Zithrolide

Zithrolide

azithromycin

Manufacturer:

Pharmaniaga Manufacturing Berhad

Distributor:

Pharmaniaga Logistics
Full Prescribing Info
Contents
Azithromycin.
Action
Pharmacology: Pharmacodynamics: Azithromycin is a nitrogen-containing macrolide or azalide with actions and uses similar to those of erythromycin.
Mechanism of Action: Inhibition of protein synthesis in bacteria binding in 50s ribosomal subunit and preventing translocation of peptides.
Pharmacokinetics: Following oral administration in human, about 40% of a dose of azithromycin is bioavailable. Absorption from the capsule formulation, but not the tablet formulation, is reduced by food. Peak plasma concentrations are achieved 2-3 hrs after a dose but azithromycin is extensively distributed to the tissues and tissue concentrations subsequently remain much higher than those in the blood; in contrast to most other antibacterials, plasma concentrations are of little value as a guide to efficacy. High concentrations are taken up into white blood cells.
There is little diffusion into the cerebrospinal fluid when the meninges are not inflamed. Small amounts of azithromycin are demethylated in the liver, and is excreted in the bile as unchanged drug and metabolites. About 6% of an oral dose (representing about 20% of the amount in the system circulation) is excreted in the urine. The terminal excretion half-life is probably in excess of 40 hrs.
Microbiology: Azithromycin demonstrates activity in in vitro against a wide range of bacteria including: Gram-Positive Aerobic Bacteria: Staphylococcus aureus, Streptococcus pyogenes (group A β-hemolytic streptococci), Streptococcus pneumoniae, α-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 spp, Yersinia spp, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella spp, Pasteurella spp, Vibrio cholera and shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter spp, Aeromonas hydrophilla and Klebsiella spp are variable and susceptibility tests should be performed. Proteus spp, Serratia spp, Morganella spp and Pseudomonas aeruginosa are usually resistant.
Anaerobic Bacteria: Bacteroides fragilis and Bacteroides spp, Clostridium perfringens, Peptococcus spp and Peptostreptococcus spp, 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 spp and Listeria monocytogenes.
Opportunistic Pathogens Associated with Human Immunodeficiency Virus (HIV) Infections: Mycobacterium avium-intracellulare complex, Pneumocystis carinii and Toxoplasma gondii.
Indications/Uses
For infections caused by susceptible organisms in lower respiratory tract infection including bronchitis and pneumonia, skin and soft tissue infections, acute otitis media, upper respiratory tract infections including sinusitis and pharyngitis/tonsilitis. (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 disease in men and women, treatment of uncomplicated genital infections due to Chlamydia trachomatis. Treatment of Chancroid due to H. ducreyi and uncomplicated genital infection due to non-multiresistant Neisseria gonorrhoea, concurrent infection with Treponema pallidum should be excluded.
Either alone or in combination with rifabutin, for prophylaxis against Mycobacterium avium-intracellulare complex (MAC) infection, an opportunistic infection prevalent in patients with advanced HIV.
In combination with ethambutol for the treatment of disseminated MAC (DMAC) infection in patients with advanced HIV infection.
Dosage/Direction for Use
Adults and Elderly: For the treatment of sexually transmitted diseases (STD) caused by Clamydia trachomatis or susceptible Neisseria gonnorhoea and chancroid due to H. ducreyi, 1 g as a single oral dose. Prophylaxis against MAC infections in patients with HIV infection, 1200 mg once weekly.
For all other indications, the total dosage of 1500 mg should be given as 500 mg daily for 3 days or can be given over 5 days with 500 mg given on day 1, then 250 mg daily on days 2-5.
For the treatment of DMAC infections in patients with advanced HIV infection, the recommended dose is 600 mg once daily. Azithromycin should be administered in combination with other antimycobacterial agents that have shown in vitro activity against MAC, eg, ethambutol at the approved dose.
Children: With a single exception of the treatment of Streptococcal pharyngitis, the total dose in children is 30 mg/kg which should be given as a single daily dose of 10 mg/kg daily for 3 days or as an alternative, given over 5 days with a single dose of 10 mg/kg on 1 day, then 5 mg/kg on days 2-5. Treatment of acute otitis media in children may be given as either a single dose of 30 mg/kg. Zithrolide tablets should only be administered to children weighing >45 kg. Safety and efficacy for the prevention of MAC in children have not been established. Based on paediatric pharmacokinetics data, a dose of 20 mg/kg would be similar to the adult dose of 1200 mg but with a higher maximum plasma concentration (Cmax).
Paediatric Streptococci Pharyngitis: Single dose of 10 mg/kg or 20 mg/kg for 3 days has been shown to be effective; however, do not exceed a daily dose of 500 mg.
Special Populations: Renal Impairment: The same dosage in patients with normal renal function maybe used in patients with mild renal impairment (creatinine clearance >40 mL/min). There are no data regarding azithromycin usage in patients with more severe renal impairment.
Hepatic Impairment: The same dosage as in patients with normal hepatic function may be used in patients with mild to moderate hepatic impairment.
Administration: Azithromycin should be administered as a single daily dose. Azithromycin tablet can be taken with food.
Overdosage
Adverse events experience in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdosage with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhea. In the event of an overdosage, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.
Contraindications
Known hypersensitivity to azithromycin or to any of the macrolide antibiotics. Because of the theoretical possibilty of ergotism, Zithrolide and ergot derivatives should not be co-administered.
Special Precautions
