Consumer medicine information

Azithromycin Alphapharm

Azithromycin

BRAND INFORMATION

Brand name

Azithromycin Alphapharm

Active ingredient

Azithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about AZITHROMYCIN ALPHAPHARM.

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 ALPHAPHARM 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 ALPHAPHARM is used for

AZITHROMYCIN ALPHAPHARM is used to treat Pneumonia, a lung infection caused by certain bacteria including Legionella pneumophila.

This medicine is an antibiotic, which belongs to a group of medicines called azalides.

The azalides are a sub-class of a group of antibiotics called macrolides.

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

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

Ask your doctor if you have any questions about why AZITHROMYCIN ALPHAPHARM has been prescribed for you. Your doctor may have prescribed AZITHROMYCIN ALPHAPHARM for another reason.

This medicine is not addictive.

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

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

Before you are given AZITHROMYCIN ALPHAPHARM

When you must not be given it

You must not be given AZITHROMYCIN ALPHAPHARM if you have an allergy to:
Azithromycin or any other ketolide or macrolide antibiotic (e.g. roxithromycin, erythromycin, clarithromycin, telithromycin) or 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.

Before you are given it, tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • any kidney problems
  • any liver problems
  • any heart problems
  • inflammation of the large bowel
  • a fungal infection
  • low levels of potassium or magnesium in your blood
  • myasthenia gravis

Tell your doctor 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 ALPHAPHARM.

AZITHROMYCIN ALPHAPHARM must not be given if the expiry date (EXP) or use by date printed on the pack has passed. If you take this medicine after this date, it may not work.

AZITHROMYCIN ALPHAPHARM must not be given if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given this medicine, talk to your doctor.

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 ALPHAPHARM. These include:

  • ergot derivatives (such as ergotamine, a medicine used to treat migraines)
  • antacids (a medicine used to treat indigestion or heartburn)
  • coumarin-type oral anticoagulants (a medicine used to prevent blood clots such as warfarin)
  • ciclosporin (a medicine used to prevent organ transplant rejection or to treat certain problems with the immune system)
  • digoxin (a medicine used to treat abnormal heart rhythm e.g. atrial fibrillation)
  • 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 AZITHROMYCIN ALPHAPHARM 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 ALPHAPHARM.

Talk to your doctor about the need for additional contraception while taking AZITHROMYCIN ALPHAPHARM.

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

How AZITHROMYCIN ALPHAPHARM is given

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

How much is given

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

The usual dose of AZITHROMYCIN ALPHAPHARM is 500 mg given as an injection into a vein for 2 to 5 days.

Following this, you may be given oral Azithromycin daily for another 2-7 days, to complete a 7 to 10 day course of antibiotics.

This treatment may be followed by a course of oral antibiotics.

How it is given

AZITHROMYCIN ALPHAPHARM is given as an injection by a doctor or trained nurse.

AZITHROMYCIN ALPHAPHARM is a powder which is mixed with Water for Injections and then diluted by the pharmacist. It is then injected into a vein which takes approximately 60 minutes.

It may be given with or without food.

This will avoid any possible effect of the antacid on the absorption of AZITHROMYCIN ALPHAPHARM

If too much is given (overdose)

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

Immediately telephone your doctor or 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 ALPHAPHARM. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are being treated

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 ALPHAPHARM has been stopped. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any diarrhoea medicine without first checking with your doctor.

If you get a sore, white mouth or tongue while taking, or soon after stopping AZITHROMYCIN ALPHAPHARM, tell your doctor. Also tell your doctor if you get vaginal itching or discharge. This may mean you have a yeast infection called thrush. Sometimes the use of AZITHROMYCIN ALPHAPHARM allows yeast to grow and the above symptoms to occur. AZITHROMYCIN ALPHAPHARM does not work against yeast.

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

If you are about to start any new medicines, tell your doctor and pharmacist that you are taking AZITHROMYCIN ALPHAPHARM.

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

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 AZITHROMYCIN ALPHAPHARM 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 AZITHROMYCIN ALPHAPHARM to anyone else, even if they have the same condition as you.

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

Side effects

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

Like other medicines, AZITHROMYCIN ALPHAPHARM 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:

  • pain or inflammation 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
  • dizziness, headache, spinning sensation
  • tiredness, drowsiness, fatigue
  • muscle or joint aches
  • rash
  • hearing loss or ringing in the ears
  • altered taste and smell.

These side effects are usually mild.

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

  • severe persistent diarrhoea
  • 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
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • dark urine or blood in the urine or bowel motions
  • aggressive reaction, nervousness, agitation or anxiety
  • severe upper stomach pain, often with nausea and vomiting.

These are serious side effects. Serious side effects are rare. You may need urgent medical attention.

If any of the following happen, stop taking AZITHROMYCIN ALPHAPHARM 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 ALPHAPHARM:

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

AZITHROMYCIN ALPHAPHARM 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 using AZITHROMYCIN ALPHAPHARM

Storage

AZITHROMYCIN ALPHAPHARM is stored in the pharmacy or on the ward. It is kept in a cool dry place where the temperature stays below 25°C.

Disposal

The hospital staff will dispose of any left-over AZITHROMYCIN ALPHAPHARM.

Product description

What it looks like

AZITHROMYCIN ALPHAPHARM is a white to off-white powder, or cake presented in a 10 mL glass vial.

AZITHROMYCIN ALPHAPHARM contains 500 mg of azithromycin powder for solution for infusion, providing 100 mg/mL solution following reconstitution.

Active Ingredient

The active ingredient is azithromycin.

