally for 3 days121.27
(0.89 to 1.81)
(1.01 to 1.56)
Nelfinavir750 mg three times a day for 11 days1,200 mg orally on day 9140.90
(0.81 to 1.01)
(0.78 to 0.93)
Sildenafil100 mg on days 1 and 4500 mg/day orally for 3 days121.16
(0.86 to 1.57)
(0.75 to 1.12)
Theophylline4 mg/kg IV on days 1, 11, 25500 mg orally on day 7, 250 mg/day on days 8–11101.19
(1.02 to 1.40)
(0.86 to 1.22)
Theophylline300 mg orally twice a day for 15 days500 mg orally on day 6, then 250 mg/day on days 7–1081.09
(0.92 to 1.29)
(0.89 to 1.31)
Triazolam0.125 mg on day 2500 mg orally on day 1, then 250 mg/day on day 2121.06*1.02*
160 mg/800 mg/day orally for 7 days1200 mg orally on day 7120.85
(0.75 to 0.97)/0.90
(0.78 to 1.03)
(0.80 to 0.95/0.96
(0.88 to 1.03)
Zidovudine500 mg/day orally for 21 days600 mg/day orally for 14 days51.12
(0.42 to 3.02)
(0.52 to 1.70)
Zidovudine500 mg/day orally for 21 days1200 mg/day orally for 14 days41.31
(0.43 to 3.97)
(0.69 to 2.43)
Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. [see Drug Interactions (7)]
Co-administered DrugDose of Co-administered DrugDose of AzithromycinnRatio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean CmaxMean AUC
- 90% Confidence interval not reported
Efavirenz400 mg/day for 7 days600 mg orally on day 7141.22
(1.04 to 1.42)
Fluconazole200 mg orally single dose1,200 mg orally single dose180.82
(0.66 to 1.02)
(0.94 to 1.22)
Nelfinavir750 mg three times a day for 11 days1,200 mg orally on day 9142.36
(1.77 to 3.15)
(1.80 to 2.50)

12.4 Microbiology

Mechanism of Action

Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.


Azithromycin demonstrates cross resistance with erythromycin. The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides, and streptogramin B (MLSB phenotype).

Antimicrobial Activity

Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)]

Gram-Positive Bacteria

Staphylococcus aureus
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-Negative Bacteria

Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae

Other Bacteria

Chlamydophila pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Beta-hemolytic streptococci (Groups C, F, G)
Viridans group streptococci

Gram-Negative Bacteria

Bordetella pertussis
Legionella pneumophila

Anaerobic Bacteria

Prevotella bivia
Peptostreptococcus species

Other Bacteria

Ureaplasma urealyticum

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:

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