Consumer medicine information

Azith

Azithromycin

BRAND INFORMATION

Brand name

Azith

Active ingredient

Azithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Azith.

What is in this leaflet

This leaflet answers some common questions about AZITH.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking AZITH against the benefits expected for you.

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

Keep this leaflet with your medicine. You may need to read it again.

What AZITH is used for

AZITH is an antibiotic which contains azithromycin as the active ingredient. Azithromycin belongs to a group of medicines called azalides which are a sub-class of a group of antibiotics called macrolides.

AZITH is used to treat pneumonia, a lung infection caused by certain bacteria such as Legionella pneumophila.

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

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

Ask your doctor if you have any questions about why AZITH has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is available only with a doctor's prescription.

There is no evidence that it is addictive.

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

Before you are given it

When you must not be given it

You must not be given AZITH if you have ever had an allergic reaction to:

  • azithromycin
  • any other ketolide or macrolide antibiotic (e.g. roxithromycin, erythromycin, clarithromycin, 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.

AZITH must not be given to children. The safety and effectiveness of this medicine in children has not been established.

AZITH must not be given if the expiry date printed on the pack 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 be given AZITH, 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 are pregnant or plan to become pregnant. Your doctor will discuss the possible risks and benefits of taking this medicine during pregnancy.

Tell your doctor if you are breastfeeding or plan to breastfeed. Your doctor will discuss the possible risks and benefits of during breast-feeding.

Tell your doctor if you have or have had any of the following medical conditions:

  • diabetes mellitus (sugar diabetes)
  • kidney problems
  • liver problems
  • heart problems
  • myasthenia gravis

If you have not told your doctor about any of the above, tell them before you start being given AZITH.

Taking other medicines

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

Some medicines may interfere with AZITH. These include:

  • antacids, a medicine used to treat indigestion
  • Colchicine, a medicine used to treat gout
  • coumarin-type oral anticoagulants, a medicine used to prevent blood clots
  • ciclosporin, a medicine used in transplant patients
  • digoxin, a medicine used to treat abnormal heart rhythm e.g. atrial fibrillation
  • ergot derivatives such as ergotamine, which is used to treat migraines
  • terfenadine or astemizole, medicines used to treat allergies and hayfever
  • zidovudine, a medicine used to treat patients with AIDS.
  • some medicines used to treat heart rhythm problems (heart arrhythmia) such as amiodarone, disopyramide, ibutilide and sotalol
  • antipsychotic medicines used to treat schizophrenia or bipolar mania such as haloperidol, quetiapine and risperidone
  • medicines used to treat depression (antidepressants) such as fluoxetine, sertraline and venlafaxine
  • fluoroquinolone antibiotics such as ciprofloxacin, lomefloxacin, moxifloxacin and norfloxacin.

These medicines may be affected by AZITH 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 avoid while having this medicine.

Talk to your doctor about the need for additional contraception while taking AZITH. Some antibiotics may decrease the effectiveness of some birth control pills, although this has not been shown with AZITH.

How it is given

AZITH is a sterile powder which is dissolved in sterile water for injections and then diluted before use. It is given as a slow injection into a vein, known as a continuous infusion or a 'drip'.

It will take at least 60 minutes for the solution containing your dose of AZITH to be infused into your vein.

Your doctor or nurse will prepare the infusion for you.

How much to be given

Your doctor will decide the dose of AZITH you will be given by infusion and for how long.

You may then be given oral azithromycin to take in order to complete a 7 to 10 day course of antibiotic therapy.

Things to be aware of

If you are given too much (overdose)

As AZITH is given under the close supervision of your doctor, it is unlikely that you will receive too much.

However, if you experience any side effects after being given AZITH, tell your doctor immediately.

While you are using it

Things you must do

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

Tell your doctor, pharmacist or nurse immediately if you get severe diarrhoea. Do this even if it occurs several weeks after AZITH 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.

Tell your doctor if you get a sore, white mouth or tongue while taking, or soon after stopping AZITH.

Tell your doctor if you get vaginal itching or discharge. This may mean you have a yeast infection called thrush. Sometimes the use of AZITH allows yeast to grow and the above symptoms to occur. AZITH does not work against yeast.

