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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-amoxiclav 875 mg/125 mg Film- coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains 1006.25 mg amoxicillin trihydrate equivalent to 875 mg amoxicillin and potassium clavulanate equivalent to 125 mg - clavulanic acid.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film coated tablet.

White to off white oval shaped film coated tablet with brakline on both side.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide in to equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Amoxicillin-clavulanate is indicated for the treatment of the following bacterial infections when amoxicillin resistant P-lactamase-producing strains are suspected as the cause (see section 5.1). In other situations, amoxicillin alone should be considered:

•    Upper respiratory tract infections (including ENT): recurrent tonsillitis, acute sinusitis, acute otitis media;

•    Lower respiratory tract infections: acute bacterial exacerbations of chronic bronchitis, community-acquired pneumonia;

•    Urinary tract infections: cystitis (especially when recurrent or complicated -excluding prostatitis), pyelonephritis;

•    Skin and soft tissue infections: cellulitis, animal bites and severe dental abscess with spreading cellulitis;

•    Other infections: septic abortion, puerperal sepsis, intra-abdominal sepsis.

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

4.2 Posology and method of administration

Route of administration: oral use

Co-amoxiclav is not recommended for use in children below 12 years of age due to a lack of data on safety and or efficacy.

Dosage depends on the age, weight and renal function of the patient and the severity of the infection. Dosages are expressed throughout in terms of amoxicillin-/clavulanate content except when doses are stated in terms of an individual component.

To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of amoxicillin-clavulanate is optimised when taken at the start of a meal.

Treatment should not be extended beyond 14 days without review. Therapy can be started parenterally and continued with an oral preparation

Usual dosages for the treatment of infection: Adults and children over 12 years of age only

More suitable paediatric formulations of amoxicillin-clavulanate are available for the treatment in children.

Elderly

No adjustment needed; dose as for adults. If there is evidence of renal impairment, dose should be adjusted as for renally impaired adults.

Renal impairment

No dose adjustment is needed when creatinine clearance is >30 ml/min. In patients with renal impairment (creatinine clearance <30 ml/min) and on haemodialysis, the 875 mg /125 mg tablets should not be used. Dose adjustment is needed in these patients and more suitable formulations are available.

Hepatic impairment

Dose with caution; monitor hepatic function at regular intervals.

There are insufficient data on which to base a dosage recommendation.

4.3 Contraindications

Amoxicillin-clavulanate is contraindicated:

•    in patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and cephalosporins and to any of the excipients.

•    in patients with a previous history of amoxicillin-clavulanate-associated jaundice/hepatic dysfunction.

4.4 Special warnings and precautions for use

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

Before initiating therapy with amoxicillin-clavulanate, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

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

Change 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 Dosage and Administration- Renal impairment).

Co-amoxiclav 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.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.

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 Overdosage).

Each Co-amoxiclav 875/125 mg Film- coated Tablets contains 25 mg (i.e. 0.64 mmol) of potassium.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use with amoxicillin-clavulanate 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 should be used with care in patients on anticoagulation therapy.

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 amoxicillin-clavulanate and allopurinol.

In common with other antibiotics, amoxicillin-clavulanate may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

4.6 Pregnancy and lactation

This product should only be used in pregnancy or lactation if considered essential by the physician.

Reproduction studies in animals (mice and rats at doses up to 10 times the human dose) with orally and parenterally administered amoxicillin-clavulanate 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 amoxicillin-clavulanatemay be associated with an increased risk of necrotising enterocolitis in neonates.

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

4.7 Effects on ability to drive and use machines

Co-amoxiclav has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Data from large clinical trials was used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e., those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. The following convention has been used for the classification of frequency: very common > 1/10 common > 1/100 and <1/10 uncommon > 1/1000 and <1/100 rare > 1/10,000 and <1/1000 very rare <1/10,000.

Not known (cannot be estimated from the available data).

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 4.4)

Immune system disorders

Very rare: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis

Nervous system disorders

Uncommon: Dizziness, headache

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

Gastrointestinal disorders

Very common: Diarrhoea Common: Nausea, vomiting Uncommon: Indigestion

Very rare: Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis), black hairy tongue.

Hepatobiliary disorders

Uncommon: A moderate rise in AST and/or ALT and alkaline phosphatases has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown.

Very rare: Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins.

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

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 occurs, treatment should be discontinued.

Renal and urinary disorders

Very rare: Interstitial nephritis, crystalluria (see section 4.9)

4.9 Overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. GI symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Co-amoxiclav can 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).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: P-lactam antibacterials, combination of penicillin and beta-lactamase inhibitor ATC code: JOICR02

Mode of action

Amoxicillin is a semisynthetic penicillinthat 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 that is usually followed by cell lysis and bacterial death.

