Augmentin®-Duo 400/57.

Augmentin-Duo 400/57 contains 400 mg amoxicillin and 57 mg clavulanic acid per 5ml (co-amoxiclav 400/57).

The amoxicillin is present as amoxicillin trihydrate and the clavulanic acid is present as potassium clavulanate.

Dry powder for reconstitution in water, at time of dispensing, to form an oral sugar-free suspension.

Augmentin-Duo 400/57 is an antibiotic agent with a notably broad spectrum of activity against the commonly occurring bacterial pathogens in general practice and hospital. The β-lactamase inhibitory action of clavulanate extends the spectrum of amoxicillin to embrace a wider range of organisms, including many resistant to other β-lactam antibiotics.

Augmentin-Duo 400/57, for twice-daily (b.i.d) oral dosing, is indicated for short-term treatment of bacterial infections at the following sites when amoxicillin resistant βlactamase-producing strains are suspected as the cause. In other situations, amoxicillin alone should be considered.

- Upper Respiratory Tract Infections (including ENT) in particular sinusitis, otitis media, recurrent tonsillitis. These infections are often caused by Streptococcus pneumoniae, Haemophilus influenzae*, Moraxella catarrhalis* and Streptococcus pyogenes.

- Lower Respiratory Tract Infections in particular acute exacerbations of chronic bronchitis (especially if considered severe), bronchopneumonia. These infections are often caused by Streptococcus pneumoniae, Haemophilus influenzae* and Moraxella catarrhalis*.

- Urinary Tract Infections in particular cystitis (especially when recurrent or complicated - excluding prostatitis). These infections are often caused by Enterobacteriaceae* (mainly Escherichia coli*), Staphylococcus saprophyticus, Enterococcus species.*

- Skin and Soft Tissue Infections in particular cellulitis, animal bites and severe dental abscess with spreading cellulitis. These infections are often caused by Staphylococcus aureus*, Streptococcus pyogenes and Bacteroides species*.

- A comprehensive list of sensitive organisms is provided in Section 5.

* Some members of these species of bacteria produce β-lactamase, rendering them insensitive to amoxicillin alone.

Mixed infections caused by amoxicillin-susceptible organisms in conjunction with Augmentin-Duo 400/57-susceptible β-lactamase-producing organisms may be treated with Augmentin-Duo 400/57. These infections should not require the addition of another antibiotic resistant to β-lactamases.

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

Children aged 2 months to 2 years

Children under 2 years should be dosed according to body weight

* The 35 ml presentation is supplied with a syringe dosing device - See Sections 6.5 and 6.6

There is insufficient experience with Augmentin-Duo' to make dosage recommendations for children under 2 months old.

Infants with immature kidney function

For children with immature renal function Augmentin-Duo 400/57 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 Augmentin-Duo 400/57 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.

Penicillin hypersensitivity.

Attention should be paid to possible cross-sensitivity with other β-lactam antibiotics, e.g. cephalosporins.

A previous history of co-amoxiclav- or penicillin-associated jaundice/hepatic dysfunction.

Changes in liver function tests have been observed in some patients receiving co-amoxiclav. The clinical significance of these changes is uncertain but co-amoxiclav should be used with caution in patients with evidence of hepatic dysfunction.

Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for several weeks after treatment has ceased.

In patients with renal impairment, dosage should be adjusted according to the degree of impairment (see Section 4.2).In patients with moderate or severe renal impairment Augmentin-Duo 400/57 is not recommended.

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).

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity (see Section 4.3).

Erythematous rashes have been associated with glandular fever in patients receiving amoxicillin.

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

Augmentin-Duo 400/57 contains 16.64 mg aspartame per 5 ml dose and therefore care should be taken in phenylketonuria.

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with co-amoxiclav may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.

Prolongation of bleeding time and prothrombin time have been reported in some patients receiving co-amoxiclav. Co-amoxiclav should be used with care in patients on anti-coagulation therapy.

In common with other antibiotics, co-amoxiclav may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. See local/national guidelines or BNF for specific advice.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of co-amoxiclav and allopurinol.

Penicillins reduce the excretion of methotrexate (potential increase in toxicity).

Use in pregnancy

Reproduction studies in animals (mice and rats) with orally and parenterally administered co-amoxiclav have shown no teratogenic effects In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with Augmentin 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 lactation

Co-amoxiclav may be administered during the period of lactation. With the exception of the risk of sensitisation, associated with the excretion of trace quantities in breast milk, there are no known detrimental effects for the breast-fed infant.

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

The following convention has been utilised for the classification of undesirable effects: -

Very common >1/10), common >1/100, <1/10), uncommon >1/1000, <1/100), rare >1/10,000, <1/1000), very rare (<1/10,000)

The majority of side effects listed below are not unique to co-amoxiclav and may occur when using other penicillins.

Infections and infestations

Common: Mucocutaneous candidiasis

Blood and lymphatic system disorders

Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia

Very rare: Reversible agranulocytosis and haemolytic anaemia.

Prolongation of bleeding time and prothrombin time (see section 4.5)

Immune system disorders

Very rare: As with other antibiotics, severe allergic reactions, including angioneurotic oedema, anaphylaxis, serum sickness-like syndrome and hypersensitivity vasculitis.

If hypersensitivity reaction is reported, the treatment must be discontinued.

Nervous system disorders

Uncommon: Dizziness, headache

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

Gastrointestinal disorders

Adults

Very Common: Diarrhoea

Common: Nausea, vomiting

Children

Common: Diarrhoea, nausea, vomiting

All populations

Nausea is more often associated with higher oral dosages. If gastrointestinal side effects are evident, they may be reduce by taking co-amoxiclav at the start of a meal

Uncommon: Indigestion

Very rare: Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis)

Black hairy tongue

Superficial tooth discolouration has been reported in children. Good oral hygiene may help prevent tooth discolouration as it can usually be removed by brushing

Hepato-biliary disorders

Uncommon: Moderate rise in AST and/or ALT, the significance is unknown.

Very rare: Hepatitis and cholestatic jaundice

Hepatic events have been reported predominately in males and elderly patients and may be associated with prolonged treatment.

These events have been rarely reported in children.

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.

Skin and subcutaneous tissue disorders

Uncommon: Skin rash, pruritus, urticaria

Rare: Erythema multiforme

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, Bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (AGEP)

If any hypersensitivity dermatitis reaction is reported, the treatment must be discontinued.

Renal and urinary disorders

Very rare: Interstitial nephritis, Crystalluria (see Section 4.4 and 4.9)

Overdosage

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. Co-amoxiclav may be removed from the circulation by haemodialysis.

Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4 Special warnings and special precautions for use)

Drug abuse and dependence

Drug dependency, addiction and recreational abuse have not been reported as a problem with this compound.

Augmentin-Duo400/57 contains a combination of amoxicillin and clavulanic acid, co-amoxiclav 400/57.

Microbiology

Amoxicillin is a semi-synthetic antibiotic with a broad spectrum of antibacterial activity against many Gram-positive and Gram-negative micro-organisms. Amoxicillin is, however, susceptible to degradation by β-lactamases and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in micro-organisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance. It is generally less effective against chromosomally-mediated type 1 β-lactamases.

The presence of clavulanic acid in Augmentin-Duo 400/57 protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other penicillins and cephalosporins. Thus Augmentin-Duo 400/57 possesses the distinctive properties of a broad spectrum antibiotic and a β-lactamase inhibitor. Augmentin-Duo 400/57 is bactericidal to a wide range of organisms including:

Gram-positive

Aerobes: Enterococcus faecalis*, Enterococcus faecium*, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Staphylococcus aureus*, Coagulase negative staphylococci* (including Staphylococcus epidermidis*), Corynebacterium species, Bacillus anthracis*, Listeria monocytogenes.

Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus.

Gram-negative

Aerobes: Haemophilus influenzae*, Moraxella catarrhalis* (Branhamella catarrhalis), Escherichia coli*, Proteus mirabilis*, Proteus vulgaris*, Klebsiella species*, Salmonella species*, Shigella species*, Bordetella pertussis, Brucella species, Neisseria gonorrhoeae*, Neisseria meningitidis*, Vibrio cholerae, Pasteurella multocida.

Anaerobes: Bacteroides species* including B. fragilis.

* Some members of these species of bacteria produce β-lactamase, rendering them insensitive to amoxicillin alone.

a. Absorption:

The two components of Augmentin-Duo 400/57, amoxicillin and clavulanic acid, are each fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of co-amoxiclav is optimised when taken at the start of a meal.

b. Pharmacokinetics

Pharmacokinetic studies have been performed in children, including one study [25000/382] which has compared co-amoxiclav t.i.d and b.i.d. All of these data indicate that the elimination pharmacokinetics seen in adults also apply to children with mature kidney function.

The mean AUC values for amoxicillin are essentially the same following twice-a-day dosing with the 875/125 mg tablet or three-times-a-day dosing with the 500/125 mg tablet, in adults. No differences between the 875 mg bid and 500mg t.i.d dosing regimes are seen when comparing the amoxicillin T_½, or C_max after normalisation for the different doses of amoxicillin administered. Similarly, no differences are seen for the clavulanate T_½, C_max or AUC values after appropriate dose normalisation [Study 360].

The time of dosing of co-amoxiclav relative to the start of a meal has no marked effects on the pharmacokinetics of amoxicillin in adults. In a study of the 875/125 mg tablet [Study 362], the time of dosing relative to ingestion of a meal had a marked effect on the pharmacokinetics of clavulanate. For clavulanate AUC and C_max, the highest mean values and smallest inter-subject variabilities were achieved by administering co-amoxiclav at the start of a meal, compared to the fasting state or 30 or 150 minutes after the start of a meal.

The mean C_max, T_max, T_½ and AUC values for amoxicillin and clavulanic acid are given below for an 875 mg/125 mg dose of co-amoxiclav administered at the start of a meal [Study 362].

Mean Pharmacokinetic Parameters

* Median values

Amoxicillin serum concentrations achieved with co-amoxiclav are similar to those produced by the oral administration of equivalent doses of amoxicillin alone.

c. Distribution:

Following intravenous administration therapeutic concentrations of both amoxicillin and clavulanic acid may be detected in the tissues and interstitial fluid. Therapeutic concentrations of both drugs have been found in gall bladder, abdominal tissue, skin, fat, and muscle tissues; fluids found to have therapeutic levels include synovial and peritoneal fluids, bile and pus.

Neither amoxicillin nor clavulanic acid is highly protein bound, studies show that about 25% for clavulanic acid and 18% for amoxicillin of total plasma drug content is bound to protein. From animal studies there is no evidence to suggest that either component accumulates in any organ.

Amoxicillin, like most penicillins, can be detected in breast milk. There are no data available on the passage of clavulanic acid into breast milk.

Reproduction studies in animals have shown that both amoxicillin and clavulanic acid penetrate the placental barrier. However, no evidence of impaired fertility or harm to the foetus was detected.

d. Elimination:

As with other penicillins, the major route of elimination for amoxicillin is via the kidney, whereas for clavulanate elimination is by both non-renal and renal mechanisms. Approximately 60-70% of the amoxicillin and approximately 40-65% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 375 or 625 mg tablet.

Amoxicillin is also partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to 10-25% of the initial dose. Clavulanic acid is extensively metabolised in man to 2,5-dihydro-4-(2- hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy- butan-2-one and eliminated in urine and faeces and as carbon dioxide in expired air.

No further information of relevance.

Xantham gum, aspartame, colloidal silica, silicon dioxide, crospovidone, carmellose sodium, magnesium stearate, sodium benzoate, strawberry flavour.

None known.

Glass Bottles

Dry powder: 24 months when stored at temperatures at or below 25°C.

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

Sachets

18 months when stored at temperatures at or below 25°C.

The dry powder should be stored in well-sealed containers in a dry place.

Clear, glass bottles containing an off-white dry powder. The 35 ml presentation is supplied in a carton with a polystyrene syringe dosing device.

or

Single-dose sachets. Four sachets are supplied in a carton.

When reconstituted, an off-white suspension is formed

Glass bottles:

At time of dispensing, the dry powder should be reconstituted to form an oral suspension, as detailed below:

The 35 ml presentation is provided with a syringe dosing device which should be used in place of the cap following reconstitution. This device is used to dose patients under 2 years according to the schedule in Section 4.2.

Sachets:

Single-dose sachets contain powder for a 2.5 ml dose.

Directions for use: Check that the sachet is intact before use

1. Cut sachet along dotted line

2. Empty contents into a glass

3. Half fill sachet with water

4. Pour into the glass, stir well and drink immediately

If two or four sachets have to be taken at once then they can be mixed in the same glass.

SmithKline Beecham plc

980 Great West Road

Brentford

Middlesex TW8 9GS

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex, UB11 1BT

PL 10592/0070

2 January 2002

9 July 2007

POM