Sandoz Inc

Azithromycin

Generic

ID: 00781809131

NaN

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Tablet

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600 mg

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TL;DR — Quick Summary

Key facts from the full medication guide below

RECENT MAJOR CHANGES SECTION 1 INDICATIONS AND USAGE 1.1 Sexually Transmitted Diseases 1.2 Mycobacterial Infections 1.3 Usage

🩺What it's for

Azithromycin tablets are 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.

💊How to take it

[See Indications and Usage (1)]. Sexually Transmitted Diseases (2.1) Mycobacterial Infections (2.2)

ℹ️Common side effects

The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Infantile Hypertrophic Pyloric Stenosis (IHPS) [see Warnings and Precautions (5.3)] QT Prolongation [see Warnings and Precautions (5.4)] Cardiovascular Death [see Warnings and Precautions (5.5)] Clostridiodes difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.6)] Exacerbation of…

⚠️Serious risks

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) Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs.

📋Interactions & cautions

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.

📦Storage & missed dose

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 0781-8091-31 in bottles of 30 tablets Store at controlled room temperature 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Dispense in a tight container.

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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 ( 14.2 )]. 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. Single 1 gram Dose Regimen Overall, the most common adverse reactions 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. Adverse reactions that occurred in patients on the single 1 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%).

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 (<500 cells/mm3). Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium avium disease in severely immunocompromised HIV-infected patients [see Clinical Studies (14)]. Chronic therapy (median duration: 87.5 days, range: 1 to 229 days) that resulted in laboratory abnormalities in >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.

Risk Summary Available data from published literature and postmarketing experience over several decades with azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at doses up to 3, 2, and 1 times, respectively, an adult human daily dose of 600 mg based on body surface area. Decreased viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day 6 of pregnancy through weaning at a dose equivalent to 3 times an adult human daily dose of 600 mg based on body surface area (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in pregnant women. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications. Animal Data Azithromycin administered during the period of organogenesis did not cause fetal malformations in rats and mice at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface area, this dose is approximately 3 (rats) and 2 (mice) times an adult human daily dose of 600 mg. In rabbits administered azithromycin at oral doses of 10, 20, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food consumption were observed in all groups; no evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is approximately equal to an adult human daily dose of 600 mg based on body surface area. In a pre-and postnatal development study, azithromycin was administered orally to pregnant rats from day 6 of pregnancy until weaning at doses of 50 or 200 mg/kg/day. Maternal toxicity (reduced food consumption and body weight gain; increased stress at parturition) was observed at the higher dose. Effects in the offspring were noted at 200 mg/kg/day during the postnatal development period (decreased viability, delayed developmental landmarks). These effects were not observed in a pre-and postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day 15 of pregnancy until weaning.

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 (mcg hr/mL) T (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6* 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 6.8 40 %CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4* %CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8* 84.5 %CV (18%) (52%) (26%) (25%) 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763* 82.8 %CV (49%) (28%) (33%) (42%) *AUC0-24 0-last With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady state. In asymptomatic HIV-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. 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 hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration 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 Patients with Renal Impairment Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 250 mg capsules), the mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively, in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). Patients with Hepatic Impairment The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Male and Female Patients There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended 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 Interaction Studies Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2. Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2 [see Drug Interactions (7.3)]. Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Co-Administered 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 BID x 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

[See Indications and Usage (1)]. Prevention of Disseminated MAC Disease Two randomized, double-blind clinical trials were performed in patients with CD4 counts <100 cells/mcL. The first trial (Study 155) compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcgL. The second trial (Study 174) randomized 723 patients to either azithromycin (1200 mg once weekly), rifabutin (300 mg daily), or the combination of both. The mean CD4 count was 51 cells/mcgL. The primary endpoint in these trials was disseminated MAC disease. Other endpoints included the incidence of clinically significant MAC disease and discontinuations from therapy for drug-related side effects. MAC Bacteremia In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are in the following table: Cumulative Incidence Rate, %: Placebo (n=89) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 69.7 13.5 6.7 10.1 12 47.2 19.1 15.7 18.0 18 37.1 22.5 18.0 22.5 Cumulative Incidence Rate, %: Azithromycin (n=85) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 84.7 3.5 9.4 2.4 12 63.5 8.2 16.5 11.8 18 44.7 11.8 25.9 17.6 The difference in the one-year cumulative incidence rates of disseminated MAC disease (placebo azithromycin) is 10.9%. This difference is statistically significant (p=0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference. In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table: Cumulative Incidence Rate, %: Rifabutin (n=223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 83.4 7.2 8.1 1.3 12 60.1 15.2 16.1 8.5 18 40.8 21.5 24.2 13.5 Cumulative Incidence Rate, %: Azithromycin (n=223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 85.2 3.6 5.8 5.4 12 65.5 7.6 16.1 10.8 18 45.3 12.1 23.8 18.8 Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n=218) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 89.4 1.8 5.5 3.2 12 71.6 2.8 15.1 10.6 18 49.1 6.4 29.4 15.1 Comparing the cumulative one-year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin azithromycin) in the one-year rates (7.6%) is statistically significant (p=0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin azithromycin/rifabutin) in the cumulative one-year incidence rates (12.5%) is statistically significant (p<0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference. In Study 174, sensitivity testing1 was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin, or the combination. The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical relevance of these in vitro MICs as an indicator of susceptibility or resistance is not known. Clinically Significant Disseminated MAC Disease In association with the decreased incidence of bacteremia, patients in the groups randomized to either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss, and anemia. Discontinuations From Therapy for Drug-Related Side Effects In Study 155, discontinuations for drug-related toxicity occurred in 8.2% of subjects treated with azithromycin and 2.3% of those given placebo (p=0.121). In Study 174, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p=0.026) or rifabutin alone (15.9%; p=0.209). Safety As these patients with advanced HIV disease were taking multiple concomitant medications and experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse reactions to study medication. Overall, the nature of adverse reactions seen on the weekly dosage regimen of azithromycin over a period of approximately one year in patients with advanced HIV disease were similar to that previously reported for shorter course therapies. INCIDENCE OF ONE OR MORE TREATMENT-RELATEDIncludes those reactions considered possibly or probably related to study drug ADVERSE REACTIONS>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 <8 g/dL 1/51 2% 4/170 2% 4/114 4% 8/107 8% Platelet Count <50 103/mm3 1/71 1% 4/260 2% 2/182 1% 6/181 3% WBC Count <1 103/mm3 0/8 0% 2/70 3% 2/47 4% 0/43 0% Neutrophils <500/mm3 0/26 0% 4/106 4% 3/82 4% 2/78 3% SGOT >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 <4 to >256 mcg/mL and clarithromycin MICs ranged from <1 to >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.