Zynomax

Zynomax

azithromycin

Manufacturer:

Duopharma Manufacturing (Bangi)

Distributor:

Duopharma Marketing
Full Prescribing Info
Contents
Azithromycin.
Action
Pharmacotherapeutic group: Macrolides. ATC code: J01FA.
Pharmacology: Pharmacodynamics: Azithromycin is the first of a subclass of macrolides 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 mode of action of azithromycin is inhibition of protein synthesis in bacteria by binding to the 50s ribosomal subunit and preventing translocation of peptides. Azithromycin demonstrates activity in vitro against a wide range of bacteria including: Gram-positive Aerobic Bacteria: Staphylococcus aureus, Streptococcus pyogenes (group A beta-hemolytic streptococci), Streptococcus pneumoniae, alpha-hemolytic streptococci (viridans group) and other streptococci, and Corynebacterium diphtheriae. Azithromycin demonstrates cross-resistance with erythromycin-resistant Gram-positive strains, including Streptococcus faecalis (enterococcus) and most strains of methicillin-resistant staphylococci.
Gram-negative Aerobic Bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter species, Yersinia species, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella species, Pasteurella species, Vibrio cholerae and parahaemolyticus, Plesiomonas shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila and Klebsiella species are variable and susceptibility tests should be performed. Proteus species, Serratia species, Morganella species, and Pseudomonas aeruginosa are usually resistant.
Anaerobic Bacteria: Bacteroides fragilis and Bacteroides species, Clostridium perfringens, Peptococcus species and Peptostreptococcus species, Fusobacterium necrophorum and Propionibacterium acnes.
Organisms of Sexually Transmitted Diseases: Azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae, and Haemophilus ducreyi.
Other Organisms: Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Campylobacter species and Listeria monocytogenes.
Opportunistic Pathogens Associated with HIV Infections: Mycobacterium avium-intracellulare complex, Pneumocystis carinii and Toxoplasma gondii.
Commonly Susceptible Species: Aerobic Gram-positive bacteria: Staphylococcus aureus, Streptococcus agalactiae, Streptococci (Groups C, F, G) and Viridans group streptococci.
Aerobic Gram-negative bacteria: Bordetella pertussis, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis and Neisseria gonorrhoeae.
Others: Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumonia and Ureaplasma urealyticum.
Species For Which Acquired Resistance Has Been Reported: Aerobic Gram-positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes.
Note: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.
Inherently resistant organisms: Enterobacteriaceae, Pseudomonas.
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 2-3 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 tissue 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.
Following oral administration of daily doses of 600 mg azithromycin, mean maximum plasma concentration (C max) was 0.33 μg/ml and 0.55 μg/ml at Day 1 and Day 22 respectively.
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, by hydroxylation of the desosamine and aglycone rings, and by 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 mild to moderate renal impairment were not affected following a single one gram dose of immediate release azithromycin. Statistically significant differences in AUC0-120, Cmax and CLr were observed between the group with severe renal impairment and the group with normal renal function.
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.
Indications/Uses
Zynomax 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. Zynomax is generally effective in the eradication of streptococci from the oropharynx, however, data establishing the efficacy of Zynomax and the subsequent prevention of rheumatic fever are not available at present.)
In sexually transmitted diseases in men and women, Zynomax is indicated in the treatment of uncomplicated genital infections due to Chlamydia trachomatis. It is also indicated in the treatment of chancroid due to Haemophilus ducreyi and uncomplicated genital infection due to non-multiresistant Neisseria gonorrhoeae; concurrent infection with Treponema pallidum should be excluded.
Powd for oral susp: Zynomax Powder for Oral Suspension 200mg/5ml is indicated, either alone or in combination with rifabutin, for prophylaxis against Mycobacterium avium-intracellulare complex (MAC) infection, an opportunistic infection prevalent in patients with advanced human immunodeficiency virus (HIV).
Dosage/Direction for Use
Oral Zynomax should be administered as a single daily dose. The period of dosing with regard to infection is given as follows. Zynomax can be taken with or without food.
In Adults: For the treatment of sexually transmitted disease caused by Chlamydia trachomatis, or non-multiresistant Neisseria gonorrhea, the dose is 1000 mg as a single oral dose.
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 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 30 mg/kg should be given as 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 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, Zynomax given as a single dose of 10mg/kg or 20mg/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, Zynomax should be measured as closely as possible. For children weighing 15 kg or more, Zynomax should be administered according to the guide provided as follows: (See table.)

