Azithromycin Drug Information
Generic name: AZITHROMYCIN
Uses of Azithromycin
Adult Patients •
Acute bacterial exacerbations of chronic bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. • Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis. or Streptococcus pneumoniae. • Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy. • Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. • Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. • Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae. • Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.
Pediatric Patients •
Acute otitis media (>6 months of age) caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. • Community-acquired pneumonia (>6 months of age) due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy. • Pharyngitis/tonsillitis (>2 years of age) caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.
Limitations of Use Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: • patients with cystic fibrosis, • patients with nosocomial infections, • patients with known or suspected bacteremia, • patients requiring hospitalization, • elderly or debilitated patients, or • patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets and other antibacterial drugs, azithromycin tablets 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.
Dosage & Administration of Azithromycin
Pediatric Patients 1 DUE TO THE INDICATED ORGANISMS 1 see dosing tables below for maximum doses evaluated by indication Azithromycin for oral suspension can be taken with or without food. PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS, AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, ) Based on Body Weight OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen) Dosing Calculated on Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established. *Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established. The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established.
In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, 8 patients who vomited within 30 minutes of dosing were re-dosed at the same total dose. Pharyngitis/Tonsillitis: The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.) PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age 2 years and above, ) Based on Body
| 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 bronchitis (mild to moderate) | 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5 or 500 mg once daily for 3 days. |
| Acute bacterial sinusitis | 500 mg once daily for 3 days. |
| Genital ulcer disease (chancroid) Non-gonococcal urethritis and cervicitis | One single 1 gram dose. |
| Gonococcal urethritis and cervicitis | One single 2 gram dose. |
| Infection | Recommended Dose/Duration of Therapy |
|---|---|
| Acute otitis media (6 months of age and older) | 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. |
| Acute bacterial sinusitis (6 months of age and older) | 10 mg/kg once daily for 3 days. |
| Community-acquired pneumonia (6 months of age and older) | 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. |
| Pharyngitis/tonsillitis (2 years of age and older) | 12 mg/kg once daily for 5 days. |
| Infection* | Recommended Dose/Duration of Therapy |
|---|---|
| Community-acquired pneumonia 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 | 500 mg once daily for 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 once daily for 3 days |
| Genital ulcer disease (chancroid) | One single 1 gram dose |
| Non-gonococcal urethritis and cervicitis | One single 1 gram dose |
| Gonococcal urethritis and cervicitis | One single 2 gram dose |
| DUE TO THE INDICATED ORGANISMS [see ] | |
| Infection* | Recommended Dose/Duration of Therapy |
|---|---|
| Acute otitis media | 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. |
| Acute bacterial sinusitis | 10 mg/kg once daily for 3 days. |
| Community-acquired pneumonia | 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. |
| Pharyngitis/tonsillitis | 12 mg/kg once daily for 5 days. |
| DUE TO THE INDICATED ORGANISMS [see Indications and Usage (1.2) ] 1 see dosing tables below for maximum doses evaluated by indication | |
| Weight in kG | 100 mg/5 mL | 100 mg/5 mL | 200 mg/5 mL | 200 mg/5 mL | Total mg per Treatment Course | Total mg per Treatment Course |
|---|---|---|---|---|---|---|
| Day 1 | Days 2 to 5 | Day 1 | Days 2 to 5 | |||
| 5 | 2.5 mL; (½ tsp) | 1.25 mL; (¼ tsp) | 7.5 mL | 150 mg | ||
| 10 | 5 mL; (1tsp) | 2.5 mL; (½ tsp) | 15 mL | 300 mg | ||
| 20 | 5 mL; (1 tsp) | 2.5 mL; (½ tsp) | 15mL | 600mg | ||
| 30 | 7.5 mL; (1½ tsp) | 5 mL; (1 tsp) | 22.5 mL | 900mg | ||
| 40 | 10 mL; (2 tsp) | 5 mL; (1 tsp) | 30 mL | 1200mg | ||
| 50 + | 12.5 mL; (2½ tsp) | 6.25 mL; (1¼ tsp) | 37.5 mL | 1500mg |
| OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen) | ||||
| Dosing Calculated on 10 mg/kg/day. | ||||
| Weight | 100 mg/5 mL | 200 mg/5 mL | Total mL per Treatment Course | Total mg per Treatment Course |
| Kg | Days 1 to 3 | Days 1 to 3 | ||
| 5 | 2.5 mL; (1/2 tsp) | 7.5 mL | 150 mg | |
| 10 | 5 mL; (1 tsp) | 15 mL | 300 mg | |
| 20 | 5 mL (1 tsp) | 15 mL | 600 mg | |
| 30 | 7.5 mL (1½ tsp) | 22.5 mL | 900 mg | |
| 40 | 10 mL (2 tsp) | 30 mL | 1200 mg | |
| 50 and above | 12.5 mL (2 ½ tsp) | 37.5 mL | 1500 mg | |
| OTITIS MEDIA: (1-Day Regimen) | |||
| Dosing Calculated on 30 mg/kg as a single dose. | |||
| Weight | 200 mg/5 mL | Total mL per Treatment Course | Total mg per Treatment Course |
| Kg | 1-Day Regimen | ||
| 5 | 3.75 mL;(3/4 tsp) | 3.75 mL | 150 mg |
| 10 | 7.5 mL;(1½ tsp) | 7.5 mL | 300 mg |
| 20 | 15 mL;(3 tsp) | 15 mL | 600 mg |
| 30 | 22.5 mL;(4½ tsp) | 22.5 mL | 900 mg |
| 40 | 30 mL;(6 tsp) | 30 mL | 1200 mg |
| 50 and above | 37.5 mL;(7½ tsp) | 37.5 mL | 1500 mg |
| PHARYNGITIS/TONSILLITIS: (5-Day Regimen) | |||
| Dosing Calculated on 12 mg/kg/day for 5 days. | |||
| Weight Day 1 to 5 Total mL Total mG | |||
| 8 | 2.5 mL; (½ tsp) | 12.5 mL | 500 mg |
| 17 | 5 mL; (1 tsp) | 25 mL | 1000 mg |
| 25 | 7.5 mL; (1½ tsp) | 37.5 mL | 1500 mg |
| 33 | 10 mL; (2 tsp) | 50 mL | 2000 mg |
| 40 | 12.5 mL; (2½ tsp) | 62.5 mL | 2500 mg |
Side Effects of Azithromycin
Clinical Trials Experience
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 side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious adverse reactions of angioedema and cholestatic jaundice were reported.
Approximately 0.7% of the patients (adults and pediatric patients) from the 5-day multiple-dose clinical trials discontinued azithromycin therapy because of treatment-related adverse reactions. In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related adverse reactions was 0.6%. In clinical trials in pediatric patients given 30 mg/kg, either as a single dose or over 3 days, discontinuation from the trials due to treatment-related adverse reactions was approximately 1%.
Most of the adverse reactions leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. Adults Multiple-dose regimens: Overall, the most common treatment-related adverse reactions in adult patients receiving multiple-dose regimens of azithromycin were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%), and abdominal pain (2 to 3%) being the most frequently reported. No other adverse reactions occurred in patients on the multiple-dose regimens of azithromycin with a frequency greater than 1%.
Adverse reactions that occurred with a frequency of 1% or less included the following: Cardiovascular: Palpitations, 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, pruritus, photosensitivity, and angioedema.
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. The majority of these complaints were mild in nature. Pediatric Patients Single and Multiple-dose regimens: The types of adverse reactions in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients.
Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent adverse reactions (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea, and rash. The incidence, based on dosing regimen, is described in the table below: Community-Acquired Pneumonia: For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5, the most frequent adverse reactions attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea, and rash. The incidence is described in the table below: Pharyngitis/Tonsillitis: For the recommended dosage regimen of 12 mg/kg on Days 1 to 5, the most frequent adverse reactions attributed to treatment were diarrhea, vomiting, abdominal pain, nausea, and headache.
The incidence is described in the table below: With any of the treatment regimens, no other adverse reactions occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Gastrointestinal: Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, and oral moniliasis. Hematologic and Lymphatic: Anemia and leukopenia.
Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness, and insomnia. General: Fever, face edema, fatigue, fungal infection, malaise, and pain. Allergic: Rash and allergic reaction.
Respiratory: Cough, pharyngitis, pleural effusion, and rhinitis. Skin and Appendages: Eczema, fungal dermatitis, pruritus, sweating, urticaria, and vesiculobullous rash. Special Senses: Conjunctivitis.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria, and angioedema.
Cardiovascular: Arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation, torsades de pointes, and cardiovascular death. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and reports of tongue discoloration.
General: Asthenia, paresthesia, fatigue, malaise, and anaphylaxis. Genitourinary: Interstitial nephritis and acute renal failure and vaginitis. Hematopoietic: Thrombocytopenia.
Liver/Biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure. Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation, and syncope. Psychiatric: Aggressive reaction and anxiety.
Skin/Appendages: Pruritus, serious skin reactions including erythema multiforme, AGEP, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS. Special Senses: Hearing disturbances including hearing loss, deafness and/or tinnitus, and reports of taste/smell perversion and/or loss.
Laboratory Abnormalities Adults
Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, neutrophils, and blood glucose; elevated serum creatine phosphokinase, potassium, ALT, GGT, AST, BUN, creatinine, blood glucose, platelet count, lymphocytes, neutrophils, and eosinophils; with an incidence of less than 1%: leukopenia, neutropenia, decreased sodium, potassium, platelet count, elevated monocytes, basophils, bicarbonate, serum alkaline phosphatase, bilirubin, LDH, and phosphate. The majority of subjects with elevated serum creatinine also had abnormal values at baseline. When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 5000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality. Pediatric Patients: One, Three, and Five-Day Regimens Laboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over 5 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1 to 5%. Laboratory data for patients receiving 30 mg/kg as a single dose were collected in one single center trial.
No patient had an absolute neutrophil count <500 cells/mm 3. In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.
| Dosage Regimen | Diarrhea % | Abdominal Pain % | Vomiting % | Nausea % | Rash % |
|---|---|---|---|---|---|
| 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% |
| Dosage Regimen | Diarrhea/Loose stools % | Abdominal Pain % | Vomiting % | Nausea % | Rash % |
|---|---|---|---|---|---|
| 5-day | 5.8% | 1.9% | 1.9% | 1.9% | 1.6% |
| Dosage Regimen | Diarrhea % | Abdominal Pain % | Vomiting % | Nausea % | Rash % | Headache % |
|---|---|---|---|---|---|---|
| 5-day | 5.4% | 3.4% | 5.6% | 1.8% | 0.7% | 1.1% |
Warnings & Cautions for Azithromycin
Hypersensitivity
Serious 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. 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 presently unknown.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that allergic symptoms may reappear when symptomatic therapy has been discontinued.
Hepatotoxicity
Abnormal 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.
QT Prolongation
Prolonged 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. 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
Clostridioides difficile -associated diarrhea has been reported with use of nearly all antibacterial agents, including azithromycin, 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 of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Exacerbation of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
Use in Sexually Transmitted Infections Azithromycin, at the recommended dose, should not be relied upon to treat syphilis. Antibacterial agents used to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate testing for gonorrhea performed at the time of diagnosis.
Appropriate antibacterial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.
Development of Drug-Resistant Bacteria
Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Drug Interactions with Azithromycin
Nelfinavir Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted.
Warfarin
Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.
Potential Drug-Drug Interaction with Macrolides Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products.
Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.
Pregnancy Safety for Azithromycin
Pregnancy 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 4, 2, and 2 times, respectively, an adult human daily dose of 500 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 4 times an adult human daily dose of 500 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 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 4 (rats) and 2 (mice) times an adult human daily dose of 500 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 estimated to be 2 times an adult human daily dose of 500 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.
Pediatric Use of Azithromycin
Pediatric Use Safety and effectiveness in the treatment of pediatric patients with acute otitis media, acute bacterial sinusitis and community-acquired pneumonia under 6 months of age have not been established. Use of azithromycin for the treatment of acute bacterial sinusitis and community-acquired pneumonia in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled trials in adults. Pharyngitis/Tonsillitis: Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under 2 years of age have not been established.
Contraindications for Azithromycin
Hypersensitivity
Azithromycin tablets are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drug.
Hepatic Dysfunction
Azithromycin tablets are contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
Overdosage Information for Azithromycin
Adverse reactions experienced at higher than recommended doses were similar to those seen at normal doses particularly nausea, diarrhea, and vomiting. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
Clinical Studies of Azithromycin
Adult Patients Acute Bacterial Exacerbations of Chronic Bronchitis In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for 3 days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Days 21 to 24. The following outcomes were the clinical cure rates at the Days 21 to 24 visit for the bacteriologically evaluable patients by pathogen: Acute Bacterial Sinusitis In a randomized, double-blind, double-dummy controlled clinical trial of acute bacterial sinusitis, azithromycin (500 mg once daily for 3 days) was compared with amoxicillin/clavulanate (500/125 mg three times a day for 10 days).
Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. In an open label, non-comparative study requiring baseline transantral sinus punctures, the following outcomes were the clinical success rates at the Day 7 and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for 3 days with the following pathogens: Clinical Success Rates of
Pediatric Patients From the perspective of evaluating pediatric clinical trials, Days 11 to 14 were considered on-therapy evaluations because of the extended half-life of azithromycin. Days 11 to 14 data are provided for clinical guidance. Days 24 to 32 evaluations were considered the primary test of cure endpoint.
Pharyngitis/Tonsillitis In three double-blind controlled studies, conducted in the United States, azithromycin (12 mg/kg once a day for 5 days) was compared to penicillin V (250 mg three times a day for 10 days) in the treatment of pharyngitis due to documented Group A β-hemolytic streptococci (GABHS or S. pyogenes ). Azithromycin was clinically and microbiologically statistically superior to penicillin at Day 14 and Day 30 with the following clinical success (i.e., cure and improvement) and bacteriologic efficacy rates (for the combined evaluable patient with documented GABHS): Three U.S. Streptococcal Pharyngitis Studies Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to azithromycin following therapy.
Trial 2 In 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. 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. Ninety-two patients were evaluable for clinical and microbiologic efficacy. Each patient received active drug and placebo matched for the comparator.
Efficacy using azithromycin 30 mg/kg given as a single dose Trial 5 A double-blind, controlled, randomized trial was performed at nine clinical centers. 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.
| 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%) |
| Pathogen | Day 7 | Day28 |
|---|---|---|
| S. pneumoniae | 23/26 (88%) | 21/25 (84%) |
| H. influenzae | 28/32 (87%) | 24/32 (75%) |
| M. catarrhalis | 14/15 (93%) | 13/15 (87%) |
| 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%) |
| Pathogen | Day 11 | Day 30 |
|---|---|---|
| Azithromycin | Azithromycin | |
| 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 (100%) |
| Overall | 177/217 (82%) | 97/137 (73%) |
| Day 11 | Day 30 | ||||
|---|---|---|---|---|---|
| Pathogen | Azithromycin | Control | Azithromycin | Control | |
| S. pneumoniae | 25/29 (86%) | 26/26 (100%) | 22/28 (79%) | 18/22 (82%) | |
| H. influenzae | 9/11 (82%) | 9/9 (100%) | 8/10 (80%) | 6/8 (75%) | |
| M. catarrhalis | 7/7 (100%) | 5/5 (100%) | 5/5 (100%) | 2/3 (66%) | |
| S. pyogenes | 2/2 (100%) | 5/5 (100%) | 2/2 (100%) | 4/4 (100%) | |
| Overall | 43/49 (88%) | 45/45 (100%) | 37/45 (82%) | 30/37 (81%) | |
| Presumed Bacteriologic Eradication | ||
| Day 10 | Days 24 to 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%) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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