ZITHROMAX

azithromycin dihydrate

500 mg and 600mg Tablets

Powder for Oral Suspension 200 mg/5 mL

Azithromycin is an azalide antibiotic derived from erythromycin A (See Further Information).

Presentation

ZITHROMAX is available as white capsule shaped film coated tablets scored on one side, embossed "ZTM 500" and 'Pfizer' on the other containing azithromycin dihydrate equivalent to 500 mg azithromycin; white capsule-shaped film coated tablets scored on one side, embossed "ZTM 600" and "Pfizer" on the other containing azithromycin dihydrate equivalent to 600 mg azithromycin, and as a white to off-white dry-blend powder for reconstitution as an oral suspension containing azithromycin dihydrate equivalent to 200 mg/5 mL azithromycin.

The tablets contain starch-pregelatinised maize, calcium hydrogen phosphate anhydrous, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate. The tablet film coating contains lactose, hypromellose, titanium dioxide and glycerol triacetate.

The powder for oral suspension contains sucrose, sodium phosphate tribasic anhydrous, hydroxypropyl cellulose, xanthan gum, artificial cherry, creme de vanilla and banana flavours, as excipients. An oral dosing spoon or calibrated syringe is enclosed.

Uses

Actions

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. Nucleic acid synthesis is not affected.

Azithromycin demonstrates activity in-vitro against a wide range of bacteria including:

Gram-positive aerobic bacteria: Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic streptococci). Streptococcus pneumoniae, alpha-haemolytic streptococci (viridans group) and other streptococci. 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.

Activity against: Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila, Klebsiella species are variable and susceptibility tests should be performed.

Proteus species, Serratia species, Morganella species, Pseudomonas aeruginosa are usually resistant.

Anaerobic bacteria: Bacteroides fragilis, Bacteroides species, Clostridium perfringens, Peptococcus species, Peptostreptococcus species, Fusobacterium necrophorum, Propionibacterium acnes.

Organisms of sexually transmitted diseases: azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae, Haemophilus ducreyi.

Other organisms: Azithromycin is also active against Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae (TWAR), Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, , Campylobacter species, Listeria monocytogenes.

Opportunistic Pathogens Associated with HIV Infections - Mycobacterium avium intracellulare complex, Pneumocystis carinii and Toxoplasma gondii.

A cross-resistance between azithromycin and clarithromycin has been observed with some Mycobacterium avium complex (MAC) isolates. The various mechanisms of cross-resistance between azithromycin and clarithromycin for M. avium complex organisms have not been fully characterised. The clinical significance of azithromycin and clarithromycin cross resistance is unknown.

Pharmacokinetics

Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailability is approximately 37%. Administration of Zithromax capsules following a substantial meal reduces the bioavailability by at least 50%. The time taken to peak plasma levels is 2 - 3 hours. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days.

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.

Pharmacokinetic studies have shown markedly higher azithromycin levels in tissues than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that it is heavily tissue bound. Serum protein binding is low. Concentrations in target tissues, such as lung, tonsil and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.

Approximately 12% of an intravenously administered dose is excreted in the urine over 3 days as the parent compound; the majority in the first 24 hours. Very high concentrations of unchanged compound 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.

There are no data on the pharmacokinetics of azithromycin in patients with impaired renal function. In patients with mild to moderately impaired hepatic function the pharmacokinetics of azithromycin are not affected (urinary recovery of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance in these patients).

Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients.

Powder for Oral Suspension

Bioavailability studies in the fed and fasted state have been conducted with azithromycin. Administration of azithromycin immediately following a high fat meal resulted in a slight increase in the rate of absorption but no change in the fraction of the dose absorbed. This effect is probably of no clinical significance.

Indications

Zithromax is indicated for infections caused by susceptible organisms; in lower respiratory tract infections including bronchitis and pneumonia, in skin and soft tissue infections, in otitis media and in upper respiratory tract infections including sinusitis and pharyngitis/tonsillitis. (Penicillin is the usual agent of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Zithromax is generally effective in the eradication of streptococci from the oropharynx, however, data establishing the efficacy of Zithromax in the subsequent prevention of rheumatic fever are not available).

In sexually transmitted diseases in men and women, Zithromax is indicated in the treatment of uncomplicated genital infections due to Chlamydia trachomatis. It is also indicated in the treatment of uncomplicated genital infections due to non multi-resistant Neisseria gonorrhoeae; concurrent infection with Treponema pallidum should be excluded.

Azithromycin 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 and Administration

ZITHROMAX should be administered as a single daily dose.

The period of dosing with regard to infection is given below.

Tablets may be taken with food. Administration of Zithromax capsules following a substantial meal reduces bioavailability by at least 50%. Therefore, each dose should be taken at least 1 hour before or 2 hours after food.

No significant reduction in bioavailability is observed when Zithromax oral suspension or Zithromax tablets are administered following a substantial meal.

Adults (including elderly patients)

Oral

For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis or susceptible Neisseria gonorrhoeae: one gram taken as a single oral dose.

For prophylaxis against MAC infections in patients with human immunodeficiency virus (HIV): 1200 mg once per week.

Following IV therapy for the treatment of Community Acquired Pneumonia: 500 mg as a single daily dose to complete a 7 to 10 day course of therapy.

Following IV therapy for the treatment of Pelvic Inflammatory Disease: 250 mg as a single daily dose to complete a 7 day course of therapy.

For all other indications: a total dose of 1.5g should be given as 500 mg daily for 3 days, or alternatively, 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.

Children

Oral

Directions for use

Tap the bottle to loosen the powder

For the 600 mg presentation, add 9 mL of water. Shake well to produce 20 mL of suspension, which includes a 5 mL overfill for dispensing. Just prior to use, shake well.

After reconstitution, the suspension should be stored below 30^oC and any remaining suspension discarded after 10 days.

The following measuring devices are provided:

Contraindications

The use of this product is contraindicated in patients with a history of allergic reactions to azithromycin, other macrolide antibiotics or any of the other capsule, tablet or oral suspension ingredients (See Presentation).

Warnings and Precautions

Rare serious allergic reactions, including angioedema and anaphylaxis, have been reported. Some of these reactions with Zithromax have resulted in recurrent symptoms and required a longer period of observation and treatment.

No dose adjustment is needed in patients with mild renal impairment (creatinine clearance > 40 mL/min) however, there are no data regarding Zithromax usage in patients with more severe renal impairment, thus caution should be exercised before prescribing Zithromax in these patients.

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 recovery of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Nonetheless, since liver is the principal route of elimination for azithromycin, the use of Zithromax 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 azithromycin. However, because of the theoretical possibility of ergotism, Zithromax and ergot derivatives should not be co-administered.

As with any antibiotic preparation, observation for signs of superinfection with non-suspectible organisms, including fungi is recommended.

In investigation studies where higher doses were used, for prolonged periods of time, reversible hearing impairment was seen in some patients.

Use During Pregnancy and Lactation

Animal reproduction studies have demonstrated that azithromycin crosses the placenta, but have revealed no evidence of harm to the foetus. There are no data on secretion in breast milk. Safety for use in human pregnancy and lactation has not been established. Zithromax should be used in pregnant or lactating women only where adequate alternatives are not available.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay and mouse bone marrow clastogenic assay.

Adverse Reactions

Zithromax is well tolerated with a low incidence of side effects. The majority of side effects observed were mild to moderate in severity. A total of 0.3% of patients discontinued due to side effects. The majority of side effects were gastrointestinal in origin, with diarrhoea and loose stools, abdominal discomfort (pain/cramps), nausea, vomiting and flatulence, occasionally observed (none more than 3%).

Reversible elevations in liver transaminases have been seen occasionally.

Transient episodes of mild reduction in neutrophil counts have occasionally been observed in clinical trials, although a causal relationship to Zithromax has not been established.

Allergic reactions ranging from rash to angioedema and anaphylaxis have occurred.

Clinical trials

Multiple-dose regimen

Overall, the most common side effects in patients receiving the multiple-dose regimen of azithromycin were related to the gastrointestinal system with diarrhoea/loose stools (5%), nausea (3%) and abdominal pain (3%) being the most frequently reported. No other side effects occurred in patients on the multiple-dose regimen with a frequency >1%. Side effects that occurred with a frequency of 1% or less included the following:

Allergic

rash, photosensivity and angioedema.

Cardiovascular

palpitations, chest pain.

Gastrointestinal

dyspepsia, flatulence, vomiting, melaena, and cholestatic jaundice.

Genitourinary

moniliasis, vaginitis, and nephritis.

Nervous system

dizziness, headache, vertigo and somnolence.

General

fatigue.

Single 1-gram dose regimen

Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Side effects that occurred in patients on the single 1-gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhoea/loose stools (7%), nausea (5%), abdominal pain (5%) vomiting (2%), vaginitis (2%) and dyspepsia (1%).

Laboratory abnormalities:

Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows:

With an incidence of 1 - 2%:

elevated serum creatinine phosphokinase, potassium, ALT (SGPT), GGT and AST (SGOT).

With an incidence of < 1%

leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate.

When follow-up was provided, changes in laboratory tests appeared to be reversible.

In multiple-dose trials involving > 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality.

Incidence of the Most Frequent (>5% in any Treatment Group) Treatment Related (%) Adverse Events in HIV Infected Patients Receiving Prophylaxis for Disseminated MAC

The most common laboratory test abnormalities were haematological (mainly decreases in haemoglobin and white cell count) and increases in AST and ALT.

Post marketing experience

Common (>1%)

Uncommon (> 0.1% and <1%)

Rare (<0.1%)

*hearing impairment has been reported with macrolide antibiotics.

Interactions

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 ZITHROMAX.

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.

Didanosine

Daily doses of 1200 mg azithromycin given concomitantly with didanosine for 2 weeks had no effect on the pharmacokinetics of didanosine.

Ergot

The theoretical possibility of ergotism contraindicates the concurrent use of Zithromax with ergot derivatives (see under Warnings and Precautions above).

Cyclosporin

In the absence of conclusive data from pharmacokinetic or clinical studies investigating potential interaction between azithromycin and cyclosporin, caution should be exercised before concurrent administration of these compounds. If coadministration 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 microbial metabolism of digoxin in the gut in some patients. Since Zithromax, an azalide, is related to the macrolides, the possibility of raised digoxin levels should be borne in mind for those patients receiving concomitant digoxin and Zithromax.

Antacids

In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with Zithromax, no effect on overall bioavailability was seen although peak serum concentrations were reduced by up to 30%. In patients receiving both Zithromax and antacids, the drugs should not be taken simultaneously.

Methylprednisolone

In a pharmacokinetic interaction study in healthy volunteers, ZITHROMAX had no significant effect on the pharmacokinetics of methylprednisolone.

Protease Inhibitors

There are no data on potential drug interactions between azithromycin and protease inhibitors.

Rifabutin

Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment with azithromycin and rifabutin. Although neutropenia has been associated with use of rifabutin, a causal relationship to combination with azithromycin has not been established.

Theophylline

There is no evidence of any pharmacokinetic interaction when ZITHROMAX and theophylline are coadministered to healthy volunteers.

Terfenadine, Astemizole

In a study in normal subjects addition of azithromycin did not result in any significant changes in cardiac repolaristaion (QTc interval) measured during the steady state dosing of terfenadine. However, there have been cases reported where the possibility of such an interaction could not be entirely excluded. As some macrolide antibiotics have been reported to induce cardiac arrhythmias if given concurrently with terfenadine or astemizole, and as azithromycin is chemically related to macrolides, it is recommended that caution should be exercised in administering azithromycin to patients who are already receiving terfenadine or astemizole.

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.

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.

Pharmaceutical Precautions

Store prepared suspension at room temperature. Discard any remaining suspension 10 days after reconstitution.

Package Quantities

Further Information

Azithromycin is the first of a class of antibiotics designated chemically as azalides. 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.

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.

In high dose animal studies, giving drug concentrations 40 fold higher than those expected in clinical practice, azithromycin has been noted to cause reversible phospholipidosis generally without discernible toxicological consequences. There is no evidence that this is of relevance to the normal use of Zithromax in humans

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