Consumer medicine information

Azithromycin Mylan

Azithromycin

BRAND INFORMATION

Brand name

Azithromycin Mylan

Active ingredient

Azithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Azithromycin Mylan.

What is in this leaflet

This leaflet answers some common questions about Azithromycin Mylan.

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 Azithromycin Mylan 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 Azithromycin Mylan is used for

This medicine is used to treat infections in different parts of the body caused by bacteria.

It is commonly used to treat Chlamydia.

This medicine is also used to prevent infections by a bacterium called Mycobacterium Avium-intracellulare Complex (MAC) in some people.

It contains the active ingredient azithromycin.

Azithromycin Mylan 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.

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

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive

Before you take Azithromycin Mylan

When you must not take it

You must not take Azithromycin Mylan if you have an allergy to:

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

If you are not sure if you are allergic to any of the above, ask your doctor.

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
  • Skin rash, itching or hives.

You must not take Azithromycin Mylan after the expiry date (EXP) or use by 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 this medicine, talk to your doctor.

Before you start to take it

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

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

  • any kidney problems
  • any liver problems
  • any heart problems including abnormalities of the rhythm
  • cystic fibrosis
  • myasthenia gravis; muscle weakness
  • low levels of potassium in your blood
  • if you are pregnant or if you plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you are given Azithromycin Mylan.

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 Azithromycin Mylan. 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 to prevent organ transplant rejection or to treat certain problems with the immune system)
  • digoxin (a medicine used to treat heart failure)
  • ergot derivatives (such as ergotamine, a medicine used to treat migraines)
  • terfenadine or astemizole (medicines used to treat allergies and hayfever)
  • zidovudine (a medicine used to treat patients with AIDS)
  • medicines used to treat diarrhoea such as Lomotil ®.
  • Some medicines used to treat heart rhythm problems 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 Azithromycin Mylan, 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 taking Azithromycin Mylan.

How to take Azithromycin Mylan

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much to take

Your doctor will decide how much Azithromycin Mylan you should receive and the length of time for which you should receive it.

The dose will depend on your infection.

The usual dose to treat Chlamydia is two 500mg tablets taken as a single dose.

For other infections Azithromycin Mylan is usually taken once a day. Sometimes the dose is taken once a week. Your doctor will decide the right dose for you.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

How to take it

Swallow the tablets whole with a full glass of water.

If you need to break Azithromycin Mylan, hold the tablet with both hands and snap along the break line.

When to take Azithromycin Mylan

This medicine may be taken with or without food.

If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of Azithromycin Mylan. This will avoid any possible effect of the antacid on the absorption of this medicine.

How long to take Azithromycin Mylan

Continue taking your medicine until you finish the pack or for as long as your doctor tells you.

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

Do not stop taking it because you are feeling better.

If you forget to take it

If you are taking Azithromycin Mylan for three days or longer and you miss a dose, take it as soon as you remember (within a 24-hour period) then continue as normal.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If too much is given (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Azithromycin Mylan. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include upset stomach, diarrhoea or skin rashes.

While you are taking Azithromycin Mylan

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 Mylan 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 Azithromycin Mylan. 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 Mylan does not work against yeast.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Azithromycin Mylan.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Tell your doctor immediately if during treatment your baby develops irritability with feeding or starts vomiting. This may be a sign of a stomach disorder in the infant.

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.

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 take Azithromycin Mylan to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Azithromycin Mylan.

Like other medicines, Azithromycin Mylan can cause some side effects. If they occur, most are likely to be minor and temporary. However, some maybe 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 taking it

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

  • 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, fatigue
  • muscle or joint aches
  • rash
  • hearing loss or ringing in the ears
  • altered taste and smell
  • visual impairment.

These side effects are usually mild.

Tell your doctor immediately and before you take the next dose if you notice any of the following:

  • severe persistent diarrhoea (loose bowel motions)
  • fast or irregular heart beat
  • symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal
  • decreased feeling or sensitivity, especially in the skin
  • hives, itching or skin rash
  • fever
  • aggressive reaction, nervousness, agitation or anxiety
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • Dark urine or blood in the urine or bowel motions
  • severe upper stomach pain, often with nausea and vomiting.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, stop taking Azithromycin Mylan and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • blisters or ulcers on the skin, in the mouth or airways that may occur after a period of fever
  • diarrhoea, usually with blood and mucus, stomach pain and fever
  • yellowing of the eyes or skin, also called jaundice
  • chest pain
  • fainting
  • convulsions (fits)

These are very serious side effects. You may need urgent medical attention or hospitalisation. 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 Azithromycin Mylan:

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

Azithromycin Mylan 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.

