COCLAVMOX 500/125, amoxicillin (as trihydrate) 500 mg and clavulanic acid (as potassium) 125 mg tablets strip pack

Australia - English - Department of Health (Therapeutic Goods Administration)

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Active ingredient:
amoxicillin trihydrate,potassium clavulanate
Available from:
Micro Labs Pty Ltd
INN (International Name):
amoxicillin trihydrate,potassium clavulanate
Authorization status:
Registered
Authorization number:
289509

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COCLAVMOX TABLETS

AUSTRALIAN

PRODUCT

INFORMATION-

COCLAVMOX

875/125

AND

COCLAVMOX 500/125 (Amoxicillin and clavulanic acid) FILM-COATED TABLETS

1.

NAME OF THE MEDICINE

Amoxicillin (as trihydrate) and clavulanic acid (as potassium).

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

COCLAVMOX

tablets

combination

products

containing

semisynthetic

antibiotic,

amoxicillin (as the trihydrate) and the β-lactamase inhibitor, potassium clavulanate (as the

potassium salt of clavulanic acid).

COCLAVMOX 875/125 & COCLAVMOX 500/125 tablets also contain the inactive ingredients:

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.

3.

PHARMACEUTICAL FORM

COCLAVMOX 500 /125 tablets contain amoxicillin (as trihydrate) 500 mg and clavulanic acid

(as potassium clavulanate) 125 mg. White colored capsule shaped film coated tablet debossed

with ‘Ɩ 06’ on one side and plain on other side.

COCLAVMOX 875 /125 tablets contain amoxicillin (as trihydrate) 875 mg and clavulanic acid

(as potassium clavulanate) 125 mg. White colored capsule shaped film coated tablet debossed

with ‘Ɩ 07’ on one side and plain on other side.

4.

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

COCLAVMOX tablets are indicated for short term treatment of bacterial infections at the

following sites when caused by sensitive organisms (refer to Microbiology):

Urinary Tract Infections (uncomplicated and complicated)

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 Infection

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.

COCLAVMOX 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

COCLAVMOX tablets

should be taken immediately before or with the first mouthful of

food, to minimise potential gastrointestinal intolerance and to optimise absorption.

Adults:

The usual adult dose is one COCLAVMOX 500/125 tablets every 12 hours. For more severe

infections, the dose should be one COCLAVMOX 875/125 Tablets every 12 hours.

Note: Since both COCLAVMOX 875/125 tablets and COCLAVMOX 500/125 tablets contain

the same amount of clavulanic acid (125mg, as the potassium salt), two COCLAVMOX

500/125 tablets are not equivalent to one COCLAVMOX 875/125 tablet. Therefore, two

COCLAVMOX

500/125

tablets

should

substituted

COCLAVMOX

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.

COCLAVMOX 875/125 tablets should not be used in patients with moderate to severe renal

impairment (creatinine clearance ≤ 30mL/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 COCLAVMOX 500/125 tablets:

Mild Impairment:

No change in dosage.

(Creatinine clearance > 30mL/min)

Moderate Impairment: One COCLAVMOX 500/125 tablet 12 hourly

COCLAVMOX TABLETS

(Creatinine clearance 10 - 30mL/min)

Severe Impairment: One COCLAVMOX 500/125 tablets every 24

hours

(Creatinine Clearance < 10mL/min)

Haemodialysis decreases serum concentrations of both amoxicillin and clavulanic acid and an

additional dose should be administered at the end of dialysis.

4.3

CONTRAINDICATIONS

A history of allergic reaction to β-lactams eg. penicillins or cephalosporin is a contraindication.

COCLAVMOX tablets are contraindicated in patients with a previous history of amoxicillin and

clavulanic acid-associated jaundice or hepatic dysfunction.

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Before

initiating

therapy

with

amoxicillin-clavulanate,

careful

enquiry

should

made

concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.

SERIOUS

OCCASIONALLY

FATAL

HYPERSENSITIVITY

(ANAPHYLACTOID)

REACTIONS

HAVE

BEEN

REPORTED

PATIENTS

PENICILLIN

THERAPY.

ALTHOUGH

ANAPHYLAXIS

MORE

FREQUENT

FOLLOWING

PARENTERAL

THERAPY,

OCCURRED

PATIENTS

ORAL

PENICILLINS.