Tell your doctor if you become pregnant while taking AZITH.

Tell all other doctors, dentists and pharmacists who are treating you that you are taking AZITH, especially if you are being started on any new medicines.

Things to be careful of

Protect your skin when you are in the sun, especially between 10 am and 3 pm. If outdoors, wear protective clothing and use a 30+ sunscreen. If your skin does appear to be burning tell your doctor immediately. Some macrolide antibiotics like AZITH may cause skin to be more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn.

Things you must not do

Do not stop taking your medicine 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 your medicine to anyone else even if they have the same condition as you.

Do not use your medicine to treat any other medical complaints unless your doctor tells you to.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are having AZITH.

Like other medicines, AZITH 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 to answer any questions you may have.

Tell your doctor if you notice any of the following side effects 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, loose bowel motions
  • rash
  • dizziness, headache, spinning sensation
  • tiredness, drowsiness, fatigue
  • muscle or joint aches
  • hearing loss or ringing in the ears
  • altered taste and smell
  • inability to feel or touch as normal.

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

  • aggressive reaction, nervousness and anxiety
  • severe persistent diarrhoea
  • fast or irregular heartbeat, chest pain
  • jaundice, yellowing of the skin and eyes
  • fainting
  • difficulty breathing
  • swelling of the face, lips or tongue
  • hives, itching or skin rash
  • symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal
  • severe blistering or peeling of the skin
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal
  • blood in the urine or bowel motions
  • little or no urine
  • convulsions (fits)
  • severe upper stomach pain, often with nausea and vomiting.

The above list includes serious side effects which may require medical attention. These side effects are rare.

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 AZITH:

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

AZITH 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. 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 people.

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

After using AZITH

Storage

AZITH is stored in the pharmacy or on the ward. It should be kept in a cool dry place, protected from light where the temperature stays below 25°C.

Disposal

The hospital staff will dispose of any leftover AZITH.

Product description

What it looks like

AZITH 500 mg powder for injection is a white powder in a glass vial. The powder is dissolved and then diluted, providing 100 mg/mL solution following reconstitution.

Available in packs of 1 vial.

Ingredients

Active ingredient:

Each AZITH vial contains 500 mg azithromycin.

Inactive ingredients:

  • sodium hydroxide
  • anhydrous citric acid.

AZITH 500 mg powder for injection does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Supplier

AZITH is supplied in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian Registration Number:

AZITH 500 mg: AUST R 146755

This leaflet was prepared in October 2019

Azith_cmi\Aug19/00

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Azith

Active ingredient

Azithromycin

Schedule

S4

 

1 Name of Medicine

Azithromycin (as monohydrate).

6.7 Physicochemical Properties

Chemical name.

9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A.

Molecular formula.

C38H72NO12.

Molecular weight.

749.0.

Chemical structure.


CAS number.

83905-01-5.
Azithromycin is the first of a class of antibiotics designated chemically as azalides, a subclass of macrolides. Chemically it is derived by insertion of a nitrogen atom into the lactone ring of erythromycin A.

2 Qualitative and Quantitative Composition

Each Azith 500 mg vial contains azithromycin monohydrate as active ingredient equivalent to 500 mg azithromycin, providing 100 mg/mL solution following reconstitution.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection for infusion.

5 Pharmacological Properties

Pharmacotherapeutic group: Antibacterial agent: macrolide ATC code: J01 FA 10.

5.1 Pharmacodynamic Properties

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.

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), Streptococcus pneumoniae, alpha-haemolytic 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, H. parainfluenzae, Haemophilus 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 human immunodeficiency virus (HIV) infections.

Mycobacterium avium-intracellulare complex (MAC).
Oral azithromycin demonstrates activity in vivo against the following bacteria.

Gram positive aerobic bacteria.

Staph. aureus, Strep. pyogenes (group A beta-haemolytic Streptococci), Strep. pneumoniae, alpha-haemolytic Streptococci (viridans group) and other Streptococci.

Gram negative aerobic bacteria.

H. influenzae (including beta-lactamase producing H. influenzae), H. parainfluenzae, Moraxella catarrhalis.

Other organisms.

Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae.

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 (minimal inhibitory concentration [MIC]) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. CLSI). 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 (CAP).

The efficacy of azithromycin in the treatment of 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. 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, non-comparative 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, non-comparative 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%).

5.2 Pharmacokinetic Properties

Absorption.

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). 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.

Distribution.

Following oral administration in humans, azithromycin is widely distributed throughout the body.

Metabolism.

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.

Excretion.

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.
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 non-stimulated phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

5.3 Preclinical Safety Data

Genotoxicity.

Azithromycin showed no genotoxic potential in a range of standard laboratory tests for gene mutations and chromosomal damage.

Carcinogenicity.

No animal studies have been done to determine the carcinogenic potential of azithromycin.

4 Clinical Particulars

4.1 Therapeutic Indications

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 pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae.

4.3 Contraindications

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any other macrolide or ketolide antibiotic or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Rare, serious, allergic reactions, including angioedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) (rarely fatal) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients on azithromycin therapy (see Section 4.3 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 drug 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.

Ergot derivatives.

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.

Superinfection.

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

Clostridium difficile associated diarrhoea (CDAD).

Antibiotic associated pseudomembranous colitis has been reported with the use of 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 drug discontinuation alone. However, in moderate to severe cases, appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

Prolongation of the QT interval.

There has been limited assessment of the potential for Azith to prolong the QT interval. In clinical studies no significant ECG abnormalities were reported in subjects who received Azith. Ventricular arrhythmias associated with prolonged QT interval, including ventricular tachycardia and torsades de pointes have been reported with macrolide products including azithromycin. Prescribers should consider the risk of QT prolongation (which can be fatal) when weighing the risks and benefits of azithromycin for at risk groups. Azithromycin should be used with caution in patients:
predisposed to QT interval prolongation;
taking other medications known to prolong the QT interval such as antiarrhythmics of classes IA and III; antipsychotic agents; antidepressants; and fluoroquinolones;
with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia;
with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency;
who are elderly, as they may be more susceptible to drug-associated effects on the QT interval.

Myasthenia gravis.

Exacerbations of the symptoms of myasthenia gravis have been reported in patients receiving azithromycin therapy.

Administration precaution.

Do not administer Azith 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.

Hepatotoxicity.

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 Section 5.2 Pharmacokinetic Properties).
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.

Use in 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 AUC0 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 the elderly.

No dose adjustment is necessary in elderly patients requiring azithromycin therapy. Also see Prolongation of the QT interval.

Paediatric use.

The safety and effectiveness of azithromycin powder for solution for infusion for the treatment of infections in children have not been established.
Infantile hypertrophic pyloric stenosis (IHPS) has been reported following the use of azithromycin in neonates (treatment up to 42 days of life). Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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.

Drugs that should not be administered concomitantly with azithromycin.

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.

Ergot.

Due to the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see Section 4.4 Special Warnings and Precautions for Use, Ergot derivatives).

Drugs that require dosage adjustment when administered concomitantly with azithromycin.

Ciclosporin.

In a pharmacokinetic study with healthy volunteers that were administered an oral dose of 500 mg/day azithromycin for three days and were then administered a single oral dose of ciclosporin 10 mg/kg, the resulting Cmax and AUC0 to 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, ciclosporin levels should be monitored and the dose adjusted accordingly.

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

Atorvastatin.

Co-administration 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). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.

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, co-administration 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 pharmacokinetic 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 post-marketing period of potentiated anticoagulation 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.

Didanosine.

Co-administration 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.

Co-administration 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.

Co-administration 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 co-administration 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 administered as 800 mg 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, co-administration 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.

Co-administration of azithromycin 1,200 mg and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse events were observed and no dose adjustment is required.

Rifabutin.

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

Sildenafil.

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 co-administered to healthy volunteers.

Triazolam.

In 14 healthy volunteers, co-administration 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 and colchicine.