Some of these side effects (for example certain liver conditions, and blood abnormalities) can only be found when your doctor does tests from time to time to check your progress.

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

After taking Azithromycin Mylan

Storage

Keep your medicine in the original container until it's time to take them. If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Azithromycin Mylan or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Azithromycin Mylan comes in one type of tablet:

Azithromycin Mylan 500mg - white to off-white, oval, film-coated tablet, plain on one side, with a breaking notch and 'A500' embossed on the other side.

Available in blister packs of 2 or 3 tablets.

Active Ingredient

Azithromycin Mylan contains 500mg of azithromycin (as dihydrate).

Other Ingredients

It also contains the following inactive ingredients:

  • microcrystalline cellulose
  • maize starch
  • sodium starch glycollate
  • colloidal anhydrous silica
  • magnesium stearate
  • sodium lauryl sulfate
  • lactose monohydrate
  • hypromellose
  • titanium dioxide
  • macrogol 4000

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

Supplier

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

Australian registration numbers:

Azithromycin Mylan 500 mg film coated tablet: AUST R 158290 (blisters).

This leaflet was prepared in January 2020.

Azithromycin Mylan_cmi\Aug19/00

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Azithromycin Mylan

Active ingredient

Azithromycin

Schedule

S4

 

1 Name of Medicine

Azithromycin dihydrate.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

117772-70-0.
Azithromycin dihydrate is practically insoluble in water, freely soluble in ethanol and in methylene chloride. Azithromycin contains a methyl substituted nitrogen atom at position 9a of the lactone ring.

2 Qualitative and Quantitative Composition

Azithromycin dihydrate is a white or almost white powder.
Azithromycin Mylan is supplied as a white, film-coated, oval shaped, plain on one side, with a breaking notch and 'A500' embossed on the other side. Each film-coated tablet contains 500 mg of azithromycin dihydrate as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Azithromycin acts by binding to the 50S ribosomal subunit of susceptible organisms, thus interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

Microbiology.

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

Gram-positive aerobic bacteria.

Staphylococcus aureus, Streptococcus pyogenes (group A beta-hemolytic Streptococci), Streptococcus pneumoniae, alpha-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 (including beta-lactamase producing Haemophilus influenzae), Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter species, Yersinia species, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella species, Pasteurella species, Vibrio cholerae and parahaemolyticus, Plesiomonas shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila and Klebsiella species are variable and susceptibility tests should be performed. Proteus species, Serratia species, Morganella species, and Pseudomonas aeruginosa are usually resistant.

Anaerobic bacteria.

Bacteroides fragilis and Bacteroides species, Clostridium perfringens, Peptococcus species, Peptostreptococcus species, Fusobacterium necrophorum and Propionibacterium acnes.

Organisms of sexually transmitted diseases.

Azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae and Haemophilus ducreyi.

Other organisms.

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

Opportunistic pathogens associated with HIV infections.

Mycobacterium avium-intracellulare complex.
Azithromycin demonstrates activity in vivo against the following bacteria:

Gram-positive aerobic bacteria.

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

Gram-negative aerobic bacteria.

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

Other organisms.

Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae.

Opportunistic pathogens associated with HIV infections.

Mycobacterium avium-intracellulare complex.

Note.

Erythromycin- and penicillin-resistant Gram-positive isolates may demonstrate cross-resistance to azithromycin.
In Australia, macrolide resistance for Streptococcus pneumoniae and Staphylococcus aureus has been increasing since the late 1990's. 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 medicines, the test should be repeated. This category implies possible clinical applicability in body site 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.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Susceptibility testing for Mycobacterium avium complex (MAC).

The disk diffusion techniques and dilution methods for susceptibility testing against Gram-positive and Gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimal inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been established or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible to azithromycin have not been established.

Clinical trials.

Trachoma.

Trachoma - children and adults.

Information from clinical trial data and published reports of studies supports the efficacy of 20 mg/kg to 1 g, taken either as a single dose or once weekly for up to three weeks, in the treatment of trachoma in children and adults. The single dose schedule has not been compared with the three weekly dosing schedule in clinical trials.

Trachoma - repeat courses.

While the statistically significant superiority of a single dose of azithromycin given as a single dose and repeated at 6 months versus a single dose of azithromycin to adults or children with active trachoma has not been determined, information from clinical trial data suggests that the trachoma free period may be extended by a repeat single dose of azithromycin at 6 months.