As with erythromycin and other macrolides, rare serious allergic reactions including angioedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with Zithrolide have resulted in recurrent symptoms, and required a longer period of observation and treatment. Since liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic diseases. In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. 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. As with any antibiotics preparation, observation for signs of superinfection with nonsusceptible organisms, including fungi is recommended. 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. It 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 2 months after the administration of antibacterial agents. In patients with severe renal impairment (GFR <10 mL/min), a 33% increase in systemic exposure to azithromycin was observed. Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrythmia and Torsade de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation.
Use in pregnancy & lactation: Animal reproduction studies have demonstrated that azithromycin crosses the placenta, but have revealed no evidence of harm to the foetus. There are no adequate and well controlled studies in pregnant women. Since animal studies are not always predictive of human response, Zithrolide should be used during pregnancy only if adequate alternatives are not available.
No data on secretion of azithromycin in breast milk are available, so that Zithrolide should only be used in lactating women where adequate alternatives are not available.
Use In Pregnancy & Lactation
Animal reproduction studies have demonstrated that azithromycin crosses the placenta, but have revealed no evidence of harm to the foetus. There are no adequate and well controlled studies in pregnant women. Since animal studies are not always predictive of human response, Zithrolide should be used during pregnancy only if adequate alternatives are not available.
No data on secretion of azithromycin in breast milk are available, so that Zithrolide should only be used in lactating women where adequate alternatives are not available.
Adverse Reactions
Zithrolide is well tolerated with a low incidence of side effect. Palpitations and arrhythmias including ventricular tachycardia (as seen with other macrolides) have been reported although a causal relationship to azithromycin has not been established.
Dizziness/vertigo, convulsions (as seen with other macrolides), headache, somnolence, paraesthesia and hyperactivity.
Anorexia, nausea, vomiting/diarrhea (rarely resulting in dehydration), loose stools, dyspepsia, abdominal discomfort (pain/cramps), constipation, flatulence, pseudomembranous colitis and rare reports of tongue discolouration.
Asthenia has been reported although a causal relationship has not been established, moniliasis and anaphylaxis (rarely fatal).
Interstitial nephritis and acute failure.
Thrombocytopenia.
Abnormal liver function including 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.
Arthralgia.
Aggressive reaction, nervousness, agitation and anxiety.
Vaginitis.
Allergic reactions including pruritus, rash, photosensitivity, oedema, urticaria and angioedema. Rarely, serious skin reactions including erythema multiforme, Stevens-Johnsons syndrome and toxic epidermal necrolysis have occured.
Hearing impairment has been reported with macrolide antibiotics. There have been reports of hearing impairment, including hearing loss, deafness and/or tinnitus 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 theses events were reversible.
There have been reports of taste perversion. Transient episodes of mild neutropenia have occasionally been observed in clinical trials, although a causal relationship to azithromycin has not been established.
Drug Interactions
Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effects on overall bioavailability was seen although peak serum concentrations were reduced by up to 30%. In patients receiving both azithromycin and antacids, the drug should not be taken simultaneously.
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: A single dose of cimetidine administered 2 hrs before Zithrolide had no effect on the pharmacokinetics of azithromycin.
Cyclosporin: In the absence of conclusive data from pharmacokinetics or clinical studies investigating potential interaction between azithromycin and cyclosporin, caution should be exercised before concurrent administration of these drugs. If co-administration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Digoxin: Some of the macrolide antibiotics have been reported to impair the metabolism of digoxin (in the gut) in some patients. Therefore, in patients receiving concomitant Zithrolide and digoxin, the possibility of raised digoxin levels should be bourne in mind, and digoxin levels monitored.
Ergot Derivatives: Because of the theoretical possibility of ergotism, Zithrolide and ergot derivatives should not be co-administered.
Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, Zithrolide had no significant effect on the pharmacokinetics of methylprednisolone.
Terfenadine: Pharmacokinetic 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 occured.
Theophylline: There is no evidence of any pharmacokinetic interaction when azithromycin and theophylline are co-administered in healthy volunteers.
Coumarin-Type Oral Anticoagulants: In a pharmacodynamic interaction study, azithromycin did not alter the anticoagulant effect of a single dose warfarin 15 mg administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulant subsequent to co-administration 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.
Zidovudine: Single 1000 mg doses, and multiple 1200 mg or 600 mg doses of azithromycin did not affect 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.
Didanosine: Co-administration of daily doses of azithromycin 1200 mg with didanosine in 6 subjects did not appear to affect the pharmacokinetics of didanosine as compared with placebo.
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.
Storage
Store below 30°C. Protect from light.
MIMS Class
ATC Classification
J01FA10 - azithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.
Presentation/Packing
FC tab 250 mg (white to off-white, oblong, biconvex tablet with Pharmaniaga icon on 1 side and scored on the other) x 6's. 500 mg (white to off-white, oblong, biconvex tablet with Pharmaniaga icon on 1 side and plain on the other) x 3's.
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