Azithromycin - Azithromycin Monohydrate injection, Powder, Lyophilized, For Solution
(Azithromycin Monohydrate)Azithromycin - Azithromycin Monohydrate injection, Powder, Lyophilized, For Solution Prescribing Information
Azithromycin for injection is a macrolide antibacterial drug indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
Azithromycin for injection is a macrolide antibacterial drug indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
Azithromycin for injection is a macrolide antibacterial drug indicated for mild to moderate infections caused by designated, susceptible bacteria:
- Community-acquired pneumonia in adults
- Pelvic inflammatory disease
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.
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Azithromycin for injection should be followed by azithromycin by the oral route as required
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.
In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC24was 9.60 ± 4.80 mcg·hr/mL.
The mean Cmax, 24-hour trough and AUC24values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ± 0.86 mcg·hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2 to 5 days.
a500 mg (2 mg/mL) for 2 to 5 days in community-acquired pneumonia patients. | |||||||||
b500 mg (1 mg/mL) for 5 days in healthy subjects. | |||||||||
Infusion Concentration, Duration | Time after starting the infusion (hr) | ||||||||
0.5 | 1 | 2 | 3 | 4 | 6 | 8 | 12 | 24 | |
2 mg/mL, 1 hr a | 2.98 ± 1.12 | 3.63 ± 1.73 | 0.60 ± 0.31 | 0.40 ± 0.23 | 0.33 ± 0.16 | 0.26 ± 0.14 | 0.27 ± 0.15 | 0.20 ± 0.12 | 0.20 ± 0.15 |
1 mg/mL, 3 hr b | 0.91 ± 0.13 | 1.02 ± 0.11 | 1.14 ± 0.13 | 1.13 ± 0.16 | 0.32 ± 0.05 | 0.28 ± 0.04 | 0.27 ± 0.03 | 0.22 ± 0.02 | 0.18 ± 0.02 |
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in Cmaxbut a 61% increase in AUC24reflecting a threefold rise in C24trough levels.
Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, Cmax, trough level, and AUC24were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·hr/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (Cmax: 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5.0 mcg·hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.
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.
Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix.
Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients. Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were less than 0.01 mcg/mL in the presence of non-inflamed meninges.
Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.
In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenous-dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hr was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.
Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmaxand AUC0-120increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmaxand AUC0-120increased 61% and 35%, respectively in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min).
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.
There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.
Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration 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
Pharmacokinetic studies with intravenous azithromycin have not been performed in children.
Drug interaction studies were performed with oral 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 1and 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 1is 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 Cmaxand AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2
* - 90% Confidence interval not reported | |||||
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 | |
Mean C max | Mean AUC | ||||
| Atorvastatin | 10 mg/day for 8 days | 500 mg/day orally on days 6 to 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 to 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 to 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 to 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) | 0.9 (0.81 to 1) |
| 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 | 0.9 (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 to 11 | 10 | 1.19 (1.02 to 1.4) | 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 to 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)/ 0.9 (0.78 to 1.03) | 0.87 (0.8 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 1.7) |
| Zidovudine | 500 mg/day orally for 21 days | 1,200 mg/day orally for 14 days | 4 | 1.31 (0.43 to 3.97) | 1.3 (0.69 to 2.43) |
* - 90% Confidence interval not reported | |||||
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 | |
Mean C max | 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 2.5) |
Azithromycin for Injection, USP is supplied as white to off-white lyophilized powder in a single-dose vial equivalent to 500 mg of azithromycin for intravenous administration.
- Pediatric use: Safety and effectiveness in the treatment of patients under 16 years of age have not been established. ()
8.4 Pediatric UseSafety and effectiveness of azithromycin for injection in children or adolescents under 16 years have not been established. In controlled clinical studies, azithromycin has been administered to pediatric patients (age 6 months to 16 years) by the oral route. For information regarding the use of azithromycin for oral suspension in the treatment of pediatric patients,
[see Indications and Usage , and Dosage and Administration ]of the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles. - Geriatric use: Elderly patients may be more susceptible to development of torsades de pointes arrhythmias. ()
8.5 Geriatric UsePharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration 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.
In multiple-dose clinical trials of intravenous azithromycin in the treatment of community-acquired pneumonia, 45% of patients (188/414) were at least 65 years of age and 22% of patients (91/414) were at least 75 years of age. No overall differences in safety were observed between these subjects and younger subjects in terms of adverse reactions, laboratory abnormalities, and discontinuations. Similar decreases in clinical response were noted in azithromycin- and comparator-treated patients with increasing age.
Azithromycin for injection contains 114 mg (4.96 mEq) of sodium per vial. At the usual recommended doses, patients would receive 114 mg (4.96 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and non-dietary sources may be clinically important with regard to such diseases as congestive heart failure.
Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients
[see Warnings and Precautions ].
- Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide antibacterial drug. ()
4.1 HypersensitivityAzithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drugs.
- Patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. ()
4.2 Hepatic DysfunctionAzithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
- Serious (including fatal) allergic and skin reactions. Discontinue azithromycin and initiate appropriate therapy if reaction occurs. ()
5.1 HypersensitivitySerious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy
[see Contraindications ].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 unknown at present.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that the allergic symptoms may reappear after symptomatic therapy has been discontinued.
- Hepatotoxicity: Severe and sometimes fatal, hepatoxicity has been reported. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. ()
5.2 HepatotoxicityAbnormal 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.
- 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. ()
5.3 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.
- 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 proarrhythmic conditions, and with other drugs that prolong the QT interval. ()
5.4 QT ProlongationProlonged 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.
- Cardiovascular Death: Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. Consider balancing this potential risk with treatment benefits when prescribing azithromycin. ()
5.5 Cardiovascular DeathSome observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular mortality observed in these studies ranged from 20 to 400 per million azithromycin treatment courses. This potential risk was noted to be greater during the first five days of azithromycin use and does not appear to be limited to those patients with preexisting cardiovascular diseases. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. Consider balancing this potential risk with treatment benefits when prescribing azithromycin.
- Clostridioides difficile-Associated Diarrhea: Evaluate patients if diarrhea occurs. ()
5.6Clostridioides difficile-Associated DiarrheaClostridioides difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin for injection, 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 ofC. difficile.C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains ofC. difficilecause 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 antibacterial 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 antibacterial use not directed against
C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment ofC. difficile, and surgical evaluation should be instituted as clinically indicated. - Azithromycin may exacerbate muscle weakness in persons with myasthenia gravis. ()
5.7 Exacerbation of Myasthenia GravisExacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.