Click on icon to see table/diagram/image

Tab: Zynomax tablets should only be administered to children weighing more than 45kg.
Powd for oral susp: Safety and efficacy for prevention or treatment of MAC in children have not been established. Based on pediatric pharmacokinetic data, a dose of 20 mg/kg would be similar to the adult dose of 1200 mg but with a higher Cmax.
Elderly: The same dosage as in adult patients is used in the elderly.
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 Zynomax is administered to patients with severe renal impairment (GFR < 10 ml/min).
Patients with Hepatic Impairment: The same dosage as in patients with normal hepatic function may used in patients with mild to moderate hepatic impairment.
Overdosage
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.
Contraindications
The use of Zynomax is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any excipient.
Special Precautions
As with erythromycin and other macrolides, rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), dermatologic reactions including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) (rarely fatal), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Some of these reactions with Zynomax 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.
Since liver is the principal route of elimination for Zynomax, the use of Zynomax should be undertaken with caution in patients with significant hepatic disease.
In patients receiving ergot derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and Zynomax. However, because of the theoretical possibility of ergotism, Zynomax and ergot derivatives should not be coadministered.
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Zynomax, 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.
In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to Zynomax was observed.
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 Zynomax. Prescribers should consider the risk of QT prolongation, which can be fatal, when weighing the risks and benefits of Zynomax 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.
Elderly patients: elderly patients may be more susceptible to drug-associated effects on the QT interval.
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.
In the event of severe acute hypersensitivity reactions, such as 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)], Zynomax should be discontinued immediately and appropriate treatment should be urgently initiated.
Effects on Ability to Drive and Use Machines: There is no evidence to suggest that Zynomax may have an effect on the patient's ability to drive or operate machinery.
Use In Pregnancy & Lactation
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, Zynomax should be used during pregnancy only if clearly needed.
There are no data on secretion in breast milk. As many drugs are excreted in human milk, Zynomax should not be used in the treatment of a lactating woman unless the physician feels that the potential benefits justify the potential risks to the infant.
Side Effects
Zynomax is well tolerated with a low incidence of side effects. The following undesirable effects have been reported: Blood and Lymphatic System Disorders: Transient episodes of mild neutropenia, thrombocytopenia.
Ear and Labyrinth Disorders: Hearing impairment (including hearing loss, deafness and/or tinnitus), vertigo.
Gastrointestinal Disorders: Nausea, vomiting/diarrhea (rarely resulting in dehydration), loose stools, abdominal discomfort (pain/cramps), and flatulence, dyspepsia, constipation, pseudomembranous colitis, pancreatitis, and rare reports of tongue discoloration, infantile hypertrophic pyloric stenosis.
Hepatobiliary Disorders: Abnormal liver function, hepatitis and cholestatic jaundice have been reported, as well as rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death. However, a causal relationship has not been established.
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, toxic epidermal necrolysis and DRESS have been reported. 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, asthenia has been reported, although a causal relationship has not been established; fatigue, and malaise.
Infections and Infestations: Moniliasis and vaginitis.
Immune System Disorders: Anaphylaxis (rarely fatal)
Metabolism and Nutrition Disorders: Anorexia.
Psychiatric Disorders: Aggressive reaction, nervousness, agitation, and anxiety.
Nervous System Disorders: Dizziness, convulsions (as seen with other macrolides), headache, hyperactivity, hypoesthesia, paresthesia, somnolence, and syncope. There have been rare reports of taste/smell perversion and/or loss. However, a causal relationship has not been established.
Cardiac Disorders: Palpitations and arrhythmias including ventricular tachycardia (as seen with other macrolides) have been reported. There have been rare reports of QT prolongation and torsades de pointes. A causal relationship between Zynomax and these effects has not been established.
Vascular Disorders: Hypotension.
Musculoskeletal and Connective Tissue Disorders: Arthralgia.
Renal and Urinary Disorders: Interstitial nephritis and acute renal failure.
Drug Interactions
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 oral azithromycin and antacids, the drugs should not be taken simultaneously.
Cetirizine: Coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant charges in the QT interval.
Digoxin: Some of the macrolide antibiotics have been reported to impair the microbial metabolism of digoxin in the gut in some patients. In patients receiving concomitant azithromycin, a related azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.
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.
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, the concurrent use of azithromycin with ergot derivatives is not recommended.
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.
Carbamazepine: No significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
Cimetidine: Single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetic of azithromycin, no alteration of azithromycin pharmacokinetics was seen.
Coumarin-Type Oral Anticoagulants: Azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin. Although a causal relationship has not been established, consideration should be given to the monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.
Cyclosporin: 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.
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.
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: Azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam: 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: Coadministration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations.
Rifabutin: Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia is seen when taken with rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established.
Sildenafil: 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: 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 an interaction when azithromycin and theophylline are co-administered.
Trimethoprim/ Sulfamethoxazole: Coadministration of trimethoprim/sulfamethoxazole had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole.
Caution For Usage
Instruction for Use and Handling, and Disposal: Add 7ml of water and shake well.
Shake immediately prior to use.
For children weighing less than 15 kg, the suspension should be measured as closely as possible. For children weighing 15 kg or more, the suspension should be administered using an appropriate measuring device.
Storage
Store below 30°C for both tablet and powder reconstituted suspension.
Protect from light and moisture.
Shelf-Life: For dry powder, the reconstituted suspension form lasts up to 5 days.
MIMS Class
ATC Classification
J01FA10 - azithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.
Presentation/Packing
Tab 250 mg (white, capsule shaped, film coated tablets plain on both sides) x 1 x 6's. Powd for oral susp 200 mg/5 mL x 15 mL.
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