Azithromycin Dihydrate

Name: Azithromycin Dihydrate

Indications and Usage for Azithromycin Dihydrate

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.

Sexually Transmitted Diseases

Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis.

Mycobacterial Infections

Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease

Azithromycin, 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, 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)].

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 Dihydrate Dosage and Administration

[see Indications and Usage (1)]

Azithromycin for oral suspension (single dose 1 g packet) can be taken with or without food after constitution. However, increased tolerability has been observed when tablets are taken with food.

Azithromycin for oral suspension (single dose 1 g packet) is not for pediatric use. For pediatric suspension see the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles.

Directions for administration of azithromycin for oral suspension in the single dose packet (1 g): The entire contents of the packet should be mixed thoroughly with two ounces (approximately 60 mL) of water. Drink the entire contents immediately; add an additional two ounces of water, mix, and drink to ensure complete consumption of dosage. The single dose packet should not be used to administer doses other than 1000 mg of azithromycin.

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 gram (1000 mg) dose of azithromycin. This dose can be administered as one single dose packet (1 g).

Mycobacterial Infections

Prevention of Disseminated MAC Infections

The recommended dose of azithromycin for the prevention of disseminated Mycobacterium avium complex (MAC) disease is: 1200 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.

Contraindications

Hypersensitivity

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug.

Hepatic Dysfunction

Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

Azithromycin Dihydrate - Clinical Pharmacology

Mechanism of Action

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

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.

Pharmacokinetics

The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18–40 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)

(hr)
Urinary Excretion
(% of dose)
* AUC0–24; † 0–last.
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%) - -

With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2–5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady state.

In asymptomatic HIV-positive adult subjects receiving 600 mg azithromycin tablets 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

The 1 gram single-dose packet is bioequivalent to four 250 mg azithromycin capsule.

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 µg /mL to 7% at 2 µg/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 µg/mL. Concentration remained above 32 µg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma Cmax ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%) respectively. The clinical relevance of these findings is unknown.

Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 µg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 µg/mL (±33%). The mean leukocyte-to-serum Cmax ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown.

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 hr. 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 <10 mL/min) compared to subjects with normal renal function (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
* - 90% Confidence interval not reported
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 ×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)
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-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
* - 90% Confidence interval not reported
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)

Microbiology

Mechanism of Action

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

Resistance

The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides, and streptogramin B (MLSB phenotype). The mechanism of acquired mutational resistance in isolates of Mycobacterium avium complex (i.e., 23S rRNA genemutation) is the same for both clarithromycin and azithromycin.

Antimicrobial Activity

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

Mycobacteria

  Mycobacterium avium complex (MAC) consisting of:   Mycobacterium avium   Mycobacterium intracellulare

Other Microorganisms

  Chlamydia trachomatis

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Mycobacteria

Susceptibility testing of azithromycin is not recommended because of the technical difficulties associated with testing azithromycin (i.e., poor solubility at the high concentration of drug that must be tested). Clarithromycin is the most appropriate class drug for testing the macrolides 1.

Clinical Studies

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 <100 cells/µL. 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 testing2 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-RELATED* ADVERSE REACTIONS† IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR
Study 155 Study 174
Placebo Azithromycin 1200 mg weekly Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin + Rifabutin
(N=91) (N=89) (N=233) (N=236) (N=224)
* Includes those reactions considered possibly or probably related to study drug † >2% adverse reaction rates for any group (except uveitis)
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 & 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 VALUES*
Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin & Rifabutin
* excludes subjects outside of the relevant normal range at baseline † Upper Limit of Normal
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 × ULN† 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 *95.1% CI on difference
* [95% confidence interval] on difference in rates (azithromycin-clarithromycin) † Primary endpoint
Patients with positive culture at baseline 68 57
Week 24
  Two consecutive negative blood cultures† 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 µg/mL and clarithromycin MICs ranged from <1 to >32 µg/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 µg/mL and clarithromycin MICs >32 µg/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.

PRINCIPAL DISPLAY PANEL - One gram Packet Carton

GREENSTONE® BRAND

azithromycin
for oral suspension

one gram*
single dose packet

contains
ONE DOSE REGIMEN

Rx only

AZITHROMYCIN 
azithromycin tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-3080
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Azithromycin Dihydrate (AZITHROMYCIN ANHYDROUS) AZITHROMYCIN ANHYDROUS 600 mg
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS DIBASIC CALCIUM PHOSPHATE  
CROSCARMELLOSE SODIUM  
MAGNESIUM STEARATE  
SODIUM LAURYL SULFATE  
HYPROMELLOSE, UNSPECIFIED  
TITANIUM DIOXIDE  
LACTOSE, UNSPECIFIED FORM  
TRIACETIN  
Product Characteristics
Color WHITE Score no score
Shape OVAL (modified) Size 19mm
Flavor Imprint Code G;3080
Contains     
Packaging
# Item Code Package Description
1 NDC:59762-3080-1 30 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA050730 06/12/1996
AZITHROMYCIN 
azithromycin powder, for suspension
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-3051
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Azithromycin Dihydrate (AZITHROMYCIN ANHYDROUS) AZITHROMYCIN ANHYDROUS 1 g
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
SODIUM PHOSPHATE, TRIBASIC, ANHYDROUS  
SUCROSE  
Product Characteristics
Color      Score     
Shape Size
Flavor CHERRY, BANANA Imprint Code
Contains     
Packaging
# Item Code Package Description
1 NDC:59762-3051-2 3 PACKET in 1 BOX
1 1 POWDER, FOR SUSPENSION in 1 PACKET
2 NDC:59762-3051-1 10 PACKET in 1 BOX
2 1 POWDER, FOR SUSPENSION in 1 PACKET
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA050693 02/12/1999
Labeler - Greenstone LLC (825560733)
Registrant - Pfizer Inc (113480771)
Establishment
Name Address ID/FEI Operations
Pfizer Pharmaceuticals LLC 829084552 MANUFACTURE(59762-3051, 59762-3080), PACK(59762-3051, 59762-3080)
Establishment
Name Address ID/FEI Operations
Pfizer Ireland Pharmaceuticals 896090987 API MANUFACTURE(59762-3051, 59762-3080)
Establishment
Name Address ID/FEI Operations
Pfizer Pharmaceuticals LLC 829084545 MANUFACTURE(59762-3051, 59762-3080), PACK(59762-3051, 59762-3080)
Revised: 05/2017   Greenstone LLC
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