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Capsules: Infections caused by susceptible organisms in lower respiratory tract including bronchitis and pneumonia, skin and soft tissue infections, otitis media, upper respiratory tract infections including sinusitis and pharyngitis, tonsilitis, also in the treatment of uncomplicated genital infections due to chlamydia trachomatis.
Powder for Oral Suspension: Infections caused by susceptible organisms in lower respiratory tract including bronchitis and pneumonia, skin and soft tissue infections, otitis media, upper respiratory tract infections including sinusitis and pharyngitis, tonsilitis, also in the treatment of uncomplicated genital infections due to chlamydia trachomatis.
Intravenous: Treatment of infections caused by susceptible strains of the designated microorganisms in the following conditions: community-acquired pneumonia and pelvic inflammatory disease.
Prolonged-release granules for oral suspension in adults: Adults (18 years of age and above): 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.
Oral azithromycin should be administered as a single daily dose. The period of dosing with regard to infection is given below. Administration of azithromycin capsules following a substantial meal reduces bioavailability by at least 50%. Therefore, in common with many other antibiotics, each dose of the capsules should be taken at least 1 hour before or 2 hours after food. Powder for oral suspension can be taken with or without food.
In Adults: For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis, , the dose is 1000 mg as a single oral dose.
ZITHROMAX IV: For the treatment of adult patients with CAP due to the indicated organisms, the recommended dose of intravenous azithromycin is 500 mg as a single daily dose by the IV route for at least two days. Intravenous therapy should be followed by oral azithromycin at a single daily dose of 500 mg to complete a 7 to 10 day course of therapy. The timing of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response. For the treatment of adult patients with PID due to the indicated organisms, the recommended dose of intravenous azithromycin is 500 mg as a single dose by the IV route for one or two days. Intravenous therapy should be followed by azithromycin by the oral route at a single daily dose of 250 mg to complete a 7-day course of therapy. The timing of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial anaerobic agent may be administered in combination with azithromycin.
For all other indications in which the oral formulation is administered, the total dosage of 1500 mg should be given as 500 mg daily for 3 days. As an alternative, the same total dose can be given over 5 days with 500 mg given on day 1, then 250 mg daily on days 2 to 5.
Intravenous Administration: After reconstitution and dilution, the recommended route of administration for intravenous azithromycin is by IV infusion only. Do not administer as an intravenous bolus or an intramuscular injection. The infusate concentration and rate of infusion for azithromycin intravenous (IV) should be either 1 mg/ml over 3 hours or 2 mg/ml over 1 hour. An intravenous dose of 500 mg azithromycin should be infused for a minimum duration of one (1) hour.
In Children: Children over 45kg body weight and adults, including elderly patients: The total dose of azithromycin is 1500mg which should be given over three days (500mg once daily). In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000mg as a single oral dose.
In general, the total dose in children is 30 mg/kg. Treatment for pediatric streptococcal pharyngitis should be dosed at a different regimen. The total dose of 30 mg/kg should be given as a single daily dose of 10 mg/kg daily for 3 days, or given over 5 days with a single daily dose of 10 mg/kg on day 1, then 5 mg/kg on days 2-5. As an alternative to the above dosing, treatment for children with acute otitis media can be given as a single dose of 30 mg/kg.
For pediatric streptococcal pharyngitis, azithromycin given as a single dose of 10 mg/kg or 20 mg/kg for 3 days has been shown to be effective; however, a daily dose of 500 mg must not be exceeded. In clinical trials comparing these two dosage regimens, similar clinical efficacy was observed but greater bacteriologic eradication was evident at the 20 mg/kg per day dose. However, penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including prophylaxis of rheumatic fever. For children weighing less than 15 kg, azithromycin suspension should be measured as closely as possible. For children weighing 15 kg or more, azithromycin suspension, should be administered according to the guide provided below. There is no information on children less than 6 months of age.
In the Elderly: The same dosage as in adult patients is used in the elderly. Elderly patients may be more susceptible to development of torsades de pointes arrhythmia than younger patients.
In Patients with Renal Impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 – 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min.
In Patients with Hepatic Impairment: The same dosage as in patients with normal hepatic function may be used in patients with mild to moderate hepatic impairment. Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin.
For full details see prescribing information.
For the treatment of patients 16 years of age and above with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Adults: 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.
Hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients. Patients receiving ergot derivatives.
Hypersensitivity As with erythromycin and other macrolides, rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and 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.