Pharyngitis/tonsillitis.

In a clinical trial (study 96-001), 501 children aged 2-12 years with a clinical diagnoses of acute tonsillitis received azithromycin 10 mg/kg/day or 20 mg/kg/day for 3 days or penicillin V, 50 mg/kg (in 3 divided doses) for 10 days. (Note the recommended dose for penicillin V in Australia is 20 mg/kg/day). Similar clinical efficacy but greater bacteriological eradication was evident at the 20 mg/kg/day dose (the daily dose did not exceed 500 mg).
Group A beta-haemolytic Streptococci (GABHS) eradication rates and clinical response rates are detailed in Table 3.

5.2 Pharmacokinetic Properties

Absorption.

Tablets.

Following oral administration of a 500 mg dose, azithromycin is absorbed from the gastrointestinal tract with an absolute bioavailability of 37%. The maximum serum concentration (Cmax) of 0.2-0.6 microgram/mL is achieved in 2-3 hours with an area under the curve AUC(∞) of 4.4 microgram.h/mL.
Food has no significant effect on the bioavailability of azithromycin tablets, even after a high fat meal.
Pharmacokinetics in elderly subjects is substantially the same and no dosage adjustment is necessary. The extent of absorption is unaffected by co-administration with antacid; however, Cmax is reduced by up to 30%. Administration of an 800 mg dose of cimetidine two hours prior to azithromycin had no effect on azithromycin absorption. Azithromycin did not affect the plasma levels or pharmacokinetics of carbamazepine, methylprednisolone, zidovudine or multiple oral doses of theophylline (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Distribution.

Serum concentrations decline in a polyphasic pattern, resulting in an average terminal half-life of 68 hours. The high values for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/minute) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Azithromycin concentrations in the cerebrospinal fluid are very low. Concentrations in the peritoneal fluid are also very low.
Azithromycin is distributed widely throughout the body. Rapid movement of azithromycin from blood into tissues results in significantly higher azithromycin concentrations in tissue than in plasma (from 1-60 times the maximum observed concentration in plasma). It appears to be concentrated intracellularly. Concentrations in tissues, such as lung, tonsil and prostate, etc exceed the MIC90 for likely pathogens after a single dose of 500 mg, and remain high after serum or plasma concentrations decline to below detectable levels. Mean peak concentrations observed in peripheral leucocytes, the site of MAC infection, were 140 microgram/mL and remained above 32 microgram/mL for approximately 60 hours following a single 1200 mg oral dose.
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 microgram/mL to 7% at 2 microgram/mL.

Metabolism.

Very high concentrations of unchanged drug have been found, together with 10 metabolites, formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by cleavage of the cladinose conjugate. Comparison of HPLC and microbiological assays in tissues suggests that metabolites play no part in the microbiological activity of azithromycin.

Excretion.

Approximately 12% of an intravenously administered dose is excreted in the urine over 3 days as the parent drug, the majority in the first 24 hours. Biliary excretion of azithromycin is a major route of elimination for unchanged drug following oral administration.
Following a single oral dose of azithromycin 1 gram, the pharmacokinetics in subjects with mild to moderate renal impairment (GFR 10-80 mL/min) were not affected. Statistically significant differences in AUC0-120 (8.8 microgram.h/mL vs. 11.7 microgram.h/mL), Cmax (1.0 microgram/mL vs. 1.6 microgram/mL) and CLr (2.3 mL/min/kg vs. 0.2 mL/min/kg) were observed between subjects with severe renal impairment (GFR < 10 mL/min) 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.
Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients.

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 studies have been done to determine the carcinogenic potential of azithromycin in animals.

4 Clinical Particulars

4.1 Therapeutic Indications

Azithromycin is indicated for use in adults for the treatment of the following infections of mild to moderate severity:

1. Lower respiratory tract infections.

Acute bacterial bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis.
Community acquired pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae in patients suitable for outpatient oral treatment.
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.

2. Upper respiratory tract infections.

Acute sinusitis due to Streptococcus pneumoniae or Haemophilus influenzae.
Acute streptococcal pharyngitis.

Note.

Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin appears to be almost as effective in the treatment of streptococcal pharyngitis. However, substantial data establishing the efficacy of azithromycin in the subsequent prevention of rheumatic fever are not available at present.

3. Uncomplicated skin and skin structure infections.

Uncomplicated infections due to Staphylococcus aureus, Streptococcus pyogenes or Streptococcus agalactiae. Abscesses usually require surgical drainage.

4. Sexually transmitted diseases.

Uncomplicated urethritis and cervicitis due to Chlamydia trachomatis.

Note.

At the recommended dose azithromycin cannot be relied upon to treat gonorrhoea or syphilis. As with other medicines for the treatment of non-gonococcal infections, it may mask or delay the symptoms of incubating gonorrhoea or syphilis. Appropriate tests should be performed for the detection of gonorrhoea or syphilis and treatment should be instituted as required.
Azithromycin is also indicated for the treatment of Chlamydia trachomatis conjunctivitis and trachoma.
Azithromycin is also indicated for the prevention of infection due to Mycobacterium avium-intracellulare complex (MAC) disease, when used as the sole agent or in combination with rifabutin at its approved dose, in adults and children aged more than 12 years with HIV infection and CD4 cell count less than or equal to 75 cells/microL (see Section 4.4 Special Warnings and Precautions for Use). Disseminated infection due to Mycobacterium avium-intracellulare complex should be excluded by a negative blood culture prior to commencement of therapy.

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 inactive ingredients in the product (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.
In the treatment of pneumonia, azithromycin has been shown to be safe and effective only in the treatment of community-acquired pneumonia (CAP) of mild severity due to Streptococcus pneumoniae or Haemophilus influenzae in patients appropriate for outpatient oral therapy. Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors such as any of the following:
patients with cystic fibrosis;
patients with nosocomially acquired infections;
patients with known or suspected bacteraemia;
patients requiring hospital admission;
elderly or debilitated patients; or
patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).

Clostridium difficile associated diarrhoea (CDAD).

Antibiotic-associated pseudomembranous colitis has been reported with use of nearly all antibacterial agents, 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.
Medicines which delay peristalsis e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.

Hypersensitivity.

Rare, serious, allergic reactions, including angioedema and anaphylaxis (rarely fatal), dermatologic reactions including 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. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

Prolongation of the QT interval.

Ventricular arrhythmias associated with prolonged QT interval, including ventricular tachycardia and torsades de pointes, have been reported in treatment 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 including:
patients predisposed to QT interval prolongation;
patients currently receiving treatment with other medications known to prolong QT interval such as antiarrhythmics of classes IA and III, antipsychotic agents, antidepressants, and fluoroquinolones;
patients with electrolyte disturbance, particularly in cases of hypokalemia and hypomagnesemia;
patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency;
Elderly: elderly patients 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.

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.

Other.

The majority of cases of disseminated Mycobacterium avium complex infection occur in patients with CD4 counts below 50 cells/microL. Some authorities recommend delay of initiation of prophylaxis until the cell count has fallen to 50 cells/microL.
No evidence exists from formal studies to determine the need for, and frequency of, repeat dosing in the treatment of trachoma.

Use in hepatic impairment.

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 Pharmacological Properties; 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.
Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see Section 4.8 Adverse Effects (Undesirable Effects)). Liver function tests/investigations should be performed in cases where signs and symptoms of liver dysfunction occur such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy.

Use in renal impairment.

No dose adjustment is needed in patients with mild or moderate renal impairment (GFR 10-80 mL/min). After oral administration of a single dose of azithromycin 1 g in subjects with severe renal impairment (GFR < 10 mL/min), mean AUC0-120h 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.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

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.

There are no reported laboratory test interactions.

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.

Medicines that should not be concomitantly administered with azithromycin.

Antacids.

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

Ergot.

The theoretical possibility of ergotism contraindicates the concurrent use of azithromycin with ergot derivatives (see Section 4.4 Special Warnings and Precautions for Use, Ergot derivatives).

Medicines that require dosage adjustment when administered concomitantly with azithromycin.

Ciclosporin.

In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these medicines. If coadministration of these medicines is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Medicines 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). However, postmarketing 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, coadministration of a 5-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 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin-type oral anticoagulants.

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time, when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Didanosine.

Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects for 2 weeks had no effect on the steady state pharmacokinetics of didanosine as compared with placebo.

Efavirenz.

Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions. No dose adjustment is necessary when azithromycin is given with efavirenz.

Fluconazole.

Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole however 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 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days. No adjustment of the dose is necessary when azithromycin is 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 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir.

Coadministration of 1200 mg azithromycin and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects 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 with azithromycin and rifabutin. Although neutropenia has been associated with 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 3 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 0.125 mg triazolam on day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole.

Coadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 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 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Other interactions.

Digoxin and colchicine.

Some of the macrolide antibiotics have been reported to impair the metabolism of 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.

In three 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: Medicines 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.
No studies have been carried out in pregnant women. Azithromycin was not foetotoxic or teratogenic in mice and rats at doses that were moderately maternotoxic (up to 200 mg/kg/day). At 200 mg/kg/day, mouse and rat foetal tissues homogenate concentrations were 5 to 10-fold higher than corresponding maternal plasma concentrations.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
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 trials, most of the reported adverse events were mild to moderate in severity and were reversible on discontinuation of the drug. Approximately 0.7% of patients discontinued azithromycin therapy because of treatment-related adverse events. Most of the adverse events leading to discontinuation were related to the gastrointestinal tract, e.g. nausea, vomiting, diarrhoea or abdominal pain. Rare, but potentially serious, adverse events were angioedema (1 case) and cholestatic jaundice (1 case).
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.

Adults.

Multiple-dose regimen.

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

Allergic.

Rash, photosensitivity, angioedema.

Cardiovascular.

Palpitations, chest pain.

Gastrointestinal.

Dyspepsia, flatulence, vomiting, melaena, cholestatic jaundice.

Genitourinary.

Moniliasis, vaginitis, nephritis.

Nervous system.

Dizziness, headache, vertigo, somnolence.

General.

Fatigue.

Single 1 gram dose regimen.

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

Laboratory abnormalities.

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

Incidence > 1%.

Elevated serum creatinine phosphokinase, potassium, ALT (SGPT), GGT and AST (SGOT), lymphocytes and neutrophils; decreased neutrophils.

Incidence < 1%.

Leukopenia, neutropenia, thrombocytopenia; elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate, monocytes, basophils, bicarbonate; decreased sodium, potassium.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose trials involving > 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality.

HIV infected patients receiving prophylaxis for disseminated MAC.

The most frequent adverse events are listed in Table 1.
The most common laboratory test abnormalities were haematological (mainly decreases in haemoglobin and white cell count) and increases in AST and ALT.

Children.

The side effect profile in children is comparable with that of adults. No new adverse events have been reported in children. In the treatment of Streptococcal pharyngitis the 20 mg/kg/day dose is associated with a higher rate of adverse events. These are mainly gastrointestinal and remain mild to moderate.
The following adverse events, where a causal relationship to treatment could not be ruled out, were reported at an occurrence of ≥ 1%. See Table 2.

Post marketing experience.

In post marketing experience, 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.

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, hepatitis and cholestatic jaundice, hepatic necrosis and hepatic failure, which have rarely resulted in death.

Immune system disorders.

Anaphylaxis (rarely fatal).

Metabolism and nutritional disorders.

Anorexia.

Musculoskeletal and connective tissue disorders.

Arthralgia.

Nervous system disorders.

Dizziness, convulsions, headache, hyperactivity, hypoesthesia, paraesthesia, somnolence, 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, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).

Special senses.

Hearing disturbances and/or hearing impairment including hearing loss, deafness and/or tinnitus; vertigo. Taste/smell perversion and/or loss.

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

Azithromycin should be given as a single daily dose. The tablets may be taken with food.

Adults.

Sexually transmitted uncomplicated urethritis and cervicitis due to Chlamydia trachomatis.

1 g as a single dose.

Conjunctivitis and trachoma due to Chlamydia trachomatis.

1 g either as a single dose or once weekly for up to three weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Following IV therapy for the treatment of community acquired pneumoniae.

500 mg as a single daily dose to complete a 7 to 10 day course of therapy.

Prevention of disseminated MAC.

1200 mg taken as a single dose once weekly, either alone, or in combination with rifabutin, at its recommended dosage.

All other indications (including outpatients initiated on oral treatment of CAP due to S. pneumoniae or H. influenzae).

Total dose of 1.5 g given as 500 mg on day 1, then 250 mg daily on days 2 to 5 or alternatively as 500 mg daily for 3 days.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Most adverse events experienced in higher than recommended doses were similar 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 medicines, 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 2-3 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

Each Azithromycin Mylan film coated tablet also contains microcrystalline cellulose, maize starch, sodium starch glycollate - type A, colloidal anhydrous silica, magnesium stearate, sodium lauryl sulfate and Opadry OY-L-28900 white (containing lactose monohydrate, hypromellose, titanium dioxide, macrogol 4000 and purified water).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 and moisture.

6.5 Nature and Contents of Container

Azithromycin Mylan 500 mg tablets:
Container type: PVC/Aluminium blisters.
Pack sizes: blister packs of 2 and 3 tablets.
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