Consumer medicine information

DBL Azithromycin for Injection

Azithromycin

BRAND INFORMATION

Brand name

DBL Azithromycin for Injection

Active ingredient

Azithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Azithromycin for Injection.

What is in this leaflet

This leaflet answers some common questions about DBL™ Azithromycin for Injection. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking DBL™ Azithromycin for Injection against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with your medicine.

You may need to read it again.

What DBL™ Azithromycin for Injection is used for

DBL™ Azithromycin for Injection is used to treat Pneumonia, a lung infection caused by certain bacteria including Legionella pneumophila.

Azithromycin is an antibiotic, which belongs to a group of medicines called azalides. The azalides are a sub-class of a group of antibiotics called macrolides.

It works by killing or stopping the growth of bacteria causing your infection.

This medicine will not work against viral infections such as colds or flu.

Ask your doctor if you have any questions about why DBL™ Azithromycin for Injection has been prescribed for you.

Your doctor may have prescribed it for another reason.

DBL™ Azithromycin for Injection is only available with a doctor's prescription.

This medicine is not addictive.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you are given DBL™ Azithromycin for Injection

When you must be given it

You must not be given DBL™ Azithromycin for Injection if you are allergic to:

  • azithromycin
  • any other macrolide or ketolide antibiotics (e.g., clarithromycin, erythromycin, roxithromycin, telithromycin)
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing;
  • swelling of the face, lips, tongue or other parts of the body;
  • rash, itching or hives on the skin.

Do not take this medicine if the expiry date (EXP) printed on the packaging has passed or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have any other health problems, including:

  • any liver problems
  • any kidney problems
  • any heart problems.
  • a fungal infection
  • inflammation of the large bowel

Tell your doctor if you are pregnant or plan to become pregnant.

Your doctor will discuss the possible risks and benefits of being given Azithromycin during pregnancy.

Tell your doctor if you are breast-feeding or plan to breastfeed.

Your doctor will discuss the possible risks and benefits of being given Azithromycin during breast-feeding.

If you have not told your doctor about any of the above, tell them before you start taking Azithromycin.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with DBL™ Azithromycin for Injection. These include:

  • ergot derivatives (such as ergotamine, which is used to treat migraines)
  • antacids, medicines used to treat heartburn and indigestion
  • coumarin-type oral anti-coagulants (a medicine used to prevent blood clots eg warfarin)
  • cyclosporin (a medicine used to prevent organ transplant rejection or to treat certainproblems with the immune system)
  • digoxin (a medicine used to treat heart failure)
  • terfenadine or astemizole (medicines used to treat allergies)
  • zidovudine, a medicine used to treat patients with AIDS

These medicines may be affected by Azithromycin or may affect how well it works.

You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Azithromycin.

Talk to your doctor about the need for additional contraception while taking DBL™ Azithromycin for Injection.

Some antibiotics may decrease the effectiveness of some birth control pills, although this has not been shown with Azithromycin.

How to take DBL™ Azithromycin for Injection

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand these instructions, ask your doctor or pharmacist for help.

How much you will be given

Your doctor will decide how much Azithromycin you should receive and the length of time for which you should receive it. The usual dose of Azithromycin is 500 mg given as an injection into a vein for 2 to 5 days.

You may then be given 500 mg oral Azithromycin once a day for another 2 - 7 days (to complete a 7 to 10 day course of antibiotics).

Your doctor will decide the right dose for you.

How to take it

Continue taking Azithromycin until you finish the course or until your doctor recommends.

Do not stop taking it because you are feeling better.

If you do not complete the full course prescribed by your doctor, the infection may not clear completely or your symptoms may return.

If you take too much (Overdose)

As DBL™ Azithromycin is given under the close supervision of your doctor, it is very unlikely that you will receive too much. If you experience any side effects tell your doctor immediately.

