DESCRIPTION
SPL UNCLASSIFIED SECTION
DESCRIPTION
CLINICAL PHARMACOLOGY
Pharmacokinetics
| TISSUE OR FLUID | TIME AFTERDOSE (h) | TISSUE OR FLUIDCONCENTRATION(mcg/g or mcg/mL) | CORRESPONDINGPLASMA 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 |
| Pharmacokinetic Parameter[mean (SD)] | 3-Day Regimen(20 mg/kg x 3 days) | 5-Day Regimen
(12 mg/kg x 5 days) |
| n | 11 | 17 |
| Cmax (mcg/mL) | 1.1 (0.4) | 0.5 (0.4) |
| Tmax (hr) | 2.7 (1.9) | 2.2 (0.8) |
| Auc0-24 mcg•hr/mL | 7.9 (2.9) | 3.9 (1.9) |
Drug-Drug Interactions
|
Carbamazepine | 200 mg/day x 2 days, then 200 mg
BID x 18 days | 500 mg/day PO for days 16-18 | 7 | 0.97
(0.88 to 1.06) | 0.96
(0.88 to 1.06) |
| Cetirizine | 20 mg/day x 11 days | 500 mg PO on day 7, then 250 mg/day on days 8-11 | 14 | 1.03
(0.93 to 1.14) | 1.02
(0.92 to 1.13) |
| Didanosine
| 200 mg PO BID x 21 days | 1,200 mg/day PO on days 8-21 | 6 | 1.44
(0.85 to 2.43) | 1.14
(0.83 to 1.57) |
|
Efavirenz | 400 mg/day x 7 days | 600 mg PO on day 7 | 14 | 1.04* | 0.95* |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 1.04
(0.98 to 1.11) | 1.01
(0.97 to 1.05) |
| Indinavir | 800 mg TID x 5 days | 1,200 mg PO on day 5 | 18 | 0.96
(0.86 to 1.08) | 0.90
(0.81 to 1.00) |
| Midazolam | 15 mg PO on day 3 | 500 mg/day PO x 3 days | 12 | 1.27
(0.89 to 1.81) | 1.26
(1.01 to 1.56) |
| Nelfinavir | 750 mg TID x 11 days | 1,200 mg PO on day 9 | 14 | 0.90
(0.81 to 1.01) | 0.85
(0.78 to 0.93) |
| Rifabutin | 300 mg/day x 10 days | 500 mg PO on day 1, then 250 mg/day on days 2-10 | 6 | See footnote
below | NA |
| Sildenafil | 100 mg on days 1 and 4 | 500 mg/day PO x 3 days | 12 | 1.16
(0.86 to 1.57) | 0.92
(0.75 to 1.12) |
| Theophylline | 4 mg/kg IV on days 1, 11, 25 | 500 mg PO on day 7, 250 mg/day on days 8-11 | 10 | 1.19
(1.02 to 1.40) | 1.02
(0.86 to 1.22) |
| Theophylline | 300 mg PO BID x 15 days | 500 mg PO on day 6, then 250 mg/day on days 7-10 | 8 | 1.09
(0.92 to 1.29) | 1.08
(0.89 to 1.31) |
| Triazolam | 0.125 mg on day 2 | 500 mg PO on day 1, then 250 mg/day on day 2 | 12 | 1.06* | 1.02* |
| Trimethoprim/ Sulfamethoxazole | 160 mg/800mg/day PO x 7 days | 1,200 mg PO on day 7 | 12 | 0.85
(0.75 to 0.97)/ | 0.87
(0.80 to 0.95/
0.96
(0.88 to 1.03) |
| Zidovudine | 500 mg/day PO x 21 days | 600 mg/day PO x 14 days | 5 | 1.12(0.42 to 3.02) | 0.94
(0.52 to 1.70) |
| Zidovudine | 500 mg/day PO x 21 days | 1,200 mg/day PO x 14 days | 4 | 1.31
(0.43 to 3.97) | 1.30
(0.69 to 2.43) |
| Mean Cmax | Mean AUC |
| Efavirenz | 400 mg/day x 7 days | 600 mg PO on day 7 | 14 | 1.22
(1.04 to 1.42) | 0.92* |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 0.82
(0.66 to 1.02) | 1.07
(0.94 to1.22) |
| Nelfinavir | 750 mg TID x 11 days | 1,200 mg PO on day 9 | 14 | 2.36
(1.77 to 3.15) | 2.12
(1.80 to 2.50) |
| Rifabutin | 300 mg/day x 10 days | 500 mg PO on day 1, then 250 mg/day on days 2-10 | 6 | See footnote
below | NA |
Microbiology:
INDICATIONS AND USAGE
Adults:
Pediatric Patients:
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
Information for Patients:
Drug Interactions:
Pregnancy:
Pediatric Use:
Geriatric Use:
ADVERSE REACTIONS
Clinical:
| 1-day | 4.3% | 1.4% | 4.9% | 1.0% | 1.0% |
| 3-day | 2.6% | 1.7% | 2.3% | 0.4% | 0.6% |
| 5-day | 1.8% | 1.2% | 1.1% | 0.5% | 0.4% |
|
| 5-day | 5.8% | 1.9% | 1.9% | 1.9% | 1.6% |
|
| 5-day | 5.4% | 3.4% | 5.6% | 1.8% | 0.7% | 1.1% |
|
Post-Marketing Experience:
Laboratory Abnormalities:
DOSAGE AND ADMINISTRATION
Adults:
| Infection* | Recommended Dose/Duration of Therapy |
| Community-acquired pneumonia (mild severity)
Pharyngitis/tonsillitis (second line therapy)