THESE

REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF

PENICILLIN

HYPERSENSITIVITY

AND/OR

HISTORY

SENSITIVITY

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

PENICILLIN,

CAREFUL

INQUIRY

SHOULD

MADE

CONCERNING

PREVIOUS

HYPERSENSITIVITY

REACTIONS

PENICILLINS,

CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS,

COCLAVMOX

TABLETS

SHOULD

DISCONTINUED

APPROPRIATE

THERAPY

INSTITUTED.

SERIOUS

ANAPHYLACTOID

REACTIONS

REQUIRE

IMMEDIATE

EMERGENCY

TREATMENT

WITH

ADRENALINE.

OXYGEN,

INTRAVENOUS

STEROIDS,

AIRWAY

MANAGEMENT,

INCLUDING

INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

COCLAVMOX TABLETS

Antibiotic

associated

pseudomembranous

colitis

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, eg. 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 COCLAVMOX 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.

COCLAVMOX 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.

superinfections

occur

(usually

involving

Aerobacter,

Pseudomonas

Candida), the drug should be discontinued and/or appropriate therapy instituted.

COCLAVMOX TABLETS

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 COCLAVMOX have occurred

predominantly in males and elderly patients and may be associated with prolonged treatment.

These events have been very rarely reported in children.

Use in hepatic impairment

COCLAVMOX

tablets

should

used

with

care

patients

with

evidence

hepatic

dysfunction.

Data is currently insufficient for a dosage recommendation. Dose with caution, and monitor

hepatic function at regular intervals.

Use in renal impairment

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).

COCLAVMOX 875/125 tablets should not be used in patients with moderate to severe renal

impairment (creatinine clearance ≤ 30mL/min).

COCLAVMOX 500/125 tablets should be used with care in patients with moderate or severe

renal impairment. The dosage of amoxicillin and clavulanic acid tablets should be adjusted as

recommended in the “

4.2 DOSE AND METHOD OF ADMINISTRATION” section

Use in the elderly

No data available.

Peadiatric use

Children weighing 40 Kg and more should be dosed according to adult recommendations.

It is recommended that amoxicillin and clavulanic acid suspensions * should be used for children

weighing less than 40 kg.

COCLAVMOX TABLETS

*Amoxicillin and clavulanic acid as a suspension formulation is not available in this brand,

however is available in other brands.

Effects on laboratory tests

Oral

administration

amoxicillin

clavulanic

acid

tablets

will

result

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 estriol, estriol-glucuronide, conjugated estrone and estradiol

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

known

whether

this

potentiation

ampicillin

rashes

allopurinol

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

alcohol

should

avoided

during

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

lower

estrogen

reabsorption

reduced

efficacy

combined

oral

contraceptives.

In the literature there are rare cases of increased international normalised ratio in patients

maintained

acenocoumarol

warfarin

prescribed

course

amoxicillin.

administration is necessary, the prothrombin time or international normalised ratio should be

carefully monitored with the addition or withdrawal of amoxicillin.

COCLAVMOX TABLETS

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

rats

dosed

with

ratio

formulation

amoxicillin

clavulanate.

Use in Pregnancy- Pregnancy Category B1

(Category

B1).

Animal

studies

with

orally

parenterally

administered

amoxicillin

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

foetal

membrane

(pPROM),

prophylactic

treatment

with

amoxicillin

clavulanic acid tablets 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.

Use in Lactation

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

Adverse effects on the ability to drive or operate machinery have not been observed.

4.8

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

Amoxicillin and Clavulanic acid is generally well tolerated. The majority of events were of a

mild and transient nature.

COCLAVMOX TABLETS

Clinical Trials

During clinical trials, the most frequently reported adverse events related or possibly related to

amoxicillin and clavulanic acid (875/125mg) 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 (875/125mg), however it should be noted that causality has not necessarily been

established for these events:

The most frequently (

1%) reported adverse experiences in decreasing order for the

BD regimen

875/125mg q 12hr

Total Number of Patients

584

Adverse Event

Frequency (%)

Diarrhoea #

14.9

Nausea

Headache

Abdominal pain

Vomiting

Genital moniliasis

Vaginitis

3.4*

Back Pain

Dizziness

Fungal infection

Rash

Sinusitis

Fatigue

Genital pruritus

Injury

Pain

Urinary tract infection

Insomnia

Myalgia

During clinical trials, the most frequently reported adverse events related or possibly related to

amoxicillin and clavulanic acid (500/125mg) therapy were diarrhoea (12.8%), nausea (5.2%),

headache (4.8%), abdominal pain (4.5%).