Immediately telephone your doctor or Poisons Information Centre (telephone in Australia - 13 11 26: in New Zealand 0800 764 766) for advice if you think that you or anyone else may have taken too much DBL™ Azithromycin for Injection. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are receiving DBL™ Azithromycin for Injection

Things you must do

If the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.

If you get severe diarrhoea, tell your doctor, pharmacist or nurse immediately.

Do this even if it occurs several weeks after Azithromycin has been stopped. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care.

Do not take any diarrhoea medicine without first checking with your doctor.

If you get a sore, white mouth or tongue while taking, or soon after stopping DBL™ Azithromycin for Injection, tell your doctor. Also tell your doctor if you get vaginal itching or discharge.

This may mean you have a yeast infection called thrush. Sometimes the use of this medicine allows yeast to grow and the above symptoms to occur. Azithromycin does not work against yeast.

If you become pregnant while taking DBL™ Azithromycin for Injection, tell your doctor.

If you are about to start any new medicines, tell your doctor and pharmacist that you are taking DBL™ Azithromycin for Injection.

Tell all doctors, dentists and pharmacists who are treating you that you are taking this medicine.

Things you must not do

Do not stop taking Azithromycin or lower the dosage without checking with your doctor.

If you do not complete the full course prescribed by your doctor, all the organisms causing your infection may not be killed. These organisms may continue to grow and multiply so that your infection may not clear completely or may return.

Do not give DBL™ Azithromycin for Injection to anyone else, even if they have the same condition as you.

Do not use DBL™ Azithromycin for Injection to treat any other medical complaints unless your doctor tells you to.

Things to be careful of

Protect your skin when you are in the sun, especially between 10am and 3pm.

Some macrolide antibiotics may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn.

If outdoors, wear protective clothing and use a 30+ sunscreen. If your skin does appear to be burning tell your doctor immediately.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DBL™ Azithromycin for Injection.

Like other medicines, Azithromycin can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist to answer any questions you may have.

Do not be alarmed by the following list of side effects. You may not experience any of them.

While you are receiving it

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • pain at the site of infusion and pain during infusion
  • oral thrush - white, furry, sore tongue and mouth
  • vaginal thrush - sore and itchy vagina and/or white discharge
  • nausea (feeling sick), loss of appetite, vomiting, stomach pain, indigestion, wind, constipation, diarrhoea, loose bowel motions
  • dizziness, headache, spinning sensation
  • tiredness, drowsiness
  • muscle or joint aches
  • hearing loss or ringing in the ears
  • altered taste and smell.

Tell your doctor immediately if you notice any of the following:

  • severe persistent diarrhoea (loose bowel motions)
  • fast or irregular heart beat
  • chest pain
  • symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal
  • severe blistering or peeling of the skin
  • difficulty breathing
  • swelling of the face, lips or tongue
  • hives, itching or skin rash
  • fainting
  • yellowing of the eyes or skin, also called jaundice
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • signs of infections such as fever, severe chills, sore throat or mouth ulcers
  • blood in the urine or bowel motions
  • convulsions (fits)
  • severe upper stomach pain, often with nausea and vomiting.

These symptoms are usually rare but may be serious and need urgent medical attention.

After finishing it

Tell your doctor immediately if you notice any of the following side effects, particularly if they occur several weeks after stopping treatment with DBL™ Azithromycin for Injection:

  • severe stomach cramps
  • watery and severe diarrhoea, which may be bloody
  • fever, in combination with one or both of the above.

Azithromycin can cause some bacteria, which are normally present in the bowel and normally harmless to multiply and therefore cause the above symptoms. You may need urgent medical attention. However this side effect is rare.

Do not take any medicine for this diarrhoea without first checking with your doctor.

Tell your doctor if you notice anything else that is making you feel unwell.

Other side effects not listed above may also occur in some patients.

After using DBL™ Azithromycin for Injection

Storage

DBL™ Azithromycin for Injection is stored in the pharmacy or on the ward. It is kept in a cool dry place where the temperature stays below 25°C.

Disposal

The hospital staff will dispose of any left over product.

Product description

What it looks like

DBL™ Azithromycin for Injection is a white or almost white powder in a glass vial.

Ingredients

A vial of DBL™ Azithromycin for Injection contains 500 mg of azithromycin (as monohydrate) as the active ingredient.

It also contains:

  • citric acid
  • sodium hydroxide

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

DBL™ Azithromycin for Injection is supplied by:

Pfizer Australia Pty Ltd
38 – 42 Wharf Road
West Ryde, NSW 2114
Australia

Toll Free number: 1800 675 229

DBL™ Azithromycin for Injection is available in the following strengths:

  • 500 mg /vial AUST R 161682

This leaflet was updated in June 2017.

BRAND INFORMATION

Brand name

DBL Azithromycin for Injection

Active ingredient

Azithromycin

Schedule

S4

 

Name of the medicine

Azithromycin monohydrate.

Excipients.

Anhydrous citric acid 384.6 mg as a solubilising/ buffering agent and sodium hydroxide q.s. to adjust pH to within the range of 6.3 to 7.0. It contains no antimicrobial preservative.

Description

Molecular Formula: C38H72N2O12.H2O. Molecular weight: 767.02. CAS Registry No: 121479-24-4. ATC code: J01FA10. Chemical name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14 heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6 azacyclopentadecan-15-one OR 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A.
Azithromycin is an antibacterial agent or bacteriostatic protein synthesis inhibitor belonging to the class of macrolides. Azithromycin is the first of a class of antibiotics designated chemically as azalides, a subclass of macrolides. Azithromycin is a semi-synthetic product derived from a fermentation product (erythromycin). Azithromycin differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated at position 9A into the lactone ring.
Azithromycin monohydrate is a white or almost white powder. It is practically insoluble in water, freely soluble in anhydrous ethanol and in methylene chloride.
DBL Azithromycin for Injection is a sterile lyophilized powder for intravenous infusion following reconstitution. Each 10 mL vial contains azithromycin monohydrate equivalent to azithromycin 500 mg along with the following inactive ingredients: anhydrous citric acid 384.6 mg as a solubilising/ buffering agent and sodium hydroxide q.s. to adjust pH to within the range of 6.3 to 7.0. It contains no antimicrobial preservative and is for use in one patient on one occasion only. Discard any residual solution.
Reconstitution, according to label directions, results in approximately 5 mL with each 1 mL containing azithromycin monohydrate equivalent to 100 mg of azithromycin.

Pharmacology

Mechanism of action.

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.

Pharmacokinetics.

Absorption/ distribution.

Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailability is approximately 37%. Administration of azithromycin capsules following a substantial meal reduces bioavailability. The time taken to peak plasma levels is two to three hours. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of two to four days. In elderly volunteers (> 65 years), slightly higher AUC values were seen after a five day regimen than in young volunteers (< 40 years), but these are not considered clinically significant, and hence no dose adjustment is recommended.
In patients hospitalised with community acquired pneumonia receiving single daily one hour intravenous infusions for two to five days of azithromycin 500 mg at a concentration of 2 mg/mL, the mean Cmax +/- S.D. achieved was 3.63 +/- 1.60 microgram/mL, while the 24 hour trough level was 0.20 +/- 0.15 microgram/mL, and the AUC24 was 9.60 +/- 4.80 microgram.hour/mL. The mean Cmax, 24 hour trough and AUC24 values were 1.14 +/- 0.14 microgram/mL, 0.18 +/- 0.02 microgram/mL, and 8.03 +/- 0.86 microgram.hour/mL, respectively, in normal volunteers receiving a three hour intravenous infusion of azithromycin 500 mg at a concentration of 1 mg/mL.
Comparison of the plasma pharmacokinetic parameters following the first and fifth daily doses of intravenous azithromycin 500 mg showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels.
Pharmacokinetic studies 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. High concentrations of azithromycin were found in gynaecological tissue 96 hours after a single oral dose of azithromycin 500 mg.

Metabolism/ elimination.

In a multiple dose study in 12 normal volunteers utilising a 500 mg (1 mg/mL) one hour intravenous dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hours was about 11% after the first dose and 14% after the fifth dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion 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 ten 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.
Following a single oral dose of azithromycin 1 g, the pharmacokinetics in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/minute) were not affected. Statistically significant differences in AUC (0 to 120) (8.8 versus 11.7 microgram.hour/mL), Cmax (1.0 versus 1.6 microgram/mL) and CLr (2.3 versus 0.2 mL/minute/kg) were observed between subjects with severe renal impairment (GFR < 10 mL/minute) and subjects with normal renal function.
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.
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 nonstimulated phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

Pharmacodynamics.

Microbiology.

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

Gram positive aerobic bacteria.

Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic Streptococci), Strep. pneumoniae, alpha-haemolytic Streptococci (viridans group) and other Streptococci, and Corynebacterium diphtheriae. Azithromycin demonstrates cross resistance with erythromycin resistant Gram positive strains, including Strep. faecalis (enterococcus) and most strains of methicillin resistant Staphylococci.

Gram negative aerobic bacteria.

Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Acinetobacter sp., Yersinia sp., Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella sp., Pasteurella sp., Vibrio cholerae and Vibrio parahaemolyticus, Plesiomonas shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter sp., Aeromonas hydrophila and Klebsiella sp. are variable and susceptibility tests should be performed. Proteus sp., Serratia sp., Morganella sp. and Pseudomonas aeruginosa are usually resistant.

Anaerobic bacteria.

Bacteroides fragilis and Bacteroides sp., Clostridium perfringens, Peptococcus sp. and Peptostreptococcus sp., 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 H. ducreyi.

Other organisms.

Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Campylobacter sp. and Listeria monocytogenes.

Opportunistic pathogens associated with HIV infections.

Mycobacterium avium-intracellulare complex.
Intravenous azithromycin demonstrates activity in vivo against the following bacteria: Staph. aureus, Strep. pneumoniae, H. influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila.
In Australia, macrolide resistance for Strep. pneumoniae and Staph. aureus has been increasing since the late 1990s. Resistance rates of 15% or more are regularly reported. The use of macrolides should be guided by culture susceptibility results and practice guidelines.

Susceptibility testing.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of 'susceptible' indicates that the pathogen is likely to be inhibited when the patient is given the recommended dose. A report of 'intermediate' indicates that the result should be considered equivocal and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.
A report of 'resistant' indicates that the pathogen is not likely to be inhibited when the patient is given the recommended dose; other therapy should be selected.

Clinical Trials

Community acquired pneumonia.

The efficacy of azithromycin in the treatment of community acquired pneumonia (CAP) was assessed in an open, randomised comparative trial, conducted in the US between 1993 and 1995. Azithromycin (500 mg IV (intravenously) as a single dose for two to five days, followed by 500 mg/day orally to complete seven to ten days of therapy) was compared to cefuroxime (2.225 g/day in three divided doses administered IV for two to five days followed by 1 g/day in two divided doses to complete seven to ten days therapy), with erythromycin as required. Two hundred and ninety one (291) patients were evaluable for efficacy. Clinical success (cure + improvement) at 10 to 14 days post-therapy was 77.4% in the azithromycin group versus 74.1% in the comparator group.
In a separate open, noncomparative study, 94 patients received azithromycin by IV infusion (for two to five days) followed by azithromycin orally (to complete a total of seven to ten days therapy) for the treatment of CAP. The clinical success rate (cure + improvement) at 10 to 14 days post-therapy was 88% (74/84) and at four to six weeks was 86% (73/85) among evaluable patients.
These two studies indicated an overall cure rate for patients serologically positive for Legionella pneumophila of 84% (16/19). Additionally, in an open, noncomparative study patients diagnosed as positive for Legionella pneumophila (serogroup 1) using a specific urinary antigen test were treated with azithromycin IV followed by oral azithromycin. At 10 to 14 days, 16 out of 17 evaluable patients were clinically cured and at four to six weeks, 20 out of 20 evaluable patients were clinically cured.
In patients that were treated with azithromycin with a pathogen identified, the clinical success rates observed were Streptococcus pneumoniae 98/102 (92.5%), Haemophilus influenzae 54/62 (87.1%), Staphylococcus aureus 8/10 (90%), Mycoplasma 40/43 (93%), Chlamydia pneumoniae 39/44 (88.6%) and Legionella 34/39 (87.2%).

Indications

DBL Azithromycin for Injection is indicated for community acquired pneumonia caused by susceptible organisms in patients who require initial intravenous therapy. In clinical studies efficacy has been demonstrated against Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophilia, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae.

Contraindications

Known hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide antibiotic or to any excipients.

Precautions

Rare, serious, allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported in patients on azithromycin therapy (see Contraindications). Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is unknown at present.
If an allergic reaction occurs, the medicine should be discontinued and appropriate therapy should be instituted. Doctors should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including azithromycin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases may respond to medicine discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Cl. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Hypertoxin producing strains of Cl. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.
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, azithromycin and ergot derivatives should not be coadministered.
As with any antibiotic preparation, observation for signs of superinfection with nonsusceptible organisms, including fungi, is recommended.
Do not administer DBL Azithromycin for Injection as a bolus or as an intramuscular injection. Reconstitute and dilute the powder for infusion as directed and administer as an intravenous infusion over not less than 60 minutes. All patients who received infusate concentrations above 2.0 mg/mL experienced local infusion site reactions and, therefore, higher concentrations should be avoided. There has been limited assessment of the potential for azithromycin to prolong the QT interval. In clinical studies no significant ECG abnormalities were reported in subjects who received azithromycin. Ventricular arrhythmias associated with prolonged QT interval, including ventricular tachycardia and torsades de pointes have been reported with macrolide products. Azithromycin should be used with caution in patients predisposed to QT interval prolongation or in patients taking other medications known to prolong the QT interval.

Impaired renal function.

No dose adjustment is needed in patients with mild or moderate renal impairment (glomerular filtration rate (GFR) 10 to 80 mL/minute). After oral administration of a single dose of azithromycin 1 g in subjects with severe renal impairment (GFR < 10 mL/minute), mean AUC (0 to 120 hours) and mean Cmax were increased by approximately 30 and 60%, respectively, when compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to patients with severe renal impairment.

Impaired hepatic function.

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 azithromycin should be undertaken with caution in patients with significant hepatic disease (see Pharmacology, Pharmacokinetics, Metabolism/ elimination).

Carcinogenesis, mutagenesis, impairment of fertility.

No animal studies have been done to determine the carcinogenic potential of azithromycin. Azithromycin showed no genotoxic potential in a range of standard laboratory tests for gene mutations and chromosomal damage. No animal studies of fertility have been conducted by the IV route. In three oral fertility and general reproduction studies in rats, there was decreased fertility at doses of 20 and 30 mg/kg/day. The clinical significance of this is unknown.

Use in pregnancy.

(Category B1)
Studies in mice and rats have demonstrated that azithromycin crosses the placenta. Following an oral dose of 200 mg/kg/day, azithromycin concentrations in mouse and rat foetal tissue homogenates were five to tenfold higher than corresponding maternal plasma concentrations. No animal studies of embryofoetal development have been conducted by the IV route. Azithromycin was not foetotoxic or teratogenic in mice and rats at oral doses that were moderately maternotoxic. Plasma levels for azithromycin were lower than the clinical Cmax in both species at the high dose of 200 mg/kg/day. Azithromycin powder for solution for infusion should only be used in pregnant women where adequate alternatives are not available.
Australian categorisation definition of Category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have not shown evidence of an increased occurrence of foetal damage.

Use in lactation.

There are no data on the possible secretion of azithromycin into animal or human breast milk. Azithromycin should only be used in breastfeeding women where adequate alternatives are not available.

Use in children.

The safety and effectiveness of azithromycin powder for solution for infusion for the treatment of infections in children have not been established.

Effect on ability to drive or operate machinery.

There is no evidence to suggest that azithromycin powder for solution for infusion may have an effect on the patient's ability to drive or operate machinery.

Interactions

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.
The following information on drug interactions refers to oral azithromycin.

Drugs that should not be concomitantly administered with azithromycin.

Ergot.

Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended.

Antacids.

In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with oral azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by up to 30%. In patients receiving both oral azithromycin and aluminium and magnesium containing antacids, the drugs should not be taken simultaneously. Administration of oral antacids is not expected to affect the disposition of azithromycin given intravenously.

Drugs that require dosage adjustment when administered concomitantly with azithromycin.

Cyclosporin.

In a pharmacokinetic study with healthy volunteers that were administered an oral dose of azithromycin 500 mg/day for three days and were then administered a single oral dose of cyclosporin 10 mg/kg, the resulting Cmax and AUC (0 to 5) were found to be significantly elevated. Consequently, caution should be exercised before concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Drugs that have been studied with no clinically significant interaction shown.

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).

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.

Cetirizine.

In healthy volunteers, coadministration of a five day regimen of azithromycin with cetirizine 20 mg at steady state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Cimetidine.

In a study investigating the effects of a single dose of cimetidine given two 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 dose of warfarin 15 mg administered to healthy volunteers. There have been reports received in the postmarketing 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.

Didanosine.

Coadministration of daily doses of azithromycin 1,200 mg with didanosine in six subjects did not appear to affect the pharmacokinetics of didanosine as compared with placebo.

Efavirenz.

Coadministration of a single dose of azithromycin 600 mg and efavirenz 400 mg daily for seven days did not result in any clinically significant pharmacokinetic interactions. No dose adjustment is necessary when azithromycin is given with efavirenz.

Fluconazole.

Coadministration with a single dose of azithromycin 1,200 mg did not alter the pharmacokinetics of a single dose of fluconazole 800 mg. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole, but a clinically insignificant decrease in Cmax (18%) of azithromycin was observed. No dose adjustment is necessary when azithromycin is given with fluconazole.

Indinavir.

Coadministration of a single dose of azithromycin 1,200 mg had no statistically significant effect on the pharmacokinetics of indinavir 800 mg t.i.d (three times daily) for five days. No adjustment of the dose of azithromycin is necessary when given with indinavir.

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 three days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of midazolam 15 mg.

Nelfinavir.

Coadministration of azithromycin 1,200 mg and nelfinavir at steady state (750 mg three times daily) increases azithromycin concentration. No clinically significant adverse events were observed and no dose adjustment is required.

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 (500 mg daily for three days) on the AUC and Cmax of sildenafil or its major circulating metabolite.

Terfenadine, astemizole.

In a study in normal subjects addition of azithromycin did not result in any significant changes in cardiac repolarisation (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.

Theophylline.

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

Triazolam.

In 14 healthy volunteers, coadministration of azithromycin 500 mg on day 1 and 250 mg on day 2 with triazolam 0.125 mg 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 seven days with azithromycin 1,200 mg on the seventh day 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. No dose adjustment is necessary.

Zidovudine.

Single 1,000 mg doses and multiple 1,200 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.

Other interactions.

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 or a related azalide antibiotic and digoxin the possibility of raised digoxin levels should be borne in mind.

Adverse Effects

Clinical trials.

In clinical studies of azithromycin given by the intravenous route followed by the oral route in community acquired pneumonia, the most frequent treatment related events occurring at an incidence of greater than or equal to 1% in azithromycin treated patients (n = 871) were diarrhoea (4.7%), IV site pain (4.4%), nausea (4.2%), abdominal pain (2.8%), rash (1.5%), vomiting (1.4%), dyspepsia (0.9%) and LFTs abnormal (0.7%). Local inflammation at the infusion site has also been reported.
In clinical studies, the incidence of IV site disorders (infection/ inflammation/ oedema/ pain/ reactions) associated with the 1 and 2 mg/mL infusion solution concentration was 4.2 and 5.6%, respectively.
A total of 2.4% patients discontinued azithromycin therapy either by the intravenous or oral route due to treatment-related clinical or laboratory adverse events. Treatment-related laboratory abnormalities occurred in 0.6% of patients.

Adults.

Multiple dose regimen (oral).

The most frequently reported adverse events in patients receiving a multiple dose regimen of azithromycin orally were diarrhoea/ loose stools (5%), nausea (3%) and abdominal pain (3%). No other adverse events occurred in patients on the multiple dose regimen with a frequency > 1%. Events that occurred with a frequency of 1% or less included the following.

Allergic.

Rash, photosensitivity and angioedema.

Cardiovascular.

Palpitations, chest pain.

Gastrointestinal.

Dyspepsia, flatulence, vomiting, melaena and cholestatic jaundice.

Genitourinary.

Moniliasis (candidiasis), vaginitis and nephritis.

Nervous system.

Dizziness, headache, vertigo and somnolence.

General.

Fatigue.
Hearing impairment has been reported in investigational studies, mainly where higher doses were used, for prolonged periods of time. In those cases where follow-up information was available the majority of these events were reversible.

In postmarketing experience with azithromycin, the following adverse events have been reported.

Infections and infestations.

Moniliasis and vaginitis.

Body as a whole.

Asthenia, anaphylaxis (rarely fatal), fatigue and malaise.

Cardiovascular.

Hypotension; 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 azithromycin and these effects has not been established.

Central and peripheral nervous system.

Dizziness, syncope, convulsions (as seen with other macrolides), headache, somnolence, hypoesthesia, paraesthesia and hyperactivity.

Gastrointestinal.

Vomiting/ diarrhoea (rarely resulting in dehydration), dyspepsia, pancreatitis, anorexia, constipation, pseudomembranous colitis, rare reports of tongue discolouration.

Genitourinary.

Acute renal failure, interstitial nephritis.

Haemopoeitic.

Thrombocytopenia.

Liver/ biliary.

Abnormal liver function including hepatitis and cholestatic jaundice, hepatic necrosis and hepatic failure, which have rarely resulted in death. However, a causal relationship has not been established.

Musculoskeletal.

Arthralgia.

Psychiatric.

Aggressive reaction, nervousness, agitation, anxiety.

Skin/ appendages.

Pruritus, rash, photosensitivity, urticaria, oedema, angioedema, serious skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Special senses.

Hearing disturbances* including hearing loss, deafness and/or tinnitus, vertigo. Taste/ smell perversion and/or loss, however a causal relationship has not been established.
*Hearing impairment has been reported with macrolide antibiotics.

Dosage and Administration

The dose of DBL Azithromycin for Injection for the treatment of adult patients with community acquired pneumonia is as follows:
Azithromycin 500 mg as a single daily intravenous dose for at least two days. Intravenous therapy should be followed by oral therapy of azithromycin 500 mg administered as a single daily dose to complete a seven to ten day course of therapy. The timing of the conversion to oral therapy should be done at the discretion of the doctor and in accordance with clinical response.
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 intramuscular injection.

Use in the elderly.

No dose adjustment is necessary in elderly patients requiring azithromycin therapy.

Use in patients with renal impairment.

No dose adjustment is needed in patients with mild or moderate renal impairment (glomerular filtration rate (GFR) 10 to 80 mL/minute). After oral administration of a single dose of azithromycin 1 g in subjects with severe renal impairment (GFR < 10 mL/minute), mean AUC (0 to 120 hours) and mean Cmax were increased by approximately 30 and 60%, respectively, when compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to patients with severe renal impairment.

Use 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. Refer to Precautions, Impaired hepatic function.

Use in children.

The safety and effectiveness of azithromycin powder for solution for infusion for the treatment of infections in children have not been established.

Administration.

DBL Azithromycin for Injection, after reconstitution and dilution is for administration by intravenous infusion. It is not to be given as a bolus or as an intramuscular injection. Other intravenous substances, additives or medications should not be added to DBL Azithromycin for Injection or infused simultaneously through the same intravenous line.
The infusate concentration and rate of infusion for DBL Azithromycin for Injection should be either 1 mg/mL over three hours (500 mL) or 2 mg/mL over one hour (250 mL).
Preparation of the solution for intravenous administration is as follows.

Reconstitution.

DBL Azithromycin for Injection is supplied as a powder for injection in single use vials. After removing the flip off top, swab the top of the vial (stopper) with 70% isopropyl alcohol. Allow the surface to dry before piercing the stopper with a sterile needle and reconstitute the product as follows. Prepare the initial solution of the azithromycin powder for injection by adding sterilised Water for Injections 4.8 mL to the 500 mg vial and shaking the vial until all of the drug is dissolved. It is recommended that a standard 5 mL (nonautomated) syringe be used to ensure that the exact amount of 4.8 mL of sterilised water for injections is dispensed. Each mL of reconstituted solution contains azithromycin 100 mg.
If particulate matter is evident in reconstituted fluids, the drug solution should be discarded. Dilute this solution further prior to administration as instructed below.

Dilution.

To provide azithromycin over a concentration range of 1.0 to 2.0 mg/mL, transfer 5 mL of the azithromycin 100 mg/mL solution into the appropriate amount of any of the diluents listed below.
For final infusion solution concentration of 1.0 mg/mL, amount of diluent to be added is 500 mL.
For final infusion solution concentration of 2.0 mg/mL, amount of diluent to be added is 250 mL.
It is recommended that the diluted solution of azithromycin be infused over a period of not less than 60 minutes.
Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident, the drug solution should be discarded.
Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours at 25°C. When diluted according to the instructions, the diluted solution is chemically and physically stable for 24 hours at room temperature or for seven days if stored under refrigeration.
However, as this product contains no antimicrobial agent, to reduce microbiological hazard, use as soon as practicable after reconstitution/ preparation. If storage is necessary, hold at 2 to 8°C for not more than 24 hours.
This product is for single use in one patient on one occasion only. Discard any residue.
The reconstituted solution can be diluted with:
Normal Saline (0.9% sodium chloride);
½ Normal Saline (0.45% sodium chloride);
Lactated Ringer's solution;
5% Glucose in water;
5% Glucose in lactated Ringer's solution;
5% Glucose in ½ Normal Saline (0.45% sodium chloride) with 20 mEq KCl;
5% Glucose in ⅓ Normal Saline (0.3% sodium chloride);
5% Glucose in ½ Normal Saline (0.45% sodium chloride).
Other intravenous substances, additives or medications should not be added to DBL Azithromycin for Injection or infused simultaneously through the same intravenous line.

Overdosage

Most adverse events experienced in higher than recommended doses were similar to those in type and may be more frequent than those seen at normal doses. The incidence of tinnitus and ototoxicity is more frequent in overdosage than at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
As with many cationic amphiphilic drugs, phospholipidosis has been observed in some tissues of mice, rats and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems in dogs administered doses which, based on pharmacokinetics, are as low as two to three times greater than the recommended human dose and in rats at doses comparable to the human dose. This effect is reversible after cessation of azithromycin treatment. The significance of these findings for humans with overdose of azithromycin is unknown.
In case of overdose, immediately contact the Poisons Information Centre for advice (In Australia, call 131 126).

Presentation

DBL Azithromycin for Injection 10 mL vial contains azithromycin (as monohydrate) powder for injection 500 mg.
DBL Azithromycin for Injection is available in the following pack sizes: 1 vial per pack (not marketed); 10 vials per pack.

Storage

Store below 25°C.

Poison Schedule

S4.