Skin/skin structure (uncomplicated) | 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. |
| Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate) | 500 mg QD x 3 days
OR
500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. |
| Acute bacterial sinusitis | 500 mg QD x 3 days |
| Genital ulcer disease (chancroid) | One single 1 gram dose |
| Non-gonoccocal urethritis and cervicitis | One single 1 gram dose |
| Gonococcal urethritis and cervicitis | One single 2 gram dose |
| Kg | Lbs. | Day 1 | Days 2-5 | Day 1 | Days 2-5 |
| 5 | 11 | 2.5 mL (½ tsp) | 1.25 mL (¼ tsp) | 7.5 mL | 150 mg |
| 10 | 22 | 5 mL (1 tsp) | 2.5 mL (½ tsp) | 15 mL | 300 mg |
| 20 | 44 | 5 mL (1 tsp) | 2.5 mL (½ tsp) | 15 mL | 600 mg |
| 30 | 66 | 7.5 mL (1½ tsp) | 3.75 mL (3/4tsp) | 22.5 mL | 900 mg |
| 40 | 88 | 10 mL (2 tsp) | 5 mL (1tsp) | 30 mL | 1200 mg |
| 50 and above | 12.5 mL (2 ½ tsp) | 6.25 mL (1¼ tsp) | 37.5 mL | 1500 mg |
| Kg | Lbs. | Day 1-3 | Day 1-3 |
| 5 | 11 | 2.5 mL (½ tsp) | 7.5 mL | 150 mg |
| 10 | 22 | 5 mL (1 tsp) | 15 mL | 300 mg |
| 20 | 44 | 5 mL (1 tsp) | 15 mL | 600 mg |
| 30 | 66 | 7.5 mL (1½ tsp) | 22.5 mL | 900 mg |
| 40 | 88 | 10 mL (2 tsp) | 30 mL | 1200 mg |
| 50 and above | 110 and above | 12.5 mL (2 ½ tsp ) | 37.5 mL | 1500 mg |
| Kg | Lbs. | Day1 |
| 5 | 11 | 3.75 mL (3/4 tsp) | 3.75 mL | 150 mg |
| 10 | 22 | 7.5 mL (1½ tsp) | 7.5 mL | 300 mg |
| 20 | 44 | 15 mL (3 tsp) | 15 mL | 600 mg |
| 30 | 66 | 22.5 mL (4 ½ tsp) | 22.5 mL | 900 mg |
| 40 | 88 | 30 mL (6tsp) | 30 mL | 1200 mg |
| 50 and above | 110 and above | 37.5 mL (7½ tsp) | 37.5 mL | 1500 mg |
| Kg | Lbs. | Day 1-5 |
| 8 | 18 | 2.5 mL (½ tsp) | 12.5 mL | 500 mg |
| 17 | 37 | 5 mL (1 tsp) | 25 mL | 1000 mg |
| 25 | 55 | 7.5 mL (1 ½ tsp) | 37.5 mL | 1500 mg |
| 33 | 73 | 10 mL (2 tsp) | 50 mL | 2000 mg |
| 40 | 88 | 12.5 mL (2 ½ tsp) | 62.5 mL | 2500 mg |
HOW SUPPLIED
CLINICAL STUDIES
(See INDICATIONS AND USAGE and Pediatric Use.)Pediatric PatientsFrom the perspective of evaluating pediatric clinical trials, Days 11-14 were considered on-therapy evaluations because of the extended half-life of azithromycin. Day 11-14 data are provided for clinical guidance. Day 24-32 evaluations were considered the primary test of cure endpoint.Acute Otitis MediaSafety and efficacy using azithromycin 30 mg/kg given over 5 daysProtocol 1In a double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent.In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9% with azithromycin and 31% with the control agent. The most common side effects were diarrhea/loose stools (4% azithromycin vs. 20% control), vomiting (2% azithromycin vs. 7% control), and abdominal pain (2% azithromycin vs. 5% control).Protocol 2In a non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i.e., cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin.Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group
In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9%. The most common side effect was diarrhea (4%). Protocol 3In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol 2 (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason, Protocol 3 was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. The combined clinical success rate (i.e., cure and improvement) of those patients with a baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control.Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. At the Day 11 and Day 30 visits, the following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group
In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 4% with azithromycin and 31% with the control agent. The most common side effect was diarrhea/loose stools (2% azithromycin vs. 29% control).Safety and efficacy using azithromycin 30 mg/kg given over 3 daysProtocol 4In a double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator.For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i.e., cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Day 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent.In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 10.6% with azithromycin and 20% with the control agent. The most common side effects were diarrhea/loose stools (5.9% azithromycin vs. 14.6% control), vomiting (2.1% azithromycin vs. 1.1% control), and rash (0% azithromycin vs. 4.3% control).Safety and efficacy using azithromycin 30 mg/kg given as a single doseProtocol 5A double blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator.Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Day 12-16) and Test of Cure (Day 28-32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator. In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16.8% with azithromycin, and 22.5% with the comparator. The most common side effects were diarrhea (6.4% with azithromycin vs. 12.7% with the comparator), vomiting (4% with each agent), rash (1.7% with azithromycin vs. 5.2% with the comparator) and nausea (1.7% with azithromycin vs. 1.2% with the comparator).Protocol 6In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1).For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i.e., cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Day 24-28, the clinical success rate (cure) was 85%
|
| Day 11Azithromycin | Day 30Azithromycin |
| S. pneumoniae | 61/74 (82%) | 40/56 (71%) |
| H. influenzae | 43/54 (80%) | 30/47 (64%) |
| M. catarrhalis | 28/35 (80%) | 19/26 (73%) |
| S. pyogenes | 11/11 (100%) | 7/7 |
| Overall | 177/217 (82%) | 97/137 (73%) |
| S. pneumoniae | 25/29 (86%) | 26/26 (100%) | 22/28 (79%) | 18/22 (82%) |
| H. influenzae | 9/11 (82%) | 9/9 | 8/10 (80%) | 6/8 |
| M. catarrhalis | 7/7 | 5/5 | 5/5 | 2/3 |
| S. pyogenes | 2/2 | 5/5 | 2/2 | 4/4 |
| Overall | 43/49 (88%) | 45/45 (100%) | 37/45 (82%) | 30/37 (81%) |
|
|
| Day 10 | Day 24-28 |
| S. pneumoniae | 70/76 (92%) | 67/76 (88%) |
| H. influenzae | 30/42 (71%) | 28/44 (64%) |
| M. catarrhalis | 10/10 (100%) | 10/10 (100%) |
| Overall | 110/128 (86%) | 105/130 (81%) |
| Day 14 | Day 30 |
| Bacteriologic Eradication |
| Azithromycin | 323/340 (95%) | 255/330 (77%) |
| Penicillin V | 242/332 (73%) | 206/325 (63%) |
| Clinical Success (Cure plus improvement) |
| Azithromycin | 336/343 (98%) | 310/330 (94%) |
| Penicillin V | 284/338 (84%) | 241/325 (74%) |
|
Adult Patients
| Pathogen | Azithromycin (3 Days) | Clarithromycin(10 Days) |
| S. pneumoniae | 29/32 (91%) | 21/27 (78%) |
| H. influenzae | 12/14 (86%) | 14/16 (88%) |
| M. catarrhalis | 11/12 (92%) | 12/15 (80%) |
| S. pneumoniae | 23/26 (88%) | 21/25 (84%) |
| H. influenzae | 28/32 (87%) | 24/32 (75%) |
| M. catarrhalis | 14/15 (93%) | 13/15 (87%) |
ANIMAL TOXICOLOGY
- National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2 (ISBN 1-56238-394-9). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2000.
- National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1 (ISBN 1-56238-393-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2000.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing – Eleventh Informational Supplement. NCCLS Document M100-S11, Vol. 21, No. 1 (ISBN 1-56238-426-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2001.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
AZITHROMYCIN 500MG PACKAGE LABEL