Consumer medicine information

APO-Azithromycin Tablets

Azithromycin

BRAND INFORMATION

Brand name

APO-Azithromycin

Active ingredient

Azithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Azithromycin Tablets.

What is in this leaflet

This leaflet answers some common questions about azithromycin. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Azithromycin is used to treat infections in different parts of the body caused by bacteria, such as chlamydia. Azithromycin belongs to a group of medicines called macrolide antibiotics.

How it works

Azithromycin works by killing or stopping the growth of bacteria causing your infection. Azithromycin 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 this medicine for another reason.

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

This medicine is not addictive.

There is not enough information to recommend the use of azithromycin tablets in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

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

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you 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:

  • liver or kidney problems
  • heart problems, including heart rhythm abnormalities
  • electrolyte disturbance, particularly low levels of potassium or magnesium in your blood
  • myasthenia gravis

Tell your doctor if you have pneumonia and any of the following risk factors:

  • cystic fibrosis
  • infection occurring in hospital
  • infection of the blood
  • hospital admission
  • elderly
  • significant health problems (including immunodeficiency)

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding. Do not take this medicine until you and your doctor have discussed the risks and benefits involved.

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

Taking other medicines

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

Some medicines may interact with azithromycin. These include:

  • antacids, used to treat indigestion
  • colchicine (a medicine used to treat gout)
  • medicines used to prevent blood clots
  • ciclosporin, used to treat immune system problems
  • digoxin, used to treat heart failure
  • ergot derivatives (e.g. ergotamine, used to treat migraines)
  • terfenadine or astemizole, used to treat allergies
  • zidovudine, used to treat patients with AIDS
  • lomotil, used to treat diarrhoea
  • some medicines used to treat heart rhythm problems (e.g. amiodarone, disopyramide, ibutilide, sotalol)
  • antipsychotic medicines (e.g. haloperidol, quetiapine, risperidone)
  • medicines used to treat depression (e.g. fluoxetine, sertraline, venlafaxine)
  • fluoroquinolone antibiotics (e.g. ciprofloxacin, lomefloxacin, moxifloxacin, norfloxacin)

These medicines may be affected by this medicine 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 and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

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

How to take this medicine

Follow all directions given to you by your doctor and pharmacist carefully. They may differ to 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 tell you how much of this medicine you should take, depending on your condition and whether you are taking any other medicines.

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

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

How to take it

Swallow the tablets whole with liquid.

If you are taking an antacid (e.g., Gastrogel, Mylanta), take it at least one hour before or two hours after this medicine dose. This will avoid any possible effect of the antacid on the absorption of azithromycin.

When to take it

Take this medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

This medicine may be taken with or without food.

How long to take it for

Continue taking your medicine until you finish the pack or until your doctor says to. Do not stop taking it because you are feeling better.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If you are taking your medicine 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 missed doses. This may increase the chance of you experiencing side effects.

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

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

If you take too much (overdose)

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

While you are taking this medicine

Things you must do

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

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

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

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

If you get severe diarrhoea, tell your doctor immediately. Do this even if it occurs several weeks after you have stopped taking your medicine. 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, 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 allows yeast to grow and the above symptoms to occur. Azithromycin does not work against yeast.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may want to check your progress to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

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

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

If you do not complete the full course, 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.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you.

Protect your skin when you are in the sun, especially between 10am and 3pm. Some macrolide antibiotics may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn.

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

Side effects

Tell your doctor and pharmacist as soon as possible if you do not feel well while you are taking azithromycin.

This medicine helps most people with infections, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

Tell your doctor if you notice any of the following:

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

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible and before you take your next dose of azithromycin 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
  • 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
  • blood in the urine or bowel motions
  • severe upper stomach pain, often with nausea and vomiting

The above list includes serious side effects and you may need urgent medical attention.

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

  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin (signs of an allergic reaction)
  • 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
  • convulsions (fits)

The above list includes very serious side effects and are usually very rare. You may need urgent medical attention or hospitalisation.

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

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

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

Storage and disposal

Storage

Keep your medicine in the pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

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

Do not store your medicine, 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 this medicine 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 leftover.

Product description

What it looks like

White, oval, biconvex film coated tablets engraved "APO" on one side and "AZ500" on the other side.

Bottles: AUST R 195919

Blisters: AUST R 195910

Available in bottles of 100 tablets and blisters of 1, 2, 3 and 15 tablets.

* Not all pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 500mg of azithromycin dihydrate as the active ingredient.

It also contains the following:

  • calcium hydrogen phosphate dihydrate
  • hydroxypropylcellulose
  • croscarmellose sodium
  • magnesium Stearate
  • Opadry II 31K58875 White.

