Generic Name: azithromycin
Dosage Form: tablets and oral suspension
Zithromax®
(azithromycin tablets)
and
(azithromycin for oral suspension)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zithromax® (azithromycin) and other antibacterial drugs, Zithromax (azithromycin) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Zithromax Description
Zithromax (azithromycin tablets and azithromycin for oral suspension) contain the active ingredient azithromycin, an azalide, a subclass of macrolide antibiotics, for oral administration. 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. Its molecular formula is C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula:
Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12•2H2O and a molecular weight of 785.0.
Zithromax tablets contain azithromycin dihydrate equivalent to 600 mg azithromycin. The tablets are supplied as white, modified oval-shaped, film-coated tablets. They also contain the following inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate and an aqueous film coat consisting of hypromellose, titanium dioxide, lactose and triacetin.
Zithromax for oral suspension is supplied in a single dose packet containing azithromycin dihydrate equivalent to 1 g azithromycin. It also contains the following inactive ingredients: colloidal silicon dioxide, sodium phosphate tribasic, anhydrous; spray dried artificial banana flavor, spray dried artificial cherry flavor, and sucrose.
Zithromax - Clinical Pharmacology
Pharmacokinetics
Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body. Rapid distribution of azithromycin into tissues and high concentration within cells result in significantly higher azithromycin concentrations in tissues than in plasma or serum. The 1 g single dose packet is bioequivalent to four 250 mg azithromycin capsules.
The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-seropositive adults (age 18–40 years old) are portrayed in the following chart:
DOSE/DOSAGE FORM (serum, except as indicated) | Subjects | Day No. | Cmax (µg/mL) | Tmax (hr) | C24 (µg/mL) | AUC (µg∙hr/mL) | T½ (hr) | Urinary Excretion (% of dose) |
|---|---|---|---|---|---|---|---|---|
| ||||||||
| 500 mg/250 mg capsule | 12 | Day 1 | 0.41 | 2.5 | 0.05 | 2.6* | – | 4.5 |
| and 250 mg on Days 2–5 | 12 | Day 5 | 0.24 | 3.2 | 0.05 | 2.1* | – | 6.5 |
| 1200 mg/600 mg tablets | 12 | Day 1 | 0.66 | 2.5 | 0.074 | 6.8† | 40 | – |
| %CV | (62%) | (79%) | (49%) | (64%) | (33%) | |||
| 600 mg tablet/day | 7 | 1 | 0.33 | 2.0 | 0.039 | 2.4* | ||
| %CV | 25% | (50%) | (36%) | (19%) | ||||
| 7 | 22 | 0.55 | 2.1 | 0.14 | 5.8* | 84.5 | - | |
| %CV | (18%) | (52%) | (26%) | (25%) | - | |||
| 600 mg tablet/day (leukocytes) | 7 | 22 | 252 | 10.9 | 146 | 4763* | 82.8 | - |
| %CV | (49%) | (28%) | (33%) | (42%) | - | - | ||
In these studies (500 mg Day 1, 250 mg Days 2–5), there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin following single 500 mg oral and I.V. doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2–5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady-state.
In asymptomatic HIV-seropositive adult subjects receiving 600-mg Zithromax tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing.
When azithromycin capsules were administered with food, the rate of absorption (Cmax) of azithromycin was reduced by 52% and the extent of absorption (AUC) by 43%.
When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% and the AUC by 14%.
The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%).
The AUC of azithromycin in 250 mg capsules was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with Zithromax (azithromycin); however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.
When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin (500 mg Day 1, 250 mg Days 2–5) in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.
The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table:
| TISSUE OR FLUID | TIME AFTER DOSE (h) | TISSUE OR FLUID CONCENTRATION (µg/g or µg/mL)* | CORRESPONDING PLASMA OR SERUM LEVEL (µg/mL) | TISSUE (FLUID) PLASMA (SERUM) RATIO* |
|---|---|---|---|---|
| ||||
| SKIN | 72–96 | 0.4 | 0.012 | 35 |
| LUNG | 72–96 | 4.0 | 0.012 | >100 |
| SPUTUM† | 2–4 | 1.0 | 0.64 | 2 |
| SPUTUM‡ | 10–12 | 2.9 | 0.1 | 30 |
| TONSIL§ | 9–18 | 4.5 | 0.03 | >100 |
| TONSIL§ | 180 | 0.9 | 0.006 | >100 |
| CERVIX¶ | 19 | 2.8 | 0.04 | 70 |
The 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, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 µg/mL) in the presence of non-inflamed meninges.
Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 µg/mL. Concentrations remained above 32 µg/mL for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte to plasma Cmax ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%), respectively. The clinical relevance of these findings is unknown.
Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-seropositive adults, mean maximum concentration in peripheral leukocytes was 252 µg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 µg/mL (±33%). The mean leukocyte to serum Cmax ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown.
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. 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.
Renal Insufficiency
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), the mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively in subjects with 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 end-stage renal disease (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.
The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses adequate to reach therapeutic steady-state plasma levels is not known. (See PRECAUTIONS.)
Mechanism of Action
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.
Microbiology
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.
Aerobic Gram-Positive Microorganisms
- Staphylococcus aureus
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
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 Gram-Negative Microorganisms
- Haemophilus influenzae
- Moraxella catarrhalis
"Other" Microorganisms
- Chlamydia trachomatis
Beta-lactamase production should have no effect on azithromycin activity.
Azithromycin has been shown to be active in vitro and in the prevention and treatment of disease caused by the following microorganisms:
Mycobacteria
- Mycobacterium avium complex (MAC) consisting of:
- Mycobacterium avium
- Mycobacterium intracellulare.
The following in vitro data are available, but their clinical significance is unknown.
Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 µg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Aerobic Gram-Positive Microorganisms
- Streptococci (Groups C, F, G)
- Viridans group streptococci
Aerobic Gram-Negative Microorganisms
- Bordetella pertussis
- Campylobacter jejuni
- Haemophilus ducreyi
- Legionella pneumophila
Anaerobic Microorganisms
- Bacteroides bivius
- Clostridium perfringens
- Peptostreptococcus species
"Other" Microorganisms
- Borrelia burgdorferi
- Mycoplasma pneumoniae
- Treponema pallidum
- Ureaplasma urealyticum
The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a 10% CO2 atmosphere will result in lowering of media pH (7.2 to 6.6) within 18 hours and in an apparent reduction of the in vitro potency of azithromycin. Thus, the initial pH of the growth medium should be 7.2–7.4, and the CO2 content of the incubation atmosphere should be as low as practical.
Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water.
Dilution Techniques
Quantitative methods are used to determine minimal inhibitory concentrations that provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar or microdilution) or equivalent with azithromycin powder. The MIC values should be interpreted according to the following criteria:
| MIC (µg/mL) | Interpretation |
|---|---|
| ≤ 2 | Susceptible (S) |
| 4 | Intermediate (I) |
| ≥ 8 | Resistant (R) |
A report of "Susceptible" indicates that the pathogen is likely to respond to monotherapy with azithromycin. 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 also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable drug concentrations are unlikely to be inhibitory and that other therapy should be selected.
Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.)
Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard azithromycin powder should provide the following MIC values:
| Microorganism | MIC (µg/mL) |
|---|---|
| Escherichia coli ATCC 25922 | 2.0–8.0 |
| Enterococcus faecalis ATCC 29212 | 1.0–4.0 |
| Staphylococcus aureus ATCC 29213 | 0.25–1.0 |
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 that has been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses the 15-µg azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimal inhibitory concentration (MIC) for azithromycin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 µg azithromycin disk should be interpreted according to the following criteria:
| Zone Diameter (mm) | Interpretation |
|---|---|
| ≥ 18 | (S) Susceptible |
| 14–17 | (I) Intermediate |
| ≤ 13 | (R) Resistant |
Interpretation should be as stated above for results using dilution techniques.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 15-µg azithromycin disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | Zone Diameter (mm) |
|---|---|
| Staphylococcus aureus ATCC 25923 | 21–26 |
Azithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates. Azithromycin has also been shown to be active against phagocytized M. avium complex (MAC) organisms in mouse and human macrophage cell cultures as well as in the beige mouse infection model.
Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic acid-albumin dextrose-catalase (OADC), have been used to determine azithromycin MIC values for Mycobacterium avium complex strains. In general, azithromycin MIC values decreased 4 to 8 fold as the pH of Middlebrook 7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same pH. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. The relationship between azithromycin and clarithromycin MIC values has not been established. In general, azithromycin MIC values were observed to be 2 to 32 fold higher than clarithromycin independent of the susceptibility method employed.
