AUGMENTIN SUSPENSION 400 MG5 ML

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed according to a physician’s prescription only

Augmentin Suspension 400 mg/5 ml

Each 5 ml of suspension contains:

400 mg amoxicillin (as trihydrate)

57 mg clavulanic acid (as potassium salt)

List of the additional ingredients is detailed in section 6.

Read the entire leaflet carefully before using the medicine. This

leaflet contains concise information about the medicine. If you have

further questions, refer to the physician or pharmacist.

This medicine has been prescribed for you/your child. Do not pass

it on to others. It may harm them even if it seems to you that their

medical condition is similar.

1. What is the medicine intended for?

Augmentin is used in adults, children and babies to treat the following

infections:

middle ear and sinus infections

respiratory tract infections

urinary tract infections

skin and soft tissue infections including dental infections

bone and joint infections.

recurrent tonsil infections.

There is no clinical data about patients under two months of age.

Augmentin is an antibiotic that works by killing bacteria that cause

infections. It contains two different medicines called amoxicillin and

clavulanic acid. Amoxicillin belongs to a group of medicines called

“penicillins” whose action can sometimes be stopped (become

inactive). The other active component (clavulanic acid) prevents this

from happening.

Therapeutic group

Amoxicillin: Penicillin antibiotic group

Clavulanic acid: Beta-lactamase enzyme inhibitors

2. Before using the medicine

Do not use the medicine if:

you or your child are/is sensitive (allergic) to amoxicillin, clavulanic

acid, penicillin or any of the additional ingredients contained in

the medicine (listed in section 6)

you or your child have/has ever had a severe allergic reaction

to any other antibiotic. This can include a skin rash or swelling

of the face or throat

you or your child have/has ever had liver problems or jaundice

(yellowing of the skin) when taking an antibiotic.

→

Do not take Augmentin or do not give Augmentin to your

child if any of the above apply to you or to your child. If you

are not sure, talk to the physician or pharmacist before giving/

taking Augmentin.

Special warnings regarding the use of this medicine:

Check with the physician or pharmacist before giving your child

Augmentin or taking Augmentin if:

you or your child have/has glandular fever

you or your child are/is being treated for liver or kidney problems

you or your child are/is not passing water properly.

If you are not sure if any of the above apply to you or to your child, talk

to the physician or pharmacist before giving/taking Augmentin.

In some cases, the physician may check the type of bacteria that is

causing the infection. Depending on the results, you or your child may

be given a different strength of Augmentin or a different medicine.

Conditions you need to look out for

Augmentin can make some existing conditions worse, or cause serious

side effects. These include allergic reactions, convulsions (fits) and

inflammation of the large intestine. You must look out for certain

symptoms while you or your child are/is taking Augmentin, to reduce

the risk of any problems. See ‘Conditions you need to look out for’

in section 4.

Blood and urine tests

If you or your child are/is undergoing blood tests (such as red blood cell

status tests or liver function tests) or urine tests (to check glucose levels),

let the physician know that you/your child are/is taking Augmentin. This

is because Augmentin can affect the results of these types of tests.

Other medicines and Augmentin

If you/your child are/is taking, have/has recently taken or might

take other medicines, including non-prescription medicines,

herbal medicines and nutritional supplements, tell the physician

or pharmacist. Especially:

If you/your child are/is taking allopurinol (used for gout) with

Augmentin, it may be more likely that your child/you will have an

allergic skin reaction.

If you/your child are/is taking probenecid (used for gout), the

physician may decide to adjust the dose of Augmentin.

If medicines that help prevent blood clotting (such as warfarin or

acenocoumarol) are taken with Augmentin, then extra blood tests

may be needed.

Augmentin can affect how methotrexate (a medicine used to treat

cancer or rheumatic diseases) works.

Augmentin can affect how mycophenolate mofetil (a medicine used

to prevent the rejection of transplanted organs) works.