Hepatotoxicity Since liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease.
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.
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
Clostridium difficile-associated diarrhea Clostridium difficile associated diarrhea (CDAD) 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 antimicrobial 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.
Renal Impairment In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed. Azithromycin 40 mg/ml powder for oral suspension: Caution in diabetic patients: 5 ml of reconstituted suspension contain 3.87 g of sucrose.
Diabetes Due to the sucrose content (3.87 g / 5 ml of reconstituted suspension), this medicinal product is not indicated for persons with fructose intolerance (hereditary fructose intolerance), glucose-galactose malabsorption or saccharase-isomaltase deficiency. Prolongation of the QT interval Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including 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 congenital or documented QT prolongation a history of torsades de pointes, bradyarrhythmias or uncompensated heart failure
– Patients currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of classes IA ( quinidine,procainamide) and III(dofetilide,aminodarone,sotalol); antipsychotic agents; antidepressants; and fluoroquinolones
– Patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia
– Patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency
– Elderly patients: elderly patients may be more susceptible to drug-associated effects on the QT interval
Intravenous Administration Azithromycin for injection should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes. Do not administer as an intravenous bolus or an intramuscular injection. Azithromycin prolonged-release granules: Azithromycin prolonged-release granules for oral suspension contain 19.36 g of sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Azithromycin prolonged-release granules for oral suspension contain 148 mg of sodium.
For full details see prescribing information.
Azithromycin is well tolerated with a low incidence of side effects.
In clinical trials, the following undesirable effects have been reported:
Blood and Lymphatic System Disorders: Transient episodes of mild neutropenia have occasionally been observed in clinical trials.
Ear and Labyrinth Disorders: Hearing impairment (including hearing loss, deafness and/or tinnitus) has been reported in some patients receiving azithromycin. Many of these have been associated with prolonged use of high doses in investigational studies. In those cases where follow-up information was available the majority of these events were reversible.
Gastrointestinal Disorders: Nausea, vomiting, diarrhea, loose stools, abdominal discomfort (pain/cramps), and flatulence. Hepatobiliary Disorders: Abnormal liver function. Skin and Subcutaneous Tissue Disorders: Allergic reactions including rash and angioedema.
General Disorders and Administration Site Conditions: Local pain and inflammation at the site of infusion.
The following undesirable effects have been reported in association with DMAC prophylaxis and treatment clinical trials:
The most frequent (>5% in any treatment group) adverse reactions in HIV-infected patients receiving azithromycin for prophylaxis for DMAC were diarrhea, abdominal pain, nausea, loose stools, flatulence, vomiting, dyspepsia, rash, pruritus, headache, and arthralgia. When azithromycin 600 mg is given daily for the treatment of DMAC infection for prolonged periods, the most frequently reported treatment-related side effects are abdominal pain, nausea, vomiting, diarrhea, flatulence, headache, abnormal vision, and hearing impairment.
The following have been reported with clinical trials in adults with azithromcyin prolonged- release granules: The data described below reflect exposure to azithromycin prolonged-release granules in 1292 adult patients in Phase III studies. The population studied had acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community acquired pneumonia, or pharyngitis/tonsillitis.
Overall, the most common adverse reactions in adult patients receiving a single 2 g dose of azithromycin prolonged-release granules for oral suspension were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of gastrointestinal adverse reactions was 17% for azithromycin prolonged-release granules for oral suspension and 10% for pooled comparators.
