Consumer medicine information

APO-Roxithromycin

Roxithromycin

BRAND INFORMATION

Brand name

APO-Roxithromycin Tablets

Active ingredient

Roxithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

Read this leaflet carefully before taking your medicine.

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

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

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.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Roxithromycin. It contains the active ingredient roxithromycin.

It is used to treat:

  • acute pharyngitis (sore throat and discomfort when swallowing)
  • tonsillitis
  • sinusitis
  • acute bronchitis (infection of the bronchi causing coughing)
  • worsening of chronic bronchitis
  • pneumonia (lung infection characterised by fever, malaise, headache)
  • skin and soft tissue infections
  • non gonoccocal urethritis
  • impetigo (bacterial infection causing sores on the skin).

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.

How it works

Roxithromycin is an antibiotic that belongs to a group of medicines called macrolides.

These antibiotics work by killing or stopping the growth of the bacteria that are causing your infection.

Roxithromycin, like other antibiotics, does not work against viral infections such as the flu.

There is no evidence that this medicine is addictive.

Use in children

This medicine is not recommended for use in children weighing less than 40 kg.

When you must not take it

Do not take this medicine if:

  • You have severe liver problems.
  • You are taking certain medicines for migraine headache called ergot alkaloids.
  • You are hypersensitive to, or have had an allergic reaction to, roxithromycin or any other macrolide antibiotics (e.g. azithromycin, clarithromycin or erythromycin), or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include cough, 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; fainting or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • kidney problems (impaired function).
  • liver problems (hepatic cirrhosis with jaundice and/or ascites).
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  2. You are currently breast-feeding or you plan to breast-feed. Do not take this medicine whilst breast-feeding until you and your doctor have discussed the risks and benefits involved.
  3. You are planning to have surgery or an anaesthetic.
  4. You are currently receiving or are planning to receive dental treatment.
  5. You are taking or are planning to take any other medicines; this includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with roxithromycin. These include:

  • theophylline, a medicine used to treat asthma
  • some medicines for migraine headache called ergot alkaloids
  • disopyramide, a medicine to treat irregular heart rhythms
  • terfenadine and astemizole, over the counter medicines used to treat allergies
  • warfarin, a medicine used to prevent blood clots
  • digoxin, a medicine used to treat heart failure
  • midazolam, used to induce sleep before operations
  • cyclosporin, a medicine used to prevent organ transplant rejection or to treat certain problems with the immune system
  • cisapride, a medicine used to treat gastrointestinal problems
  • pimozide, an antipsychotic medicine
  • rifabutin and bromocriptine (which use the CYP3A liver enzyme).

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with roxithromycin.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

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

Adults
The recommended adult dosage is 300 mg per day, which may be taken according to one of the following dosage regimens:

  • one 300 mg tablet once a day, or
  • one 150 mg tablet twice a day, or
  • two 150 mg tablets once a day.

However, depending on your condition and how you react to the medicine, your doctor may tell you to take a different dose.

Children
The dosage of roxithromycin given to children is dependent upon the child's weight.

The recommended dosage for children weighing 40 kg and over is 300 mg per day, taken according to the following dosage regimen:

  • one 150 mg tablet in the morning and one 150 mg tablet in the evening.

This medicine is not recommended for use in children weighing less than 40 kg.

How to take it

Swallow roxithromycin tablets whole with a glass of water.

When to take it

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

Roxithromycin should be taken at least 15 minutes before food or on an empty stomach (i.e. more than 3 hours after a meal). Roxithromycin works best if you take it on an empty stomach.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

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

For treating infections, roxithromycin is usually taken for 5 to 10 days. However, your doctor may prescribe roxithromycin for longer periods.

Check with your doctor if you are not sure how long to take this medicine for.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

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

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breast-feeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

If you get severe diarrhoea, tell your doctor immediately. Do this even if it occurs several weeks after you have stopped taking roxithromycin.

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. Do this even if it occurs several weeks after roxithromycin has been stopped.

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

If you get a sore, white mouth or tongue while taking roxithromycin or soon after stopping roxithromycin, tell your doctor.

Tell your doctor if you get vaginal itching or discharge.

This may mean you have a fungal/yeast infection called thrush. Sometimes the use of roxithromycin allows fungi/yeast to grow and the above symptoms to occur. Roxithromycin does not work against fungi/yeast.

Go to your doctor regularly for a check-up.

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

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours
  • Take your medicine to treat any other condition unless your doctor tells you to
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

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

Things to be careful of

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

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking roxithromycin or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

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 discharge
  • nausea, vomiting, stomach pain, diarrhoea, flatulence, reflex
  • loss of appetite
  • red and/or itchy skin
  • headache, dizziness, deafness/ringing in the ears
  • hallucinations
  • confusion
  • tiredness
  • altered taste
  • rash.

Tell your doctor as soon as possible if you notice any of the following, particularly if they occur several weeks after stopping treatment with roxithromycin.

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

These are serious side effects. You may have a serious condition affecting your bowel. You may need urgent medical attention.

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

  • Upper abdominal pain, which may radiate up to your back, nausea or vomiting (possible symptoms of pancreatitis).

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

  • severe persistent diarrhoea
  • progressive skin rash often with blisters or mucosal lesions (e.g. around the eyes, nose, mouth and genitals).

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

Allergic reactions

If you think you are having an allergic reaction to roxithromycin, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing.
  • swelling of the face, lips, tongue, or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay 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 or pharmacist tells you to stop taking this medicine or they have passed their expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Roxithromycin 150mg looks like

White to off-white round convex, film-coated tablets.

Blister Pack of 10 tablets.

What APO-Roxithromycin 300mg looks like

White to off-white round convex, film-coated tablets.

Blister Pack of 5 tablets.

Ingredients

Each tablet contains 150 or 300 mg of roxithromycin as the active ingredient.

It also contains the following inactive ingredients:

  • maize starch
  • hydroxypropylcellulose
  • silica - colloidal anhydrous
  • sodium starch glycollate
  • poloxamer
  • povidone
  • magnesium stearate
  • talc - purified
  • propylene glycol
  • glucose
  • titanium dioxide
  • hypromellose.

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Roxithromycin 150 mg tablets (blister): AUST R 133748.

APO-Roxithromycin 300 mg tablets (blister): AUST R 133749.

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

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

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

This leaflet was last updated in November 2015.

BRAND INFORMATION

Brand name

APO-Roxithromycin Tablets

Active ingredient

Roxithromycin

Schedule

S4

 

1 Name of Medicine

Roxithromycin.

6.7 Physicochemical Properties

Chemical name: (3R, 4S, 5S, 6R, 7R, 9R, 11S, 12R, 13S, 14R)-4- [(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]- 14-ethyl-7,12,13-trihydroxy-10-[(E)-[(2-methoxyethoxy)-methoxy]imino]- 3,5,7,9,11,13,-hexamethyl-6-[(3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy]-oxacyclotetradecan-2-one.
Molecular formula: C41H76N2O15.
Molecular weight: 837.07.

Chemical structure.


CAS number.

80214-83-1.

2 Qualitative and Quantitative Composition

Roxithromycin is a semi-synthetic macrolide antibiotic. Each roxithromycin film-coated tablet contains either 150 mg or 300 mg of roxithromycin as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

150 mg tablets.

White to off-white, round, convex and film-coated tablets.

300 mg tablets.

White to off-white, round, convex and film-coated tablets.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Microbiology.

Roxithromycin is bacteriostatic at low concentrations and bactericidal at high concentrations. It binds to the 50S subunit of the 70S ribosome, thereby disrupting bacterial protein synthesis.
A prolonged postantibiotic effect has been observed with roxithromycin. Whilst the clinical significance of this remains uncertain, it supports the rationale for once daily dosing. Although clinical data have demonstrated the efficacy and safety of once daily dosing in adults, these have not been demonstrated in children.
At plasma concentrations achieved with the recommended therapeutic doses, roxithromycin has been demonstrated to have in vitro and clinical activity against the following microorganisms: Streptococcus pneumoniae, Streptococcus pyogenes, Mycoplasma pneumoniae, Moraxella catarrhalis, Ureaplasma urealyticum and Chlamydia spp.
Roxithromycin has been demonstrated to have clinical activity against the following microorganisms which are partially sensitive in vitro to roxithromycin: Haemophilus influenzae and Staphylococcus aureus (except methicillin resistant Staph. aureus [MRSA]).
The following strains of microorganisms are resistant: multiresistant Staph. aureus, Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp.

Susceptibility tests.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. National Committee for Clinical Laboratory Standards [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 if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable: other therapy should be selected.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.
Using the NCCLS method of susceptibility testing with a 15 microgram roxithromycin disc, susceptible organisms other than Haemophilus influenzae produce zones of inhibition of diameter 21 mm or greater. A zone diameter of 10 to 20 mm should be considered intermediate and a zone diameter of 9 mm or less indicates resistance. A bacterial isolate may be considered susceptible if the minimal inhibitory concentration (MIC) value for roxithromycin is less than or equal to 1 mg/L. Organisms are considered resistant if the MIC value is greater than 8 mg/L.
For H. influenzae, zones of inhibition of diameter 10 mm or greater indicate susceptibility when CO2 incubation and the HTM agar is used with a 15 microgram roxithromycin disc. An isolate may be considered susceptible if the MIC value for roxithromycin is less than or equal to 8 mg/L.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Roxithromycin is absorbed after oral administration with an absolute bioavailability of approximately 50%. Peak plasma concentrations following administration of 150 and 300 mg film coated tablets are achieved in young and elderly adult patients approximately one to two hours postdose. As food intake decreases absorption, roxithromycin should be administered at least 15 minutes before food or, alternatively, on an empty stomach (i.e. more than three hours after a meal).
Absorption is not linear; with increasing doses in the range 150 to 300 mg, peak plasma levels and area under the curve (AUC) do not increase in proportion to the dose.
After repeated administration of 2.5 mg/kg every 12 hours to children, the average peak plasma concentration at steady state was 9 mg/L and the AUC was 61 mg.hour/L.
Following administration of a single oral dose of roxithromycin 150 mg to healthy young adults, the mean peak plasma concentration was 6.6 mg/L and the AUC was 69 mg.hour/L. At steady state following doses of 150 mg twice daily, the mean peak plasma concentration was 9.3 mg/L and the AUC was 71 mg.hour/L.
In elderly patients the mean peak plasma concentration following a single 150 mg dose was 9.1 mg/L and the AUC was 148 mg.hour/L. At steady state, a dosage regimen of 150 mg twice daily produced a mean peak plasma concentration of 11.3 mg/L and an AUC of 83 mg.hour/L.
Following administration of a single oral dose of roxithromycin 300 mg tablets to healthy young adults, the mean peak plasma concentration was 9.7 mg/L and the AUC was 98 mg.hour/L. At steady state following doses of 300 mg once daily, the mean peak plasma concentration was 10.9 mg/L and the AUC was 77 mg.hour/L.
In elderly patients, the mean peak plasma concentration following a single 300 mg dose was 10.8 mg/L and the AUC was 197 mg.hour/L.

Distribution.

Roxithromycin is 92 to 96% bound to plasma proteins (principally alpha-1-acid glycoprotein, but also albumin) at concentrations less than 4.2 mg/L. The binding is saturable; in subjects with normal plasma levels of alpha-1-acid glycoprotein, the extent of binding decreases when plasma concentrations of roxithromycin exceed 4.2 mg/L. At a plasma concentration of 8.4 mg/L approximately 87% of the drug is protein bound.
Roxithromycin is highly concentrated in polymorphonuclear leucocytes and macrophages, where levels 30 times those in serum have been reported.

Metabolism.

The mean half-life of roxithromycin is approximately 12 hours in young adults and 20 hours in children. The apparently longer half-life in children does not cause excessive accumulation; minimum concentration (Cmin) and AUC values are comparable for adults and children.
The half-life is prolonged to 25 hours in patients with impaired hepatic function and 18 hours in patients with renal insufficiency.
The mean half-life in elderly patients is approximately 27 hours.
Roxithromycin undergoes limited metabolism in the body, presumably in the liver. The major metabolite is descladinose roxithromycin. Two minor metabolites have also been identified. Plasma levels of roxithromycin are approximately twice those of all metabolites; a similar ratio is seen in the urine and faeces.

Excretion.

Approximately 7% of a dose is excreted in the urine and 13% is eliminated via the lungs. Faecal excretion, which represents the unabsorbed fraction and the small proportion excreted by the liver, accounts for approximately 53% of the dose. The fate of the remainder is unknown.
When roxithromycin plasma levels are above 4.2 mg/L, renal clearance increases because reduced plasma protein binding (see Distribution) causes increased levels of unbound roxithromycin which may be excreted by the kidneys.

5.3 Preclinical Safety Data

Genotoxicity.

Roxithromycin has shown no mutagenic potential in standard laboratory tests for gene mutation and chromosomal damage.

Carcinogenicity.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of roxithromycin.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults.

Roxithromycin is indicated for the treatment of the following types of mild to moderately severe infections in adults caused by or likely to be caused by susceptible microorganisms:
Upper respiratory tract infection: acute pharyngitis, tonsillitis and sinusitis.
Lower respiratory tract infection: acute bronchitis and acute exacerbations of chronic bronchitis; community acquired pneumonia.
Skin and skin structure infections.
Non-gonococcal urethritis.

