SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-Amoxiclav 457mg/5ml Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution, each 5ml of oral suspension contains 400 mg amoxicillin (as trihydrate) and 57 mg clavulanic acid (as potassium salt).

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral suspension.

White powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of bacterial infections induced by gramnegative and grampositive amoxicillin-resistant microorganisms whose resistance is caused by P-lactamases which however are sensitive to the combination of amoxicillin and clavulanic acid.

Co-amoxiclav oral suspension is suitable for treatment of the following indications when known or likely to be due to susceptible organisms (see section 5.1):

•    Infections of the upper respiratory tract (including ear-nose-throat) in particular sinusitis, otitis media, recurrent tonsillitis.

•    Infections of the lower respiratory tract, in particular acute exacerbations of chronic bronchitis and bronchopneumonia.

•    Genital and urinary tract infections.

•    Infections of the skin and soft tissues

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

4.2 Posology and method of administration

The usual recommended daily dosage is:

25/3.6 mg/kg/day in mild to moderate infections (upper respiratory tract infections, e.g. recurrent tonsillitis, lower respiratory infections and skin and soft tissue infections)

45/6.4 mg/kg/day for the treatment of more serious infections (upper respiratory tract infections, e.g. otitis media and sinusitis, lower respiratory tract infections, e.g. bronchopneumonia and urinary tract infections)

The tables below give guidance for children.

Children over 2 years

25/3.6 mg/kg/day	2 - 6 years (13 - 21 kg)	2.5 ml Co-Amoxiclav 457 Suspension b.i.d.
	7 - 12 years (22 -40 kg)	5.0 ml Co-Amoxiclav 457 Suspension b.i.d.
45/6.4 mg/kg/day	2 - 6 years (13 - 21 kg)	5.0 ml Co-Amoxiclav 457 Suspension b.i.d.
	7 - 12 years (22 -40 kg)	10.0 ml Co-Amoxiclav 457 Suspension b.i.d.

Children aged 2 months to 2 years

Children under 2 years should be dosed according to body weight

	(ml/b.i.d.)	(ml/b.i.d.)
2	0.3	0.6
3	0.5	0.8
4	0.6	1.1
5	0.8	1.4
6	0.9	1.7
7	1.1	2.0
8	1.3	2.3
9	1.4	2.5
10	1.6	2.8
11	1.7	3.1
12	1.9	3.4
13	2.0	3.7
14	2.2	3.9
15	2.3	4.2

There is insufficient experience with Co-Amoxiclav Oral Suspension to make dosage recommendations for children under 2 months old.

Infants with immature kidney function

For children with immature renal function Co-Amoxiclav Oral Suspension 457 is not recommended.

Renal impairment

For children with a GFR of >30 ml/min no adjustment in dosage is required. For children with a GFR of <30 ml/min Co-Amoxiclav Oral Suspension 457 is not recommended.

Hepatic impairment

Dose with caution; monitor hepatic function at regular intervals. There is, as yet, insufficient evidence on which to base a dosage recommendation.

Method of administration

To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of co-amoxiclav is optimised when taken at the start of a meal. Duration of therapy should be appropriate to the indication and should not exceed 14 days without review. Therapy can be started parenterally and continued with an oral preparation.

As a precaution, therapy over at least 10 days is indicated in the treatment of infections with P-haemolytic streptococci in order to guard against late complications (e.g. rheumatic fever, glomerulonephritis).

4.3 Contraindications

Hypersensitivity to amoxicillin, clavulanic acid, P-lactams (e.g. penicillins, cephalosporins) owing to the danger of anaphylactic shock, or to any of the excipients.

Co-amoxiclav oral suspension should not be used in patients in whom hepatic functional impairment has occurred during previous treatment with amoxicillin/clavulanic acid.

Amoxicillin/clavulanic acid must not be used in patients with severe hepatic functional impairment. Patients with infectious mononucleosis (glandular fever) and patients with lymphatic leukaemia have a higher risk of developing exanthema if given amoxicillin/clavulanic acid. Consequently amoxicillin/clavulanic acid should not be administered to patients with these conditions.

Phenylketonuria since the product contains aspartame.

4.4 Special warnings and precautions for use

Mixed infections caused by organisms susceptible to amoxicillin and beta-lactamase-producing organisms susceptible to amoxicillin/clavulanic acid do not usually require the addition of another beta-lactam antibiotic.

The therapy should only be applied with caution in patients with pre-existing hepatic impairment. Caution is necessary on treatment of patients with high-grade hepatic functional impairment and in older patients (60 years and older): liver function tests are indicated in such patients (see section 4.8).

In case of severe and persistent diarrhoea, the possibility of pseudomembranous colitis caused by Clostridium difficile must be considered and amoxicillin/clavulanic acid therapy must not be continued. Antiperistaltics are contraindicated.

Co-amoxiclav oral suspension should be used with caution in patients with severe allergies or asthma since such patients are more likely to respond with allergic reactions.

Before initiating therapy inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other substances.

Serious and occasionally fatal hypersensitivity reactions have been reported in patients with a history of penicillin hypersensitivity.

Amoxicillin may precipitate in the bladder catheter if present in urine at high concentrations at room temperature, therefore, the catheter should be checked at regular intervals in such cases.

On long term use - the same as with other broad spectrum antibiotics -superinfections with resistant bacteria or yeasts are possible.

Regular checks on renal and hepatic function and haematological studies are indicated during long term treatment.

4.5 Interaction with other medicinal products and other forms of interaction

Amoxicillin/clavulanic acid and other antibiotics or chemotherapeutics Co-amoxiclav oral suspension should not be combined with bacteriostatic chemotherapeutics/antibiotics (such as tetracyclines, macrolides, sulphonamides or chloramphenicol) since an antagonistic effect has been observed in vitro.

Amoxicillin/clavulanic acid and probenecid

Concomitant administration of probenecid leads to an increase in and prolongation of serum and bile amoxicillin concentrations owing to inhibition of renal excretion. However this does not affect the excretion of clavulanic acid.

Amoxicillin/clavulanic acid and allopurinol

Concomitant administration of allopurinol during therapy with Co-amoxiclav oral suspension may promote the occurrence of allergic cutaneous reactions (exanthema).

Amoxicllin/clavulanic acid and sufasalasin

Aminopenicillin may reduce the plasmatic concentration of sufasalasin. Amoxicllin/clavulanic acid and methotrexate

Interaction between amoxicillin and methotrexate leading to methotrexate toxicity has been reported. Serum methotrexate levels should be closely monitored in patients who receive concomitant amoxicillin. Amoxicillin decreases the renal clearance of methotrexate probably by competition at the common tubular secretion system.

Amoxicllin/clavulanic acid and digoxin

An increase in absorption of digoxin is possible on concurrent administration with Co-amoxiclav oral suspension.

Amoxicillin/clavulanic acid and disulfiram

Co-amoxiclav oral suspension cannot be used concomitantly with disulfiram.

Amoxicllin/clavulanic acid and anticoagulants

A tendency to bleed can be potentiated due to concomitant administration of Co-amoxiclav oral suspension and anticoagulants of the cumarin class.

Amoxicllin/clavulanic acid and hormonal contraceptives In rare cases amoxicillin can adversely affect the efficacy of hormonal contraceptives. Supplementary non-hormonal contraceptive measures should be taken.

Influence on results of diagnostic laboratory tests

Nonenzymic methods for determining urinary sugar can yield falsely positive results. Likewise the urobilinogen test can be affected.

4.6 Pregnancy and lactation

Data on approximately 560 exposed pregnancies indicate no adverse effects of amoxicillin/clavulanic acid on pregnancy or on the health of the foetus/newborn child. However a single study in women with premature rupture of the amnion reported that prophylactic treatment with amoxicillin/clavulanic acid can be associated with an increased risk of necrotising enterocolitis in neonates. As a precautionary measure Co-amoxiclav oral suspension should only be used in pregnancy if in the judgement of the physician the potential benefits outweigh the possible hazards.

Both substances pass into the embryo/foetus by way of the placenta and are eliminated into breastmilk (nothing is known of the effects of clavulanic acid on the suckled infant). Consequently, diarrhoea and colonisation of the mucosae by yeasts are possible in the suckled infant so that in some cases it may be necessary to wean the infant. The possibility of sensitisation should be taken into account.

4.7 Effects on ability to drive and use machines

Amoxicillin/clavulanic acid has a minor or moderate influence on the ability to drive and use machines. Amoxicillin/clavulanic acid may sometimes be associated with adverse reactions such as mental confusion, rarely dizziness and even less often convulsions that may impair the ability to drive a vehicle, to operate machines and/or to work safely (see section 4.8).

4.8 Undesirable effects

Approximately 5% of patients can be expected to experience adverse reactions. Gastrointestinal disorders with loose stools, nausea and vomiting occur more frequently at higher doses and have been reported more frequently compared to treatment with amoxicillin alone.

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)

Infections and infestations

Uncommon

Prolonged and repeated use of the preparation can result in superinfections and colonisation with resistant organisms or yeasts.

Blood and the lymphatic system disorders

Rare

Thrombocystosis, haemolytic anaemia Very rare

Changes in blood count in form of leucopenia, agranulocytosis, granulocytopenia, thrombocytopenia, pancytopenia, anaemia or myelosuppression and prolongation of the bleeding and prothrombin time have been observed in isolated cases. These manifestations are reversible after discontinuation of therapy.