COCLAVMOX TABLETS

The following adverse events have been observed during clinical trials with amoxicillin and

clavulanic acid (500/125mg), however it should be noted that causality has not necessarily been

established for these events:

The most frequently (

1%) reported adverse experiences in decreasing order for the

BD regimen

500/125mg q 12hr

Total Number of Patients

462

Adverse Event

Frequency (%)

Diarrhoea

12.8

Nausea

Headache

Upper Respiratory Infection

Genital moniliasis

Vomiting

Dyspepsia

Injury

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 ≥1/10000 and <1/1000

very rare <1/10000

Infections and Infestations

common:

mucocutaneous candidiasis.

Gastrointestinal disorders:

very common:

diarrhoea

common:

nausea, vomiting

uncommon:

indigestion

COCLAVMOX TABLETS

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

agranulocytosis)

these

usually

reversible

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 ,acute generalised exanthematous putulosis (AGEP) and drug reaction with

eosinophilia and systemic symptoms (DRESS) have been reported rarely. Whenever such

reactions occur, COCLAVMOX tablets should be discontinued, unless in the opinion of the

physician no alternative treatment is available and continued use of COCLAVMOX tablets is

considered essential. Serious and occasional fatal hypersensitivity (anaphylactic) reactions and

angioneurotic

oedema

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)

COCLAVMOX TABLETS

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.

4.9

OVERDOSE

Serious and severe clinical symptoms are unlikely to occur after overdosage with amoxicillin and

clavulanic acid 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

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:

COCLAVMOX TABLETS

Table 1 – Acquired resistance data for amoxicillin/clavulanic acid in Australia according to

NCCLS guidelines (M100-S10) for amoxicillin/clavulanic acid

Percentage of Strains

Number of Pathogens (n)

Intermediate

Resistant

Streptococcus pneumoniae *

1020

Haemophilus influenzae #

*: - Data collected between March to November 1997.

#: - Data collected in 1999.

Table 2 – MIC Distribution for Sensitive/intermediate S. pneumoniae Isolates

MIC ≤ 1

MIC >1 < 2

MIC ≥ 2

96.8%

2.3%

0.9%

Table 3– Acquired resistance data for amoxicillin/clavulanic acid from other countries

Breakpoints

Number of

Pathogen (n)

Percentage acquired

resistance (%)

Sensitive aerobe gram

positive

Enterococcus faecalis

Staphylococcus aureus

Staphylococcus aureus

(MSSA

)

2,458

Coagulase negative

staphylococci

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pneumoniae

(Pen-S)

Streptococcus pyogenes

Streptococcus species

Sensitive aerobe gram

negative

Escherichia coli

Haemophilus influenzae

Haemophilus influenzae

(BLN

)

Haemophilus influenzae

(BLP)

Klebsiella pneumoniae

Klebsiella oxytoca

1,540

COCLAVMOX TABLETS

Moraxella catarrhalis

Proteus sp.

Sensitive anaerobe

Clostridium species

Clostridium difficile

Peptostreptococcus species

Bacteroides fragilis

Bacteroides fragilis group

Fusobacterium species

Intermediate aerobe gram

negative

Acinetobacter

Resistant aerobe gram

positive

Staphylococcus aureus

(MRSA)

59.2

Resistant aerobe gram

negative

Citrobacter

Enterobacter

Morganella

Providencia

Serratia

S. maltophilia

The percent acquired resistance data provided in the above table has been collected from the

following countries during the time period specified: US, 1996; Canada, 1993-1994; US/Canada,

1996-1997;

France,

1994-1995;

Arabia,

1994-1995;

1996-1997;

1991-1993;

Belgium, 1993-1994; UK, Netherlands, 1989-1995.

Note:

Resistance can vary from region to region and information on local resistance should be

taken into account.

Table 4- MIC Interpretive Standards (μg/mL) according to NCCLS guidelines (M100-S10)

for amoxicillin and amoxicillin/clavulanic acid

Organisms

Antimicrobial Agents

MIC (μg/mL)

Interpretive Standards

S

I

R

Enterobacteriaceae

amoxicillin/clavulanic acid

≤ 8/4

16/8

≥ 32/16

Non-

Enterobacteriaceae*

Staphylococcus

amoxicillin/clavulanic acid

≤ 4/2

≥ 8/4

COCLAVMOX TABLETS

Enterococcus

sp.*

Haemophilus

amoxicillin/clavulanic acid

≤ 4/2

≥ 8/4

Streptococcus

pneumoniae

amoxicillin

amoxicillin/clavulanic acid

≤ 2

≤ 2/1

≥ 8

≥ 8/4

Streptococcus

other than

S.

pneumoniae

*No interpretive standards for amoxicillin or amoxicillin/clavulanic acid.

**A streptococcal isolate that is susceptible to penicillin can be considered susceptible to

ampicillin, amoxicillin and amoxicillin/clavulanic acid.

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.

The following in vitro data are available but their clinical significance is unknown.

Table 5- In Vitro Activity of amoxicillin/clavulanic acid

N

MIC 90 (μg/mL)

GRAM POSITIVE AEROBES:

Enterococcus faecalis

Staphylococcus aureus

Staphylococcus aureus

(MSSA)

Staphylococcus aureus

(MRSA)

Staphylococcus epidermidis

Staphylococcus saprophyticus

Coagulase negative staphylococci

Streptococcus agalactiae

0.06

Streptococcus pneumoniae

1,476

Streptococcus pyogenes

0.12

Streptococcus viridans

GRAM NEGATIVE AEROBES:

Escherichia coli

Haemophilus influenzae

2,268

Haemophilus influenzae

(BLN)

Haemophilus influenzae

(BLP)

Klebsiella pneumoniae

COCLAVMOX TABLETS

Klebsiella oxytoca

Moraxella catarrhalis

0.25

Neisseria gonorrheae

Neisseria meningitidis

0.06

Proteus mirabilis

Proteus vulgaris

GRAM POSITIVE ANAEROBES:

Clostridium species

Clostridium perfringens

0.06

Clostridium difficile

Peptostreptococcus species

Clostridium perfringens

0.06

Clostridium perfringens

0.12

Clostridium perfringens

0.25

Clostridium difficile

Clostridium difficile

Clostridium difficile

Propionibacterium

0.06

Peptostreptococcus

Ruminococcus

0.25

Peptostreptococci

0.25

Peptostreptococcus sp

Peptostreptococcus

GRAM NEGATIVE ANAEROBES:

Bacteroides fragilis

Bacteroides fragilis group

Fusobacterium species

0.125

Bacteroides fragilis

Bacteroides fragilis

Bacteroides fragilis

Bacteroides fragilis

Bacteroides thetaiotamicron

Bacteroides vulgatus

Other

Bacteroides

sp. of

B. fragilis

group

Bacteroides fragilis

group

-B. fragilis

Prevotella sp

Prevotella, Porphyromonas and

Bacteroides

0.25

Fusobacterium

0.125

Fusobacterium

0.125

B. capillosus

P. bivia

P. disiens

0.25

COCLAVMOX TABLETS

Note:

Methicillin resistant strains are resistant to amoxicillin and clavulanic acid tablets.

Proteus

vulgaris

Klebsiella

species

susceptible

amoxicillin

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 mcg amoxicillin and clavulanic acid (20

mcg amoxicillin + 10 mcg 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/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.

Table 6-

Recommended Amoxicillin and Clavulanic acid Susceptibility Ranges

1, 2

ORGANISMS

RESISTANT

INTERMEDIATE

SUSCEPTIBLE

Gram Negative

Enteric Bacteria

≤ 13mm

14-17mm

≥ 18mm

Staphylococcus

Haemophilus spp

≤ 19mm

--------

≥ 20mm

COCLAVMOX TABLETS

The non-β-lactamase-producing organisms which are normally susceptible to ampicillin, such

as Streptococci, will have similar zone sizes as for ampicillin discs.

quality

control

cultures

should

have

following

assigned

daily

ranges

Amoxicillin/Clavulanic acid:

Discs

Mode MIC (mg/L)

E. coli (ATCC25922)

19-25mm

4/2 - 8/4

S. aureus (ATCC25923)

28-36mm

0.25/0.12 - 0.5/0.25

E. coli (ATCC35218)

18-22mm

4/2 - 8/4

The Mode MIC is expressed as the concentration of amoxicillin/clavulanic acid.

Organisms which show susceptibility to Amoxicillin and Clavulanic acid but are resistant to

methicillin/oxacillin should be considered resistant.

Clinical trials

Amoxicillin and clavulanic acid (875/125mg) 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 (875/125mg) tablets every 12 hours

(q12h) to amoxicillin and clavulanic acid (500/125mg) (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%

14.3%,

respectively).

However,

there

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

clavulanic

acid

(500/125mg)

tablets

q8h)

versus

8.3%

(amoxicillin

clavulanic acid (875/125mg) 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.

COCLAVMOX TABLETS

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

(250/125mg) tablets:

Two pivotal studies in 908 patients treated for between 5 and 10 days for either uncomplicated

Skin and Skin Structure Infections or Acute Exacerbation of Chronic Bronchitis 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,

serum

levels

clavulanic

acid

significantly

reduced.

optimise

absorption

clavulanic acid amoxicillin and clavulanic acid 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 (875mg/125mg) tablets every 12 hours

was compared with amoxicillin and clavulanic acid (500mg/125mg) every 8 hours at the start of

a light meal. The following mean pharmacokinetic parameters were observed for amoxicillin for

amoxicillin

clavulanic

acid

(875/125mg)

taken

every

hours

amoxicillin

clavulanic acid (500mg/125mg) taken every 8 hours respectively: peak plasma concentration

) of 11.64 and 7.19 μg/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 μg.h/mL, half life (t½) of 1.19

COCLAVMOX TABLETS

and 1.15 hours, time to peak plasma concentration (T

) of 1.50 and 1.50 hours and the time

above the minimum inhibitory concentration (T

24 hours) of 10.46 hours and 13.30 hours.

The following pharmacokinetic parameters were observed for clavulanic acid for amoxicillin and

clavulanic acid (875/125mg) tablets taken every 12 hours and amoxicillin and clavulanic acid

(500mg/125mg) taken every 8 hours respectively: C

of 2.18 and 2.40 μg /mL, AUC

(0-24 hours)

of 10.16 and 15.72 μg.h/mL, t½ of 0.96 and 0.98 hours and T

of 1.25 and 1.50 hours, and

24 hours) of 6.08 hours and 9.43 hours.

The t

and C

for clavulanate for amoxicillin and clavulanic acid 875/125mg were not

significantly different from amoxicillin and clavulanic acid 500/125mg. However, the AUC

(0-24

hours)

was reduced, as would be expected with the lower daily dose of clavulanate ie 250mg in

amoxicillin

clavulanic

acid

875/125mg

375mg

amoxicillin

clavulanic

acid

500mg/125mg.

Oral administration of amoxicillin and clavulanic acid (500mg/125mg) every 12 hours was

compared with amoxicillin and clavulanic acid tablets (250mg/125mg) every 8 hours at the start

of a light meal.

The following mean pharmacokinetic parameters were observed for amoxicillin for amoxicillin

and clavulanic acid tablets (500/125mg) taken every 12 hours and amoxicillin and clavulanic

acid tablets (250mg/125mg) taken every 8 hours respectively: peak plasma concentration (C

of 6.51 and 3.32 μg/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 μg.h/mL, half life (t½) of 1.26 and 1.36

hours, time to peak plasma concentration (T

) of 1.50 and 1.50 hours and the time above the

minimum inhibitory concentration (T

24 hours) of 8.54 hours and 9.49 hours.

The following pharmacokinetic parameters were observed for clavulanic acid for amoxicillin and

clavulanic acid tablets (500/125mg) taken every tablets every 12 hours and amoxicillin and

clavulanic acid tablets (250mg/125mg) taken every 8 hours respectively: C

of 1.75 and 1.47

μg/mL, AUC

(0-24 hours)

of 8.6 and 12.6 μg.h/mL, t½ of 1.01 and 1.01 hours and T

of 1.50 and

1.50 hours, and (T

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

COCLAVMOX TABLETS

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

bound.

From

animal

studies,

there

evidence

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 125mg of radiolabelled potassium clavulanate orally to normal volunteers 68%

of the administered radioactivity was recovered in the urine in 24 hours. Of this 34% (ie. 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

further

(ie.

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

genotoxic

potential

amoxicillin/clavulanic

acid

investigated

assays

chromosomal

damage

(mouse

micronuclucleus

test

dominant

lethal

test)

gene

conversion. All were negative.

Carcinogenicity

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

potential.

COCLAVMOX TABLETS

6

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Refer to Section 2 - Qualitative and quantitative composition.

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

COCLAVMOX Tablets should be stored below 25

C and protected from moisture.

6.5

NATURE AND CONTENTS OF CONTAINER

Aluminium/aluminium strip or PA/Aluminium/PVC/Aluminium blister packs x 10 tablets.

Aluminium/aluminium strip or PA/Aluminium/PVC/Aluminium blister packs x 10 tablets.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

In Australia, any unused medicine or waste material should be disposed of in accordance with

local requirements.

6.7

PHYSICOCHEMICAL PROPERTIES

Chemical structure

Chemically,

amoxicillin

D-(-)-α-amino-p-hydroxybenzylpenicillin.

susceptible

hydrolysis by β-lactamases. Amoxicillin trihydrate may be represented structurally as:

COCLAVMOX TABLETS

CAS Number

61336-70-7

Clavulanic

acid

produced

fermentation

Streptomyces

clavuligerus.

irreversible inhibitor of many β-lactamase enzymes except type 1 (Richmond). It is a β-lactam

compound with only weak antibacterial activity. Chemically potassium clavulanate is potassium

Z-(2R,5R)-3-(ß-hydroxyethylidene) clavam-2-carboxylate, and may be represented structurally

CAS Number

61177-45-5

Molecular Formula:

Amoxicillin trihydrate:

S.3H

Potassium clavulanate:

Molecular Weight:

Amoxicillin trihydrate:

419.4

Potassium clavulanate:

237.3

7

MEDICINE SCHEDULE (POISONS STANDARD)

8

SPONSOR

Micro Labs Pty Ltd

15 Melliodora Crescent,

Greensborough, VIC-3088

Australia.

Email: pvsupport@microlabs.in

COCLAVMOX TABLETS

9

DATE OF FIRST APPROVAL

07/04/2016

10

DATE OF REVISION

26/05/2021

Summary table of changes

Section Changed

Summary of new information

All sections reformatted inline with new form.

4.8

Addition of

1. Aseptic meningitis as a new adverse reaction.

2. Reporting suspected adverse effects and

3. Drug Reaction with Eosinophilia and Systemic

Symptoms (DRESS)

4.1

4.4

4.8

4.9

Section is updated with additional cross references

of other sections

Read the complete document

Public Summary

Summary for ARTG Entry:

289509

COCLAVMOX 500/125, amoxicillin (as trihydrate) 500 mg and clavulanic acid (as potassium) 125 mg

tablets strip pack

ARTG entry for

Medicine Registered

Sponsor

Micro Labs Pty Ltd

Postal Address

15 Melliodora Crescent,GREENSBOROUGH, VIC, 3088

Australia

ARTG Start Date

7/08/2017

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. COCLAVMOX 500/125, amoxicillin (as trihydrate) 500 mg and clavulanic acid (as potassium) 125 mg tablets

strip pack

Product Type

Single Medicine Product

Effective date

7/08/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

COCLAVMOX 500/125 tablets are indicated for short term treatment of bacterial infections at the following sites when caused by sensitive organisms

(refer to 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

beta-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 beta-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.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Strip Pack

Al/Al

24 Months

Store below 25

degrees Celsius

Neither child resistant

closure nor restricted

flow insert

Protect from Moisture

Pack Size/Poison information

Pack Size

Poison Schedule

Alu/Alu strip packs of 10 tablets packed in monocarton

(S4) Prescription Only Medicine

Components

1. COCLAVMOX 500/125, amoxicillin (as trihydrate) 500 mg and clavulanic acid (as potassium) 125 mg tablets strip pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

White colored capsule shaped film coated tablet debossed with 'I 06' on

one side and plain on other side.

Active Ingredients

amoxicillin trihydrate

573.892 mg

potassium clavulanate

151.917 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 24.11.2017 at 09:22:37 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

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