Adverse reactions following azithromycin prolonged-release granules for oral suspension treatment that occurred with a frequency of <1% included the following:
Infections and infestations: pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, oral candidiasis, respiratory disorder, rhinitis, vaginal infection Blood and the lymphatic system disorders: leukopenia, eosinophilia Metabolism and nutrition disorders: decreased appetite Psychiatric disorders: insomnia Nervous system disorders: paraesthesia, dizziness, dysgeusia Eye disorders: visual impairment Ear and labyrinth disorders: vertigo, ear disorder Cardiac disorders: palpitations Vascular disorders: hot flush Respiratory, thoracic and mediastinal disorders: dyspnoea, epistaxis Gastrointestinal disorders: gastritis, dysphagia, abdominal distension, constipation, dry mouth, dyspepsia, eructation, mouth ulceration, salivary hypersecretion, flatulence Skin and subcutaneous tissue disorders: pruritus, urticaria, rash, dermatitis, dry skin, hyperhidrosis Musculoskeletal, connective tissue and bone disorders: osteoarthritis, myalgia, back pain, neck pain Renal and urinary disorders: dysuria, renal pain Reproductive system and breast disorders: metrorrhagia, testicular disorder General disorders and administration site conditions: chest pain, oedema, face oedema, oedema peripheral, asthenia, pain, pyrexia, malaise Investigations: blood alkaline phosphatase increased, aspartate aminotransferase increased, alanine aminotransferase increased Injury and poisoning: post procedural complication
Laboratory Abnormalities: In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Azithromycin prolonged-release granules for oral suspension clinical trials: – with an incidence of ≥ 1%: increased basophils, eosinophils, monocytes, and neutrophils; decreased bicarbonate; abnormal lymphocytes – with an incidence of < 1%: increased alanine aminotransferase, aspartate aminotransferase, bicarbonate, bilirubin, blood urea, chloride, creatinine, glucose, and platelets; decreased hematocrit; abnormal potassium, sodium, and white blood cell count Where follow-up was provided, changes in laboratory tests appeared to be reversible. In post-marketing experience, the following additional undesirable effects have been reported: Infections and Infestations: Moniliasis and vaginitis.
Blood and Lymphatic System Disorders: Thrombocytopenia.
Immune System Disorders: Anaphylaxis (rarely fatal)
Metabolism and Nutrition Disorders: Anorexia.
Psychiatric Disorders: Aggressive reaction, nervousness, agitation, and anxiety. Nervous System Disorders: Dizziness, convulsions, headache, hyperactivity, hypoesthesia, paresthesia, somnolence, insomnia, asthenia, and syncope. There have been rare reports of taste/smell perversion and/or loss.
Ear and Labyrinth Disorders: Deafness, tinnitus, hearing impaired,vertigo Cardiac Disorders: Palpitations and arrhythmias including ventricular tachycardia have been reported. There have been rare reports of QT prolongations and torsades de pointes.
Vascular Disorders: Hypotension.
Gastrointestinal Disorders: Vomiting/diarrhea (rarely resulting in dehydration), dyspepsia, constipation, digestive disorders, anorexia, pseudomembranous colitis, pancreatitis, and rare reports of tongue discoloration Hepatobiliary Disorders: Hepatitis and cholestatic jaundice have been reported, as well as rare cases of hepatic necrosis and hepatic failure, which have resulted in death(see Section 4.4 Special warnings and precautions for use, Hepatotoxicity). Skin and Subcutaneous Tissue Disorders: Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria, and angioedema. Rarely, serious skin reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported.
Musculoskeletal and Connective Tissue Disorders: Arthralgia.
Renal and Urinary Disorders: Interstitial nephritis and acute renal failure.
Reproductive system and breast disorders: Vaginitis.
General Disorders and Administration Site Conditions: Asthenia has been reported, fatigue, and malaise.
Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously. Co-administration of azithromycin prolonged-release granules for oral suspension with a single 20 ml dose of co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.
Cetirizine: In healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (Dideoxyinosine): Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.
Digoxin: Concomitant administration of macrolide antibiotics including azithromycin with P-glycoprotein substrates such as digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.
Zidovudine: Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Ergot: Due to the theoretical possibility of ergotism, Zithromax and ergot derivatives should not be coadministered. Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.
Atorvastatin: Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, postmarketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported. Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.
Coumarin-Type Oral Anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.
Cyclosporin: In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz: Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole: Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
Indinavir: Coadministration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.
Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam: In healthy volunteers, coadministration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.
Nelfinavir: Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750mg three times daily) resulted in a 100% increase azithromycin absorption and bioavailability. There was no significant effect upon the rate of absorption or the rate of clearance. The clinical consequences of this interaction are unknown, caution should be exercised when prescribing azithromycin to patients tanking nelfinavir.
Rifabutin: Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established.
Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500mg daily for 3 days) on the AUC and Cmax, of sildenafil or its major circulating metabolite. Terfenadine: Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other anti-infectives in conjunction with terfenadine, pharmacokinetic interaction studies have been performed. These studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred. As with other macrolides, azithromycin should be administered with caution in combination with terfenadine.
Theophylline: Theophylline levels may be increased in patients taking azithromycin.
Triazolam: In 14 healthy volunteers, coadministration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole: Coadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies. For full details see prescribing information.
Pregnancy and Lactation
Use in pregnancy: Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should not be used during pregnancy unless clearly necessary.
Use in lactation: Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk. In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic and supportive measures are indicated as required