Immune system disorders Rare

Typical type I allergic reactions (such as urticaria, purpura), angio-oedema and anaphylaxis can occur less frequently.

Erythema multiforme, Lyell syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised erythematous pustulosis, bullous exfoliative dermatitis, serume sickness and vasculitis associated with hypersensitivity rarely occur.

Drug fever.

Psychiatric disorders

Very rare

Hyperactivity, anxiety, sleeplessness, mental confusion and aggression.

Nervous system disorders

Rare

Dizziness, headache and convulsions are rare. Convulsions may occur with impaired renal function or in those receiving high doses.

Gastrointestinal disorders

Common

Gastro-intestinal disturbances such as nausea, vomiting and diarrhoea and pruritis ani have been observed. These side effects are generally of a mild and transitory nature.

Rare

Pseudomembranous colitis, haemorrhagic colitis, mucocutaneous candidiasis, superficial tooth discolouration.

Very rare

Development of a black tongue.

A single study in women with premature rupture of the amnion reported that prophylactic treatment with amoxicillin/clavulanic acid can be associated with an increased risk of necrotising enterocolitis in neonates.

Hepato-biliary disorders

Rare

In rare cases a moderate rise in AST and/or ALT values has been reported. Very rare

Hepatitis and cholestatic jaundice have been reported rarely. Hepatic events occur predominantly in males and elderly patients, particularly those over 60 years of age. The risk of these events occurring increases with treatment for more than 14 days.

These side effects are very rarely reported in children.

Signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until some weeks after treatment has ceased. Hepatic events are usually transient. However they may be severe and in very rare cases a fatal outcome has been reported. These have mostly occurred in patients with a serious underlying disease, or patients taking potentially hepatotoxic agents in addition to amoxicillin/clavulanic acid.

Skin and subcutaneous tissue disorders

Common

Allergic skin reactions occur significantly more often than with other penicillins and generally are maculopapular in nature.

In some cases ‘fifth day rash’ (a morbilliform exanthema) is reported. This is dependent on the size of the dose and the patients condition.

Renal and urinary disorders

Very rare

Interstitial nephritis has occurred on a single occasion. Crystalluria has been reported.

Reproductive system and breast disorders

Uncommon

Vaginal itching and discharge.

4.9 Overdose

a) Symptoms of intoxication

In case of overdosage, gastrointestinal symptoms such as nausea, vomiting and diarrhoea and disturbances of the fluid and electrolyte balance are possible. Also

convulsions may exist. Reduced level of consciousness, muscle fasciculations, myocolonic jerks, coma, maemolytic reactions, renal failure and acidosis are possible. Shock can occur within 20 to 40 minutes in exceptional circumstances.

b) Management of intoxication

There is no specific antidote to an overdose. Treatment consists of haemodialysis and symptomatic measures paying attention to water and electrolyte balance. Administration of medicinal charcoal and gastric lavage are useful only in cases of very high overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties ATC Code: J01CA

Pharmacotherapeutic group: p-lactam antibacterials; combination of penicillin and beta-lactamase inhibitor

Amoxicillin

Amoxicillin is a bactericidal semisynthetic aminobenzyl penicillin (p-hydroxy ampicillin). It inhibits cross-linking of structures of the cell wall by binding to transpeptidases. The resulting instability leads by way of lysis to death of the cell.

Clavulanic Acid

Clavulanic acid is a natural product of Streptomyces clavuligerus and its structure resembles that of the penicillin nucleus. It possesses only slight antibacterial activity itself but it irreversibly inhibits chromosome-coded beta-lactamases of Richmond classes II, IV and VI and plasmid-coded beta-lactamases of Richmond classes III and V.

By concomitant administration of clavulanic acid and amoxicillin the latter is protected from degradation by beta-lactamases. Consequently the combination of amoxicillin and clavulanic acid is active against numerous amoxicillin-resistant bacterial strains.

Breakpoints

The MIC breakpoints (NCCLS 2004) are expressed as the amoxicillin concentration. Bacteria are usually considered susceptible at <4pg/ml and resistant at >8 pg/ml, whilst M.catarrhalis P-lactamase negative are considered susceptible at <0.25 pg/ml and resistant at >0.5 pg/ml and H influenza P-lactamase negative are considered susceptible at <2 pg/ml. Str. pneumoniae are considered susceptible to A/C at MIC <2 pg/ml and resistant at >8 pg/ml.

+ Rates of resistance vary within Europe

Resistance

Organisms that are normally resistant to amoxicillin by non-beta-lactamase-mediated mechanisms (such as impermeability, altered penicillin-binding proteins or drug efflux pumps) or via the manufacture of enzymes that are not inhibited by clavulanic acid would also be resistant to amoxicillin/clavulanate.

5.2 Pharmacokinetic properties

Amoxicillin:

The absolute bioavailability of amoxicillin depends on the dose and ranges between approximately 72 and 94%. Absorption is not affected by intake of food.

Peak plasma concentrations are present about 1 to 2 hours after administration of amoxicillin. The apparent distribution volume ranges between approximately 0.3 and 0.4 l/kg and binding to serum proteins is approximately 17-20%. Amoxicillin diffuses through the placental barrier and a small fraction is excreted into breast milk.

Amoxicillin is largely excreted through the kidneys (52 ± 15% of a dose in unchanged form within 7 hours) and a small fraction is excreted in the bile. Total clearance ranges between approximately 250and 370 ml/min. The serum half-life of amoxicillin in subjects with intact renal function is approximately 1 hour (0.9 - 1.2h), in patients with creatinine clearance ranging between 10 and 30 ml/min it is about 6 hours and in anuria it ranges between 10 and 15 hours.

Clavulanic acid:

The absolute bioavailability of clavulanic acid of approximately 60% differs markedly from individual to individual. Peak concentrations of clavulanic acid are present after approximately 1 to 2 hours. The apparent distribution volume is about 0.2 l/kg and the serum protein binding rate is approximately 22%. Clavulanic acid diffuses through the placental barrier. No exact data are as yet available in regard to excretion into breast milk.

The substance is partly metabolised (approximately 50 - 70%) and about 40% is eliminated through the kidneys (18-38% of the dose in unchanged form).

The total clearance is approximately 260 ml/min. The serum half-life of clavulanic acid in subjects with intact renal function is approximately 1 hour, in patients with creatinine clearance ranging between 20 and 70 ml/min it is approximately 2.6 hours and in anuria it ranges between 3 and 4 hours.

Pharmacologically relevant pharmacokinetic interactions between amoxicillin and clavulanic acid have not been observed so far.

Both amoxicillin and clavulanic acid are haemodialysable.

5.3 Preclinical safety data

a)    Acute toxicity

The LD₅₀ of clavulanic acid (potassium salt) is determined by the potassium content. Administration of clavulanic acid (potassium salt) together with amoxicillin does not result in any unexpected or synergistic toxicity.

b)    Chronic toxicity/subchronic toxicity

The animal species used in chronic toxicity studies were rats and dogs.

Solely after high doses (corresponding to 20- to 50-fold the maximal human dose) were mild haematological and blood-chemical changes observed, which regressed completely following discontinuation of therapy.

c)    Mutagenic and tumorigenic potential

In-vitro and in-vivo studies did not reveal any signs of any mutagenic effects of the combination of amoxicillin and clavulanic acid.

d)    Reproduction toxicity

Reproduction toxicity studies in rats did not show any adverse effects of the combination on fertility and no teratogenic effects were evident. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, strength of contractions and duration of contractions. The relevance of these findings in humans is unknown.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Xanthan gum (E415) Aspartame (E951)

Silicon dioxide (E551) Colloidal silica Anhydrous citric acid Hypromellose

Flavour Orange Dry Powder Flavour Raspberry Dry Powder Flavour Golden Dry Powder

6.2 Incompatibilities

None known.

6.3 Shelf life

Dry powder: 2 years.

Reconstituted suspensions: 7 days when stored in a refrigerator (2-8°C).

6.4 Special precautions for storage

Powder for suspension: Do not store above 25°C. Keep the bottle tightly closed.

Reconstituted suspension: Store at 2-8°C. Do not freeze.

6.5 Nature and contents of container

107ml glass, round shaped bottle containing an off-white dry powder. The bottle is fitted with a polypropylene child resistant cap and packed in cartons with a 20ml measuring cup with 2.5ml graduations

Or

107ml glass, round shaped bottle containing an off-white dry powder. The bottle is fitted with bromobutyl plug and polypropylene tamper evident cap with pilfer proof ring and packed in cartons with a 20ml measuring cup with 2.5ml graduations

6.6 Special precautions for disposal

At time of dispensing, 58ml of water is added to the dry powder to form 70ml of oral suspension.

The Pharmacist should shake the suspension for 2 minutes and should then check for any particulates.

When reconstituted, an off-white suspension is formed

7. Marketing Authorisation Holder

Medreich Plc Warwick House Plane Tree Crescent Feltham TW13 7HF

8    MARKETING AUTHORISATION NUMBER(S)

PL 21880/0011

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/06/2009

10    DATE OF REVISION OF THE TEXT

25/06/2013