Consumer medicine information

Amoxycillin and Clavulanic Acid 500mg/125mg APOTEX Tablets

Amoxicillin; Clavulanic acid

BRAND INFORMATION

Brand name

Amoxycillin/Clavulanic Acid 500/125 Apotex

Active ingredient

Amoxicillin; Clavulanic acid

Schedule

What is in this leaflet

This leaflet answers some common questions about amoxycillin and clavulanic acid. 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

Amoxycillin and clavulanic acid is used to treat a wide range of infections caused by bacteria. These infections may affect the chest (bronchitis or pneumonia), bladder (cystitis), sinuses (sinusitis), ears (otitis media) or skin.

How it works

Amoxycillin is a type of penicillin antibiotic. Clavulanic acid is used to help the amoxycillin work better against certain types of bacteria.

Amoxycillin and clavulanic acid works by killing the bacteria that cause these infections. It will not work against viral infections such as colds or the flu, which are caused by viruses.

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.

These tablets are not recommended for children weighing less than 40 kg.

Before you take this medicine

When you must not take it

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

amoxicillin
other penicillins or cephalosporins
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 if you have previously experienced liver problems after taking amoxycillin and clavulanic acid, or any other medicines.

Do not take this medicine if you have severe kidney problems.

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 problems
kidney problems
glandular fever (mononucleosis)
leukaemia

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

Tell your doctor if you are planning to have surgery, dental treatment or an anaesthetic.

Tell your doctor if you have to test your urine for sugar. Amoxycillin and clavulanic acid may affect the results of these tests.

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 or pharmacist 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 amoxycillin and clavulanic acid. These include:

warfarin or other medicines used to prevent blood clots
medicines used to treat gout (e.g. probenecid, allopurinol)
other antibiotics used to treat infections
the contraceptive pill

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 an additional method of contraception while taking this medicine. Some antibiotics may decrease the effectiveness of some birth control pills.

How to take this medicine

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

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

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.

The usual dose is one tablet twice a day (approximately every 12 hours).

How to take it

Swallow the tablet whole with a full glass of water.

The tablets may be broken in half but should not be chewed.

When to take it

Take the tablet immediately before or with the first mouthful of food. This medicine works best when taken this way and may help to prevent stomach upsets.

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.

Space the doses as evenly as possible throughout the day. If you are taking the tablets twice a day, take a dose about every 12 hours.

How long to take it for

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

It is important to keep taking your medicine even if you feel well. 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.

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

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

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 the dose that you missed. This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask 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.

If you take too much amoxycillin and clavulanic acid, you may experience nausea, vomiting, cramps and diarrhoea

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.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

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

Take this medicine exactly as your doctor has prescribed.

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise your doctor may think that it was not working as it should and change your treatment unnecessarily.

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

If you develop itching with swelling or skin rash or difficulty breathing while you are taking amoxycillin and clavulanic acid, do not take any more and contact your doctor immediately.

If you get severe diarrhoea, tell your doctor or pharmacist immediately. Do this even if it occurs several weeks after amoxycillin and clavulanic acid has been stopped. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any diarrhoea medicine without first checking with your doctor.

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

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.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. This medicine may cause dizziness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Alcohol should be avoided during and for several days after treatment with this medicine. Some people who drink alcohol while taking antibiotics similar to amoxycillin and clavulanic acid tablets have experienced adverse effects.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking amoxycillin and clavulanic acid.

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, but 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 or pharmacist if you notice any of the following and they worry you:

diarrhoea (several loose bowel movements per day), indigestion, pain in the stomach, nausea (feeling sick) or vomiting (being sick)
headache, dizziness, tiredness, hot flushes, sinusitis
muscle or back pain
problem getting to sleep, feeling hyperactive
tooth discolouration.

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

Tell your doctor as soon as possible if you notice any of the following:

white, furry, sore tongue and mouth (oral thrush), abnormal taste, black hairy tongue
soreness or itching of the vagina or vaginal discharge (vaginitis or vaginal thrush), pain when urinating (cystitis)
itching or any type of skin rash or blistering, peeling or flaking skin, which may or may not be accompanied by a fever or swollen lymph nodes
dark urine or pale stools, yellowing of the skin or eyes (jaundice)
severe stomach cramps, severe watery or bloody diarrhoea
unusual bleeding or bruising

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

If any of the following happen, stop taking this medicine and tell 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)
fever, chills, fatigue, headache and body aches, nausea or vomiting, and sensitivity to light (symptoms of aseptic meningitis)
inflammation of the bowel (colitis), liver (hepatitis) or kidney (nephritis)
blood disorders
crystals in the urine (crystalluria)

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may 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 the 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 that is left over.

Product description

What it looks like

500/125 - Off-white, oval, biconvex, film-coated tablet, scored on both sides.

Available in blister packs of 10 tablets. AUST R 317064.

Ingredients

Each tablet contains the following active ingredients:

500 mg of amoxicillin (as amoxicillin trihydrate)
125 mg of clavulanic acid (as potassium clavulanate)

It also contains the following:

magnesium stearate
purified talc
povidone
croscarmellose sodium
microcrystalline cellulose
triethyl citrate
ethylcellulose
sodium lauryl sulfate
cetyl alcohol
hypromellose
titanium dioxide.

Contains 24.5 mg potassium per tablet. This medicine does not contain gluten, lactose, sucrose, tartrazine or other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in September 2021.

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Amoxycillin/Clavulanic Acid 500/125 Apotex

Active ingredient

Amoxicillin; Clavulanic acid

Schedule

1 Name of Medicine

Amoxicillin trihydrate and potassium clavulanate.

2 Qualitative and Quantitative Composition

Each tablet contains the following ingredients:

Active ingredients.

See Table 1.

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

3 Pharmaceutical Form

Amoxycillin/Clavulanic Acid 500/125 Apotex tablets.

Off-white, oval, biconvex, film-coated and scored on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Amoxicillin and clavulanic acid tablets are indicated for short term treatment of bacterial infections at the following sites when caused by amoxicillin/clavulanic acid sensitive, beta-lactamase producing organisms (see Section 5.1 Pharmacodynamic Properties, Microbiology):
Skin and skin structure infections.
Urinary tract infections (complicated and uncomplicated).
Upper respiratory tract infections, such as sinusitis, otitis media and recurrent tonsillitis.
Lower respiratory tract infections, including community acquired pneumonia and acute exacerbations of chronic bronchitis.
Appropriate culture and susceptibility studies should be performed to identify the causative organism(s) and determine its (their) susceptibility to amoxicillin and clavulanic acid tablets. However, when there is reason to believe an infection may involve any of the beta-lactamase producing organisms listed, see Section 5.1 Pharmacodynamic Properties, Microbiology, therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies. Once these results are known, therapy should be adjusted if appropriate.
The treatment of mixed infections caused by amoxicillin susceptible organisms and beta-lactamase producing organisms susceptible to amoxicillin and clavulanic Acid tablets should not require the addition of another antibiotic due to the amoxicillin content of this product.

4.2 Dose and Method of Administration

Dosage.

Adults.

The usual adult dose is one Amoxycillin/Clavulanic Acid 500/125 Apotex tablet every 12 hours.

Note.

Although the proportion of amoxicillin increases with increasing strength of amoxicillin/clavulanic acid tablet preparations, the amount of clavulanic acid remains the same. Therefore, the tablets are not directly substitutable.
Treatment should usually be continued for 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Treatment should not exceed 14 days without review.

Method of administration.

Amoxicillin/clavulanic acid tablet preparations should be taken immediately before or with the first mouthful of food, to minimise potential gastrointestinal intolerance and to optimise absorption.

Renal impairment.

Both amoxicillin and clavulanic acid are excreted by the kidneys and the serum half-life increases in patients with renal failure. No adjustment to the initial dose is necessary, but the dosing interval should be extended according to the degree of renal impairment. The following schedule is proposed for amoxicillin/clavulanic acid tablets preparations:

Mild impairment (creatinine clearance > 30 mL/minute).

No change in dosage.

Moderate impairment (creatinine clearance 10 to 30 mL/minute).

Amoxycillin/Clavulanic Acid 500/125 Apotex - one tablet, 12-hourly only.

Severe impairment (creatinine clearance < 10 mL/minute).

Amoxycillin/Clavulanic Acid 500/125 Apotex - one tablet every 24 hours.
Haemodialysis decreases serum concentrations of both amoxicillin and clavulanic acid and an additional dose should be administered at the end of dialysis.

Hepatic impairment.

Data are currently insufficient for a dosage recommendation. Dose with caution, and monitor hepatic function at regular intervals.

Children.

Children weighing 40 kg and more should be dosed according to the adult recommendations. Treatment should usually be continued for 48 to 72 hours beyond the time that the child becomes asymptomatic or evidence of bacterial eradication has been obtained. Treatment should not exceed ten days except for lower respiratory tract infection due to H. influenzae where treatment may be extended up to 14 days.
Children weighing less than 40 kg should not use amoxicillin/clavulanic acid tablet preparations.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
History of allergic reactions to beta-lactams, e.g. penicillins cephalosporins carbapenems or monobactams.
Previous history of amoxicillin/clavulanic acid associated jaundice/hepatic dysfunction.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.
Serious and occasionally fatal hypersensitivity (including anaphylactoid and severe cutaneous adverse reactions) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to amoxicillin or clavulanic acid (see Section 4.8 Adverse Effects (Undesirable Effects)). If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued and the appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation, should also be administered as indicated.

Pseudomembranous colitis.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including amoxicillin. 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 antibiotic agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement therapy should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.

General.

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.
Since amoxicillin and clavulanic acid tablets contain amoxicillin, an aminopenicillin, it is not the treatment of choice in patients presenting with sore throat or pharyngitis because of the possibility that the underlying cause is infectious mononucleosis, in the presence of which there is a high incidence of rash if amoxicillin is used.
Amoxicillin and clavulanic acid tablets should be given with caution to patients with lymphatic leukaemia since they are especially susceptible to amoxicillin induced skin rashes.
Amoxicillin-clavulanate should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin-clavulanate and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Aerobacter, Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted.
Cholestatic hepatitis, which may be severe but is usually reversible, has been reported. Signs and symptoms may not become apparent until several weeks after treatment has ceased. In most cases resolution has occurred with time. However, in extremely rare circumstances, deaths have been reported. These have almost always been cases associated with serious underlying disease or concomitant medications.
Hepatic events subsequent to amoxicillin/clavulanic acid therapy have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. Hepatitis and cholestatic jaundice have also been reported rarely. These events have been noted with other penicillins and cephalosporins.

Use in hepatic impairment.

Amoxicillin/clavulanic acid should be used with care in patients with evidence of hepatic dysfunction.
Data is currently insufficient for a dosage recommendation. Dose with caution, and monitor hepatic function at regular intervals.

Use in renal impairment.

Amoxycillin/Clavulanic Acid 500/125 Apotex should be used with care in patients with moderate or severe renal impairment. The dosage of Amoxycillin/Clavulanic Acid 500/125 Apotex should be adjusted as recommended (see Section 4.2 Dose and Method of Administration).
Convulsions may occur in patients with impaired renal function or in those receiving high doses.
In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria (see Section 4.9 Overdose).

Use in the elderly.

No data available.

Paediatric use.

Children weighing 40 kg and more should be dosed according to the adult recommendations. Children weighing less than 40 kg should not use amoxicillin/clavulanic acid tablet preparations. (See Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

Oral administration of amoxicillin/clavulanic acid will result in high urine concentrations of amoxicillin. Since high urine concentrations of ampicillin may result in false positive reactions when testing for the presence of glucose in urine using Clinitest, Benedict's solution or Fehling's solution, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix or Tes-Tape) be used.
The presence of clavulanic acid in amoxicillin/clavulanic acid tablets may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.
Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated oestriol, oestriol glucuronide, conjugated oestrone and oestradiol has been noted. This effect may also occur with amoxicillin and therefore amoxicillin/clavulanic acid tablet preparations.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Probenecid decreases the renal tubular secretion of amoxicillin but does not affect clavulanic acid excretion. Concurrent use with amoxicillin/clavulanic acid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.
The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricaemia present in these patients. There are no data with amoxicillin/clavulanic acid and allopurinol administered concurrently.
No information is available about the concurrent use of amoxicillin/clavulanic acid and alcohol. However, the ingestion of alcohol whilst being treated with some other beta-lactam antibiotics has precipitated a disulfiram like reaction in some patients. Therefore, the ingestion of alcohol should be avoided during and for several days after treatment with Amoxicillin/clavulanic acid tablet.
In common with other broad-spectrum antibiotics, amoxicillin/clavulanic acid may affect the gut flora, leading to lower oestrogen re-absorption and reduced efficacy of oral contraceptives. Patients should be warned accordingly.
In the literature, there are rare cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin.
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) has been reported following commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Amoxicillin/clavulanic acid at oral doses of up to 1200 mg/kg/day had no effect on fertility and reproductive performance in rats dosed with a 2:1 ratio formulation of amoxicillin and clavulanate.
(Category B1)
Animal studies with orally and parenterally administered amoxicillin/clavulanic acid have shown no teratogenic effects. There is limited experience of the use of amoxicillin/clavulanic acid in human pregnancy. In women with preterm, premature rupture of the foetal membrane (pPROM), prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, especially during the first trimester, unless considered essential by the doctor.

Use in labour and delivery.

Oral ampicillin class antibiotics are generally poorly absorbed during labour. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions and duration of contractions. However, it is not known whether the use of amoxicillin/clavulanic acid in humans during labour or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labour or increases the likelihood that forceps delivery or other obstetric intervention or resuscitation of the newborn infant will be necessary.
Both amoxicillin and clavulanic acid are excreted into breast milk. Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breastfed infant. The possibility of sensitisation should be taken into account. Therefore, caution should be exercised when amoxicillin/clavulanic acid is given to a breastfeeding woman.

4.7 Effects on Ability to Drive and Use Machines

Adverse effects on the ability to drive or operate machinery have not been observed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Amoxicillin/clavulanic acid is generally well tolerated. The majority of events were of a mild and transient nature.

Clinical trials.

Amoxicillin/clavulanic acid 875/125 tablets.

The most frequently reported adverse events related or possibly related to amoxicillin/clavulanic acid 875/125 tablets were diarrhoea (14.9%), nausea (7.9%), headache (6.8%), abdominal pain (4.5%), vomiting (3.8%), genital moniliasis (3.6%) and vaginitis (3.4%). The following adverse events have been observed during clinical trials with the amoxicillin/clavulanic acid 875/125 tablets twice daily regimen, however it should be noted that causality has not necessarily been established for these events. See Table 2.

Amoxicillin/clavulanic acid 500/125 and amoxicillin/clavulanic acid 250/125 tablets.

In clinical trials with the 250/125 and 500/125 strengths, the overall incidence of adverse effects, of suspected or unknown relationship to the drug, varied between 16 and 23.3%, depending on the dose. The majority of side effects observed were of a mild and transient nature, but therapy was discontinued because of drug related side effects in 4.2% of cases at the low dose (amoxicillin/clavulanic acid 250/125 tablets three times daily) and 7% of cases at the high dose (amoxicillin/clavulanic acid 500/125 tablets three times daily). The most frequently reported adverse effects were diarrhoea (6%), nausea (2%), vomiting (1%), abdominal pain, skin rashes, urticaria and erythema multiforme, vaginitis, abnormal taste, headache, dizziness, tiredness, and hot flushes. The incidence and severity of adverse effects, particularly nausea and diarrhoea, increased with the higher recommended dose.
In recent trials with amoxicillin/clavulanic acid 500/125 tablets, the most frequently reported adverse events related or possibly related to treatment were diarrhoea (12.8%), nausea (5.2%), headache (4.8%), abdominal pain (4.5%).
The following adverse events have been observed during clinical trials with the amoxicillin/clavulanic acid 500/125 tablets, however it should be noted that causality has not necessarily been established for these events. See Table 3.

Post-marketing.

The following adverse reactions have been reported for ampicillin class antibiotics and may occur with amoxicillin/clavulanic acid tablet preparations.
Very common: ≥ 1/10; Common: ≥ 1/100 and < 1/10; Uncommon: ≥ 1/1,000 and < 1/100; Rare: ≥ 1/10,000 and < 1/1,000; Very rare: < 1/10,000; Not known: cannot be estimated from the available data.

Infections and infestations.

Common: mucocutaneous candidiasis.
Not known: overgrowth of non-susceptible organism.

Cardiac disorders.

Very rare: Kounis syndrome (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Very common: diarrhoea.
Common: nausea, vomiting.
Uncommon: indigestion.
Rare: gastritis, stomatitis, glossitis, black 'hairy' tongue, enterocolitis, antibiotic associated colitis (including pseudomembranous colitis and haemorrhagic colitis) (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary.

Uncommon: moderate rise in AST and/or ALT.
Rare: hepatitis, cholestatic jaundice, which may be severe but is usually reversible.

Nervous system disorders.

Uncommon: dizziness, headache.
Very rare: reversible hyperactivity, aseptic meningitis and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Not known: aseptic meningitis.

Haemopoietic and lymphatic system.

Uncommon: thrombocytosis.
Rare: anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, reversible leucopenia (including neutropenia and agranulocytosis); these are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena; prolongation of bleeding time and prothrombin time.
Not known: haemolytic anaemia.

Hypersensitivity and skin.

Common: skin rashes, pruritus, urticaria.
Rare: angioneurotic oedema, anaphylaxis, serum sickness like syndrome, erythema multiforme, Stevens-Johnson syndrome, hypersensitivity, vasculitis, toxic epidermal necrolysis, bullous exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported rarely. Whenever such reactions occur, amoxicillin/clavulanic acid tablets should be discontinued, unless in the opinion of the doctor no alternative treatment is available and continued therapy is considered essential. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and angioneurotic oedema can occur with oral penicillins (see Section 4.4 Special Warnings and Precautions for Use).

Renal and urinary disorders.

Rare: interstitial nephritis.
Very rare: crystalluria (see Section 4.9 Overdose).

Miscellaneous.

Rare: superficial tooth discolouration, which can usually be removed by brushing.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Serious and severe clinical symptoms are unlikely to occur after overdosage with amoxicillin/clavulanic acid. If encountered, gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. They may be treated symptomatically, with attention to the water/electrolyte balance.
Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4 Special Warnings and Precautions for Use).
Amoxicillin may be removed from the circulation by haemodialysis.
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.

Amoxicillin/clavulanic acid preparations are a combination product containing the semi-synthetic antibiotic amoxicillin (as the trihydrate) and the beta-lactamase inhibitor potassium clavulanate (as the potassium salt of clavulanic acid).

Microbiology.

Like other penicillins, amoxicillin has a bactericidal effect on sensitive organisms during the stage of active multiplication. However, amoxicillin is susceptible to hydrolysis by beta-lactamases and the addition of clavulanic acid extends the antimicrobial spectrum of amoxicillin to include organisms normally resistant to amoxicillin due to beta-lactamase production. In vitro studies have demonstrated the susceptibility of most strains of the following organisms. (See Tables 4 to 7).

Note.

Resistance can vary from region to region and information on local resistance should be taken into account.

The MIC90 data provided in the above table has been collected from the following countries during the time period specified: US: 91-97; UK: Not Stated; France: 94-95; Belgium: 93-94.
It should be noted that NCCLS breakpoints are reviewed on a regular basis and may be amended according to the data available.
Susceptibility testing.

Dilution or diffusion techniques.

Either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited 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 solutions 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 concentration 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.

Clinical trials.

Amoxicillin/clavulanic acid 875/125 tablets twice daily versus amoxicillin/clavulanic acid 500/125 tablets three times daily.

Three studies in 1,361 patients treated for 7 to 14 days for either lower respiratory tract infections, upper respiratory infections or complicated urinary tract infections compared a regimen of amoxicillin/clavulanic acid 875/125 tablets every 12 hours to amoxicillin/clavulanic acid 500/125 tablets dosed every eight hours (584, 170 and 607 patients respectively). Comparable efficacy was demonstrated between the 12 hourly and eight hourly dosing regimens.
There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event in two of the studies was diarrhoea; incidence rates were similar for the 875/125 mg tablets every 12 hours and 500/125 mg tablets every eight hours dosing regimens (14.9 and 14.3%, respectively). However, there was a statistically significant difference (p < 0.05) in rates of severe diarrhoea or withdrawals with diarrhoea between the regimens: 1.0% for 875/125 mg 12 hourly dosing versus 2.5% for the 500/125 mg eight hourly dosing. In the third study, the most frequently reported adverse event was headache with an incidence of 5.7% (amoxicillin/clavulanic acid 500/125 tablets every eight hours) versus 8.3% (amoxicillin/clavulanic 875/125 tablets every 12 hours).
As noted previously, although there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhoea or diarrhoea related withdrawals between the regimens.

Amoxicillin/clavulanic acid 500/125 tablets twice daily versus amoxicillin/clavulanic acid 250/125 tablets three times daily.

Two studies in 908 patients treated for between five and ten days for either uncomplicated skin and skin structure infections (SSSI) or acute exacerbation of chronic bronchitis (AECB) compared a regimen of amoxicillin/clavulanic acid 500/125 tablets every 12 hours with amoxicillin/clavulanic acid 250/125 tablets every eight hours. Comparable efficacy was demonstrated between the 12 hourly and eight hourly dosing regimens.
There was no significant difference in the percentage of adverse events in each group, with the most frequently reported adverse event in the two studies being diarrhoea.
The clinical efficacy of amoxicillin/clavulanic acid 250/125 tablets given in a twice daily versus three times daily regimen have been shown to be comparable in AECB and SSSI, despite the differences in some pharmacokinetic parameters.
Given the similar TMIC and the demonstration of equivalence between AECB and SSSI it would be reasonable to extrapolate to the remaining indications. Clinical safety and efficacy in other indications have been investigated, however these supportive studies were not sufficiently designed to demonstrate the relative efficacy of the twice daily versus three times daily dosage regimens, or compared the proposed regimen with other treatments.

5.2 Pharmacokinetic Properties

Absorption.

Amoxicillin/clavulanic acid tablet preparations are stable in the presence of gastric acid. Their two components are rapidly absorbed if administered before or with a meal, but if given after meals, the serum levels of clavulanic acid are significantly reduced. To optimise absorption of clavulanic acid, amoxicillin/clavulanic acid tablet preparations should be administered at the start of a meal. The pharmacokinetics of amoxicillin are not affected by food.
Oral administration at the start of a light meal of amoxicillin/clavulanic acid 875/125 tablets every 12 hours was compared with amoxicillin/clavulanic acid 500/125 tablets every eight hours.
The following mean pharmacokinetic parameters (see Tables 8 and 9) were observed for amoxicillin and clavulanic acid following administration of amoxicillin/clavulanic acid 875/125 tablets every 12 hours and amoxicillin/clavulanic acid 500/125 tablets every eight hours:

The half-life and C_max for clavulanate for amoxicillin/clavulanic acid 875/125 tablets were not significantly different from amoxicillin/clavulanic acid 500/125 tablets. However, the AUC_{(0-24 hours)} was reduced, as would be expected with the lower daily dose of clavulanate, i.e. twice daily dose (125 x 2 mg of clavulanate) versus three times daily dose (125 x 3 mg of clavulanate).
Oral administration of amoxicillin/clavulanic acid 500/125 tablets every 12 hours was compared with amoxicillin/clavulanic acid 250/125 tablets every eight hours at the start of a light meal. The following mean pharmacokinetic parameters were observed (see Tables 10 and 11):

Distribution.

Following oral administration, both amoxicillin and clavulanic acid have been shown to diffuse in significant concentrations into pus, bile, and pleural, synovial and peritoneal fluids. Both penetrate poorly into the CSF when the meninges are normal. Amoxicillin penetrates into the CSF better through inflamed meninges, but the maximum concentrations are still much lower than the peak serum levels. There are no data at present on the CSF penetration of clavulanic acid in patients with meningeal inflammation.
Neither amoxicillin nor clavulanic acid are highly protein bound. Clavulanic acid has been variously reported to be bound to human serum in the range of 9 - 30% and amoxicillin approximately 20% bound. From animal studies, there is no evidence to suggest either component accumulates in any organ.

Metabolism.

2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid is the major metabolite.

Excretion.

As with other penicillins, renal excretion is the major route of amoxicillin clearance, while clavulanate elimination is via both renal and non-renal mechanisms. Approximately 70% of the dose of amoxicillin is excreted in urine as amoxicillin.
For clavulanic acid, following the administration of 125 mg of radiolabelled potassium clavulanate orally to normal volunteers, 68% of the administered radioactivity was recovered in the urine in 24 hours. Of this, 34% (i.e. 23% of the administered dose) is present as unchanged clavulanic acid. 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid (the major metabolite) and 1-amino-4-hydroxy-butan-2-one accounted for a further 23 and 12% (i.e. 16 and 8%, respectively, of the administered dose). Small amounts of other yet unidentified metabolites were also present.
Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of amoxicillin/clavulanic acid was investigated in assays for chromosomal damage (mouse micronucleus test and a dominant lethal test) and gene conversion. All were negative.

Carcinogenicity.

Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Magnesium stearate, purified talc, povidone, croscarmellose sodium, microcrystalline cellulose, triethyl citrate, ethylcellulose, sodium lauryl sulfate, cetyl alcohol, hypromellose and titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.
Protect from moisture.

6.5 Nature and Contents of Container

Amoxycillin/Clavulanic Acid 500/125 Apotex tablets.

Aluminium/aluminium strip packs or aluminium/aluminium blister packs.
Blister packs of 10 tablets.
Apotex Pty Ltd is the licensee of the registered trade mark APOTEX from the registered proprietor, Apotex Inc.
Not all strengths 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

Amoxicillin trihydrate is white to almost white, crystalline powder, slightly soluble in water and in alcohol, practically insoluble in ether and in fatty oils. It dissolves in dilute acids and dilute solutions of alkali hydroxides.
Potassium clavulanate is white to almost white, crystalline powder, hygroscopic, freely soluble in water, slightly soluble in alcohol, and very slightly soluble in acetone.

Chemical structure.

Amoxicillin trihydrate.

Potassium clavulanate.

Chemical names.

Amoxicillin trihydrate: (2S,5R,6R)-6-[(R)-2-amino-2-(4-hydroxyphenyl)acetamido]-3,3-dimethyl-7oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.
Potassium clavulanate: potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate.

Molecular formulae.

Amoxicillin trihydrate: C₁₆H₁₉N₃O₅S.3H₂O.
Potassium clavulanate: C₈H₈KNO₅.

Molecular weights.

Amoxicillin trihydrate: 419.5.
Potassium clavulanate: 237.3.

CAS number.

Amoxicillin trihydrate: 61336-70-7.
Potassium clavulanate: 61177-45-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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