Some of the macrolide antibiotics including azithromycin have been reported to impair the microbial metabolism of P-glycoprotein substrates such as digoxin and colchicine (in the gut) in some patients and to result in increased serum levels.
In patients receiving concomitant azithromycin, a related azalide antibiotic and digoxin the possibility of raised digoxin levels should be borne in mind. During treatment with azithromycin and after discontinuation thereof, clinical monitoring and measurement of serum digoxin levels may be necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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.
(Category B1)
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.
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 5 to 10 fold higher than corresponding maternal plasma concentrations. No animal studies of embyrofetal development have been conducted by the IV route. Azithromycin was not fetotoxic 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.
Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.8 Adverse Effects (Undesirable 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 mg/mL 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.

Post-marketing experience.

In post-marketing experience with azithromycin, the following adverse events have been reported:

Infections and infestations.

Moniliasis and vaginitis.

Blood and lymphatic system disorders.

Thrombocytopenia.

Cardiovascular disorders.

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.

Gastrointestinal disorders.

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

General disorders and administration site conditions.

Asthenia, fatigue and malaise.

Hepatobiliary disorders.

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

Immune system disorder.

Anaphylaxis (rarely fatal).

Metabolism and nutrition disorders.

Anorexia.

Musculoskeletal and connective tissue disorders.

Arthralgia.

Nervous system disorders.

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

Psychiatric disorders.

Aggressive reaction, nervousness, agitation, anxiety.

Renal and urinary tract disorders.

Acute renal failure, interstitial nephritis.

Skin and subcutaneous tissue disorders.

Allergic reactions including pruritus, rash, photosensitivity, urticaria, oedema, angioedema, serious skin reactions including erythema multiforme, acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).

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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The dose of Azith for the treatment of adult patients with community acquired pneumonia is:
Azithromycin 500 mg as a single daily intravenous dose for at least two days. Intravenous therapy should be followed by oral therapy of 500 mg azithromycin administered as a single daily dose to complete a 7 to 10 day course of therapy. The timing of the conversion to oral azithromycin 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. After oral administration of a single dose of azithromycin 1 g in subjects with severe renal impairment (GFR < 10 mL/minute), mean AUC0 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.

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 (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Azith after reconstitution and dilution is for administration by intravenous infusion. Not to be given as a bolus or as an intramuscular injection.
The infusate concentration and rate of infusion for azithromycin powder for solution for infusion should be either 1 mg/mL over three hours or 2 mg/mL over one hour.

Preparation of the solution for intravenous administration.

Reconstitution.

Prepare the initial solution of azithromycin powder for solution for infusion 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 (non-automated) 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 in Table 1.
It is recommended that a 500 mg dose of azithromycin powder for solution for infusion, diluted as above, be infused over a period of not less than 60 minutes.
Azith is supplied in single use vials. The vial contents are reconstituted with sterilised water for injections 4.8 mL (azithromycin 100 mg/mL). For administration, the required volume of the reconstituted solution is added to a compatible infusion solution to produce a final azithromycin solution of 1.0 to 2.0 mg/mL.
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 30°C. When diluted according to the instructions, the diluted solution is chemically and physically stable for 24 hours at or below 30°C or for 7 days if stored under refrigeration at 5°C.
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 only. Discard any residue.
The reconstituted solution can be diluted with:
normal saline (0.9% sodium chloride);
½ normal saline (0.45% sodium chloride);
5% glucose in water;
lactated Ringer's solution;
5% glucose in ½ normal saline (0.45% sodium chloride) with 20 mEq KCl;
5% glucose in lactated Ringer's solution;
5% glucose in 1/3 normal saline (0.3% sodium chloride);
5% glucose in ½ normal saline (0.45% sodium chloride).
It is recommended that a 500 mg dose of azithromycin powder for solution for infusion, diluted as described above should be infused over a period of not less than 60 minutes.

4.7 Effects on Ability to Drive and Use Machines

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.

4.9 Overdose

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Azith contains the excipient citric acid and sodium hydroxide.

6.2 Incompatibilities

Azith reconstituted solution may be diluted using the instructions and compatible infusion solutions provided, see Section 4.2 Dose and Method of Administration. Other intravenous substances, additives or medications should not be added to Azith or infused simultaneously through the same intravenous line.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Container type: 10 mL type I, tubular flint glass vial and closed with dark grey bromobutyl lyo slotted stopper and grey, aluminium flip-off seal.
Pack sizes: Packs of 1 and 5 vials.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes