Long term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no genotoxic or mutagenic potential in standard laboratory tests (see 16 NON-CLINICAL TOXICOLOGY).
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including azithromycin (see 8 ADVERSE REACTIONS). Prescribers should consider the risk of QT prolongation which can lead to fatal events when weighing the risks and benefits of azithromycin. Risk factors for torsade de pointes include patients:
There is information that 'QT Related Adverse Events' may occur in some patients receiving azithromycin. There have been spontaneous reports from post‑marketing experience of prolonged QT interval and torsade de pointes (see 8.5 Post-Market Adverse Reactions). These include but are not limited to: one AIDS patient dosed at 750 mg to 1 g daily experienced prolonged QT interval and torsade de pointes; a patient with previous history of arrhythmias who experienced torsade de pointes and subsequent myocardial infarction following a course of azithromycin therapy; and a pediatric case report of prolonged QT interval experienced at a therapeutic dose of azithromycin which reversed to normal upon discontinuation (see 10 CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).
In the absence of data on the metabolism and pharmacokinetics in patients with lysosomal lipid storage diseases (e.g., Tay-Sachs disease, Niemann-Pick disease) the use of ZITHROMAX in these patients is not recommended.
A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Azithromycin was administered to a limited number of subjects with GFR<10 mL/min.
Clostridium difficile-associated disease
Clostridium difficile associated disease (CDAD) has been reported with use of many antibacterial agents including azithromycin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agents. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 8 ADVERSE REACTIONS).
Severe neutropenia (WBC < 1000/mm3) may adversely affect the distribution of azithromycin and its transport to the site of infection. Antibacterials with proven efficacy in this population should be used, as outlined by the relevant guidelines for treatment of patients with severe neutropenia. Efficacy and safety of azithromycin have not been studied in patients with severe neutropenia.
Since the liver is the principal route of elimination for azithromycin, the use of oral ZITHROMAX preparations should be undertaken with caution in patients with impaired hepatic function. Azithromycin has not been studied in patients with severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).
Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with hepatic impairment.
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Rare cases of acute hepatic necrosis requiring liver transplant or causing death have been reported in patients following treatment with oral azithromycin. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur (see 8 ADVERSE REACTIONS).
Allergic reactions may occur during and soon after treatment with ZITHROMAX. 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. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Monitoring of QT/QTc intervals during treatment with ZITHROMAX may be considered by the physician as appropriate.
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. The use of azithromycin in patients with a known history of myasthenia gravis is not recommended.
The safety, efficacy and pharmacokinetics of Zithromax in patients with renal impairment have not been established. No dose adjustment is recommended for patients with GFR 10-80 mL/min. Caution should be exercised when Zithromax is administered to patients with GFR <10 mL/min. This precaution is based on a clinical study of azithromycin immediate-release tablets, in which patients with GFR <10 mL/min showed a significant (61%) increase in mean Cmax and a significant (35%) increase in systemic exposure to azithromycin, and experienced a high incidence of gastrointestinal adverse events (8 of 19 clinical study subjects). Patients with GFR 10-80 mL/min showed only slightly increased serum azithromycin levels compared to patients with normal renal function.
Due to limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing oral azithromycin in these patients (see 10 CLINICAL PHARMACOLOGY).
Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with renal impairment (including patients on dialysis).
There are no adequate and well-controlled studies in humans. In fertility studies conducted in the rat, reduced pregnancy rates were noted following administration of azithromycin. The predictive value of these data to the response in humans has not been established (see 16 NON-CLINICAL TOXICOLOGY).
Prescribing ZITHROMAX 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.
Serious allergic reactions, including angioedema, anaphylaxis, and dermatological reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermolysis, toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic symptoms (DRESS) have been reported rarely (with rare reports of fatalities), in patients on ZITHROMAX (azithromycin dihydrate) therapy (see 2 CONTRAINDICATIONS).
Azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any potential risk to the fetus.
There is a large amount of data from observational studies performed in several countries on exposure to azithromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period. While most studies do not suggest an association with adverse fetal effects such as major congenital malformations or cardiovascular malformations, there is limited epidemiological evidence of an increased risk of miscarriage following azithromycin exposure in early pregnancy.
In animal reproduction studies in mice and rats, at azithromycin doses up to 200 mg/kg/day (moderately maternally toxic), effects were noted in the rat at 200 mg/kg/day, during the prenatal development period (delayed ossification) and during the postnatal development period (decreased viability, delayed developmental landmarks, differences in performance of learning task). The 200 mg/kg/day dose in mice and rats, is approximately 0.5-fold and 1-fold, respectively, the single adult oral dose of 2 g, based on mg/m2 (body surface area). Pharmacokinetic data from the 200 mg/kg/day dose level in these studies showed that azithromycin crossed the placenta and distributed to fetal tissue at 5 to 9-fold the maternal plasma Cmax of 2 ug/mL (see 16 NON-CLINICAL TOXICOLOGY).
ZITHROMAX should not be used in the treatment of nursing women unless the expected benefit to the mother outweighs any potential risk to the infant. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Because azithromycin may accumulate in breast milk over time with continued ZITHROMAX therapy, if the lactating mother is treated with ZITHROMAX, the breast milk should be expressed and discarded during treatment.
Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. However, the safety of azithromycin has not been studied in infants less than 6 months of age.
Pediatrics (< 18 years of age):
Acute Otitis Media: Safety and efficacy in the treatment of children with otitis media under 6 months of age have not been established.
Community-acquired pneumonia: Safety and efficacy in the treatment of children with communityacquired pneumonia under 6 months of age have not been established.
Pharyngitis and tonsillitis: Safety and efficacy in the treatment of children with pharyngitis and tonsillitis under 2 years of age have not been established.
Studies evaluating the use of repeated courses of therapy have not been conducted. Safety data with the use of ZITHROMAX at doses higher than proposed and for durations longer than recommended are limited to a small number of immunocompromised children who underwent chronic treatment.
Infantile hypertrophic pyloric stenosis (IHPS)
Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.
The safety and effectiveness of ZITHROMAX for Injection in children or adolescents under 16 years have not been established.
Prevention of Disseminated Mycobacterium Avium Complex (MAC) Disease:
Safety and efficacy of ZITHROMAX for the prevention of MAC in children have not been established.
Limited safety data are available for 24 children 5 months to 14 years of age (mean 4.6 years) who received ZITHROMAX for treatment of opportunistic infections. The mean duration of therapy was 186.7 days (range 13-710 days) at doses of <5 to 20 mg/kg/day. Adverse events were similar to those observed in the adult population, most of which involved the gastrointestinal tract. While none of these children prematurely discontinued treatment due to a side effect, one child discontinued due to a laboratory abnormality (eosinophilia). Based on available pediatric pharmacokinetic data, a dose of 20 mg/kg in children would provide drug exposure similar to the 1200 mg adult dose but with a higher Cmax.
The pharmacokinetics in elderly volunteers (age 65 to 85) were similar to those in younger volunteers (age 18 to 40) for the 5-day oral therapeutic regimen. Dosage adjustment does not appear to be necessary for elderly patients with normal renal and hepatic function receiving treatment with this dosage regimen. Pharmacokinetic studies with intravenous azithromycin have not been performed in the elderly. Based on clinical trials, there appear to be no significant differences in safety or tolerance of intravenous azithromycin between elderly (age ≥ 65) and younger subjects (ages 16 to ≤ 64).
However, elderly patients may be more susceptible to development of torsade de pointes arrhythmias.
Long term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no genotoxic or mutagenic potential in standard laboratory tests (see 16 NON-CLINICAL TOXICOLOGY).
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including azithromycin (see 8 ADVERSE REACTIONS). Prescribers should consider the risk of QT prolongation which can lead to fatal events when weighing the risks and benefits of azithromycin. Risk factors for torsade de pointes include patients:
There is information that 'QT Related Adverse Events' may occur in some patients receiving azithromycin. There have been spontaneous reports from post‑marketing experience of prolonged QT interval and torsade de pointes (see 8.5 Post-Market Adverse Reactions). These include but are not limited to: one AIDS patient dosed at 750 mg to 1 g daily experienced prolonged QT interval and torsade de pointes; a patient with previous history of arrhythmias who experienced torsade de pointes and subsequent myocardial infarction following a course of azithromycin therapy; and a pediatric case report of prolonged QT interval experienced at a therapeutic dose of azithromycin which reversed to normal upon discontinuation (see 10 CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).
In the absence of data on the metabolism and pharmacokinetics in patients with lysosomal lipid storage diseases (e.g., Tay-Sachs disease, Niemann-Pick disease) the use of ZITHROMAX in these patients is not recommended.
A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Azithromycin was administered to a limited number of subjects with GFR<10 mL/min.
Clostridium difficile-associated disease
Clostridium difficile associated disease (CDAD) has been reported with use of many antibacterial agents including azithromycin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agents. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 8 ADVERSE REACTIONS).
Severe neutropenia (WBC < 1000/mm3) may adversely affect the distribution of azithromycin and its transport to the site of infection. Antibacterials with proven efficacy in this population should be used, as outlined by the relevant guidelines for treatment of patients with severe neutropenia. Efficacy and safety of azithromycin have not been studied in patients with severe neutropenia.
Since the liver is the principal route of elimination for azithromycin, the use of oral ZITHROMAX preparations should be undertaken with caution in patients with impaired hepatic function. Azithromycin has not been studied in patients with severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).
Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with hepatic impairment.
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Rare cases of acute hepatic necrosis requiring liver transplant or causing death have been reported in patients following treatment with oral azithromycin. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur (see 8 ADVERSE REACTIONS).
Allergic reactions may occur during and soon after treatment with ZITHROMAX. 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. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Monitoring of QT/QTc intervals during treatment with ZITHROMAX may be considered by the physician as appropriate.
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. The use of azithromycin in patients with a known history of myasthenia gravis is not recommended.
The safety, efficacy and pharmacokinetics of Zithromax in patients with renal impairment have not been established. No dose adjustment is recommended for patients with GFR 10-80 mL/min. Caution should be exercised when Zithromax is administered to patients with GFR <10 mL/min. This precaution is based on a clinical study of azithromycin immediate-release tablets, in which patients with GFR <10 mL/min showed a significant (61%) increase in mean Cmax and a significant (35%) increase in systemic exposure to azithromycin, and experienced a high incidence of gastrointestinal adverse events (8 of 19 clinical study subjects). Patients with GFR 10-80 mL/min showed only slightly increased serum azithromycin levels compared to patients with normal renal function.
Due to limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing oral azithromycin in these patients (see 10 CLINICAL PHARMACOLOGY).
Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with renal impairment (including patients on dialysis).
There are no adequate and well-controlled studies in humans. In fertility studies conducted in the rat, reduced pregnancy rates were noted following administration of azithromycin. The predictive value of these data to the response in humans has not been established (see 16 NON-CLINICAL TOXICOLOGY).
Prescribing ZITHROMAX 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.
Serious allergic reactions, including angioedema, anaphylaxis, and dermatological reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermolysis, toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic symptoms (DRESS) have been reported rarely (with rare reports of fatalities), in patients on ZITHROMAX (azithromycin dihydrate) therapy (see 2 CONTRAINDICATIONS).
Azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any potential risk to the fetus.
There is a large amount of data from observational studies performed in several countries on exposure to azithromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period. While most studies do not suggest an association with adverse fetal effects such as major congenital malformations or cardiovascular malformations, there is limited epidemiological evidence of an increased risk of miscarriage following azithromycin exposure in early pregnancy.
In animal reproduction studies in mice and rats, at azithromycin doses up to 200 mg/kg/day (moderately maternally toxic), effects were noted in the rat at 200 mg/kg/day, during the prenatal development period (delayed ossification) and during the postnatal development period (decreased viability, delayed developmental landmarks, differences in performance of learning task). The 200 mg/kg/day dose in mice and rats, is approximately 0.5-fold and 1-fold, respectively, the single adult oral dose of 2 g, based on mg/m2 (body surface area). Pharmacokinetic data from the 200 mg/kg/day dose level in these studies showed that azithromycin crossed the placenta and distributed to fetal tissue at 5 to 9-fold the maternal plasma Cmax of 2 ug/mL (see 16 NON-CLINICAL TOXICOLOGY).
ZITHROMAX should not be used in the treatment of nursing women unless the expected benefit to the mother outweighs any potential risk to the infant. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Because azithromycin may accumulate in breast milk over time with continued ZITHROMAX therapy, if the lactating mother is treated with ZITHROMAX, the breast milk should be expressed and discarded during treatment.
Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. However, the safety of azithromycin has not been studied in infants less than 6 months of age.
Pediatrics (< 18 years of age):
Acute Otitis Media: Safety and efficacy in the treatment of children with otitis media under 6 months of age have not been established.
Community-acquired pneumonia: Safety and efficacy in the treatment of children with communityacquired pneumonia under 6 months of age have not been established.
Pharyngitis and tonsillitis: Safety and efficacy in the treatment of children with pharyngitis and tonsillitis under 2 years of age have not been established.
Studies evaluating the use of repeated courses of therapy have not been conducted. Safety data with the use of ZITHROMAX at doses higher than proposed and for durations longer than recommended are limited to a small number of immunocompromised children who underwent chronic treatment.
Infantile hypertrophic pyloric stenosis (IHPS)
Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.
The safety and effectiveness of ZITHROMAX for Injection in children or adolescents under 16 years have not been established.
Prevention of Disseminated Mycobacterium Avium Complex (MAC) Disease:
Safety and efficacy of ZITHROMAX for the prevention of MAC in children have not been established.
Limited safety data are available for 24 children 5 months to 14 years of age (mean 4.6 years) who received ZITHROMAX for treatment of opportunistic infections. The mean duration of therapy was 186.7 days (range 13-710 days) at doses of <5 to 20 mg/kg/day. Adverse events were similar to those observed in the adult population, most of which involved the gastrointestinal tract. While none of these children prematurely discontinued treatment due to a side effect, one child discontinued due to a laboratory abnormality (eosinophilia). Based on available pediatric pharmacokinetic data, a dose of 20 mg/kg in children would provide drug exposure similar to the 1200 mg adult dose but with a higher Cmax.
The pharmacokinetics in elderly volunteers (age 65 to 85) were similar to those in younger volunteers (age 18 to 40) for the 5-day oral therapeutic regimen. Dosage adjustment does not appear to be necessary for elderly patients with normal renal and hepatic function receiving treatment with this dosage regimen. Pharmacokinetic studies with intravenous azithromycin have not been performed in the elderly. Based on clinical trials, there appear to be no significant differences in safety or tolerance of intravenous azithromycin between elderly (age ≥ 65) and younger subjects (ages 16 to ≤ 64).
However, elderly patients may be more susceptible to development of torsade de pointes arrhythmias.
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