Clavulanic acid is a beta-lactam agent structurally related to penicillins that can inactivate certain (but not all) beta-lactamase enzymes manufactured by bacteria and so can prevent enzymic degradation of amoxicillin.

Pharmacokinetic/Pharmacodynamic Relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for beta-lactam agents..

Mechanisms of resistance

There are two main mechanisms of resistance to beta-lactam antibiotics, i.e. target (PBP) alteration and inactivation by beta-lactamases. Less often impermeability or efflux pump mechanisms may cause or contribute to bacterial resistance.

Breakpoints

MIC breakpoints for co-amoxilcav shown below are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) except for Staphylococci, for which there are no EUCAST MIC breakpoints and therefore those recommended by the Clinical and Laboratory Standards Institute (CLSI; 2008) are given.

Organism    Susceptibility Breakpoints (pg/ml)¹

	Susceptible	Intermediate1 2	Resistant
Streptococcus 3 pneumomae	< 0.5	1-2	> 2
Haemophilus influenzae	< 1	-	> 1
Staphylococcus 4 spp.	< 4	-	> 8
Enterobacteriaceae5	-	-	> 8

³    Breakpoint values in the table are based on ampicillin breakpoints.

⁴    CLSI breakpoints (no intermediate value is specified). Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

⁵    The resistant breakpoint of R>8 mg/L ensures that all isolates with resistance mechanisms are reported resistant.

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.

Co-amoxiclav is bactericidal to a wide range of organisms including:

Gram-positive aerobes:

Bacillus anthracis*

Corynebacterium species Enterococcus faecalis*

Enterococcus faecium*

Listeria monocytogenes Nocardia asteroides Staphylococcus aureus#

Coagulase negative staphylococci* (including Staphylococcus epidermidis#)

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Streptococcus species

Streptococcus viridans

Gram-negative aerobes:

Bordetella pertussis Brucella species Escherichia coli^*

Gardnerella vaginalis

Haemophilus influenzae*Helicobacter pylori Klebsiella species*

Legionella species

Moraxella catarrhalis# (Branhamella catarrhalis) Neisseria gonorrhoeae#

Neisseria meningitidis#

Pasteurella multocida Proteus mirabilis#

Proteus vulgaris#

Salmonella species#

Shigella species#

Vibrio cholerae Yersinia enterocolitica^#

Gram-positive anaerobes:

Clostridium species Peptococcus species Peptostreptococcus species

Gram-negative anaerobes:

Bacteroides species# (including Bacteroides fragilis) Fusobacterium species^#

Others:

Borrelia burgdorferi Chlamydiae

Leptospira icterohaemorrhagiae Treponema pallidum

Gram-negative aerobes:

Pseudomonas sp.

Stenotrophomonas multophilia Acinetobacter spp.

Serratia spp.

^# Some members of these species of bacteria produce beta-lactamase and are therefore insensitive to amoxicillin alone.

5.2 Pharmacokinetic properties

Absorption

The two components, of amoxicillin-clavulanate, 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. Absorption of amoxicillin-clavulanate is optimised when taken at the start of a meal.

Distribution

Following i.v. 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.

Co-amoxiclav, like most penicillins, can be detected in breast milk. Trace quantities of clavulanate can also be detected in breast milk. With the exception of the risk of sensitisation associated with this excretion, there are no known detrimental effects for the breast-fed infant.

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.

Metabolism

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized 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 as carbon dioxide in expired air.

Elimination

As with other penicillins, the major route of elimination for amoxicillin is via the kidney, whereas for clavulanate it is by both renal and non-renal mechanisms. 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 a single 250/125 mg or a single 500/125 mg tablet.

Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see Interactions).

5.3 Preclinical safety data

Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity and toxicity to reproduction. Carcinogenicity studies have not been conducted with Augmentin or its components. However, potassium clavulanate alone or combined 1:2 or 1:4 with amoxicillin has been tested in a comprehensive battery of in vitro and in vivo genotoxicity tests which showed no significant genotoxic hazard.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core tablet-

Microcrystalline Cellulose (AVICEL Ph 102)

Croscarmellose sodium

Purified Talc

Magnesium Stearate

Coating -

Hypromellose (E-15)

Ethylcellulose Propylene Glycol

Hydroxy propyl cellulose Titanium dioxide

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

2 years

6.4    Special precautions for storage

Do not store above 25^oC.

6.5 Nature and contents of container

The tablets are available in blisters and are sealed in aluminium pouches. 7, 10, 12, 14, 20, 21 & 24 film-coated tablets in PVC/Al blister packs. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Bluefish Pharmaceuticals AB Torsgatan 11, 111 23 Stockholm Sweden

8    MARKETING AUTHORISATION NUMBER(S)

PL 31774/0003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/09/2009

10    DATE OF REVISION OF THE TEXT

08/04/2014

1

The reported values are for Amoxicillin concentrations. For susceptibility testing

2

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