Pregnancy, breastfeeding and fertility

If you/your child who is about to take this medicine are/is pregnant

or breastfeeding, think/thinks you/she may be pregnant or are/is

planning to become pregnant, ask your physician or pharmacist for

advice before taking this medicine.

Driving and using machines

Augmentin can have side effects and the symptoms may make you

unfit to drive. Do not drive or operate machinery unless you are feeling

well.

Important information about some of the ingredients of the

medicine

Augmentin contains 16.64 mg aspartame (E951) in each 5 ml.

Aspartame is a source of phenylalanine. This may be harmful for

patients suffering from a condition called “phenylketonuria”, a rare

genetic disorder in which phenylalanine accumulates because the

body cannot clear it properly.

Augmentin contains maltodextrin (glucose). If you have been told

by the physician that your child/you has/have an intolerance to

certain sugars, contact the physician before giving/taking this

medicinal product.

Augmentin contains 8.84 mg sodium benzoate in each 5 ml.

This medicine contains less than 23 mg sodium in 5 ml and is

therefore considered sodium-free.

3. How should you use the medicine?

Always use the preparation according to the physician's instructions.

Check with the physician or pharmacist if you are uncertain about the

dosage and treatment regimen of the preparation.

The dosage and treatment regimen will be determined by the physician

only. The usual dosage is generally:

Adults and children weighing 40 kg or over

This suspension is not usually recommended for adults and

children weighing 40 kg and over. Ask the physician or pharmacist

for advice.

Children weighing less than 40 kg

All doses are calculated on the basis of body weight in kilograms.

Your physician will advise you how much Augmentin you should

give to your baby or child.

You may be provided with a plastic measuring spoon or a plastic

measuring cup or dosing syringe. Instructions for use of the dosing

syringe are provided at the end of this leaflet. You should use them

to give the correct dose to your baby or child.

There are no clinical data about patients under two months of age.

Patients with kidney and liver problems

If you/your child have/has kidney problems, the dose might be

lowered. A different strength or a different medicine may be chosen

by the physician.

If you or your child have/has liver problems, there may be need

for more frequent blood tests to check liver function.

Do not exceed the recommended dose

Instructions for reconstitution

Check that the cap seal is intact before using.

Shake the bottle to loosen the powder.

Add the volume of water indicated below, invert and shake well.

To prepare 35 ml suspension, add 32 ml water.

To prepare 70 ml suspension, add 64 ml water.

To prepare 140 ml suspension, add 127 ml water.

How to give Augmentin

Always shake the bottle well before each dose

Give/take with a meal

Space the doses evenly throughout the day, at least 4 hours apart.

Do not take/give your child 2 doses in one hour.

Do not take/give your child Augmentin for more than two weeks.

If you/your child still feel/feels unwell you/he should go back to

see the physician.

If you accidentally have given/taken a higher dosage

If you accidentally have given your child/taken too much Augmentin,

the signs might include stomach discomfort (nausea, vomiting or

diarrhoea) or convulsions. Refer to a physician as soon as possible.

Take the medicine package to show the physician.

If a child has accidentally swallowed the medicine, refer immediately

to a physician or to a hospital emergency room and bring the package

of the medicine with you.

If you forget to give/take Augmentin

If you forgot to give your child a dose or forgot to take a dose, give/

take it as soon as you remember. You should not give your child/take

the next dose too soon, but wait about 4 hours before giving/taking

the next dose. Do not give/Do not take a double dose to make up

for a forgotten dose.

Persist with the treatment as recommended by the physician.

If your child/you stops/stop taking Augmentin

Keep giving your child/taking Augmentin until the treatment is finished,

even if

your child

/you feels/feel better. Each dose is important for

your child/for you in order to help fight the infection. If some bacteria

survive they can cause the infection to come back.

Do not take medicines in the dark! Check the label and the dose

each time you take a medicine. Wear glasses if you need them.

If you have further questions regarding the use of the medicine,

consult the physician or the pharmacist.