The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. (See CLINICAL PHARMACOLOGY)
Drug Resistance
Complete cross-resistance between azithromycin and clarithromycin has been observed with Mycobacterium avium complex (MAC) isolates. In most isolates, a single point mutation at a position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance pattern.3,4 Mycobacterium avium complex (MAC) isolates exhibiting cross-resistance show an increase in azithromycin MICs to ≥128 µg/mL with clarithromycin MICs increasing to ≥32 µg/mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after M. avium complex strains produce the 23S rRNA mutation.
Susceptibility testing for Mycobacterium avium complex (MAC)
The disk diffusion techniques and dilution methods for susceptibility testing against Gram-positive and Gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimal inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin have not been established.
The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined.
Indications and Usage for Zithromax
Zithromax (azithromycin) is indicated for the treatment of patients with mild to moderate infections (pneumonia: see WARNINGS) caused by susceptible strains of the designated microorganisms in the specific conditions listed below.
Sexually Transmitted Diseases
Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis.
Zithromax, at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating gonorrhea or syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with Zithromax 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 Zithromax (azithromycin) and other antibacterial drugs, Zithromax (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.
Mycobacterial Infections
Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease
Zithromax, taken alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infection. (See DOSAGE AND ADMINISTRATION, CLINICAL STUDIES)
Treatment of Disseminated Mycobacterium avium complex (MAC) Disease
Zithromax, taken in combination with ethambutol, is indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection. (See DOSAGE AND ADMINISTRATION, CLINICAL STUDIES)
Contraindications
Zithromax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic. Zithromax 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 Zithromax, 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 CLINICAL PHARMACOLOGY - Renal Insufficiency).
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization.
Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
Prescribing Zithromax (azithromycin) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Information for Patients
Zithromax tablets may be taken with or without food. However, increased tolerability has been observed when tablets are taken with food.
Zithromax for oral suspension in single 1 g packets can be taken with or without food after constitution.
Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously.
The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.
Patients should be counseled that antibacterial drugs including Zithromax (azithromycin) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Zithromax (azithromycin) is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zithromax (azithromycin) or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Drug Interactions
Aluminum- and magnesium-containing antacids reduce the peak serum levels (rate) but not the AUC (extent) of azithromycin (500 mg) absorption.
Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin (500 mg) absorption.
A single oral dose of 1200 mg azithromycin (2 × 600 mg Zithromax tablets) did not alter the pharmacokinetics of a single 800 mg oral dose of fluconazole in healthy adult subjects.
Total exposure (AUC) and half-life of azithromycin following the single oral tablet dose of 1200 mg were unchanged and the reduction in Cmax was not significant (mean decrease of 18%) by coadministration with 800 mg fluconazole.
A single oral dose of 1200 mg azithromycin (2 × 600 mg Zithromax tablets) had no significant effect on the pharmacokinetics of indinavir (800 mg indinavir tid for 5 days) in healthy adult subjects.
Coadministration of a single oral dose of 1200 mg azithromycin (2 × 600 mg Zithromax tablets) with steady-state nelfinavir (750 mg tid) to healthy adult subjects produced a decrease of approximately 15% in mean AUC0–8 of nelfinavir and its M8 metabolite. Mean Cmax of nelfinavir and its M8 metabolite were not significantly affected. No dosage adjustment of nelfinavir is required when nelfinavir is coadministered with azithromycin.
Coadministration of nelfinavir (750 mg tid) at steady state with a single oral dose of 1200 mg azithromycin increased the mean AUC0–∞ of azithromycin by approximately a factor of 2-times (range of up to 4 times) of that when azithromycin was given alone. The mean Cmax of azithromycin was also increased by approximately a factor of 2-times (range of up to 5 times) of that when azithromycin was given alone. Dose adjustment of azithromycin is not recommended. However, when administered in conjunction with nelfinavir, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)
Following administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days to healthy adult subjects, coadministration of 1200 mg azithromycin (2 × 600 mg Zithromax tablets) on the 7th day had no significant effects on peak concentrations (Cmax), total exposure (AUC), and the urinary excretion of either trimethoprim or sulfamethoxazole.
Coadministration of trimethoprim/sulfamethoxazole DS for 7 days had no significant effect on the peak concentration (Cmax) and total exposure (AUC) of azithromycin following administration of the single 1200 mg tablet dose to healthy adult subjects.
Administration of a 600 mg single oral dose of azithromycin had no effect on the pharmacokinetics of efavirenz given at 400 mg doses for 7 days to healthy adult subjects.
Efavirenz, when administered at a dose of 400 mg for seven days produced a 22% increase in the Cmax of azithromycin administered as a 600 mg single oral dose, while the AUC of azithromycin was not affected.
Azithromycin (500 mg Day 1, 250 mg Days 2–5) did not affect the plasma levels or pharmacokinetics of theophylline administered as a single intravenous dose. The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses resulting in therapeutic steady-state levels of theophylline is not known. However, concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Therefore, until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving azithromycin and theophylline concomitantly.
Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.
Dose adjustments are not indicated when azithromycin and zidovudine are coadministered. When zidovudine (100 mg q3h ×5) was coadministered with daily azithromycin (600 mg, n=5 or 1200 mg, n=7), mean Cmax, AUC and Clr increased by 26% (CV 54%), 10% (CV 26%) and 38% (CV 114%), respectively. The mean AUC of phosphorylated zidovudine increased by 75% (CV 95%), while zidovudine glucuronide Cmax and AUC increased by less than 10%. In another study, addition of 1 gram azithromycin per week to a regimen of 10 mg/kg daily zidovudine resulted in 25% (CV 70%) and 13% (CV 37%) increases in zidovudine Cmax and AUC, respectively. Zidovudine glucuronide mean Cmax and AUC increased by 16% (CV 61%) and 8.0% (CV 32%), respectively.
Doses of 1200 mg/day azithromycin for 14 days in 6 subjects increased Cmax of concurrently administered didanosine (200 mg q.12h) by 44% (54% CV) and AUC by 14% (23% CV). However, none of these changes were significantly different from those produced in a parallel placebo control group of subjects.
Preliminary data suggest that coadministration of azithromycin and rifabutin did not markedly affect the mean serum concentrations of either drug. Administration of 250 mg azithromycin daily for 10 days (500 mg on the first day) produced mean concentrations of azithromycin 1 day after the last dose of 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 mg/mL when coadministered with placebo. Mean concentrations 5 days after the last dose were 23 ng/mL and 21 ng/mL in the two groups of subjects. Administration of 300 mg rifabutin for 10 days produced mean concentrations of rifabutin one half day after the last dose of 60 mg/ml when coadministered with daily 250 mg azithromycin and 71 ng/mL when coadministered with placebo. Mean concentrations 5 days after the last dose were 8.1 ng/mL and 9.2 ng/mL in the two groups of subjects.
The following drug interactions have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised:
Digoxin–elevated digoxin levels.
Ergotamine or dihydroergotamine–acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Triazolam–decrease the clearance of triazolam and thus may increase the pharmacologic effect of triazolam.
Drugs metabolized by the cytochrome P450 system–elevations of serum carbamazepine, cyclosporine, hexobarbital, and phenytoin levels.
Laboratory Test Interactions
There are no reported laboratory test interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay.
Pregnancy
Teratogenic Effects. Pregnancy Category B
Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose levels (i.e., 200 mg/kg/day). These doses, based on a mg/m2 basis, are estimated to be 4 and 2 times, respectively, the human daily dose of 500 mg.
With regard to the MAC treatment dose of 600 mg daily, on a mg/m2/day basis, the doses in rats and mice are approximately 3.3 and 1.7 times the human dose, respectively.
With regard to the MAC prophylaxis dose of 1200 mg weekly, on a mg/m2/day basis, the doses in rats and mice are approximately 2 and 1 times the human dose, respectively.
No evidence of impaired fertility or harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.
Pediatric Use
In controlled clinical studies, azithromycin has been administered to pediatric patients ranging in age from 6 months to 12 years. For information regarding the use of Zithromax (azithromycin for oral suspension) in the treatment of pediatric patients, please refer to the INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections of the prescribing information for Zithromax (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles.
Safety in HIV-Infected Pediatric Patients
Safety and efficacy of azithromycin for the prevention or treatment of MAC in HIV-infected children have not been established. Safety data are available for 72 children 5 months to 18 years of age (mean 7 years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 242 days (range 3–2004 days) at doses of <1 to 52 mg/kg/day (mean 12 mg/kg/day). Adverse events were similar to those observed in the adult population, most of which involved the gastrointestinal tract. Treatment related reversible hearing impairment in children was observed in 4 subjects (5.6%). Two (2.8%) children prematurely discontinued treatment due to side effects: one due to back pain and one due to abdominal pain, hot and cold flushes, dizziness, headache, and numbness. A third child discontinued due to a laboratory abnormality (eosinophilia). The protocols upon which these data are based specified a daily dose of 10–20 mg/kg/day (oral and/o
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