Other Ingredients

It also contains the following inactive ingredients:

  • citric acid monohydrate
  • sodium hydroxide

This medicine does not contain lactose, 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 ALPHAPHARM 500 mg Powder for Injection:
AUST R 191947

This leaflet was prepared in January 2020.

Azithromycin Alphapharm_cmi\Aug19/00

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Azithromycin Alphapharm

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: C38H72N2O12. Molecular weight: 749.0.
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. The physicochemical characteristics of the API are listed below:
pKa value (azithromycin): 8.74.
Solubility: practically insoluble in water; freely soluble in ethanol and in methylene chloride.
Partition coefficient: See Table 2.
pH of reconstituted solution: between 6.4 and 6.8 (on reconstitution with 4.8 mL of WFI).

Chemical structure.


CAS number.

83905-01-5.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

Azithromycin 500 mg 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:

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, 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 and 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 human immunodeficiency virus (HIV) infections.

Mycobacterium avium-intracellulare complex (MAC).
Azithromycin (oral) 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 (MAC).
Azithromycin (IV) demonstrates activity in vivo against the following bacteria:
Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila.
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 (minimal inhibitory concentration [MIC]) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited when the patient is given the recommended dose. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body 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.

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 - 1995. Azithromycin (500 mg IV as a single dose for 2 - 5 days, followed by 500 mg/day orally to complete 7 - 10 days of therapy) was compared to cefuroxime (2.225 g/day in 3 divided doses administered IV for 2-5 days followed by 1 g/day in 2 divided doses to complete 7 - 10 days therapy), with erythromycin as required. Two hundred and ninety one patients were evaluable for efficacy. Clinical success (cure + improvement) at 10-14 days post therapy was 77.4% in the azithromycin group vs 74.1% in the comparator group.
In a separate open, non-comparative study, 94 patients received azithromycin by IV infusion (for 2 to 5 days) followed by azithromycin orally (to complete a total of 7 to 10 days therapy) for the treatment of CAP. The clinical success rates (cure + improvement) at 10-14 days post therapy was 88% (74/84) and at 4-6 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 10-14 days, 16 out of 17 evaluable patients were clinically cured and at 4-6 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.

Following oral administration in humans, bioavailability is approximately 37%. Administration of azithromycin capsules following a substantial meal reduces bioavailability. The time taken to peak plasma levels is 2-3 hours. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. In elderly volunteers (> 65 years), slightly higher AUC values were seen after a 5-day regimen than in young volunteers (< 40 years), but these are not considered clinically significant, and hence no dose adjustment is recommended.
In patients hospitalised with community acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin 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.h/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.h/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL.
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin 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 500 mg 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 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.

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 1st dose and 14% after the 5th 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 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.hr/mL vs. 11.7 microgram.hr/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.
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; or 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. Physicians 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 co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.

Superinfection.

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

Clostridium difficile-associated diarrhoea.

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 Azithromycin Alphapharm to prolong the QT interval. In clinical studies no significant ECG abnormalities were reported in subjects who received Azithromycin Alphapharm. 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 Azithromycin Alphapharm 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 (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.

No data available.

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

Drugs that should not be concomitantly administered 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 a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of ciclosporin, the resulting Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If co-administration 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 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 dose of 15 mg warfarin 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 1200 mg azithromycin with didanosine in 6 subjects did not appear to affect the pharmacokinetics of didanosine as compared to placebo.

Efavirenz.

Co-administration 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.

Co-administration with 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 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.

Co-administration 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 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 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of 15 mg midazolam.

Nelfinavir.

Co-administration of 1200 mg azithromycin 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 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 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 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.

Co-administration 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.

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 embyrofoetal development have been conducted by the IV route. Azithromycin was not foetotoxic or teratogenic in mice and rats at oral doses that were moderately maternotoxic. Plasma levels for azithromycin were lower than the clinical Cmax in both species at the high dose of 200 mg/kg/day. Azithromycin powder for solution for infusion should only be used in pregnant women where adequate alternatives are not available.
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 ≥ 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:

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

Immune system disorders.

Anaphylaxis (rarely fatal).

Metabolism and nutrition disorders.

Anorexia.

Musculoskeletal and connective tissue disorders.

Arthralgia.

Nervous system disorders.

Dizziness, convulsions, 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 and/or 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

The dose of Azithromycin Alphapharm 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 physician and in accordance with clinical response.
After re-constitution 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 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/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 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).
Azithromycin Alphapharm after reconstitution and dilution is for administration by intravenous infusion. Not to be given as a bolus or as an intramuscular injection.

Preparation of the solution for intravenous administration is as follows.

The infusate concentration and rate of infusion for azithromycin powder for solution for infusion should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour.

Reconstitution.

Prepare the initial solution of azithromycin powder for solution for infusion by adding 4.8 mL of sterilised water for injections 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 100 mg azithromycin.
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 mg/mL to 2.0 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin 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.
Azithromycin Alphapharm is supplied in single use vials. The vial contents are reconstituted with 4.8 mL sterilised water for injections (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 mg 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 on one occasion only. Discard any residue.
The reconstituted solution can be diluted with:
normal saline (0.9% sodium chloride);
½ normal saline (0.45% sodium chloride);
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 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

Azithromycin Alphapharm contains citric acid monohydrate and sodium hydroxide.

6.2 Incompatibilities

Azithromycin Alphapharm 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 Azithromycin Alphapharm, 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

Azithromycin Alphapharm.

Packaged in 10 mL type I glass tubular vial and closed with a dark grey rubber stopper and blue, aluminium flip-off seal. Pack of 1 vial.

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