Azithromycin Capsules

Overview of Azithromycin Capsules

Dosage Strengths of Azithromycin Capsules/Tablets

Compounded: 250 mg, 500 mg

Commercial: 250 mg, 500 mg

General Information

Azithromycin is a semisynthetic antibiotic belonging to the macrolide subgroup of azalides and is similar in structure to erythromycin. Azithromycin offers the advantage that it can be dosed once daily and produces less GI intolerance than does erythromycin. Azithromycin has a wider spectrum of activity than erythromycin against Mycobacterium avium complex (MAC), Haemophilus influenzae, nontuberculous mycobacteria, and Chlamydia trachomatis. Another apparent advantage over erythromycin is that azithromycin reaches higher intracellular concentrations, thus increasing its efficacy and duration of action. These advantages are demonstrated in studies that show that single doses of azithromycin are effective for the treatment of acute otitis media and sexually transmitted diseases (STDs) due to chlamydia and gonorrhea. Azithromycin is better tolerated and offers shorter treatment durations compared with clarithromycin. Azithromycin is used for the treatment of a variety of respiratory infections, including otitis media, pharyngitis/tonsillitis, pertussis, community-acquired pneumonia, and sinusitis. However, macrolides are not recommended for empiric monotherapy of acute bacterial sinusitis due to high rates of Streptococcus pneumoniae resistance (approximately 30%). Azithromycin is also used for the treatment of STDs due to chlamydia and gonorrhea, and for the prophylaxis and treatment of Mycobacterium avium complex (MAC) disease. An ophthalmic preparation is used for the treatment of bacterial conjunctivitis. Long-term azithromycin is used off-label to improve lung function and decrease pulmonary exacerbation in cystic fibrosis patients 6 years and older who have sputum cultures persistently positive for P. aeruginosa. Additionally, long-term azithromycin may be used as an add-on therapy in adults with moderate to severe asthma. Prior to starting therapy, sputum should be checked for atypical mycobacteria. While azithromycin has been studied in regimens for H. pylori eradication and some studies show efficacy, the azithromycin-containing regimens have not been as effective as regimens containing clarithromycin in terms of eradication rates. Macrolide cross-resistance is also an issue.

Updates for coronavirus disease 2019 (COVID-19):

Available data regarding the use of azithromycin as adjunctive treatment of COVID-19 due to SARS-CoV-2 are limited and inconclusive. Azithromycin is being used in some COVID-19 protocols based on preliminary data; however, the risk of adverse events, particularly when given in combination with chloroquine or hydroxychloroquine (e.g., cardiac arrhythmias), should be considered. In an open-label, non-randomized clinical trial of hydroxychloroquine (n = 26), azithromycin was administered in combination with hydroxychloroquine to prevent bacterial superinfection in 6 patients. On day 6, all patients treated with the combination (hydroxychloroquine and azithromycin) were virologically cured compared to 57.1% of patients treated with hydroxychloroquine alone (n= 20). Another small study (n = 11) reviewed the same azithromycin plus hydroxychloroquine regimen and found nasopharyngeal swabs were still positive for SARS-CoV-2 in 8 of 10 patients 5 to 6 days after treatment initiation.[65198] In a retrospective analysis of a multicenter cohort study (n = 349) in patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV), 136 patients received macrolide therapy in combination with antiviral treatment. Macrolide therapy was not associated with a reduction in 90-day mortality compared to the control group.

Mechanism of Action

Azithromycin inhibits protein synthesis in bacterial cells by binding to the 50S subunit of bacterial ribosomes. Action is generally bacteriostatic but can be bactericidal in high concentrations or against susceptible organisms. Azithromycin is more active against gram-negative organisms but has less activity against streptococci and staphylococci than does erythromycin; erythromycin-resistant gram-positive isolates demonstrate cross-resistance to azithromycin. Azithromycin concentrates in phagocytes and fibroblasts leading to high intracellular concentrations. Drug distribution to inflamed tissues is thought to occur from the concentration in phagocytes.

