DOSAGE FORMS & STRENGTHS SECTION.
3 DOSAGE FORMS AND STRENGTHS Azithromycin Tablets, USP 600 mg (debossed GG D7 on one side and plain on the reverse side) are unscored white, oval-shaped, film-coated tablets. Azithromycin Tablets 600 mg
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
600 mg Label NDC 0781-1497-31 Azithromycin Tablets, USP 600 mg Rx only 30 Tablets SANDOZ
ADVERSE REACTIONS SECTION.
6 ADVERSE REACTIONS The most common adverse reactions are diarrhea (5%), nausea (3%), abdominal pain (3%), or vomiting, (no percent given) (6) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, most of the reported adverse reactions were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued azithromycin therapy because of treatment-related adverse reactions. Serious adverse reactions included angioedema and cholestatic jaundice. Most of the adverse reactions leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain [see Clinical Studies ( 14.1 )]. Multiple-dose regimen Overall, the most common adverse reactions in adult patients receiving a multiple-dose regimen of azithromycin were related to the gastrointestinal system with diarrhea/loose stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported. No other adverse reactions occurred in patients on the multiple-dose regimen of azithromycin with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following: Cardiovascular: Palpitations and chest pain. Gastrointestinal: Dyspepsia, flatulence, vomiting, melena, and cholestatic jaundice. Genitourinary: Monilia, vaginitis, and nephritis. Nervous System: Dizziness, headache, vertigo, and somnolence. General: Fatigue. Allergic: Rash, photosensitivity, and angioedema. Chronic therapy with 1200 mg weekly regimen The nature of adverse reactions seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens [see Clinical Studies (14)]. Chronic therapy with 600 mg daily regimen combined with ethambutol The nature of adverse reactions seen with the 600 mg daily dosing regimen for the treatment of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short term dosing regimens. Five percent of patients experienced reversible hearing impairment in the pivotal clinical trial for the treatment of disseminated MAC in patients with AIDS. Hearing impairment has been reported with macrolide antibiotics, especially at higher doses. Other treatment-related adverse reactions occurring in >5% of subjects and seen at any time during a median of 87.5 days of therapy include: abdominal pain (14%), nausea (14%), vomiting (13%), diarrhea (12%), flatulence (5%), headache (5%), and abnormal vision (5%). Discontinuations from treatment due to laboratory abnormalities or adverse reactions considered related to study drug occurred in 8 of 88 (9.1%) of subjects. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions 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 reports of QT prolongation and torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration. General: Asthenia, paresthesia, fatigue, malaise, and anaphylaxis Genitourinary: Interstitial nephritis, acute renal failure, and vaginitis. Hematopoietic: Thrombocytopenia. Liver/Biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure [see Warnings and Precautions (5.2)]. Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation, and syncope. Psychiatric: Aggressive reaction and anxiety. Skin/Appendages: Pruritus, and serious skin reactions including erythema multiforme, Stevens -Johnson syndrome, toxic epidermal necrolysis, and DRESS. Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, and reports of taste/smell perversion and/or loss. 6.3 Laboratory Abnormalities Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: With an incidence of 1 to 2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT). With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate. When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality. In a phase 1 drug interaction study performed in normal volunteers, 1 of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone, and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (5% of subjects with normal baseline values in the pivotal trial for treatment of disseminated MAC in severely immunocompromised HIV-infected patients treated with azithromycin 600 mg daily in combination with ethambutol include: a reduction in absolute neutrophils to <50% of the lower limit of normal (10/52, 19%) and an increase to five times the upper limit of normal in alkaline phosphatase (3/35, 9%). These findings in subjects with normal baseline values are similar when compared to all subjects for analyses of neutrophil reductions (22/75, 29%) and elevated alkaline phosphatase (16/80, 20%). Causality of these laboratory abnormalities due to the use of study drug has not been established.