4. Side effects

As with any medicine, use of Augmentin may cause side effects in

some of the users. Do not be alarmed by reading the list of side effects.

You/your child may not experience any of them. The side effects below

may happen with this medicine.

Conditions you need to look out for:

Allergic reactions:

skin rash

inflammation of blood vessels (vasculitis) which may be visible as

red or purple raised spots on the skin, but can affect other parts

of the body

fever, joint pain, swollen glands in the neck, armpit or groin

swelling, sometimes of the face or throat (angioedema), causing

difficulty in breathing

collapse

→

Contact a physician immediately if you/your child experience/s

any of these symptoms.

Stop taking/giving Augmentin.

Inflammation of the large intestine

Inflammation of the large intestine, causing watery diarrhoea usually

accompanied by blood and mucus, stomach pain and/or fever.

→

Contact a physician as soon as possible for advice if you/your

child experience/s these symptoms.

Additional side effects

Very common side effects

These may affect more than 1 in 10 people

diarrhoea (in adults)

Common side effects

These may affect up to 1 in 10 people

thrush (candida - a fungal infection of the vagina, mouth or skin

folds)

nausea, especially when taking high doses

→

if nausea occurs, take/give Augmentin with a meal

vomiting

diarrhoea (in children)

Uncommon side effects

These may affect up to 1 in 100 people

skin rash, itching

raised itchy rash (hives)

indigestion

dizziness

headache

Uncommon side effects that may show up in blood tests:

increase in liver enzymes

Rare side effects

These may affect up to 1 in 1,000 people

skin rash, which may include blisters (looks like central dark spots

surrounded by a paler area, with a dark ring around the edge –

erythema multiforme)

→

if you notice any of these symptoms contact a physician

urgently.

Rare side effects that may show up in blood tests:

low number of cells involved in blood clotting

low number of white blood cells

Side effects of unknown frequency (frequency cannot be estimated

from the available data)

Allergic reactions (see above)

Inflammation of the large intestine (see above)

Inflammation of the protective membrane surrounding the brain

(aseptic meningitis)

Serious skin reactions:

a widespread rash with blisters and peeling skin, particularly

around the mouth, nose, eyes and genitals (Stevens-Johnson

syndrome), and a more severe form, causing extensive peeling

of the skin (more than 30% of the body surface - toxic epidermal

necrolysis)

widespread red skin rash with small pus-containing blisters

(bullous exfoliative dermatitis)

a red, scaly rash with bumps under the skin and blisters

(exanthematous pustulosis)

Flu-like symptoms with a rash, fever, swollen glands, and

abnormal blood test results (including an increase in the

amount of white blood cells [eosinophilia] and liver enzymes)

(Drug Reaction with Eosinophilia and Systemic Symptoms

[DRESS]).

→

Contact a physician immediately if you/your child experience/s

any of these symptoms.

inflammation of the liver (hepatitis)

jaundice, caused by an increase of bilirubin in the blood (a

substance produced in the liver) which may make your child’s/

your skin and whites of the eyes appear yellow

inflammation of tubes in the kidney

longer blood clotting time

hyperactivity

convulsions (in people taking high doses of Augmentin or who

have kidney problems)

black tongue which looks hairy

stained teeth (in children), usually removed by brushing

Side effects that may show up in blood or urine tests:

severe reduction in the number of white blood cells

low number of red blood cells (haemolytic anaemia)

crystals in urine.

If a side effect has appeared, if one of the side effects worsens or

when your child/you suffers/suffer from a side effect that has not

been mentioned in the leaflet, you should consult the physician.

Side effects can be reported to the Ministry of Health by clicking on

the link “Report Side Effects of Drug Treatment” found on the Ministry

of Health homepage (www.health.gov.il) that directs you to the online

form for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formT

ype=AdversEffectMedic@moh.gov.il

5. How to store the medicine?

Avoid poisoning! This medicine and any other medicine should be

kept in a closed place out of the reach and sight of children and/or

infants in order to avoid poisoning. Do not induce vomiting without

an explicit instruction from the physician.

Do not use the medicine after the expiry date (exp. date) appearing on

the package. The expiry date refers to the last day of that month.

Dry powder

Store in the original package to protect from moisture.

Store below 25°C.

Liquid suspension

Store in a refrigerator (2°C-8°C). Do not freeze.

After preparation, the suspension should be used within 7 days.

6. Additional information

In addition to the active ingredients, the medicine also contains:

Silicon dioxide (Anhydrous), Carboxymethylcellulose sodium,

Aspartame, Crospovidone (PVP), Sodium benzoate, Xanthan gum,

Colloidal anhydrous silica, Magnesium stearate, Strawberry flavour

(including maltodextrin).

See also ‘Important information about some of the ingredients of

the medicine’ in section 2.

What the medicine looks like and the content of the package:

Augmentin Suspension 400 mg/5 ml (strawberry-flavored) powder

for oral suspension is an off-white powder supplied in a clear glass

bottle. After preparation, the bottle contains 35 ml, 70 ml or 140 ml

of an off-white liquid mixture called a suspension.

Not all package sizes may be marketed.

License Holder and address: GlaxoSmithKline (Israel) Ltd.,

25 Basel St., Petach Tikva.

Manufacturer and address: SmithKline Beecham Limited,

Brentford, UK.

The format of this leaflet was determined by the Ministry of Health

and its content was checked and approved by the Ministry of

Health in March 2017 and was updated in May 2018 in accordance

with the Ministry of Health guidelines.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health: 112-75-29288

Instructions for using the dosing syringe

A syringe is supplied to administer Augmentin

The syringe is only for use with Augmentin and must not be used to

administer any other medicines, because the markings are specific

to this product. The syringe is supplied with an adaptor which allows

it to be attached to the bottle.

The dose is indicated on the oral dosing syringe in milliliters (ml).

You should take/give your child the dose recommended by the

physician.

Check that the cap seal is intact before first use.

Check the cleanliness of syringe and adaptor before use, rinse with

clean water if required.

1. Shake the bottle well before each dose.

Remove the bottle cap.

Add the amount of water indicated on the label of

the bottle. Close, invert, and shake well.

2. Remove the bottle cap.

3. Remove the adaptor from the syringe. Hold

the bottle firmly and insert the adaptor into the

neck of the bottle (the adaptor should remain

in place).

Insert the syringe into the adaptor ensuring

it is secure.

4. Invert the bottle holding the syringe in place

and withdraw the required dose as indicated

by your physician.

5. Place the bottle upright and remove the

syringe.

6. To take/give the dose, carefully put the tip of

the syringe into the mouth and slowly push

down on the plunger of the syringe (repeat

steps 4, 5 and 6 if more than one syringe is

needed to deliver the dose).

7. Rinse the syringe thoroughly in clean water.

Allow the syringe to dry completely before the

next use.

8. Replace the bottle cap.

Store in a refrigerator and always shake

before use.

After preparation, the suspension should be

used within 7 days.

Trade marks are owned by or licensed to the GSK group of

companies.

©2018 GSK group of companies or its licensor.

Aug

Sus

400

PT

v

7A

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The Content of this leaflet was approved by the Ministry of Health in November 2016 and updated according to the guidelines of

the Ministry of Health in May 2018

Augmentin 875 mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Augmentin

875 mg

Tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains amoxicillin trihydrate equivalent to 875 mg amoxicillin and

potassium clavulanate equivalent to 125 mg of clavulanic acid.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

White to off-white, capsule shaped tablets debossed with “AC” on both sides and a scoreline on one

side.

The score line is only to facilitate breaking and ease of swallowing and not to divide into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Augmentin is indicated for the treatment of the following infections in adults and children (see

sections 4.2, 4.4 and 5.1):

Acute bacterial sinusitis (adequately diagnosed)

Acute otitis media

Acute exacerbations of chronic bronchitis (adequately diagnosed)

Community acquired pneumonia

Cystitis

Pyelonephritis

Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess

with spreading cellulitis.

Bone and joint infections, in particular osteomyelitis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

There are no clinical data for Augmentin 7:1 formulations for patients under 2 months of age.

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4.2

Posology and method of administration

Posology

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are

stated in terms of an individual component.

The dose of Augmentin that is selected to treat an individual infection should take into account:

The expected pathogens and their likely susceptibility to antibacterial agents (see section

4.4)

The severity and the site of the infection

The age, weight and renal function of the patient as shown below.

The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin

and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see

sections 4.4 and 5.1).

For adults and children

40 kg, this formulation of Augmentin provides a total daily dose of 1750 mg

amoxicillin/ 250 mg clavulanic acid with twice daily dosing and 2625 mg amoxicillin/375 mg

clavulanic acid with three times daily dosing, when administered as recommended below. For

children < 40 kg, this formulation of Augmentin provides a maximum daily dose of 1000-2800 mg

amoxicillin/143-400 mg clavulanic acid, when administered as recommended below. If it is

considered that a higher daily dose of amoxicillin is required, it is recommended that another

preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses

of clavulanic acid (see sections 4.4 and 5.1).

The duration of therapy should be determined by the response of the patient. Some infections (e.g.

osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days

without review (see section 4.4 regarding prolonged therapy).

Adults and children

40 kg

Recommended doses:

standard dose: (for all indications) 875 mg/125 mg two times a day;

higher dose - (particularly for infections such as otitis media, sinusitis, lower respiratory

tract infections and urinary tract infections): 875 mg/125 mg three times a day.

Children < 40 kg

Children may be treated with Augmentin tablets

or suspensions

Recommended doses:

25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses;

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up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some

infections (such as otitis media, sinusitis and lower respiratory tract infections).

As the tablets cannot be divided, children weighing less than 25 kg must not be treated with

Augmentin tablets.

The table below presents the received dose (mg/kg body weight) in children weighing 25 kg to 40 kg

upon administering a single 875/125 mg tablet.

Body weight [kg]

Single dose

recommended [mg/kg

body weight] (see above)

Amoxicillin [mg/kg

body weight] per single

dose (1 film-coated

tablet)

21.9

25.0

29.2

35.0

12.5 – 22.5

(up to 35)

Clavulanic acid [mg/kg

body weight] per single

dose (1 film-coated

tablet)

1.8 – 3.2

(up to 5)

Children weighing less than 25 kg should preferably be treated with Augmentin suspension

No clinical data are available for Augmentin 7:1 formulations regarding doses higher than 45 mg/6.4

mg per kg per day in children under 2 years.

There are no clinical data for Augmentin 7:1 formulations for patients under 2 months of age. Dosing

recommendations in this population therefore cannot be made.

Elderly

No dose adjustment is considered necessary.

Renal impairment

No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

In patients with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an

amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose

adjustments are available.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).

Method of administration

Augmentin is for oral use.

Augmentin should be administered with a meal to minimise potential gastrointestinal intolerance.

Therapy can be started parenterally according to the SmPC of the IV-formulation and continued with

an oral preparation.

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4.3

Contraindications

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in

section 6.1.

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent

(e.g. a cephalosporin, carbapenem or monobactam).

History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

4.4

Special warnings and special precautions for use

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning

previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see

sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe

cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are

more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic

individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued

and appropriate alternative therapy instituted.

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then

consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in

accordance with official guidance.

This presentation of Augmentin is not suitable for use when there is a high risk that the presumptive

pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to

inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S.

pneumoniae.

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see

section 4.8).

Amoxicillin/clavulanic acid 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.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of

allergic skin reactions.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula

may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see section 4.8). This

reaction requires Augmentin discontinuation and contraindicates any subsequent administration of

amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic

impairment (see sections 4.2, 4.3 and 4.8).

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Hepatic events have been reported predominantly in males and elderly patients and may be associated

with prolonged treatment. These events have been very rarely reported in children. In all populations,

signs and symptoms usually occur during or shortly after treatment but in some cases may not become

apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events

may be severe, and in extremely rare circumstances, deaths have been reported. These have almost

always occurred in patients with serious underlying disease or taking concomitant medications known

to have the potential for hepatic effects (see section 4.8).

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including

amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is

important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the

administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic

acid should immediately be discontinued, a physician be consulted and an appropriate therapy

initiated. Anti-peristaltic medicinal products are contraindicated in this situation.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is

advisable during prolonged therapy.

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic

acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed

concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the

desired level of anticoagulation (see sections 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted according to the degree of impairment

(see section 4.2).

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.

In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever

testing for the presence of glucose in urine because false positive results may occur with non-

enzymatic methods.

The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin

by red cell membranes leading to a false positive Coombs test.

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus

EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of

Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with

Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results

in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by

other diagnostic methods.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially

‘sodium-free’.

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4.5

Interaction with other medicinal products and other forms of interaction

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of

interaction. However, in the literature there are 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. Moreover, adjustments in the dose of oral

anticoagulants may be necessary (see sections 4.4 and 4.8).

Methotrexate

Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion

of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of

amoxicillin but not of clavulanic acid.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active

metabolite mycophenolic acid (MPA) of approximately 50% has been reported following

commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not

accurately represent changes in overall MPA exposure. Therefore, a change in the dose of

mycophenolate mofetil should not normally be necessary in the absence of graft dysfunction.

However, close clinical monitoring should be performed during the combination and shortly after

antibiotic treatment.

4.6

Fertility, pregnancy and lactation

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,

embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on

the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of

congenital malformations. In a single study in women with preterm, premature rupture of the foetal

membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be

associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided

during pregnancy, unless considered essential by the physician.

Breastfeeding

Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the

breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are

possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility

of sensitisation should be taken into account. Amoxicillin/clavulanic acid should only be used during

breast-feeding after benefit/risk assessment by the physician in charge.

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4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However,

undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the

ability to drive and use machines (see section 4.8).

4.8

Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.

The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by

MedDRA System Organ Class are listed below.

The following terminologies have been used in order to classify the occurrence of undesirable effects.

Very common (

1/10)

Common (

1/100 to <1/10)

Uncommon (

1/1,000 to <1/100)

Rare (

1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations

Mucocutaneous candidosis

Common

Overgrowth of non-susceptible

organisms

Not known

Blood and lymphatic system disorders

Reversible leucopenia (including

neutropenia)

Rare

Thrombocytopenia

Rare

Reversible agranulocytosis

Not known

Haemolytic anaemia

Not known

Prolongation of bleeding time and

prothrombin time

Not known

Immune system disorders

Angioneurotic oedema

Not known

Anaphylaxis

Not known

Serum sickness-like syndrome

Not known

Hypersensitivity vasculitis

Not known

Nervous system disorders

Dizziness

Uncommon

Headache

Uncommon

Reversible hyperactivity

Not known

Convulsions

Not known

Aseptic Meningitis

Not known

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8

16

Gastrointestinal disorders

Diarrhoea

Very common

Nausea

Common

Vomiting

Common

Indigestion

Uncommon

Antibiotic-associated colitis

Not known

Black hairy tongue

Not known

Hepatobiliary disorders

Rises in AST and/or ALT

Uncommon

Hepatitis

Not known

Cholestatic jaundice

Not known

Skin and subcutaneous tissue disorders

Skin rash

Uncommon

Pruritus

Uncommon

Urticaria

Uncommon

Erythema multiforme

Rare

Stevens-Johnson syndrome

Not known

Toxic epidermal necrolysis

Not known

Bullous exfoliative-dermatitis

Not known

Acute generalised exanthemous

pustulosis (AGEP)

Not known

Drug reaction with eosinophilia and

systemic symptoms (DRESS)

Not known

Renal and urinary disorders

Interstitial nephritis

Not known

Crystalluria

Not known

See section 4.4

See section 4.4

Nausea is more often associated with higher oral doses. If gastrointestinal

reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid

with a meal.

Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4)

A moderate rise in AST and/or ALT has been noted in patients treated with beta-

lactam class antibiotics, but the significance of these findings is unknown.

These events have been noted with other penicillins and cephalosporins (see

section 4.4).

If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued

(see section 4.4).

See section 4.9

See section 4.4

See sections 4.3 and 4.4

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16

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected

adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

/https://sideeffects.health.gov.il

Additionally, you should also report to GSK Israel

(il.safety@gsk.com)

4.9

Overdose

Symptoms and signs of overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident.

Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

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

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous

administration of large doses. A regular check of patency should be maintained (see section 4.4).

Treatment of intoxication

Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte

balance.

Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code:

J01CR02.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes

(often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial

peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of

peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis

and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and

therefore the spectrum of activity of amoxicillin alone does not include organisms which produce

these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase

enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a

clinically useful antibacterial effect.

Pharmacokinetic/pharmacodynamic relationship

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10

16

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major

determinant of efficacy for amoxicillin.

Mechanisms of resistance

The two main mechanisms of resistance to amoxicillin/clavulanic acid are:

Inactivation by those bacterial beta-lactamases that are not themselves inhibited by

clavulanic acid, including class B, C and D.

Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance,

particularly in Gram-negative bacteria.

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on

Antimicrobial Susceptibility Testing (EUCAST)

Organism

Susceptibility Breakpoints (

g/ml)

Susceptible

Intermediate

Resistant

Haemophilus

influenzae

1

≤ 1

> 1

Moraxella catarrhalis

1

≤ 1

> 1

Staphylococcus aureus

2

≤ 2

> 2

Coagulase-negative

staphylococci

2

≤ 0.25

> 0.25

Enterococcus

1

≤ 4

> 8

Streptococcus A, B, C,

G

5

≤ 0.25

> 0.25

Streptococcus

pneumoniae

3

≤ 0.5

> 2

Enterobacteriaceae

1,4

> 8

Gram-negative

Anaerobes

1

≤ 4

> 8

Gram-positive

Anaerobes

1

≤ 4

> 8

Non-species related

breakpoints

1

≤ 2

> 8

The reported values are for amoxicillin concentrations. For susceptibility testing

purposes, the concentration of clavulanic acid is fixed at 2 mg/l.

The reported values are oxacillin concentrations.

Breakpoint values in the table are based on ampicillin breakpoints.

The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance

mechanisms are reported resistant.

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11

16

Breakpoint values in the table are based on benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and with time for selected species, and local

information on resistance is desirable, particularly when treating severe infections. As necessary,

expert advice should be sought when the local prevalence of resistance is such that the utility of the

agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive micro-organisms

Enterococcus faecalis

Gardnerella vaginalis

Staphylococcus aureus

(methicillin-susceptible)£

Coagulase-negative staphylococci (methicillin-susceptible)

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

and other beta-haemolytic streptococci

Streptococcus viridans

group

Aerobic Gram-negative micro-organisms

Capnocytophaga

spp.

Eikenella corrodens

Haemophilus influenzae

Moraxella catarrhalis

Pasteurella multocida

Anaerobic micro-organisms

Bacteroides fragilis

Fusobacterium nucleatum

Prevotella

spp.

Species for which acquired resistance may be a problem

Aerobic Gram-positive micro-organisms

Enterococcus faecium

Aerobic Gram-negative micro-organisms

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Proteus vulgaris

Inherently resistant organisms

Aerobic Gram-negative micro-organisms

Acinetobacter

Citrobacter freundii

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12

16

Enterobacter

Legionella pneumophila

Morganella morganii

Providencia

spp.

Pseudomonas

Serratia

Stenotrophomonas maltophilia

Other micro-organisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetti

Mycoplasma pneumoniae

$ Natural intermediate susceptibility in the absence of acquired mechanism of

resistance.

All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid

Streptococcus pneumoniae

that are resistant to penicillin should not be treated

with this presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4).

Strains with decreased susceptibility have been reported in some countries in the

EU with a frequency higher than 10%.

5.2

Pharmacokinetic properties

Absorption

Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both

components are rapidly and well absorbed by the oral route of administration. Following oral

administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma

profiles of both components are similar and the time to peak plasma concentration (T

) in each case

is approximately one hour.

The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (875 mg/125 mg tablets

given twice daily) was administered in the fasting state to groups of healthy volunteers are presented

below.

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13

16

Mean (

SD) pharmacokinetic parameters

Active

substance(s)

administered

Dose

(0-24h)

T 1/2

(mg)

g/ml)

g.h/ml)

Amoxicillin

AMX/CA

875 mg/125 m

11.64

2.78

1.50

(1.0-2.5)

53.52

12.31

1.19

0.21

Clavulanic acid

AMX/CA

875 mg/125 m

2.18

0.99

1.25

(1.0-2.0)

10.16

3.04

0.96

0.12

AMX – amoxicillin, CA – clavulanic acid

* Median (range)

Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are

similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic

acid alone.

Distribution

About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein.

The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for

clavulanic acid.

Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall

bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus.

Amoxicillin does not adequately distribute into the cerebrospinal fluid.

From animal studies there is no evidence for significant tissue retention of drug-derived material for

either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities

of clavulanic acid can also be detected in breast milk (see section 4.6).

Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).

Biotransformation

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up

to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in

urine and faeces and as carbon dioxide in expired air.

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14

16

Elimination

The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by

both renal and non-renal mechanisms.

Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean

total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the

amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine

during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg

tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between

27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of

drug is excreted during the first 2 hours after administration.

Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of

clavulanic acid (see section 4.5).

The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and

older children and adults. For very young children (including preterm newborns) in the first week of

life the interval of administration should not exceed twice daily administration due to immaturity of

the renal pathway of elimination. Because elderly patients are more likely to have decreased renal

function, care should be taken in dose selection, and it may be useful to monitor renal function.

Gender

Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects,

gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.

Renal impairment

The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing

renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic

acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment

must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of

clavulanic acid (see section 4.2).

Hepatic impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular

intervals.

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15

16

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology,

genotoxicity and toxicity to reproduction.

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric

irritancy and vomiting, and discoloured tongue.

Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Microcrystalline cellulose

Sodium starch glycolate, Type A

Magnesium stearate

Colloidal anhydrous silica

Tablet film-coat

Hypromellose (5 cps, 15 cps)

Titanium dioxide (E171)

Macrogol (4000,6000)

Dimeticone

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials...

Tablets in desiccated pouch packs should be used within 30 days of opening.

6.4

Special precautions for storage

Store in the original package in order to protect from moisture.

Do not store above 25°C.

6.5

Nature and contents of container

PVC/Aluminium/Polyamide laminate with aluminium lidding foil referred to as a cold formed

aluminium blister (CFB) containing 2, 4, 10, 12, 14, 16, 20, 24, 30, 100 or 500 tablets.

Aluminium PVC/PVdC blister enclosed with an aluminium laminate pouch containing a desiccant

sachet, referred to as a desiccated pouch pack (DPP) containing 14 tablets.

Not all pack sizes may be marketed.

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16

16

6.6

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

Manfacturer

Smithkline Beecham Pharmaceuticals, Worthing, UK.

Glaxo Wellcome Production, Mayenne, France

8.

License Holder and Importer

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva

9.

License Number

107-43-28610

Trade marks are owned by or licensed to the GSK group of companies.

©201

9 GSK group of companies or its licensor.

Aug Tab 875 DR v6.1