The susceptibility interpretive criteria for azithromycin are delineated by pathogen. The MICs are defined for beta-hemolytic streptococci, S. viridans group, and S. pneumoniae as susceptible at 0.5 mcg/mL or less, intermediate at 1 mcg/mL, and resistant at 2 mcg/mL or more. The MICs are defined for Staphylococcus sp. as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more. The MICs are defined for S. enterica ser. Typhi as susceptible at 16 mcg/mL or less and resistant at 32 mcg/mL or more. The MICs are defined for H. influenzae and H. parainfluenzae as susceptible at 4 mcg/mL or less. The MICs are defined for N. meningitidis as susceptible at 2 mcg/mL or less, which may be only appropriate for prophylaxis of meningococcal case contacts and does not apply to treatment of invasive disease. The MICs are defined for N. gonorrhoeae as susceptible at 1 mcg/mL or less, presuming use of a 1 g single dose regimen that includes an additional antimicrobial agent.

Macrolides have been reported to have immunomodulatory properties in pulmonary inflammatory disorders. They may downregulate inflammatory responses and reduce the excessive cytokine production associated with respiratory viral infections; however, their direct effects on viral clearance are uncertain. Immunomodulatory mechanisms may include reducing chemotaxis of neutrophils (PMNs) to the lungs by inhibiting cytokines (i.e., IL-8), inhibition of mucus hypersecretion, decreased bacterial adhesion to the epithelium, decreased production of reactive oxygen species, accelerating neutrophil apoptosis, and blocking the activation of nuclear transcription factors.

Pharmacokinetics

Azithromycin is administered orally, intravenously, and topically to the eye. Following systemic administration, it is widely distributed to body tissues and fluids including bone, prostate, ovary, uterus, stomach, liver, middle ear, lung, tonsils and adenoids, and sputum. Azithromycin exhibits significant intracellular penetration and concentrates within fibroblasts and phagocytes. As a result, tissue concentrations are significantly higher than are plasma concentrations.

Azithromycin is distributed widely into brain tissue but not into cerebrospinal fluid or the aqueous humor of the eye. Protein binding varies with plasma concentration; 51% of the drug is bound at low concentrations (0.02 mcg/ml) and this binding decreases to 7% at higher concentrations (2 mcg/ml). Azithromycin has a long half-life in both adults (40 to 68 hours) and children (32 to 64 hours), which is partially explained by its extensive tissue uptake and slow release. Elimination is largely in the feces, following excretion into the bile, with less than 14% excreted in the urine.

Contraindications/Precautions

Azithromycin does not treat viral infection (e.g., common cold). Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients should be told to complete the full course of treatment, even if they feel better earlier.

Azithromycin is contraindicated in patients with a known azithromycin or macrolide hypersensitivity. Azithromycin has a rare risk of serious hypersensitivity reactions or anaphylaxis, including angioedema and severe dermatologic reactions, including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, and toxic epidermal necrolysis. Fatalities associated with these severe reactions have been reported. There is a risk of cross sensitivity with other macrolide antibiotics. Some patients have a recurrence of allergic symptoms once symptomatic treatment is withdrawn, even though azithromycin therapy is not reinstated.

Systemic azithromycin is contraindicated in patients with a history of jaundice and/or hepatic dysfunction associated with the prior use of azithromycin. Systemically administered azithromycin should be used with caution in patients who have hepatic disease. In addition, abnormal hepatic function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported with use, including cases that have resulted in death. Monitor liver function tests in patients receiving systemic azithromycin. Discontinue treatment immediately if signs and symptoms of hepatitis and liver dysfunction occur.

Safe use of systemically-administered azithromycin in patients with severe renal impairment has not been determined; limited data are available. Azithromycin should be used cautiously in patients with preexisting severe renal impairment or renal failure (CrCl less than 10 ml/min).
Almost all antibacterial agents, including systemic azithromycin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

Macrolides are associated with QT prolongation; cases of cardiac arrhythmias and torsade de pointes (TdP) have been reported during postmarketing surveillance. Caution is warranted when using the drug in high-risk patients, including those with known prolongation of the QT interval or a history of TdP. Use azithromycin with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. In patients taking azithromycin with another drug that prolongs the QT interval (see Therapeutic Drug Monitoring for recommendations specific to using azithromycin with chloroquine or hydroxychloroquine in the treatment of COVID-19), obtain a pre-treatment QTc using a standard 12-lead ECG, telemetry, or mobile ECG device. Obtain baseline electrolytes, including calcium, magnesium, and potassium. Determine if the patient is currently on any QT-prolonging medications that can be discontinued. Document high-risk cardiovascular and comorbid conditions. If the baseline QTc is 500 msec or more and/or the patient has an inherent tendency to develop an exaggerated QTc response (i.e., change of 60 msec or more), correct contributing electrolyte abnormalities, review and discontinue other unnecessary QTc prolonging medications, and proceed with close QTc surveillance. Obtain an initial on-therapy QTc approximately 2 to 4 hours after the first dose and then again at 48 and 96 hours after treatment initiation. If the baseline QTc is 460 to 499 msec (prepubertal), 470 to 499 msec (postpubertal males), or 480 to 499 msec (postpubertal females), correct contributing electrolyte abnormalities, review and discontinue other unnecessary QTc prolonging medications, and obtain an initial on-therapy QTc 48 and 96 hours after treatment initiation. If the baseline QTc is less than 460 msec (prepubertal), less than 470 msec (postpubertal males), or less than 480 msec (postpuberal females), correct electrolyte abnormalities and obtain an initial on-therapy QTc 48 and 96 hours after treatment initiation.[65170] Data from a cohort study in adults have associated azithromycin with an increased risk of cardiovascular death. The study included persons receiving prescriptions for azithromycin (n = 347,795), amoxicillin (n = 1,348,672), ciprofloxacin (n = 264,626), levofloxacin (n = 193,906), and matched persons receiving no antibiotics (n = 1,391,180). Analysis of the data found those persons receiving a 5-day course of azithromycin had a significantly greater risk of cardiovascular death than persons not treated with antibiotics (HR: 2.88; 95% CI: 1.79 to 4.63; p less than 0.001), persons treated with 5 days of amoxicillin (HR: 2.49; 95% CI: 1.38 to 4.50; p = 0.002), and persons in the first 5 days of ciprofloxacin therapy (HR: 3.49; 95% CI: 1.32 to 9.26; p = 0.01); mortality rate did not differ from levofloxacin.

Clinical trials of oral and intravenous azithromycin and other reported clinical experience has not identified overall differences in safety and effectiveness between geriatric and younger adult subjects. Greater sensitivity of some older individuals cannot be ruled out. Health care providers are advised that geriatric patients may be more susceptible to drug-associated effects on the QT interval. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

Available data over several decades with systemic azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Developmental toxicity studies in animals showed no drug-induced fetal malformations at doses up to 4 times the adult human daily dose of 500 mg based on body surface area; however, decreased viability and delayed development were observed in the offspring of pregnant rats given azithromycin at a dose equivalent to 4 times the adult human daily dose from day 6 of pregnancy through weaning. In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, systemic azithromycin use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 1.65, 95% CI 1.34 to 2.02, 110 exposed cases); residual confounding by severity of infection may be a potential limitation of this study. In a large population-based cohort study (n = 104,605 live births) assessing systemic macrolide (n = 8,632) or penicillin (n = 95,973) use during pregnancy and the risk of major malformations, macrolide use in the first trimester was associated with increased risk of any malformation (27.7 vs. 17.7 per 1,000 live births; adjusted risk ratio 1.55, 95% CI 1.19 to 2.03), and in particular, cardiovascular malformations (10.6 vs. 6.6 per 1,000 live births; adjusted risk ratio 1.62, 95% CI 1.05 to 2.51). Specific findings for azithromycin use during the first trimester were precluded due to few events. Macrolide use during the second and third trimesters showed no increased risk of any major malformation (19.5 vs. 17.3 per 1,000 live births; adjusted risk ratio 1.13, 95% CI 0.94 to 1.36); however, a borderline association with gastrointestinal malformations was observed (adjusted risk ratio 1.89, 95% CI 1 to 3.58). Macrolide use in any trimester was associated with an increased risk of genital malformations (adjusted risk ratio 1.58, 95% CI 1.14 to 2.19), mainly hypospadias. Additionally, in another large population-based cohort study (n = 139,938 live births) assessing systemic antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, macrolide exposure was associated with an increased risk of digestive system malformations (adjusted odds ratio (aOR) 1.46, 95% CI 1.04 to 2.06, 35 exposed cases).

Azithromycin is present in human breast milk. Non-serious adverse reactions have been reported in breast-fed infants after maternal administration of azithromycin. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for azithromycin and any potential adverse effects on the breast-fed infant from azithromycin or the underlying maternal condition. Monitor the breast-fed infant for diarrhea, vomiting, or rash. There are no available data on the effects of azithromycin on milk production. Azithromycin breast milk concentrations were measured in 20 women receiving a single 2 g oral dose during labor. Azithromycin was present in breast milk up to 4 weeks after dosing. Another study of 8 women receiving azithromycin IV before incision of cesarean section showed azithromycin was present in breast milk up to 48 hours later. A prospective observational study assessing the safety of macrolide antibiotics during lactation found that 12.7% (n = 55) of babies exposed to macrolides via breast milk experienced adverse events including rash, diarrhea, loss of appetite, and somnolence. The adverse event rate was similar to that seen in babies in a control group whose mothers were treated with amoxicillin (8.3%). Only 10 mothers in the study received azithromycin, 6 received clarithromycin, 2 received erythromycin, and the remainder were treated with roxythromycin. A population-based cohort study found that babies diagnosed with infantile hypertrophic pyloric stenosis were 2.3 to 3 times more likely to have been exposed to a macrolide antibiotic through breast milk during the first 90 days of life than babies not exposed during that same time period. The study did not specify which antibiotic the mothers of affected babies were prescribed; however, the majority of macrolide prescriptions were for erythromycin (72%), with 7% for azithromycin and 1.7% for clarithromycin. Previous American Academy of Pediatrics (AAP) recommendations consider erythromycin to be usually compatible with breast-feeding; azithromycin has not been evaluated by the AAP.

Use azithromycin with caution and with proper monitoring in young infants and neonates; there have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in young infants after azithromycin therapy. Because azithromycin is sometimes used for the treatment of conditions that are associated with significant mortality or morbidity (e.g., pertussis), weigh the benefit of azithromycin therapy against the potential risk of developing IHPS. Inform parents and other caregivers to contact their physician if vomiting or irritability with feeding occurs. In a retrospective study of 148 infants given azithromycin during the first 14 days of life, IHPS developed in 3 patients (2%) for an odds ratio of 8.26 (95% CI: 2.62 to 26; p less than 0.001). Of 729 infants aged 15 to 42 days at the time of azithromycin exposure, 5 patients developed IHPS for an OR of 2.98 (95% CI: 1.24 to 7.2; p = 0.015). A male predominance was also observed, as all 8 infants who developed IHPS were boys. No infants aged 43 to 90 days at the time of azithromycin exposure developed IHPS; however, there have been 2 case reports of older infants developing IHPS (89 and 94 days old at diagnosis, respectively).

Direct sunlight (UV) exposure should be minimized during therapy with systemic azithromycin. Photosensitivity has been reported as an adverse reaction to azithromycin.

Some intravenous formulations of azithromycin contain a total of 4.96 mEq (114 mg) of sodium per 500-mg vial. The sodium amounts should be considered in patients with requirements for sodium restriction or blunted natriuresis to salt loading (i.e., cardiac disease or hypertension).
Patients who wear contact lenses should avoid wearing them while being treated for an ocular infection with azithromycin ophthalmic solution.

Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving systemic azithromycin therapy.

While azithromycin may be used to treat certain sexually transmitted diseases (STD), the drug may mask or delay the symptoms of incubating syphilis when given as part of an STD treatment regimen. All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.

Do not use azithromycin for long-term prophylaxis of bronchiolitis obliterans syndrome (BOS) in patients with cancers of the blood or lymph nodes (i.e. leukemia, lymphoma) who undergo an allogeneic stem cell transplant because of the increased risk for cancer relapse or death.

Pregnancy

Available data over several decades with systemic azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Developmental toxicity studies in animals showed no drug-induced fetal malformations at doses up to 4 times the adult human daily dose of 500 mg based on body surface area; however, decreased viability and delayed development were observed in the offspring of pregnant rats given azithromycin at a dose equivalent to 4 times the adult human daily dose from day 6 of pregnancy through weaning. In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, systemic azithromycin use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 1.65, 95% CI 1.34 to 2.02, 110 exposed cases); residual confounding by severity of infection may be a potential limitation of this study. In a large population-based cohort study (n = 104,605 live births) assessing systemic macrolide (n = 8,632) or penicillin (n = 95,973) use during pregnancy and the risk of major malformations, macrolide use in the first trimester was associated with increased risk of any malformation (27.7 vs. 17.7 per 1,000 live births; adjusted risk ratio 1.55, 95% CI 1.19 to 2.03), and in particular, cardiovascular malformations (10.6 vs. 6.6 per 1,000 live births; adjusted risk ratio 1.62, 95% CI 1.05 to 2.51). Specific findings for azithromycin use during the first trimester were precluded due to few events. Macrolide use during the second and third trimesters showed no increased risk of any major malformation (19.5 vs. 17.3 per 1,000 live births; adjusted risk ratio 1.13, 95% CI 0.94 to 1.36); however, a borderline association with gastrointestinal malformations was observed (adjusted risk ratio 1.89, 95% CI 1 to 3.58). Macrolide use in any trimester was associated with an increased risk of genital malformations (adjusted risk ratio 1.58, 95% CI 1.14 to 2.19), mainly hypospadias. Additionally, in another large population-based cohort study (n = 139,938 live births) assessing systemic antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, macrolide exposure was associated with an increased risk of digestive system malformations (adjusted odds ratio (aOR) 1.46, 95% CI 1.04 to 2.06, 35 exposed cases).

Breast-feeding

Azithromycin is present in human breast milk. Non-serious adverse reactions have been reported in breast-fed infants after maternal administration of azithromycin. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for azithromycin and any potential adverse effects on the breast-fed infant from azithromycin or the underlying maternal condition. Monitor the breast-fed infant for diarrhea, vomiting, or rash. There are no available data on the effects of azithromycin on milk production. Azithromycin breast milk concentrations were measured in 20 women receiving a single 2 g oral dose during labor. Azithromycin was present in breast milk up to 4 weeks after dosing. Another study of 8 women receiving azithromycin IV before incision of cesarean section showed azithromycin was present in breast milk up to 48 hours later. A prospective observational study assessing the safety of macrolide antibiotics during lactation found that 12.7% (n = 55) of babies exposed to macrolides via breast milk experienced adverse events including rash, diarrhea, loss of appetite, and somnolence. The adverse event rate was similar to that seen in babies in a control group whose mothers were treated with amoxicillin (8.3%). Only 10 mothers in the study received azithromycin, 6 received clarithromycin, 2 received erythromycin, and the remainder were treated with roxythromycin. A population-based cohort study found that babies diagnosed with infantile hypertrophic pyloric stenosis were 2.3 to 3 times more likely to have been exposed to a macrolide antibiotic through breast milk during the first 90 days of life than babies not exposed during that same time period. The study did not specify which antibiotic the mothers of affected babies were prescribed; however, the majority of macrolide prescriptions were for erythromycin (72%), with 7% for azithromycin and 1.7% for clarithromycin. Previous American Academy of Pediatrics (AAP) recommendations consider erythromycin to be usually compatible with breast-feeding; azithromycin has not been evaluated by the AAP.

Adverse Reactions/Side Effects

The most common adverse reactions in patients receiving systemic regimens of azithromycin were gastrointestinal-related, which tended to be more frequent in the single-dose oral regimens in adults and higher doses in pediatrics. Among the most commonly reported gastrointestinal adverse events were diarrhea or loose stools (4% to 14% of adults; 1.8% to 10% of pediatric patients), nausea (1.8% to 18% adults; 0.4% to 4% pediatrics), vomiting (up to 13% adults; 1.1% to 14% pediatrics), abdominal pain (1.9% to 14% adults; 1.2% to 4% pediatrics), flatulence (up to 5% adults; up to 1% pediatric patients), and anorexia (2% adults; up to 1% pediatrics). Adverse GI effects occurring in up to 1% of adult and pediatric patients included gastritis, constipation, and dyspepsia. In adults, melena, oral moniliasis, and mucositis were also reported in up to 1%; stomatitis was reported by 1.9% of adults. In pediatric patients, enteritis was reported in up to 1%. In HIV-infected patients receiving prophylactic azithromycin (i.e., 1,200 mg once weekly) for disseminated Mycobacterium avium complex (MAC) the incidences of the following GI-related adverse events were higher than other patient populations: diarrhea or loose stools (12.9% to 52.8%), nausea (27% to 32.6%), abdominal pain (27% to 32.2%), dyspepsia (4.7% to 9%), flatulence (9% to 10.7%), vomiting (6.7% to 9%), and anorexia 2.1%. Postmarketing adverse gastrointestinal reactions have also included pancreatitis and rare reports of tongue discoloration.

In clinical trials, elevated hepatic enzymes (ALT, AST) occurred in 4% to 6% of patients receiving intravenous azithromycin. Elevations of ALT (SGPT), GGT, and AST (SGOT) occurred with an incidence of 1% to 2% in patients receiving oral therapy. Hyperbilirubinemia was noted in up to 3% of patients. Up to 1% of drug recipients experienced cholestasis with jaundice. Postmarketing reports indicate that systemic azithromycin has been associated with abnormal liver function including cholestatic jaundice, hepatitis as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with azithromycin. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Other infections reported during treatment with systemic azithromycin therapy during clinical trials included vaginitis (up to 2.8%), fungal superinfection (less than 1%), and fungal dermatitis (less than 1%). Cases of oral candidiasis (thrush) and vaginitis have also been noted during postmarketing use of the drug.

Hematologic adverse reactions noted in more than 1% of patients treated with systemic azithromycin during clinical trials included decreased hemoglobin, hematocrit, lymphocytes (lymphopenia), and neutrophils; as well as increased platelet counts, lymphocytes (lymphocytosis), neutrophils, and eosinophils (eosinophilia). Leukopenia, neutropenia, decreased platelet counts, elevated monocytes, and elevated basophils have been reported in less than 1% of adults. In children, anemia and leukopenia occurred in up to 1% of patients. Thrombocytopenia and mild neutropenia have been reported during postmarketing surveillance.
Respiratory adverse reactions have been reported in up to 1% of pediatric patients receiving azithromycin. These adverse reactions have included asthma, bronchitis, cough, pharyngitis, pleural effusion, and rhinitis. Dyspnea has been noted in 1.9% of patients receiving the intravenous formulation of azithromycin and in up to 1% of pediatric patients. Nasal congestion and sinusitis have been reported in less than 1% of patients receiving the ophthalmic preparation of azithromycin.

An injection site reaction has been associated with the administration of intravenous azithromycin. Approximately 12% of patients treated for pneumonia experienced a side effect related to the intravenous infusion; most common were pain at the injection site (6.5%) and local inflammation or erythema (3.1%). Application site reactions occurred in 1.9% of patients receiving infusions for pelvic inflammatory disease.

During clinical trials, recipients of systemic azithromycin reported fatigue (up to 3.9%), fever (2.1%), malaise (up to 1.1%), pain (up to 1%), chills and influenza-like symptoms (less than 1%), paresthesias (less than 1%), and asthenia (less than 1%). Cases of asthenia, paresthesias, fatigue, and malaise have also been noted during postmarketing use of the drug.
Central nervous system (CNS) adverse reactions have been associated with the use of systemic azithromycin. In patients receiving systemic formulations of azithromycin during clinical trials, vertigo (up to 1%), headache (up to 5%), dizziness (up to 3.9%), and somnolence or drowsiness (up to 1%) were reported. Additional CNS adverse reactions noted in less than 1% of pediatric drug recipients included agitation, nervousness, emotional lability, hostility, hyperkinesis, insomnia, and irritability. Postmarketing CNS effects have also included convulsions (seizures), hyperactivity, and syncope. Postmarketing psychiatric adverse reactions include aggression and anxiety.

Cardiovascular adverse reactions associated with systemic azithromycin therapy reported in up to 1% of patients include chest pain (unspecified) and palpitations. Although uncommon, these are potentially serious adverse reactions. In postmarketing experience, there have been reports of arrhythmias including ventricular tachycardia, hypotension, QT prolongation, and torsade de pointes.

Conjunctivitis and uveitis were reported in up to 1% of patients receiving systemic azithromycin. Taste perversion (dysgeusia) was reported in up to 1.3% of patients receiving systemic azithromycin and in less than 1% of patients using the ophthalmic preparation. Decreased hearing (0.9% to 1.1%) and tinnitus (0.9% and 3.4%) were noted by patients receiving weekly azithromycin doses of 1,200 mg. During postmarketing use of systemic azithromycin, cases of dysgeusia, dysosmia (smell perversion) and anosmia (loss of smell), and hearing disturbances including hearing loss, deafness or tinnitus have been reported.

Dermatological and hypersensitivity-related adverse reactions have been reported with azithromycin therapy. During clinical trials, a generalized rash was reported in up to 8.1% of azithromycin recipients. More specifically, rashes were noted in 1% of adult patients receiving oral therapy, up to 5% of pediatric patients, 1.9% of patients receiving IV therapy, 3.4% to 8.1% of patients receiving a 1,200 mg once weekly dose, and in less than 1% of patients receiving ophthalmic therapy. Maculopapular rash and vesicular rash were reported in up to 1% of drug recipients. Patients also reported episodes of pruritus (up to 3.9%) and arthralgia (up to 3%). Other, less frequently reported adverse reactions (up to 1%) included photosensitivity, urticaria, bronchospasm, angioedema, and diaphoresis. Adverse events reported in less than 1% of patients using the ophthalmic solution included contact dermatitis, hives, and periocular swelling. Eczema vaccinatum (atopic dermatitis) was reported in up to 1% of pediatric patients, while dermatitis was noted in 2% of pediatric patients. Cases of angioedema, arthralgia, edema, photosensitivity, pruritus, rash, and urticaria have also been noted during postmarketing use. Serious skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Azithromycin therapy should be withdrawn if there are signs and symptoms of an allergic reaction. Some patients have a recurrence of allergic symptoms once symptomatic treatment is withdrawn, even though azithromycin therapy is not reinstated. Correlation between the long tissue half-life and duration of allergic symptoms has not yet been determined. Anaphylaxis (anaphylactoid reactions, anaphylactic shock) has been reported, including fatal cases.

Systemic azithromycin therapy has been associated with cases of acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly and is associated with a fever above 38 degrees C. Typically, the first episode of AGEP appears 2 to 3 weeks after exposure to the inciting drug; however, unintentional reexposure may cause a second episode within 2 days.

Ocular irritation was the most frequently reported adverse reaction after ophthalmic administration of azithromycin and occurred in approximately 1% to 2% of patients. Other reported adverse reactions occurring in less than 1% of patients included blurred vision, corneal erosion, ocular discharge, ocular pain (burning, stinging, and irritation upon instillation), ocular pruritus, punctate keratitis, visual impairment (reduced visual acuity), and xerophthalmia.
The exacerbation of myasthenia gravis symptoms as well as the new onset of myasthenic syndrome have been reported with systemic azithromycin therapy. While rare, this side effect has been reported with other macrolide antibacterial agents.

Laboratory abnormalities have been noted with systemic azithromycin use. These include decreased bicarbonate (up to 1%), increased bicarbonate (less than 1%), hyperkalemia (1% to 2%), hypokalemia (less than 1%), hyponatremia (less than 1%), hyperglycemia and hypoglycemia (up to 1%), elevated phosphokinase (1% to 2%), elevated serum alkaline phosphatase (less than 1%), elevated LDH (up to 3%), and elevated phosphate (less than 1%).
An increased relapse rate of cancers of the blood or lymph nodes (i.e., leukemia, lymphoma), including death, has been observed in allogeneic stem cell transplant patients who were receiving azithromycin as prophylaxis for bronchiolitis obliterans syndrome (BOS). In a clinical trial (n = 480) evaluating the effectiveness of long-term azithromycin to prevent BOS in patients who undergo donor stem cell transplants for cancers of the blood or lymph nodes, cancer relapse was observed in 32.9% of azithromycin-treated patients vs. 20.8% of patients who were given a placebo. The 2-year survival rate was 56.6% in azithromycin-treated patients vs. 70.1% in those given a placebo.

Renal adverse reactions in patients receiving systemic regimens of azithromycin included nephritis (up to 1% adults) and dysuria (up to 1% pediatric patients). Elevated BUN (azotemia) and elevated creatinine occurred in up to 1% of patients, with elevated creatinine reported in 4% to 6% of patients receiving IV therapy. Postmarketing adverse reactions have also included acute renal failure (unspecified) and interstitial nephritis.

Azithromycin has been associated with infantile hypertrophic pyloric stenosis (IHPS), particularly in newborns younger than 2 weeks of age. In a retrospective study of 148 infants given azithromycin during the first 14 days of life, IHPS developed in 3 patients (2%) for an odds ratio (OR) of 8.26 (95% CI: 2.62 to 26; p less than 0.001). Of 729 infants aged 15 to 42 days at the time of azithromycin exposure, 5 patients developed IHPS for an OR of 2.98 (95% CI: 1.24 to 7.2; p = 0.015). No infants aged 43 to 90 days at the time of azithromycin exposure developed IHPS. A male predominance was also observed, as all 8 infants who developed IHPS were boys. IHPS was also reported in 2 former 32-week premature infants (2 out of 3 triplets) who received 5 days of azithromycin after hospitalization at 7 weeks of age. The infants were diagnosed with IHPS at 89 and 94 days of age, respectively, and both infants underwent surgical pyloromyotomies. Infants, particularly males who receive azithromycin within the first few weeks of life, should be closely monitored for signs and symptoms of IHPS for 6 weeks after azithromycin treatment. Pyloric stenosis rarely affects infants older than 3 months. Pyloric stenosis has been noted in postmarketing reports.

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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