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

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113
Australia

Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.

This leaflet prepared in September 2020.

Published by MIMS November 2020

BRAND INFORMATION

Brand name

APO-Azithromycin

Active ingredient

Azithromycin

Schedule

S4

 

1 Name of Medicine

Azithromycin dihydrate.

2 Qualitative and Quantitative Composition

Each tablet contains 500 mg azithromycin (as dihydrate).
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White, oval, biconvex film coated tablets engraved "APO" on one side and "AZ500" on the other side.

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 pneumophila, 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 drugs for the treatment of nongonococcal 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.

4.2 Dose and Method of Administration

Azithromycin tablets are intended for oral administration.

Dosage.

Azithromycin should be given as a single daily dose.
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 CAP.

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

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 daily for 3 days.

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.

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.
Drugs 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 acute generalised exanthemous 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.

Prolongation of the QT interval.

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 including:
patients predisposed to QT interval prolongation;
patients taking other medications known to prolong the QT interval such as antiarrhythmics of classes IA and III, antipsychotic agents, antidepressants, and fluoroquinolones;
patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia;
patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency;
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 nonsusceptible 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.

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.

Drugs 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, the drugs should not be taken simultaneously.

Ergot.

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

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 coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

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

Atorvastatin.

Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG-CoA reductase inhibition assay). 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 postmarketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time, when azithromycin is used in patients receiving coumarin type oral anticoagulants.

Didanosine.

Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV positive subjects for 2 weeks had no effect on the steady-state pharmacokinetics of didanosine as compared to 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 was 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 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 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.

Other interactions.

Digoxin and colchicine.

Some of the macrolide antibiotics including azithromycin have been reported to impair the 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.

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)
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 fetal 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. 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.

4.7 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.

4.8 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 g dose regimen.

The most frequently reported adverse events in patients receiving a single dose regimen of 1 g 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 g 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 patient because of a renal function abnormality (see 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).

Postmarketing experience.

In postmarketing 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 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.

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 nutritional disorders.

Anorexia.

Musculoskeletal and connective tissue disorder.

Arthralgia.

Nervous system disorders.

Dizziness, somnolence, headache, syncope, convulsions, hypoesthesia, paraesthesia and hyperactivity.

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.

Vertigo, 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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/ Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Most adverse events experienced in higher than recommended doses are 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.

Treatment.

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 131126 (Australia).

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 to 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 human immunodeficiency virus (HIV) infections.

Mycobacterium avium intracellulare complex (MAC).
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.

MAC.
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.

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 MIC values against 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 each week for 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 diagnosis 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 and 4.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of a 500 mg dose, azithromycin is absorbed from the gastrointestinal tract with an absolute bioavailability of 37%. Maximum serum concentration (Cmax) of 0.3-0.4 microgram/mL is achieved in 2-3 hours with an area under the curve AUC(0-24) of 2.6 microgram hr/mL.
Food has no significant effect on the bioavailability of the azithromycin tablets, even after a high fat meal.
Pharmacokinetics in elderly subjects are substantially the same and no dosage adjustment is necessary. The extent of absorption is unaffected by coadministration 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/min) 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.

No data available.

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. 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.
Following a single oral dose of azithromycin 1 g, 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.
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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Calcium hydrogen phosphate dihydrate, hydroxypropylcellulose, croscarmellose sodium, magnesium stearate, Opadry II 31K58875 white.

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.

6.5 Nature and Contents of Container

APO-Azithromycin tablets.

500 mg tablets.

Available in bottles (white, round, HDPE bottles with blue PP Lift N Peel cap) of 100 tablets. AUST R 195919.
Available in blister packs (white, opaque PVC/Aluminium) of 1, 2, 3 and 15 tablets. AUST R 195910.
Apotex Pty Ltd is the licensee of the registered trade marks APO and APOTEX from the registered proprietor, Apotex Inc.
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Azithromycin dihydrate is a white crystalline powder practically insoluble in water, freely soluble in anhydrous ethanol and in methylene chloride. pKa1: 8.8 (exocyclic tertiary amine), pKa2: 8.1 (endocyclic tertiary amine), partition coefficient Log P (hydrophobicity): 4.02.
Azithromycin is the first of a new class of antibiotics designated chemically as azalides, a subclass of macrolides, available for oral administration. Azithromycin, chemically 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, contains a methyl substituted nitrogen atom at position 9A of the lactone ring.

Chemical structure.


Chemical Name: 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate.
Molecular Formula: C38H72N2O12.2H2O.
Molecular Weight: 785.0.

CAS number.

117772-70-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes