Consumer medicine information

Amclavox Duo 500/125 & Amclavox Duo Forte 875/125 Tablets

Amoxicillin; Clavulanic acid

BRAND INFORMATION

Brand name

Amclavox Duo 500/125, Amclavox Duo Forte 875/125

Active ingredient

Amoxicillin; Clavulanic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amclavox Duo 500/125 & Amclavox Duo Forte 875/125 Tablets.

What is in this leaflet?

Please read this leaflet carefully before you take AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.

This leaflet answers some common questions about AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Sometimes new risks are found even when a medicine has been used for many years. Your doctor has weighed the expected benefits of you taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets against the risks this medicine could 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 need to read it again.

What are AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets used for?

AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets contain two active ingredients. One of these is a penicillin called amoxicillin and the other is clavulanic acid.

AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets belong to the penicillin group of antibiotics. AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets are used for the short-term treatment of a wide range of infections caused by bacteria. These infections may affect the chest (e.g. bronchitis or pneumonia), bladder (e.g. cystitis), sinuses (e.g. sinusitis), the ears (e.g. otitis media) or the skin.

AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets work by killing the bacteria that cause these infections. AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets will not work against infections caused by viruses such as colds or the flu.

Your doctor may prescribe AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets for another use. If you want more information, ask your doctor.

There is no evidence that AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets are addictive.

Before you take AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets

Do not take AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets if:

  • You have had an allergic reaction to penicillin or similar types of antibiotics (such as cephalosporins) or any of the ingredients contained in AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.
    The ingredients are listed at the end of this leaflet.Some of the symptoms of an allergic reaction may include skin rash, itching, difficulty in breathing and swelling of the face or tongue.
  • You have previously experienced liver problems after taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets or any other medicines.
  • The expiry date (EXPIRY) printed on the pack has passed.
  • The packaging is torn or shows signs of tampering.

Do not give this medicine to anyone else; your doctor has prescribed it specifically for you and your condition.

If you are not sure whether you should start taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets, talk to your doctor.

Tell your doctor if:

  • You have ever had an allergic reaction (such as a rash) to antibiotics or other substances in the past.
  • You are allergic to foods, dyes, preservatives or any other medicines.
  • You have experienced liver problems after taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets or any other medicines.
  • You have glandular fever (mononucleosis) or leukaemia.
  • You are pregnant or think you may be pregnant or are breastfeeding. Your doctor will discuss with you the possible risks and benefits of taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets during pregnancy or while you are breastfeeding. AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets can pass to your baby from breast milk.
  • You have any kidney or liver problems. The dosage of AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets may need to be changed or you may need to be given an alternative medicine.
  • You have to test your urine for sugar. AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets may affect the results of these tests.
  • Tell your doctor or pharmacist if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. In particular, tell your doctor or pharmacist if you are taking any of the following:
    - Warfarin or other medicines used to prevent blood clots
    - Mycophenolate
    - Medicines used to treat gout (e.g. probenecid or allopurinol).
    - Other antibiotics. These may interfere with the actions of AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.
    - The contraceptive pill. As with other antibiotics, you may need to use extra birth control methods (e.g. condoms) while taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.
  • Some medicines may affect the way other medicines work. Your doctor or pharmacist will be able to tell you what to do when taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets with other medicines.

How to take AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets

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

Please read the directions label carefully. If you have any concerns about how to take this medicine, talk to your doctor or pharmacist.

How much to take:

Take as directed by your doctor or pharmacist.

The usual dose of AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets is one tablet twice a day.

How to take it:

Swallow the AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets with a full glass of water or other liquid.

AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets should be taken immediately before or with the first mouthful of food. AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets work best when taken this way. It may also help to prevent stomach upset. However, AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets still work if they are taken without food.

Space the doses as evenly as possible throughout the day. If you are taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets twice a day, take a dose about every twelve hours.

How long to take it:

Keep taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets until the course is finished or for as long as your doctor tells you.

Do not stop taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets just because you feel better as the infection can return.

Do not stop taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets or change the dose, without first checking with your doctor.

If you forget to take it:

If your next dose is due within six hours, skip the dose you missed and take your next dose at normal time. Otherwise take the missed dose as soon as you remember and then go back to taking your tablets as directed by your doctor.

Do not take a double dose to make up for the dose that you have missed. Taking more than the prescribed dose can increase the chance of unwanted side effects.

What do I do if I take too much? (Overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 131126) for advice if you think you or anyone else has taken too much, even if there are no signs of discomfort or poisoning.

Symptoms of overdose include mild to severe nausea, vomiting, cramps and diarrhoea.

If you are not sure what to do, contact your doctor, pharmacist or nearest hospital. Be sure to show the doctor the AMCLAVOX DUO & AMCLAVOX DUO FORTE pack.

While you are taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets

Things you must do:

Take AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets 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.

Tell your doctor, dentist or pharmacist you are taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets before starting any other medicines.

Some medicines may affect the way other medicines work.

Tell your doctor if the symptoms of your infection become worse, or do not improve within a few days of starting AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.

Things you must not do:

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use this medicine to treat any other complaint unless your doctor says to.

Things to be careful of:

Alcohol should be avoided during and for several days after treatment with AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets. Some people who drink alcohol while taking antibiotics similar to AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets have experienced adverse effects.

Be careful driving or operating machinery until you know how AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets affect you. Generally, these tablets do not cause any problems with your ability to drive a car or operate machinery. However, as with other medicines, AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets may cause dizziness or tiredness in some people.

If you develop severe diarrhoea either when taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets or within several weeks after treatment, tells your doctor as soon as possible. Do not take any medication to stop the diarrhoea (e.g. Lomotil® or Imodium®).

What are the side effects?

Check with your doctor as soon as possible if you think you are experiencing any side-effects or allergic reactions due to taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets, even if the problem is not listed below.

Like other medicines, AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

Tell your doctor about any effect which is troublesome or ongoing.

MILD EFFECTS

Tell your doctor if you notice any of the following that are troublesome or ongoing:

  • Diarrhoea (several loose bowel movements per day), indigestion, pain in the stomach, feeling sick or being sick
  • white, furry, sore tongue and mouth (oral thrush), abnormal taste
  • soreness or itching of the vagina or vaginal discharge (vaginal thrush)
  • aseptic meningitis, headache, dizziness, tiredness, hot flushes
  • tooth discolouration
  • unusually active (hyperactive)

MORE SERIOUS EFFECTS

Tell your doctor immediately if you notice any of the following during or after taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets:

  • rash, itching
  • dark urine or pale stools
  • yellowing of the skin or eyes (jaundice)
  • severe stomach cramps
  • severe watery or bloody diarrhoea
  • unusual bleeding or bruising

These may be symptoms of rare but serious side-effects and require urgent medical attention.

Stop taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets and immediately contact your doctor or go to the emergency department of your nearest hospital if any of the following happens:

Wheezing, hives, severe skin reaction, fainting swelling of limbs, face, lips, mouth or throat, difficult swallowing or breathing, joint discomfort or swelling, swollen lymph glands, nausea and vomiting or fever.

These may be signs of an allergic reaction or other reaction to AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets. Allergy to these antibiotics is rare.

  • Fits/seizures.

Rare events that have been reported with AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets include:

  • inflammation of the bowel (colitis)
  • inflammation of the liver (hepatitis)
  • inflammation of the kidney (nephritis)
  • blood disorders
  • crystal in the urine (crystalluria)

Remember, you should tell your doctor or pharmacist as soon as possible if any of these, or any other unusual events or problems occur during or after treatment with AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.

This is not a complete list of all possible side effects. Other may occur in some people and there may be some side effects not yet known.

Tell your doctor or pharmacist if you notice any side effects from your medicine which are not mentioned here.

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

How do I store AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets?

Keep your tablets in the original pack until it is time to take them.

If you take the tablets out of the pack, they may not keep well.

Keep the pack in a cool dry place. Do not leave it in the car on a hot day. Do not store medicine in the bathroom or near a sink.

Heat and dampness can destroy AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets.

Store all medicines out of the reach of children, such as in a locked cupboard. If your doctor tells you to stop taking AMCLAVOX DUO & AMCLAVOX DUO FORTE tablets, or if the expiry date has passed, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

  • AMCLAVOX DUO 500/125 - White coloured capsule shaped film coated tablet debossed with ‘Ɩ 06’ on one side and plain on other side. AUST R 289507. AUST R 288118.
  • AMCLAVOX DUO FORTE 875/125 - White coloured capsule shaped film coated tablet debossed with ‘Ɩ 07’ on one side and plain on other side. AUST R 289508. AUST R 288119.

Ingredients

Active Ingredients:

  • AMCLAVOX DUO 500/125 – 500 mg amoxicillin (as trihydrate) and 125 mg clavulanic acid (as potassium clavulanate).
  • AMCLAVOX DUO FORTE 875/125 –875 mg amoxicillin (as trihydrate) and 125 mg clavulanic acid (as potassium clavulanate).

Inactive Ingredients:

  • microcrystalline cellulose
  • magnesium stearate
  • sodium starch glycollate Type A
  • colloidal anhydrous silica
  • hypromellose
  • titanium dioxide
  • propylene glycol
  • purified talc
  • ethylcellulose

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

AMCLAVOX DUO & AMCLAVOX DUO FORTE Available in strip or blister packs of 10 tablets.

Supplier

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
www.arrowpharma.com.au

This leaflet was revised in July 2020.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Amclavox Duo 500/125, Amclavox Duo Forte 875/125

Active ingredient

Amoxicillin; Clavulanic acid

Schedule

S4

 

1 Name of Medicine

Amoxicillin trihydrate and potassium clavulanate.

2 Qualitative and Quantitative Composition

Amclavox Duo 500 /125 tablets contain amoxicillin (as trihydrate) 500 mg and clavulanic acid (as potassium clavulanate) 125 mg.
Amclavox Duo Forte 875 /125 tablets contain amoxicillin (as trihydrate) 875 mg and clavulanic acid (as potassium clavulanate) 125 mg.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Amclavox Duo 500 /125 tablets are white coloured capsule shaped film coated tablet debossed with 'l 06' on one side and plain on other side.
Amclavox Duo Forte 875 /125 tablets are white coloured capsule shaped film coated tablet debossed with 'l 07' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Amclavox Duo tablets are indicated for short term treatment of bacterial infections at the following sites when caused by sensitive organisms (see Microbiology):
Urinary Tract Infections (complicated and uncomplicated).
Lower Respiratory Tract Infections, including community acquired pneumonia and acute exacerbations of chronic bronchitis.
Upper Respiratory Tract Infections, such as sinusitis, otitis media and recurrent tonsillitis.
Skin and Skin Structure infections.
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 β-lactamase producing organisms listed above, 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 β-lactamase producing organisms susceptible to amoxicillin and clavulanic acid tablets preparations should not require the addition of another antibiotic due to the amoxicillin content of these products.

4.2 Dose and Method of Administration

Amclavox Duo tablets should be taken immediately before or with the first mouthful of food, to minimise potential gastrointestinal intolerance and to optimise absorption.

Dosage.

Adults.

The usual adult dose is one Amclavox Duo 500/125 tablet every 12 hours.
For more severe infections, the dose should be one Amclavox Duo Forte 875/125 tablet every 12 hours.

Note.

Since both Amclavox Duo Forte 875/125 tablets and Amclavox Duo 500/125 tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), two Amclavox Duo 500/125 tablets are not equivalent to one Amclavox Duo Forte 875/125 tablet. Therefore, two Amclavox Duo 500/125 tablets should not be substituted for one Amclavox Duo Forte 875/125 tablet for treatment of more severe infections.
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.

Renal impairment.

Amclavox Duo Forte 875/125 tablets should not be used in patients with moderate to severe renal impairment (creatinine clearance ≤ 30 mL/min).
Both amoxicillin and clavulanic acid are excreted by the kidneys and the serum half life of each 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 Amclavox Duo 500/125 tablets (see Table 1).

Dialysis.

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 is 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.
It is recommended that amoxicillin and clavulanic acid suspensions* should be used for children weighing less than 40 kg.
*Amoxicillin and clavulanic acid as a suspension formulation is not available in this brand, however is available in other brands.

4.3 Contraindications

A history of allergic reaction to β-lactams e.g. penicillins or cephalosporins is a contraindication.
Amclavox Duo tablets are contraindicated in patients with a previous history of amoxicillin/clavulanic acid-associated jaundice or hepatic dysfunction.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Before initiating therapy with amoxicillin-clavulanate, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.
Serious and occasionally fatal hypersensitivity (anaphylactoid) 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. If an allergic reaction occurs, Amclavox Duo tablets 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 with 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 Clostridium difficile should be considered. Fluids, electrolytes and protein replacement 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 Amclavox Duo tablets contain amoxicillin, an aminopenicillin, these are 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.
Amclavox Duo 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 rarely. 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 and clavulanic acid have occurred predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children.
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 hepatic impairment.

Amclavox Duo tablets should be used with care in patients with evidence of hepatic dysfunction.

Use in renal impairment.

Amclavox Duo Forte 875/125 tablets should not be used in patients with moderate to severe renal impairment (creatinine clearance ≤ 30 mL/min).
Amclavox Duo 500/125 tablets should be used with care in patients with moderate or severe renal impairment. The dosage of amoxicillin and clavulanic acid should be adjusted as recommended (see Section 4.2 Dose and Method of Administration).

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 and clavulanic acid tablets 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 Testape) be used.
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 and clavulanic acid tablets.

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 and clavulanic acid tablets 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 hyperuricemia present in these patients. There are no data with amoxicillin and clavulanic acid tablets and allopurinol administered concurrently.
No information is available about the concurrent use of amoxicillin and clavulanic acid tablets and alcohol. However, the ingestion of alcohol whilst being treated with some other beta-lactam antibiotics has precipitated a disulfiram (Antabuse) like reaction in some patients. Therefore the ingestion of alcohol should be avoided during and for several days after treatment with amoxicillin and clavulanic acid tablets.
In common with other antibiotics, amoxicillin and clavulanic acid tablets may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.
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.

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 and clavulanic acid have shown no teratogenic effects. There is limited experience of the use of amoxicillin and clavulanic acid tablets in human pregnancy. In women with preterm, premature rupture of the foetal membrane (pPROM), prophylactic treatment with amoxicillin and 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 physician.

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 and clavulanic acid tablets in humans during labour or delivery has immediate or delayed adverse effects on the foetus, prolongs the duration of labour or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.
Amoxicillin is excreted in the milk; there are no data on the excretion of clavulanic acid in human milk. Therefore, caution should be exercised when amoxicillin and clavulanic acid tablets are administered to a nursing 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)

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

Clinical trials.

During clinical trials, the most frequently reported adverse events related or possibly related to amoxicillin and clavulanic acid (875/125 mg) therapy 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 amoxicillin and clavulanic acid (875/125 mg) therapy, however it should be noted that causality has not necessarily been established for these events (see Table 2).
During clinical trials, the most frequently reported adverse events related or possibly related to amoxicillin and clavulanic acid (500/125 mg) therapy 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 amoxicillin and clavulanic acid (500/125 mg) therapy, however it should be noted that causality has not necessarily been established for these events (see Table 3).

Post marketing.

In addition, the following adverse reactions have been reported for ampicillin class antibiotics and may occur with amoxicillin and clavulanic acid tablets: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000.

Infections and infestations.

Common: mucocutaneous candidiasis.

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, convulsions. Convulsions may occur in patients with impaired renal function or those receiving high doses.

Haematopoietic and lymphatic systems.

Uncommon: thrombocytosis.
Rare: anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, reversible leukopenia (including neutropenia or agranulocytosis) these are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena, prolongation of bleeding time and prothrombin time.

Hypersensitivity and skin.

Common: skin rashes, pruritis, 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, Amclavox Duo tablets should be discontinued, unless in the opinion of the physician no alternative treatment is available and continued use of Amclavox Duo tablets is considered essential. Serious and occasional 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Serious and severe clinical symptoms are unlikely to occur after overdosage with Amclavox Duo tablets. 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.
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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Amclavox Duo tablets are combination products containing the semisynthetic antibiotic, amoxicillin (as trihydrate), and the β-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 β-lactamases and the addition of clavulanic acid in amoxicillin and clavulanic acid tablets extends the antimicrobial spectrum of amoxicillin to include organisms normally resistant to amoxicillin due to β-lactamase production. In vitro studies have demonstrated the susceptibility of most strains of the following organisms. (See Tables 4, 5, 6 and 7).
The following in vitro data are available but their clinical significance is unknown. (See Table 8).

Note.

Methicillin resistant strains are resistant to amoxicillin and clavulanic acid tablets. Proteus vulgaris and Klebsiella species may not be susceptible to amoxicillin and clavulanic acid tablets at concentrations of amoxicillin and clavulanic acid achieved in the plasma. However at concentrations of amoxicillin and clavulanic acid achievable in the urine the majority of strains are susceptible.

Susceptibility testing.

Diffusion technique.

For Kirby-Bauer method of susceptibility testing, a 30 microgram amoxicillin and clavulanic acid (20 microgram amoxicillin + 10 microgram clavulanic acid) diffusion disc should be used. With this procedure, a report from the laboratory of "Susceptible" indicates that the infecting organism is likely to respond to amoxicillin and clavulanic acid therapy and a report of "Resistant" indicates that the infecting organism is not likely to respond to therapy. An "Intermediate Susceptibility" report suggests that the infecting organism would be susceptible to amoxicillin and clavulanic acid if the infection is confined to tissues or fluids (e.g. urine) in which high antibiotic levels are attained.

Dilution techniques.

Broth or agar dilution methods may be used to determine the minimal inhibitory concentration (MIC) value susceptibility of bacterial isolates to amoxicillin and clavulanic acid. Tubes should be inoculated to contain 104 to 105 organisms/mL or plates "spotted" with 103 to 104 organisms.
The recommended dilution method employs a constant amoxicillin/ clavulanic acid ratio of 2 to 1 in all tubes with increasing concentrations of amoxicillin. MICs are reported in terms of amoxicillin concentration in the presence of clavulanic acid at constant 2 parts amoxicillin to 1 part clavulanic acid. (See Tables 9 and 10).

Clinical trials.

Amoxicillin and clavulanic acid (875/125 mg) tablets versus amoxicillin and clavulanic acid (500/125mg) tablets.

Three pivotal studies in 1,361 patients treated for between 7 and 14 days for either lower respiratory tract infections, upper respiratory infections or complicated urinary tract infections compared a regimen of amoxicillin and clavulanic acid (875/125 mg) tablets every 12 hours (q12h) to amoxicillin and clavulanic acid (500/125 mg) tablets dosed every 8 hours (q8h) (584, 170 and 607 patients respectively). Comparable efficacy was demonstrated between the q12h and q8h 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 q12h and 500/125 mg q8h 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 q12h dosing versus 2.5% for the 500/125 mg q8h dosing. In the third study the most frequently reported adverse event was headache with an incidence of 5.7% (amoxicillin and clavulanic acid (500/125 mg) tablets q8h) versus 8.3% (amoxicillin and clavulanic acid (875/125 mg) tablets q12h).
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 withdrawals with diarrhoea between the regimens.

Amoxicillin and clavulanic acid (500/125 mg) tablets versus amoxicillin and clavulanic acid (250/125 mg) tablets.

Two pivotal studies in 908 patients treated for between 5 and 10 days for either uncomplicated Skin and Skin Structure infections (SSSI) or Acute Exacerbation of Chronic Bronchitis (AECB) compared a regimen of amoxicillin and clavulanic acid (500/125 mg) tablets every 12 hours with amoxicillin and clavulanic acid (250/125 mg) tablets every 8 hours. Comparable efficacy was demonstrated between the 12 hourly and 8 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 and clavulanic acid (250/125 mg) 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 were investigated, however these supportive studies were not sufficiently designed to demonstrate the relative efficacy of the two amoxicillin and clavulanate acid dosing regimens, or compared the proposed regimen with other treatments.

5.2 Pharmacokinetic Properties

Absorption.

Amoxicillin and clavulanic acid tablets 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 Amclavox Duo tablets should be administered at the start of a meal. The pharmacokinetics of amoxicillin are not affected by food.
Oral administration of amoxicillin and clavulanic acid (875 mg/125 mg) tablets every 12 hours was compared with amoxicillin and clavulanic acid (500 mg/125 mg) tablets every 8 hours at the start of a light meal. The following mean pharmacokinetic parameters were observed for amoxicillin for amoxicillin and clavulanic acid (875/125 mg) tablets taken every 12 hours and amoxicillin and clavulanic acid (500 mg/125 mg) tablets taken every 8 hours respectively: peak plasma concentration (Cmax) of 11.64 and 7.19 microgram/mL, area under the plasma concentration-time curve between 0 and 24 hours after the first dose (AUC(0-24 hours)) of 53.52 and 53.35 microgram.h/mL, half life (t½) of 1.19 and 1.15 hours, time to peak plasma concentration (Tmax) of 1.50 and 1.50 hours and the time above the minimum inhibitory concentration (TMIC 24 hours) of 10.46 hours and 13.30 hours.
The following pharmacokinetic parameters were observed for clavulanic acid for amoxicillin and clavulanic acid (875/125 mg) tablets taken every 12 hours and amoxicillin and clavulanic acid (500 mg/125 mg) tablets taken every 8 hours respectively: Cmax of 2.18 and 2.40 microgram/mL, AUC(0-24 hours) of 10.16 and 15.72 microgram.h/mL, t½ of 0.96 and 0.98 hours and Tmax of 1.25 and 1.50 hours, and (TMIC 24 hours) of 6.08 hours and 9.43 hours.
The t½ and Cmax for clavulanate for amoxicillin and clavulanic acid (875/125 mg) tablets were not significantly different from amoxicillin and clavulanic acid (500/125 mg) tablets. However, the AUC(0-24 hours) was reduced, as would be expected with the lower daily dose of clavulanate, i.e. 250 mg in amoxicillin and clavulanic acid (875/125 mg) tablets vs 375 mg in amoxicillin and clavulanic acid (500/125 mg) tablets.
Oral administration of amoxicillin and clavulanic acid (500 mg/125 mg) tablets every 12 hours was compared with amoxicillin and clavulanic acid (250 mg/125 mg) tablets every 8 hours at the start of a light meal.
The following mean pharmacokinetic parameters were observed for amoxicillin for amoxicillin and clavulanic acid (500/125 mg) tablets taken every 12 hours and amoxicillin and clavulanic acid (250 mg/125 mg) tablets taken every 8 hours respectively: peak plasma concentration (Cmax) of 6.51 and 3.32 microgram/mL, area under the plasma concentration-time curve between 0 and 24 hours after the first dose (AUC(0-24 hours)) of 33.43 and 26.66 microgram.h/mL, half life (t½) of 1.26 and 1.36 hours, time to peak plasma concentration (Tmax) of 1.50 and 1.50 hours and the time above the minimum inhibitory concentration (TMIC 24 hours) of 8.54 hours and 9.49 hours.
The following pharmacokinetic parameters were observed for clavulanic acid for amoxicillin and clavulanic acid (500/125 mg) tablets taken every 12 hours and amoxicillin and clavulanic acid (250 mg/125 mg) tablets taken every 8 hours respectively: Cmax of 1.75 and 1.47 microgram/mL, AUC(0-24 hours) of 8.6 and 12.6 microgram.h/mL, t½ of 1.01 and 1.01 hours and Tmax of 1.50 and 1.50 hours, and (TMIC 24 hours) of 5.69 hours and 8.24 hours.

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 is 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.

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) represented 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. These metabolites were also present in the urine of rat and dog. The extent of urinary excretion of clavulanic acid and its metabolites is lower in rat urine than in dog and human urine.
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

Amclavox Duo Forte 875/125 and Amclavox Duo 500/125 tablets contain microcrystalline cellulose, magnesium stearate, sodium starch glycollate Type A and colloidal anhydrous silica. The tablet coating contains hypromellose, titanium dioxide, propylene glycol, purified talc, ethylcellulose.

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

Amclavox Duo 500 /125 tablets: Aluminium/aluminium strip or PA/Aluminium/PVC/Aluminium blister packs x 10 tablets.
Amclavox Duo Forte 875 /125 tablets: Aluminium/aluminium strip or PA/Aluminium/PVC/Aluminium blister packs x 10 tablets.
Not all strengths [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

Amoxicillin trihydrate is a white to almost white, crystalline powder, slightly soluble in water, very slightly soluble in ethanol (96%), practically insoluble in fatty oils. It dissolves in dilute acids and dilute solutions of alkali hydroxides. pKa 9.48 and log P is 0.76.
Potassium clavulanate is white to almost white, crystalline powder, hygroscopic, freely soluble in water, slightly soluble in alcohol, and very slightly soluble in acetone. pKa 2.7 and log P is -1.16.
Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is an irreversible inhibitor of many β-lactamase enzymes except type 1 (Richmond). It is a β-lactam compound with only weak antibacterial activity.

Chemical structure.

Chemically, amoxicillin trihydrate is (2S,5R,6R)-6-[[(2R)-2-Amino-2-(4-hydroxyphenyl) acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid trihydrate. It is susceptible to hydrolysis by β-lactamases. Amoxicillin trihydrate may be represented structurally as:
Chemically potassium clavulanate is potassium (2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3.2.0]-heptane-2- carboxylate, and may be represented structurally as:

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)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes