azithromycin (Azithromycin) tablet, film coated
[TEVA PHARMACEUTICALS USA]
To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets and other antibacterial drugs, azithromycin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Azithromycin tablets 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-Lribo-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. 749.00
Azithromycin, asthe monohydrate, is a white to off-white crystalline powder with a molecular formula of C38H72N2O12•H2O and a molecular weight of 767.02.
Azithromycin tablets 250 mg and 500 mg are supplied for oral administration as mottled pink, unscored, film-coated, modified-oval-shaped tablets containing azithromycin monohydrate equivalent to 250 mg or 500 mg azithromycin and the following inactive ingredients: butylated hydroxytoluene, calcium phosphate dibasic anhydrous, carmine, colloidal silicone dioxide, FD&C red # 40 lake, FD&C yellow # 6 lake, hypromellose (2910, 15cP), lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulfate, talc, titanium dioxide and triacetin.
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•h/mL;Cmax = 0.5 (0.2) mcg/mL; Tmax = 2.2 (0.9) hours.
With a regimen of 500 mg (two 250 mg capsules*1) on day 1,followed by 250 mg daily (one 250 mg capsule) on days 2 through 5, the pharmacokinetic parameters of azithromycin in plasma in healthy young adults (18 to 40 years of age) are portrayed in the chart below. Cmin and Cmax remained essentially unchanged from day 2 through day 5 of therapy.
|Pharmacokinetic Parameters (Mean)||Total n = 12|
|Day 1||Day 5|
|Urinary Excret. (% dose)||4.5||6.5|
In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 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 through 5) or 3 days (500 mg per day for days 1 through 3). Due to limited serum samples on day 2 (3 day regimen) and days 2 through 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 Regimen||5 Day Regimen|
|Pharmacokinetic Parameter||Day 1||Day 3||Day 1||Day 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)*2||14.9 (3.1)*2|
|Serum T½||71.8 hr||68.9 hr|
Median azithromycin exposure (AUC0-288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following either the 5 day or 3 day regimen was more than a 1000 fold and 800 fold greater than in serum, respectively. Administration of the same total dose with either the 5 day or 3 day regimen may be expected to provide comparable concentrations of azithromycin within MN and PMN leukocytes.
Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.
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 mgtablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.
The AUC of azithromycin was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.
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.
Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Greater azithromycin concentrations in tissues than in plasma or serum were observed. 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.
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 (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||0.012||> 100|
|SPUTUM*4||2 to 4||1.0||0.64||2|
|SPUTUM**5||10 to 12||2.9||0.1||30|
|TONSIL***6||9 to 18||4.5||0.03||> 100|
The extensive tissue distribution was confirmed by examination ofadditional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies ofazithromycin treatment of infections in these additional body sites, the clinical importance of these tissue concentration data is unknown.
Following a regimen of 500 mg on the first day and 250mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of non-inflamed meninges.
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Plasma concentrations of azithromycin following single 500mg 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.
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.
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.)
The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.
There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.
When studied in healthy elderly subjects aged 65 to 85 years, the pharmacokinetic parameters of azithromycin 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.
Drug interaction studies were performed with 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 effect 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.)
|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 x 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 x 2 days, then 200 mg BID x 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 x 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 x 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 x 7 days||600 mg PO on day 7||14||1.04*9||0.95*9|
|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 x 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 x 3 days||12||1.27 (0.89 to 1.81)||1.26 (1.01 to 1.56)|
|Nelfinavir||750 mg TID x 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 x 10 days||500 mg PO on day 1, then 250 mg/day on days 2 to 10||6||See footnote below||NA8|
|Sildenafil||100 mg on days 1 and 4||500 mg/day PO x 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 x 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*9||1.02*9|
|Trimethoprim/ Sulfamethoxazole||160 mg/800 mg/day PO x 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 x 21 days||600 mg/day PO x 14 days||5||1.12 (0.42 to 3.02)||0.94 (0.52 to 1.70)|
|Zidovudine||500 mg/day PO x 21 days||1,200 mg/day PO x 14 days||4||1.31 (0.43 to 3.97)||1.30 (0.69 to 2.43)|
Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when coadministered with azithromycin and 71 ng/mL when coadministered with placebo.
|Coadministered Drug||Dose of Coadministered Drug||Dose of Azithromycin||n||Ration (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00|
|Mean Cmax||Mean AUC|
|Efavirenz||400 mg/day x 7 days||600 mg PO on day 7||14||1.22 (1.04 to 1.42)||0.92*11|
|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 x 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 x 10 days||500 mg PO on day 1, then 250 mg/day on days 2 to 10||6||See footnote below||NA10|
Mean azithromycin concentrations one day after the last dose was 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
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.
NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.
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 trials.
Streptococci (Groups C, F, G)
Viridans group streptococci
When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician asperiodic 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.
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.
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.
|Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion (zone diameters in mm)|
|Haemophilus spp.||< 4||--||--||≥ 12||--||--|
|Staphylococcus aureus||< 2||4||> 8||≥ 18||14 to 17||<13|
|Streptococci including S. pneuomoniaeb13||< 0.5||1||> 2||≥ 18||14 to 17||< 13|
No interpretive criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested.
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.
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.
|QC Strain||Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion (zone diameters in mm)|
|Haemophilus influenzae ATCC 49247||1.0 to 4.0||13 to 21|
|Staphylococcus aureus ATCC 29213||0.5 to 2.0|
|Staphylococcus aureus ATCC 25923||21 to 26|
|Streptococcus pneumoniae ATCC 49619||0.06 to 0.25||19 to 25|
To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets and other antibacterial drugs, azithromycin tablets 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.
Azithromycin tablets are 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. As recommended dosages, durations of therapy and applicable patient populations vary among these infections, please see DOSAGE AND ADMINISTRATION for specific dosing recommendations.
Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy.
NOTE: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:
patients with cystic fibrosis,
patients with nosocomially acquired infections,
patients with known or suspected bacteremia,
patients requiring hospitalization,
elderly or debilitated patients, or
patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).
Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.
NOTE: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. Azithromycin is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to azithromycin, susceptibility tests should be performed when patients are treated with azithromycin. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.
Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage.
Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.
Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.
Azithromycin, at the recommended dose, should not be relied upon to treat 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 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 azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.
Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide antibiotic.
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.
In the treatment of pneumonia, azithromycin has only been shown to be safe and effective in the treatment of community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or debilitated patients, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).
Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
Prescribing azithromycin tablets 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.
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, Special Populations, Renal insufficiency.)
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsade 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.
Patients should be counseled that antibacterial drugs including azithromycin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When azithromycin tablets are prescribed to treat a 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 azithromycin tablets or other antibacterial drugs in the future.
Azithromycin tablets can be taken with or without food.
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.
Coadministration 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 side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)
Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.
Drug interaction studies were performed with azithromycin and other drugs likely to be coadministered. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions.) When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Coadministration with efavirenz, or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is coadministered with any of the above agents.
Interactions with the drugs listed below 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 concentrations
Ergotamine or dihydroergotamine-acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia
Terfenadine, cyclosporine, hexobarbital and phenytoin concentrations
There are no reported laboratory test interactions.
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. No evidence of impaired fertility due to azithromycin was found.
Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (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. In the animal studies, no evidence of 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.
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.
(See DOSAGE AND ADMINISTRATION.)
Acute Otitis Media (total dosage regimen: 30 mg/kg, see DOSAGE AND ADMINISTRATION): Safety and effectiveness in the treatment of children with otitis media under 6 months of age have not been established.
Acute Bacterial Sinusitis (dosage regimen: 10 mg/kg on Days 1 to 3): Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established. Use of azithromycin for the treatment of acute bacterial sinusitis in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adults and pediatric patients, and studies of acute otitis media in pediatric patients.
Community-Acquired Pneumonia (dosage regimen: 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 through 5): Safety and effectiveness in the treatment of children with community-acquired pneumonia under 6 months of age have not been established. Safety and effectiveness for pneumonia due to Chlamydia pneumoniae and Mycoplasma pneumoniae were documented in pediatric clinical trials. Safety and effectiveness for pneumonia due to Haemophilus influenzae and Streptococcus pneumoniae were not documented bacteriologically in the pediatric clinical trial due to difficulty in obtaining specimens. Use of azithromycin for these two microorganisms is supported, however, by evidence from adequate and well-controlled studies in adults.
Pharyngitis/Tonsillitis (dosage regimen: 12 mg/kg on Days 1 through 5): Safety and effectiveness in the treatment of children with pharyngitis/tonsillitis under 2 years of age have not been established.
Studies evaluating the use of repeated courses of therapy have not been conducted. (See CLINICAL PHARMACOLOGY and ANIMAL TOXICOLOGY.)
Pharmacokinetic parameters 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. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen. (See CLINICAL PHARMACOLOGY.)
In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Azithromycin tablets, 250 mg contain 0.9 mg of sodium per tablet.
Azithromycin tablets, 500 mg contain 0.11 mg of sodium per tablet.
In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious side effects of angioedema and cholestatic jaundice were reported rarely. Approximately 0.7% of the patients (adults and children) from the 5 day multiple-dose clinical trials discontinued azithromycin therapy because of treatment-related side effects. In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was 0.6%. In clinical trials in children given 30 mg/kg, either as a single dose or over 3 days, discontinuation from the trials due to treatment-related side effects was approximately 1%. (See DOSAGE AND ADMINISTRATION.) Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain.
Overall, the most common treatment-related side effects in adult patients receiving multiple-dose regimens of azithromycin were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%) and abdominal pain (2 to 3%) being the most frequently reported.
No other treatment-related side effects occurred in patients on the multiple-dose regimens of azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:
Cardiovascular: Palpitations, chest pain.
Gastrointestinal: Dyspepsia, flatulence, vomiting, melena and cholestatic jaundice.
Genitourinary: Monilia, vaginitis and nephritis.
Nervous System: Dizziness, headache, vertigo and somnolence.
Allergic: Rash, pruritus, photosensitivity and angioedema.
Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen.
Side effects that occurred in patients on the single one-gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%) and vaginitis (1%).
Overall, the most common side effects in patients receiving a single 2 gram dose of azithromycin were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%) and dizziness (1%). The majority of these complaints were mild in nature.
The types of side effects in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients.
For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (≥ 1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea, and rash. (See DOSAGE AND ADMINISTRATION.)
The incidence, based on dosing regimen, is described in the table below:
|Dosage Regimen||Diarrhea, %||Abdominal Pain, %||Vomiting, %||Nausea, %||Rash, %|
For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 through 5, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea and rash.
The incidence is described in the table below:
|Dosage Regimen||Diarrhea, Loose stools, %||Abdominal Pain, %||Vomiting, %||Nausea, %||Rash, %|
For the recommended dosage regimen of 12 mg/kg on Days 1 through 5, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache.
The incidence is described in the table below:
|Dosage Regimen||Diarrhea, %||Abdominal Pain, %||Vomiting, %||Nausea, %||Rash, %||Headache, %|
With any of the treatment regimens, no other treatment-related side effects occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:
Cardiovascular: Chest pain.
Gastrointestinal: Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis.
Hematologic and Lymphatic: Anemia and leukopenia.
Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness and insomnia.
General: Fever, face edema, fatigue, fungal infection, malaise and pain.
Allergic: Rash and allergic reaction.
Respiratory: Cough increased, pharyngitis, pleural effusion and rhinitis.
Skin and Appendages: Eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash.
Special Senses: Conjunctivitis.
Adverse events reported with azithromycin during the postmarketing 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 and vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration.
General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).
Genitourinary: Interstitial nephritis and acute renal failure and vaginitis.
Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death.
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 rare reports of taste perversion.
Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes and blood glucose; elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT), BUN, creatinine, blood glucose, platelet count, eosinophils; with an incidence of less than 1%: leukopenia, neutropenia, decreased platelet count; elevated serum alkaline phosphatase, bilirubin, LDH and phosphate. The majority of subjects with elevated serum creatinine also had abnormal values at baseline.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 5000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality.
(See INDICATIONS AND USAGE and CLlNlCAL PHARMACOLOGY.)
For pediatric patients, please refer to the INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections for the prescribing information for azithromycin for oral suspension.
|Infection*14||Recommended Dose/Duration of Therapy|
|Community-acquired pneumonia (mild severity) Pharyngitis/tonsillitis (second line therapy) Skin/skin structure (uncomplicated)||500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.|
|Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate)||500 mg QD times 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.|
|Acute bacterial sinusitis||500 mg QD times 3 days|
|Genital ulcer disease (chancroid)||One single 1 gram dose|
|Non-gonoccocal urethritis and cervicitis||One single 1 gram dose|
|Gonococcal urethritis and cervicitis||One single 2 gram dose|
Azithromycin tablets can be taken with or without food.
No dosage adjustment is recommended for subjects with renal impairment (GFR ≤ 80 mL/min). The mean AUC0-120 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.)
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.)
Azithromycin tablets, 250 mg are supplied as mottled pink, unscored, film-coated, modified-oval-shaped tablets, debossed with “93” on one side and “7146” on the other, containing azithromycin monohydrate equivalent to 250 mg of azithromycin. They are available in bottles of 30 and boxes of 1 card x 6 tablets.
Azithromycin tablets, 500 mg are supplied as mottled pink, unscored, film-coated, modified-oval-shaped tablets, debossed with “93” on one side and “7169” on the other, containing azithromycin monohydrate equivalent to 500 mg of azithromycin. They are available in bottles of 30 and boxes of 1 card x 3 tablets.
Store at 20º to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
(See INDICATIONS AND USAGE.)
In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for 3days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Day 21 to 24. For the 304 patients analyzed in the modified intent to treat analysis at the Day 21 to 24 visit, the clinical cure rate for 3 days of azithromycin was 85% (125/147) compared to 82% (129/157) for 10 days of clarithromycin.
The following outcomes were the clinical cure rates at the Day 21 to 24 visit for the bacteriologically evaluable patients by pathogen:
|Pathogen||Azithromycin (3 days)||Clarithromycin (10 days)|
|S. pneumoniae||29/32 (91%)||21/27 (78%)|
|H. influenzae||12/14 (86%)||14/16 (88 %)|
|M. catarrhalis||11/12 (92%)||12/15 (80%)|
In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, were comparable between treatment arms (25% with azithromycin and 29% with clarithromycin). The most common side effects were diarrhea, nausea and abdominal pain with comparable incidence rates for each symptom of 5 to 9% between the two treatment arms. (See ADVERSE REACTIONS.)
In a randomized, double-blind, double-dummy controlled clinical trial of acute bacterial sinusitis, azithromycin (500 mg once daily for 3 days) was compared with amoxicillin/clavulanate (500/125 mg tid for 10 days). Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. For the 594 patients analyzed in the modified intent to treat analysis at the Day 10 visit, the clinical cure rate for 3 days of azithromycin was 88% (268/303) compared to 85% (248/291) for 10 days of amoxicillin/clavulanate. For the 586 patients analyzed in the modified intent to treat analysis at the Day 28 visit, the clinical cure rate for 3 days of azithromycin was 71.5% (213/298) compared to 71.5% (206/288), with a 97.5% confidence interval of -8.4 to 8.3, for 10 days of amoxicillin/clavulanate.
In the safety analysis of this study, the overall incidence of treatment-related adverse events, primarily gastrointestinal, was lower in the azithromycin treatment arm (31%) than in the amoxicillin/clavulanate arm (51%). The most common side effects were diarrhea (17% in the azithromycin arm vs. 32% in the amoxicillin/clavulanate arm), and nausea (7% in the azithromycin arm vs. 12% in the amoxicillin/clavulanate arm). (See ADVERSE REACTIONS).
In an open label, noncomparative study requiring baseline transantral sinus punctures the following outcomes were the clinical success rates at the Day 7 and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for 3 days with the following pathogens:
|Pathogen||Azithromycin (500 mg per day for 3 Days)|
|Day 7||Day 28|
|S. pneumoniae||23/26 (88%)||21/25 (84%)|
|H.influenzae||28/32 (87%)||24/32 (75%)|
|M. catarrhalis||14/15 (93%)||13/15 (87%)|
The overall incidence of treatment-related adverse events in the noncomparative study was 21% in modified intent to treat patients treated with azithromycin at 500 mg once daily for 3 days with the most common side effects being diarrhea (9%), abdominal pain (4%) and nausea (3%). (See ADVERSE REACTIONS.)
Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs treated with azithromycin at doses which, expressed on the basis of mg/m2, are approximately equal to the recommended adult human dose, and in rats treated at doses approximately one-sixth of the recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs given daily doses of azithromycin ranging from 10 days to 30 days. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (30 mg/kg dose) at observed Cmax value of 1.3 mcg/mL (sixtimes greater than the observed Cmax of 0.216 mcg/mL at the pediatric dose of 10 mg/kg). Similarly, it has been shown in the dog (10 mg/kg dose) at observed Cmax value of 1.5 mcg/mL (seven times greater than the observed same Cmax and drug dose in the studied pediatric population). On a mg/m2 basis, 30 mg/kg dose in the neonatal rat (135 mg/m2) and 10 mg/kg dose in the neonatal dog (79 mg/m2) are approximately 0.5 and 0.3 times, respectively, the recommended dose in the pediatric patients with an average body weight of 25 kg. Phospholipidosis similar to that seen in the adult animals, is reversible after cessation of azithromycin treatment. The significance of these findings for animals and for humans is unknown.
Manufactured In Israel By:
TEVA PHARMACEUTICAL IND. LTD.
Jerusalem, 91010, Israel
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. C 11/2005
Data are from FDA and U.S. National Library of Medicine.