Children.

Roxithromycin 150 mg tablets are indicated for the treatment of the following mild to moderately severe infections in children caused by or likely to be caused by susceptible microoganisms:
Acute pharyngitis.
Acute tonsillitis.
Impetigo.
Appropriate culture and sensitivity tests should be performed when necessary to determine an organism's susceptibility and thus treatment suitability. Therapy with roxithromycin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.

4.3 Contraindications

Known hypersensitivity to macrolides, including erythromycin.
Severely impaired hepatic function (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant therapy with vasoconstrictive ergot alkaloids (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Prolonged or repeated use of antibiotics including roxithromycin may result in superinfection by resistant organisms. In the event of superinfection, roxithromycin should be discontinued and appropriate therapy instituted.
When indicated, incision, drainage or other appropriate surgical procedures should be performed in conjunction with antibiotic therapy.

Pseudomembranous colitis.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics. 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 usually 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 therapy should be provided when indicated.
Drugs that delay peristalsis, e.g. opiates and diphenoxylate with atropine, may prolong and/or worsen the condition and should not be used.
Roxithromycin, like erythromycin, has been shown in vitro to elicit a concentration-dependent lengthening in cardiac action potential duration. Such an effect is manifested only at supratherapeutic concentrations. Accordingly, the recommended doses should not be exceeded.

Clostridium difficile-associated disease.

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with roxithromycin, may be symptomatic of pseudomembranous colitis (see Section 4.8 Adverse Effects (Undesirable Effects)). If pseudomembranous colitis is suspected, roxithromycin must be stopped immediately.

QT prolongation.

In certain conditions macrolides, including roxithromycin, have the potential to prolong the QT interval. Therefore, roxithromycin should be used with caution in patients with congenital prolongation of the QT interval, with ongoing proarrhythmic conditions (i.e. uncorrected hypokalemia or hypomagnesaemia, clinically significant bradycardia), and in patients receiving Class IA and III antiarrhythmic agents (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Astemizole, cisapride, pimozide).

Myasthenia gravis.

As with other macrolides, roxithromycin may have the potential to aggravate the myasthenia gravis.

Skin conditions.

Cases of severe bullous skin reactions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) have been reported with roxithromycin (see Section 4.8 Adverse Effects (Undesirable Effects)). If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, roxithromycin treatment should be discontinued.

Ergotism.

Severe vasoconstriction ("ergotism") with possibly necrosis of the extremities has been reported when macrolide antibiotics have been associated with vasoconstrictive ergot alkaloids. Absence of treatment by these alkaloids must always be checked before prescribing roxithromycin. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Ergot alkaloids.)

Use in hepatic impairment.

The safety of roxithromycin has not been demonstrated in patients with impaired hepatic function. Caution should be exercised if roxithromycin is administered to patients with impaired hepatic function. If administered to patients with severely impaired hepatic function (e.g. hepatic cirrhosis with jaundice and/or ascites), consideration should be given to reducing the daily dosage to half the usual dosage.
Neutropenia was observed in children treated with roxithromycin. 31.6% of 402 children in clinical trials had a neutrophil count below the lower limit of the normal range (3,500/mm3) at the conclusion of therapy with roxithromycin. Of these, 4% had a neutrophil count of less than 1,500/mm3 and 1.2% had a count of less than 1,000/mm3. It is not known whether this is an effect of the drug, or whether it reflects a normal fluctuation of the neutrophil count or a response to infection in children.

Use in renal impairment.

Renal excretion of roxithromycin and its metabolites accounts for a small percentage of an oral dose. The dosage should be kept unchanged in renal insufficiency.

Use in the elderly.

No dosage adjustment is required in elderly patients.

Paediatric use.

In young animal studies, high oral doses of roxithromycin were associated with bone growth plate abnormalities. However no abnormalities were observed in the animals at doses resulting in unbound plasma roxithromycin concentrations that were 10 to 15 times higher than the unbound concentration measured in children receiving the therapeutic dose. The maintenance of such safety margins is primarily dependent on high affinity binding of roxithromycin to plasma alpha-1-acid glycoprotein and will be compromised by any circumstances attenuating the extent of this binding. It is recommended that the approved paediatric dosage regimen (i.e. 5 to 8 mg/kg/day for a maximum of ten days) be adhered to strictly.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Roxithromycin has a much lower affinity for cytochrome P450 than erythromycin, and consequently has fewer interactions. Interactions may be observed, however, with drugs that bind to alpha-1-acid glycoprotein, such as disopyramide.
Roxithromycin does not appear to interact with oral contraceptives containing oestrogens and progestogens, prednisolone, carbamazepine, ranitidine or antacids.

Theophylline.

A study in normal subjects concurrently administered roxithromycin and theophylline has shown some increase in the plasma concentration of the latter. While a change in dosage is usually not required, patients with high levels of theophylline at commencement of treatment should have levels monitored.

Theophylline and cyclosporin.

A slight increase in plasma concentrations of theophylline or cyclosporin A has been observed. This does not generally necessitate altering the usual dosage.

Ergot alkaloids.

Reactions of ergotism with possible peripheral necrosis have been reported after concomitant therapy of macrolides with vasoconstrictive ergot alkaloids, particularly ergotamine and dihydroergotamine. Because a clinical interaction with roxithromycin cannot be excluded, administration of roxithromycin to patients taking ergot alkaloids is contraindicated. Absence of treatment with these alkaloids must always be checked before prescribing roxithromycin.

Disopyramide.

An in vitro study has shown that roxithromycin can displace protein bound disopyramide; such an effect in vivo could result in increased serum levels of disopyramide. Consequently ECG and, if possible, disopyramide serum levels should be monitored.

Terfenadine.

Some macrolide antibiotics (e.g. erythromycin) may increase serum levels of terfenadine. This can result in severe cardiovascular adverse events, including QT prolongation, Torsades de Pointes and other ventricular arrhythmias. Such a reaction has not been documented with roxithromycin, which has a much lower affinity for cytochrome P450 than erythromycin. However, in the absence of a systematic interaction study, concomitant administration of roxithromycin and terfenadine is not recommended.

Astemizole, cisapride, pimozide.

Roxithromycin, like other macrolides, should be used with caution in patients receiving class IA and III antiarrhythmic agents. Drugs such as astemizole, cisapride or pimozide, which are metabolised by the hepatic isozyme CYP3A4, have been associated with QT interval prolongation and/or cardiac arrhythmias (typically torsades de pointes) as a result of an increase in their serum level subsequent to interaction with significant inhibitors of this isozyme, including some macrolide antibacterials. Although roxithromycin has no or limited ability to complex CYP3A4 and therefore to inhibit the metabolism of other drugs processed by this isozyme, a potential for clinical interaction of roxithromycin with the above mentioned drugs cannot be either ascertained or ruled out in confidence; therefore, concomitant administration of roxithromycin and such drugs is not recommended.

Vitamin K antagonists.

While no interaction was observed in volunteer studies, roxithromycin appears to interact with warfarin. Increases in prothrombin time (international normalised ratio (INR)) have been reported in patients treated concomitantly with roxithromycin and warfarin or the related vitamin K antagonist phenprocoumon, and severe bleeding episodes have occurred as a consequence. INR should be monitored during combined treatment with roxithromycin and vitamin K antagonists.

Digoxin and other cardiac glycosides.

A study in healthy volunteers has shown that roxithromycin may increase the absorption of digoxin. This effect, common to other macrolides, may very rarely result in cardiac glycoside toxicity. This may be manifested by symptoms such as nausea, vomiting, diarrhoea, headache or dizziness; cardiac glycoside toxicity may also elicit heart conduction and/or rhythm disorders. Consequently, in patients treated with roxithromycin and digoxin or another cardiac glycoside, ECG and, if possible, the serum level of the cardiac glycoside should be monitored; this is mandatory if symptoms which may suggest cardiac glycoside overdosage occur.

Midazolam.

Roxithromycin, like other macrolides, may increase the area under the midazolam concentration-time curve and the midazolam half-life, therefore the effects of midazolam may be enhanced and prolonged in patients treated with roxithromycin. There is no conclusive evidence for an interaction between roxithromycin and triazolam.

CYP3A.

Roxithromycin is a weak CYP3A inhibitor. The effect of roxithromycin on exposure to drugs predominantly cleared by CYP3A metabolism would be expected to be 2-fold or less. Caution should be exercised when roxithromycin is concomitantly prescribed with drugs metabolised by CYP3A (such as rifabutin and bromocriptine).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There was no effect on the fertility of rats treated with roxithromycin at oral doses up to 180 mg/kg/day.
(Category B1)
Reproductive studies in rats, mice and rabbits at doses of 100, 400 and 135 mg/kg/day, respectively, did not demonstrate evidence of developmental abnormalities. In rats, at doses above 180 mg/kg/day, there was evidence of embryotoxicity and maternotoxicity. The safety of roxithromycin for the human foetus has not been established.
Small amounts of roxithromycin are excreted in the breast milk. Breastfeeding or treatment of the mother should be discontinued as necessary.

4.8 Adverse Effects (Undesirable Effects)

Roxithromycin is generally well tolerated. In clinical trials, treatment discontinuation due to adverse effects occurred in only 1.2% of adult patients and 1.0% of children. The following side effects or serious adverse events possibly associated with roxithromycin have been reported.

Gastrointestinal.

Nausea, vomiting, epigastric pain (dyspepsia), diarrhoea (sometimes containing blood), anorexia, flatulence, pseudomembranous colitis. In clinical studies, the incidence of gastrointestinal events was higher with the 300 mg once daily dosage regimen than with 150 mg twice daily. Symptoms of pancreatitis have been observed; most patients had received other drugs for which pancreatitis is a known adverse effect.

Hypersensitivity.

Urticaria, rash, pruritus, angioedema. Rarely, serious allergic reactions may occur, such as asthma, bronchospasm, anaphylactic-like reactions, anaphylactic shock, purpura, glottic oedema, generalised oedema, erythema multiforme, exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome and Toxic Epidermal Necrosis (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic.

Moderate increase in serum transaminases (AST and ALT) and/or alkaline phosphatase levels have been observed and are somewhat more likely to occur in the elderly (> 65 years of age). Acute cholestatic hepatitis and acute hepatocellular injury (sometimes with jaundice), are rarely reported.

Hematological effects.

Transient eosinophilia, agranulocytosis, neutropenia, and thrombocytopenia.
Thrombocytosis has been reported in patients receiving roxithromycin 150 mg twice a day for 10 days.

Dermatological.

Mild itching (1 to 5%), nail discoloration.

Other.

Headache, bronchospasm, visual impairment, blurred vision, hallucination, confusion, dizziness, paraesthesia, tinnitus, malaise, moniliasis (candidiasis), pancreatitis, QT prolongation, disorders of taste and/or smell, temporary deafness, hypoacusis and vertigo.
Prolonged use of antibiotics including roxithromycin may result in superinfection; overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. In the event of superinfection, appropriate measures should be taken.

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 or contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

For oral administration.

Adults.

Roxithromycin should be taken at least 15 minutes before food or on an empty stomach (i.e. more than three hours after a meal).
The recommended dosage is 300 mg per day which may be taken according to one of the following dosage regimens (see Table 1).
For atypical pneumonia, the recommended dosage is 150 mg twice daily.
Roxithromycin 150 and 300 mg film coated tablets must be swallowed whole with a drink.
The usual duration of treatment is five to ten days depending on the indication and clinical response. Streptococcal throat infections require at least ten days of therapy. A small proportion of patients with non-gonococcal genital infections may require 20 days for complete cure.

Children.

The recommended dose and duration of treatment should not be exceeded in children (see Section 4.4 Special Warnings and Precautions for Use).
Roxithromycin should be taken at least 15 minutes before food or on an empty stomach (i.e. more than three hours after a meal).
Roxithromycin is administered twice daily at a dose of 5 to 8 mg/kg per day. Recommended dosage regimens are as follows:

40 kg and over.

One roxithromycin 150 mg tablet morning and evening.
Roxithromycin tablets are not recommended for children weighing less than 40 kg.
The usual duration of treatment is five to ten days depending on the indication and clinical response. Streptococcal throat infections require ten days of therapy. The duration of treatment should not exceed ten days.

4.7 Effects on Ability to Drive and Use Machines

Attention should be drawn to the possibility of dizziness, visual impairment and blurred vision.

4.9 Overdose

Symptomatic treatment should be provided as required. There is no specific antidote.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Maize starch, hyprolose, colloidal anhydrous silica, sodium starch glycollate, poloxamer, povidone, magnesium stearate, purified talc, propylene glycol, glucose, titanium dioxide, hypromellose.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 heat and moisture.

6.5 Nature and Contents of Container

APO-Roxithromycin 150 mg tablets.

Blister packs (PVC/ Al) of 10.
AUST R 133748.

APO-Roxithromycin 300 mg tablets.

Blister packs (PVC/Al) of 5.
AUST R 133749.
Not all strengths, pack types and/or 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.

Summary Table of Changes