Zithracin

Before reconstitution: A white to yellowish brown granular powder with fruity flavor.
After reconstitution: A white to yellowish brown suspension with fruity flavor.
Active Ingredient: Each 5 ml contains: Azithromycin dihydrate 209.61 mg (eq. Azithromycin 200 mg).
Excipients/Inactive Ingredients: Basic butylated methacrylate copolymer, Sodium lauryl sulfate, Stearic acid fine powder, Icing sugar, Aspartame, Sodium phosphate, Cellulose, Xanthan gum, Silicon dioxide, Tutti fruity flavour and Purified water.

Pharmacology: Pharmacodynamics: Mechanism of action: Azithromycin is the first of a subclass of macrolide antibiotics, known as azalides, and is chemically different from erythromycin. Chemically, it is derived by insertion of a nitrogen atom into the lactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0. Azithromycin binds to the 23S rRNA of the 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.
Antibacterial spectrum: Organisms that are commonly susceptible to azithromycin include: Aerobic and facultative gram-positive bacteria (erythromycin-susceptible isolates): S.aureus, Streptococcus agalactiae,* S. pneumoniae,* Streptococcus pyogenes,* other β-hemolytic streptococci (Groups C, F, G), and viridans streptococci.
Macrolide-resistant isolates are encountered relatively frequently among aerobic and facultative gram-positive bacteria, in particular among methicillin-resistant S. aureus (MRSA) and penicillin-resistant S. pneumoniae (PRSP).
Aerobic and facultative gram-negative bacteria: Bordetella pertussis, Haemophilus ducreyi,* Haemophilus influenzae,* Haemophilus parainfluenzae,* Legionella pneumophila, Moraxella catarrhalis,* and Neisseria gonorrhoeae.* Pseudomonas spp. and most Enterobacteriaceae are inherently resistant to azithromycin, although azithromycin has been used to treat Salmonella enterica infections.
Anaerobes: Clostridium perfringens, Peptostreptococcus spp., and Prevotella bivia.
Other bacterial species: Borrelia burgdorferi, Chlamydia trachomatis, Chlamydophila pneumoniae,* Mycoplasma pneumoniae,* Treponema pallidum, and Ureaplasma urealyticum.
Opportunistic pathogens associated with HIV infection: Eukaryotic microorganisms, Pneumocystis jirovecii and Toxoplasma gondii.
* The efficacy of azithromycin against the indicated species has been demonstrated in clinical trials.
Pharmacokinetics: Absorption: Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailability is approximately 37%. The time taken to peak plasma levels is 2 to 3 hours.
Distribution: In animal studies, high azithromycin concentrations have been observed in phagocytes. In experimental models, higher concentrations of azithromycin are released during active phagocytosis than from non-stimulated phagocytes. In animal models, this results in high concentrations of azithromycin being delivered to the site of infection. Pharmacokinetic studies in humans have shown markedly higher azithromycin levels in tissues than in plasma (up to 50 times the maximum observed concentration in plasma), indicating that the drug is heavily tissue bound. Concentrations in target tissues, such as lung, tonsil, and prostate, exceed the MIC90 for likely pathogens after a single dose of 500 mg.
Elimination: Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. Approximately 12% of an intravenously administered dose is excreted in the urine over 3 days as the parent drug, the majority in the first 24 hours. Biliary excretion of azithromycin is a major route of elimination for unchanged drug following oral administration. Very high concentrations of unchanged drug have been found in human bile, together with 10 metabolites, formed by N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of HPLC and microbiological assays in tissues suggests that metabolites play no part in the microbiological activity of azithromycin.
Pharmacokinetics in special patient groups: Elderly: In elderly volunteers (>65 years), slightly higher AUC values were seen after a 5-day regimen than in young volunteers (<40 years), but these are not considered clinically significant, and hence no dose adjustment is recommended.
Renal Impairment: The pharmacokinetics of azithromycin in subjects with GFR 10-80 ml/min were not affected following a single 1 gram dose of immediate-release azithromycin. Statistically significant differences in AUC_0-120 (8.8 μg·h/ml vs. 11.7 μg·h/ml), C_max (1.0 μg/ml vs. 1.6 μg/ml), and CLr (2.3 ml/min/kg vs. 0.2 ml/min/kg) were observed between the group with GFR <10 ml/min and GFR >80 ml/min.
Hepatic Impairment: In patients with mild (Class A) to moderate (Class B) hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients, urinary clearance of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance.

Oral azithromycin is indicated for infections caused by susceptible organisms; in lower respiratory tract infections, including bronchitis and pneumonia, in skin and soft tissue infections, in acute otitis media, and in upper respiratory tract infections, including sinusitis and pharyngitis/tonsillitis.
(Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin is generally effective in the eradication of streptococci from the oropharynx; however, data establishing the efficacy of azithromycin and the subsequent prevention of rheumatic fever are not available at present.)
In sexually transmitted diseases in men and women, azithromycin is indicated for the treatment of uncomplicated genital infections due to Chlamydia trachomatis. It is also indicated for the treatment of chancroid due to Haemophilus ducreyi and uncomplicated genital infections due to non-multiresistant Neisseria gonorrhoeae; concurrent infection with Treponema pallidum should be excluded.

Azithromycin Oral: Oral azithromycin should be administered as a single daily dose. The period of dosing with regard to infection is given as follows.
Azithromycin powder for oral suspension can be taken with or without food.
In Adults: For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis and Haemophilus ducreyi, or susceptible Neisseria gonorrhoeae, the dose is 1000 mg as a single oral dose.
For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.
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.
In Children: The maximum recommended total dose for any treatment is 1500 mg for children. In general, the total dose in children is 30 mg/kg. Treatment for pediatric streptococcal pharyngitis should be dosed at a different regimen (see as follows). The total dose of 30 mg/kg should be given as a single daily dose of 10 mg/kg 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 previously mentioned 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/day dose. However, penicillin is the usual drug of choice for 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 as follows. (See table.)

Click on icon to see table/diagram/image

Special populations: In the Elderly: The same dosage as in adult patients is used in the elderly. Elderly patients may be more susceptible to the development of torsades de pointes arrhythmia than younger patients.
In Patients with Renal Impairment: No dose adjustment is necessary in patients with GFR 10-80 mL/min. Caution should be exercised when azithromycin is administered to patients with 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.
Route of Administration(s): Oral azithromycin should be administered as a single daily dose. Azithromycin oral suspension can be taken with or without food.

Symptoms and Treatment of Overdose(s): Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any excipient listed in the Description.

Unsuitable for phenylketonurics.

Hypersensitivity: In the event of severe acute hypersensitivity reactions, such as angioedema, anaphylaxis, severe cutaneous adverse reactions (SCARs) [e.g. Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) & acute generalised exanthematous pustulosis (AGEP)], Zithracin should be discontinued immediately and appropriate treatment should beurgently initiated.
Hepatotoxicity: Use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
Infantile hypertrophic pyloric stenosis (IHPS): Infantile hypertrophic pyloric stenosis (IHPS) has been reported following the use of azithromycin in infants (treatment up to 42 days of life). Parents and caregivers should be informed to contact their physician if vomiting and/or irritability with feeding occurs.
Ergot derivatives: There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.
Superinfection: 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 the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. 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 2 months after the administration of antibacterial agents.
Renal impairment: In patients with severe renal impairment (GFR <10 ml/min), an increase in systemic exposure to azithromycin was observed.
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. Prescribers 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; Patients currently receiving treatment with other active substances known to prolong QT interval, such as antiarrhythmics of Classes IA and III, antipsychotic agents, antidepressants, and fluoroquinolones; Patients with electrolyte disturbance, particularly in cases of hypokalemia and hypomagnesemia; Patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency.
Myasthenia gravis: Exacerbations of the symptoms of myasthenia gravis have been reported in patients receiving azithromycin therapy.
Effects on Ability to Drive and Use Machines: There is no evidence to suggest that azithromycin may have an effect on a patient's ability to drive or operate machinery.
Use in the Elderly: elderly patients may be more susceptible to drug-associated effects on the QT interval.

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 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.
Azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any small increased risks which may exist.
Lactation: 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.
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.
Fertility: In fertility studies conducted in rats, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.

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: Frequency not known: severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) & acute generalised exanthematous pustulosis (AGEP).
General Disorders and Administration Site Conditions: Local pain and inflammation at the site of infusion.
Additional undesirable effects that have been reported in post-marketing experience: 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, and syncope. There have been rare reports of taste/smell perversion and/or loss.
Ear and Labyrinth Disorders: Deafness, tinnitus, hearing impaired, and 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, pseudomembranous colitis, pancreatitis, rare reports of tongue discoloration, and infantile hypertrophic pyloric stenosis.
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.
Skin and Subcutaneous Tissue Disorders: Allergic reactions, including pruritus, rash, photosensitivity, edema, urticaria, and angioedema. Rarely, serious cutaneous adverse reactions, including erythema multiforme, AGEP, SJS, TEN, and DRESS, have been reported.
Musculoskeletal and Connective Tissue Disorders: Arthralgia.
Renal and Urinary Disorders: Interstitial nephritis and acute renal failure.
General Disorders and Administration Site Conditions: Asthenia, fatigue, and malaise.

Antacids: Azithromycin and antacids should not be taken simultaneously, no effect on overall bioavailability was seen, but peak serum concentrations were reduced.
Cetirizine: Co-administration of a 5-day regimen of azithromycin with 20 mg cetirizine at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (Dideoxyinosine): Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared to placebo.
Digoxin and colchicine: Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates, such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.
Ergot: There is a theoretical possibility of interaction between azithromycin and ergot derivatives.
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.
Atorvastatin: Co-administration of 10 mg/day atorvastatin and azithromycin 500 mg/day did not alter the plasma concentrations of atorvastatin (based on an HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
Carbamazepine: No significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
Cimetidine: No alteration of azithromycin pharmacokinetics was seen in a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin.
Coumarin-type oral anticoagulants: 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 who 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 C_max and AUC_0-5 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: Co-administration of a single dose of 600 mg azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole: Co-administration 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, however, a clinically insignificant decrease in C_max of azithromycin was observed.
Indinavir: Co-administration 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: Azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam: Co-administration of 500 mg/day azithromycin for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of 15 mg midazolam.
Nelfinavir: Co-administration of 1200 mg azithromycin and nelfinavir at steady-state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed, and no dose adjustment was required.
Rifabutin: Co-administration 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: There was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and C_max of sildenafil or its major circulating metabolite.
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.
Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered.
Triazolam: Co-administration of 500 mg azithromycin 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: Co-administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with 1200 mg azithromycin on Day 7 had no significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole.

Store below 30°C for the powder and the reconstituted suspension.
Use within 5 days after reconstitution.
Protect from light and moisture.
Shelf Life(s): 2 years.

Macrolides

J01FA10 - azithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.

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