CLINICAL PHARMACOLOGY SECTION.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azithromycin is a macrolide antibacterial drug [see Microbiology (12.4)]. 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 of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. 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 The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in the following chart: MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. Cmax (mcg/mL) Tmax (hr) C24 (mcg/mL) AUC (mcghr/mL) T (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6 AUC0-24 4.5 and 250 mg on Days 2-5 12 5 0.24 3.2 0.05 2.1 6.5 1200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.80-last 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%) With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving azithromycin tablets 600 mg once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. 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. Absorption 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%). Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. 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 tissues in humans, 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 importance of these tissue concentration data is unknown. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentrations remained above 32 mcg/mL for approximately 60 hours. The mean half-lives for 6 males and 6 females were 34 hours and 57 hours, 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-positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/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. Metabolism In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Elimination Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. 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 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 80 mL/min). Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Gender There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender. Geriatric Patients 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 Geriatric Use (8.5)]. Pediatric Patients For information regarding the pharmacokinetics of azithromycin for oral suspension in pediatric patients, see the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles. Drug-drug Interactions 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 Drug Dose of Co-Administered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect=1.00 Mean Cmax Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6-8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8-21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04* 0.95* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 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 orally on day 7, 250 mg/day on days 8-11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally twice a day for 15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06* 1.02* Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally 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 orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) * -90% Confidence interval not reported Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs [see Drug Interactions (7.3)]. Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without co-adminis- tered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect=1.00 Mean Cmax Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) * -90% Confidence interval not reported 12.4 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 [see Indications and Usage (1)]. 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 mcg/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 Susceptibility Testing of Bacteria Excluding Mycobacteria 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 to 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 antibacterial 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 (mcg/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 minimum bacterial concentration (MBC) and achieved antibacterial compound concentrations may be appropriate to guide therapy in some infections. [see Clinical Pharmacology (12)] section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antibacterial drug product.) Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard azithromycin powder should provide the following MIC values: Microorganism MIC (mcg/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 antibacterial compounds. One such standardized procedure2 that has been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses the 15 mcg azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the MIC for azithromycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mcg azithromycin disk should be interpreted according to the following criteria: Zone Diameter (mm) Interpretation 18 Susceptible (S) 14-17 Intermediate (I) 13 Resistant (R) 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 mcg 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 In Vitro Activity of Azithromycin Against Mycobacteria Azithromycin has demonstrated in vitro activity against MAC organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on MAC isolates. Azithromycin has also been shown to be active against phagocytized 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 MAC 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 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 (12)] Drug Resistance Complete cross-resistance between azithromycin and clarithromycin has been observed with 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 MAC isolates exhibiting cross-resistance show an increase in azithromycin MICs to 128 mcg/mL with clarithromycin MICs increasing to 32 mcg/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 MAC strains produce the 23S rRNA mutation. Susceptibility Testing for 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 MIC values against 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.
4 CONTRAINDICATIONS Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide antibiotic. (4.1) Patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. (4.2) 4.1 Hypersensitivity Azithromycin tablets are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug. 4.2 Hepatic Dysfunction Azithromycin tablets are contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
INDICATIONS & USAGE SECTION.
1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat 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 is a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Azithromycin is a macrolide antibacterial indicated for mild to moderate infections caused by designated, susceptible bacteria: Sexually Transmitted Diseases (1.1) Mycobacterial Infections (1.2) To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. 1.1 Sexually Transmitted Diseases Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis 1.2 Mycobacterial Infections Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease Azithromycin tablets, taken alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated MAC disease in persons with advanced HIV infection [see Dosage and Administration (2)]. Treatment of Disseminated MAC Disease Azithromycin tablets, taken in combination with ethambutol, is indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection [see Use in Specific Populations (8.4) and Clinical Studies (14.1)].
DOSAGE & ADMINISTRATION SECTION.
2 DOSAGE AND ADMINISTRATION [see Indications and Usage (1)] Sexually Transmitted Diseases (2.1) Mycobacterial Infections (2.2 ) 2.1 Sexually Transmitted Diseases The recommended dose of azithromycin for the treatment of non-gonococcal urethritis and cervicitis due to C. trachomatis is a single 1,000 mg dose of azithromycin. 2.2 Mycobacterial Infections Prevention of Disseminated MAC Infections The recommended dose of azithromycin for the prevention of disseminated Mycobacterium avium complex (MAC) disease is: 1,200 mg taken once weekly. This dose of azithromycin may be combined with the approved dosage regimen of rifabutin. Treatment of Disseminated MAC Infections Azithromycin should be taken at a daily dose of 600 mg, in combination with ethambutol at the recommended daily dose of 15 mg/kg. Other antimycobacterial drugs that have shown in vitro activity against MAC may be added to the regimen of azithromycin plus ethambutol at the discretion of the physician or health care provider.
HOW SUPPLIED SECTION.
16 HOW SUPPLIED/STORAGE AND HANDLING Azithromycin Tablets, USP, equivalent to 600 mg azithromycin, are unscored white, oval-shaped, film-coated tablets, debossed GG D7 on one side and plain on the reverse side, and are supplied as follows: NDC 0781-1497-31 in bottles of 30 tablets Store at controlled room temperature 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Dispense in a tight container.
11 DESCRIPTION Azithromycin tablets, USP contain the active ingredient azithromycin, a macrolide antibacterial drug, 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--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)--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 monohydrate, is a white crystalline powder with a molecular formula of C38H72N2O12H2O and a molecular weight of 767.02. Each azithromycin tablet, intended for oral administration, contains azithromycin monohydrate equivalent to 600 mg of azithromycin. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, pregelatinized starch, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide and xanthan gum.
10 OVERDOSAGE Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
WARNINGS AND PRECAUTIONS SECTION.
5 WARNINGS AND PRECAUTIONS Serious (including fatal) allergic and skin reactions. Discontinue azithromycin and initiate appropriate therapy if reaction occurs. (5.1) Hepatotoxicity: Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. (5.2) Prolongation of QT interval and cases of torsades de pointes have been reported. This risk which can be fatal should be considered in patients with certain cardiovascular disorders including known QT prolongation or history torsades de pointes, those with prorrhythmic conditions, and with other drugs that prolong the QT interval. (5.3) Clostridium difficile-associated diarrhea: Evaluate patients if diarrhea occurs. (5.4) Azithromycin exacerbates muscle weakness in persons with myasthenia gravis (5.5) 5.1 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. [see Contraindications (4.1)]. Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is presently unknown. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that allergic symptoms may reappear when symptomatic therapy is discontinued. 5.2 Hepatotoxicity Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. 5.3 QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure patients on drugs known to prolong the QT interval patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval. 5.4 Clostridium difficile-Associated Diarrhea (CDAD) CDAD has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following 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. 5.5 Exacerbation of Myasthenia Gravis Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azitrhromycin therapy. 5.6 Use in Sexually Transmitted Infections Azithromycin, at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antibacterial 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 antibacterial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. 5.7 Development of Drug-Resistant Bacteria Prescribing 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.
DRUG INTERACTIONS SECTION.
7 DRUG INTERACTIONS Nelfinavir: Close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (7.1) Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time. (7.2) 7.1 Nelfinavir Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see Adverse Reactions (6)]. 7.2 Warfarin Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. 7.3 Potential Drug-Drug Interaction with Macrolides Interactions with the following 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. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin or phenytoin are used with azithromycin careful monitoring of patients is advised.
NONCLINICAL TOXICOLOGY SECTION.
13 NONCLINICAL TOXICOLOGY 13.1 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. No evidence of impaired fertility due to azithromycin was found in rats given daily doses up to 10 mg/kg (approximately 0.2 times an adult daily dose of 600 mg based on body surface area). 13.2 Animal Toxicology 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/or pancreas) in dogs and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g.) Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg/mL (1.2 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg based on the surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg/mL, approximately 1.5 times the Cmax of 1.27 mcg/mL at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg/mL, approximately 3 times the pediatric dose Cmax. The significance of the finding for animals and for humans is unknown.
USE IN SPECIFIC POPULATIONS SECTION.
8 USE IN SPECIFIC POPULATIONS Pediatric Use: Safety and effectiveness in the treatment of patients under 6 months of age have not been established. (8.4) Geriatric Use: Elderly patients may be more susceptible to development of torsades de pointes arrhythmias (8.5) 8.1 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 daily doses in rats and mice, based on body surface area, are estimated to be 3.2 and 1.6 times, respectively, an adult daily dose of 600 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. 8.3 Nursing Mothers Azithromycin has been reported to be excreted in breast milk in small amounts. Caution should be exercised when azithromycin is administered to a nursing woman. 8.4 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 azithromycin for oral suspension in the treatment of pediatric patients, [see Indications and Usage (1) and Dosage and Administration (2)] of the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles. HIV-Infected Pediatric Patients: The 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 to 2004 days) at doses of 300 mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections, including MAC. The adverse reactions were generally similar to that seen in younger patients, except for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible impairment of hearing [see Dosage and Administration (2)].
RECENT MAJOR CHANGES SECTION.
Warnings and Precautions, Hypersensitivity (5.1) 02/2016
15 REFERENCES 1.Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. 2.Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. 3.Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium chemoprophylaxis. Am J Med 1997; 102(5C):37-49. 4.Meier A, Kirshner P, Springer B, et al. Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994; 38:381-384. 5.Methodology per Inderlied CB, et al. Determination of In Vitro Susceptibility of Mycobacterium avium Complex Isolates to Antimicrobial Agents by Various Methods. Antimicrob Agents Chemother. 1987; 31:1697-1702.
INFORMATION FOR PATIENTS SECTION.
17 PATIENT COUNSELING INFORMATION Azithromycin tablets may be taken with or without food. However, increased tolerability has been observed when tablets are taken with 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. Patients should be counseled that antibacterial drugs, including azithromycin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When 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 azithromycin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibacterials, 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 antibacterial. If this occurs, patients should contact their physician as soon as possible. 05-2016M 7315 Sandoz Inc. Princeton, NJ 08540
CLINICAL STUDIES SECTION.
14 CLINICAL STUDIES 14.1 Clinical Studies in Patients with Advanced HIV Infection for the Prevention and Treatment of Disease Due to Disseminated Mycobacterium Avium Complex (MAC) [see Indications and Usage (1)] Prevention of Disseminated MAC Disease Two randomized, double-blind clinical trials were performed in patients with CD4 counts 2% adverse reaction rates for any group (except uveitis) IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR Study 155 Study 174 Placebo (N=91) Azithromycin 1200 mg weekly (N=89) Azithromycin 1200 mg weekly (N=233) Rifabutin 300 mg daily (N=236) Azithromycin + Rifabutin (N=224) Mean Duration of Therapy (days) 303.8 402.9 315 296.1 344.4 Discontinuation of Therapy 2.3 8.2 13.5 15.9 22.7 Autonomic Nervous System Mouth Dry 0 0 0 3.0 2.7 Central Nervous System Dizziness 0 1.1 3.9 1.7 0.4 Headache 0 0 3.0 5.5 4.5 Gastrointestinal Diarrhea 15.4 52.8 50.2 19.1 50.9 Loose Stools 6.6 19.1 12.9 3.0 9.4 Abdominal Pain 6.6 27 32.2 12.3 31.7 Dyspepsia 1.1 9 4.7 1.7 1.8 Flatulence 4.4 9 10.7 5.1 5.8 Nausea 11 32.6 27.0 16.5 28.1 Vomiting 1.1 6.7 9.0 3.8 5.8 General Fever 1.1 0 2.1 4.2 4.9 Fatigue 0 2.2 3.9 2.1 3.1 Malaise 0 1.1 0.4 0 2.2 Musculoskeletal Arthralgia 0 0 3.0 4.2 7.1 Psychiatric Anorexia 1.1 0 2.1 2.1 3.1 Skin and Appendages Pruritus 3.3 0 3.9 3.4 7.6 Rash 3.2 3.4 8.1 9.4 11.1 Skin discoloration 0 0 0 2.1 2.2 Special Senses Tinnitus 4.4 3.4 0.9 1.3 0.9 Hearing Decreased 2.2 1.1 0.9 0.4 0 Uveitis 0 0 0.4 1.3 1.8 Taste Perversion 0 0 1.3 2.5 1.3 Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients. Changes in Laboratory Values In these immunocompromised patients with advanced HIV infection, it was necessary to assess laboratory abnormalities developing on trial with additional criteria if baseline values were outside the relevant normal range. PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUESexcludes subjects outside of the relevant normal range at baseline Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin & Rifabutin Hemoglobin 5 ULNUpper Limit of Normal 1/41 2% 8/158 5% 3/121 3% 6/114 5% SGPT >5 ULN 0/49 0% 8/166 5% 3/130 2% 5/117 4% Alk Phos >5 ULN 1/80 1% 4/247 2% 2/172 1% 3/164 2% Treatment of Disseminated MAC Disease One randomized, double-blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV-infected patients with disseminated MAC received either azithromycin 250 mg daily (N=65), azithromycin 600 mg daily (N=91), or clarithromycin 500 mg twice a day (N=90), each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to any open-label therapy at the discretion of the investigator and followed every 3 months through the last follow-up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during treatment or post-treatment were obtained whenever possible. The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC. The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day. Efficacy results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are described in the following table: RESPONSE TO THERAPY OF PATIENTS TAKING ETHAMBUTOL AND EITHER AZITHROMYCIN 600 MG DAILY OR CLARITHROMYCIN 500 MG TWICE A DAY Azithromycin 600 mg daily Clarithromycin 500 mg twice a day [95% confidence interval] on difference in rates (azithromycin-clarithromycin) 95.1% CI on difference Patients with positive culture at baseline 68 57 Week 24 Two consecutive negative blood culturesPrimary endpoint 31/68 (46%) 32/57 (56%) [-28, 7] Mortality 16/68 (24%) 15/57 (26%) [-18, 13] The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day group. Sterilization by Baseline Colony Count Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL increased. Azithromycin 600 mg (N=68) Clarithromycin 500 mg twice a day (N=57) groups stratified by MAC colony counts at baseline no. (%) subjects in stratified group sterile at week 24 no. (%) subjects in stratified group sterile at week 24 10 cfu/mL 10/15 (66.7%) 12/17 (70.6%) 11-100 cfu/mL 13/28 (46.4%) 13/19 (68.4%) 101-1,000 cfu/mL 7/19 (36.8%) 5/13 (38.5%) 1,001-10,000 cfu/mL 1/5 (20.0%) 1/5 (20%) >10,000 cfu/mL 0/1 (0.0%) 1/3 (33.3%) Susceptibility Pattern of MAC Isolates Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from 256 mcg/mL and clarithromycin MICs ranged from 32 mcg/mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32-fold higher than clarithromycin MIC values. During treatment and post-treatment follow-up for up to 3.7 years (median: 9 months) in Study 189, a total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp increase in MIC values. All twelve MAC isolates had azithromycin MICs 256 mcg/mL and clarithromycin MICs >32 mcg/mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide.