Azithromycin Tablets 600 mg
SPL UNCLASSIFIED SECTION
DESCRIPTION
CLINICAL PHARMACOLOGY SECTION
Pharmacokinetics
|
|
DOSE/DOSAGE FORM (serum, except as indicated)
| Subjects
| Day No.
| Cmax (mcg/mL)
| Tmax (hr)
| C24 (mcg/mL)
| AUC (mcg•hr/mL)
| T½ (hr)
| Urinary Excretion (% of dose)
|
| 500 mg/250 mg capsule | 12 | Day 1 | 0.41 | 2.5 | 0.05 | 2.6a | -- | 4.5 |
| and 250 mg on Days 2-5 | 12 | Day 5 | 0.24 | 3.2 | 0.05 | 2.1a | -- | 6.5 |
| 1200 mg/600 mg tablets | 12 | Day 1 | 0.66 | 2.5 | 0.074 | 6.8b | 40 | -- |
| %CV | (62%) | (79%) | (49%) | (64%) | (33%) |
| 600 mg tablet/day | 7 | 1 | 0.33 | 2 | 0.039 | 2.4a |
| %CV | (25%) | (50%) | (36%) | (19%) |
| 7 | 22 | 0.55 | 2.1 | 0.14 | 5.8a | 84.5 | -- |
| %CV | (18%) | (52%) | (26%) | (25%) | -- |
| 600 mg tablet/day (leukocytes) | 7 | 22 | 252 | 10.9 | 146 | 4763a | 82.8 | -- |
| %CV | (49%) | (28%) | (33%) | (42%) | -- | -- |
|
| TISSUE OR FLUID | TIME AFTER DOSE (h) | TISSUE OR FLUID CONCENTRATION (mcg/g or mcg/mL)1 | CORRESPONDING PLASMA OR SERUM LEVEL (mcg/mL) | TISSUE (FLUID) PLASMA (SERUM) RATIO
|
| SKIN | 72-96 | 0.4 | 0.012 | 35 |
| LUNG | 72-96 | 4 | 0.012 | > 100 |
| SPUTUM* | 2-4 | 1 | 0.64 | 2 |
| SPUTUM** | 10-12 | 2.9 | 0.1 | 30 |
| TONSIL*** | 9-18 | 4.5 | 0.03 | > 100 |
| TONSIL*** | 180 | 0.9 | 0.006 | > 100 |
| CERVIX**** | 19 | 2.8 | 0.04 | 70 |
Renal Insufficiency
Hepatic Insufficiency
Mechanism of Action
Microbiology
Susceptibility Testing of Bacteria Excluding Mycobacteria
|
| MIC (mcg/mL) | Interpretation |
| ≤ 2 | Susceptible (S) |
| 4 | Intermediate (I) |
| ≥ 8 | Resistant (R) |
|
| 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 |
|
| Zone Diameter (mm) | Interpretation |
| ≥ 18 | (S) Susceptible |
| 14-17 | (I) Intermediate |
| ≤ 13 | (R) Resistant |
|
| Microorganism | Zone Diameter (mm) |
| Staphylococcus aureus ATCC 25923 | 21-26 |
Drug Resistance
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
General
Information for Patients
Drug Interactions
ADVERSE REACTIONS
Clinical
Post-Marketing Experience
Laboratory Abnormalities
DOSAGE AND ADMINISTRATION (See INDICATIONS AND USAGE.)
Pediatric Use
HOW SUPPLIED
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)
Prevention of Disseminated MAC Disease
|
| 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 |
| 18 | 37.1 | 22.5 | 18 | 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 |
|
| 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 |
|
| 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) |
| 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 | 2.7 |
| Central Nervous System |
| Dizziness | 0 | 1.1 | 3.9 | 1.7 | 0.4 |
| Headache | 0 | 0 | 3 | 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 | 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 | 16.5 | 28.1 |
| Vomiting | 1.1 | 6.7 | 9 | 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 | 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 |
|
| 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 x 103/mm3 | 1/71 | 1% | 4/260 | 2% | 2/182 | 1% | 6/181 | 3% |
| WBC Count | < 1 x 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 x ULNa | 1/41 | 2% | 8/158 | 5% | 3/121 | 3% | 6/114 | 5% |
| SGPT | > 5 x ULN | 0/49 | 0% | 8/166 | 5% | 3/130 | 2% | 5/117 | 4% |
| Alk Phos | > 5 x ULN | 1/80 | 1% | 4/247 | 2% | 2/172 | 1% | 3/164 | 2% |
Treatment of Disseminated MAC Disease
|
| Azithromycin 600 mg qd | Clarithromycin 500 mg bid | **95.1% CI on difference |
| 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] |
|
| Azithromycin 600 mg (N = 68) | Clarithromycin 500 mg bid (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
ANIMAL TOXICOLOGY
- National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December 1993.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests-Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.
- Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium chemoprophylaxis. American J Medicine 1997; 102(5C):37-49.
- 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.
- 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.
SPL UNCLASSIFIED SECTION
Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, Oklahoma 74146
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