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1. Co-Amoxiclav 250/62 Oral Suspension Sugar-Free
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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-amoxiclav 250/62 Oral Suspension Sugar-Free

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

When prepared as directed, each 5ml of the constituted suspension contains amoxicillin trihydrate equivalent to amoxicillin 250mg and potassium clavulanate equivalent to 62.5mg clavulanic acid.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Powder for Oral Suspension.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Uses

Co-amoxiclav oral preparations are indicated for short-term treatment of bacterial infections at the following sites when amoxicillin-resistant B-lactamase-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*.

Genito-urinary Tract and Abdominal Infections in particular cystitis (especially when recurrent or complicated -excluding prostatitis), septic abortion, pelvic or puerperal sepsis and intra-abdominal sepsis. 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 Pharmacological properties section.

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

Mixed infections caused by amoxicillin-susceptible organisms in conjunction with co-amoxiclav -susceptible B-lactamase-producing organisms may be treated with co-amoxiclav. These infections should not require the addition of another antibiotic resistant to B-lactamases.

4.2 Posology and method of administration

Usual dosages for the treatment of infection

Adults and Children over 12 years of age: This formulation is not applicable to this age group.

Children under12 years of age: The usual recommended daily dosage is 25 mg/kg/day* in divided doses every eight hours. The table below presents guidance for children.

Co-amoxiclav Suspension

Under 1 year	25 mg/kg/day*, for example a 7.5 kg child would require 2 ml co-amoxiclav 125/31 Oral Suspension Sugar-Free t.d.s.
1-6 years (10-18 kg)	5 ml co-amoxiclav 125/31 Oral Suspension Sugar-Free t.d.s.
Over 6 years (18-40 kg)	5 ml co-amoxiclav 250/62 Oral Suspension Sugar-Free t.d.s.

In more serious infections the dosage may be increased up to 50 mg/kg/day in divided doses every eight hours.

*Each 25 mg co-amoxiclav provides amoxicillin 20 mg and clavulanic acid 5 mg.

Dosage in renal impairment Children:

Mild impairment (creatinine clearance >30 ml/min): no change in dosage. Moderate to severe impairment (creatinine clearance <30 ml/min): A reduction in dosage, and/or dose frequency (to 12 hourly) should be made in proportion to the recommendation for adults.

Dosage in hepatic impairment: Dose with caution; monitor hepatic function at regular intervals.

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

4.3 Contraindications

Co-amoxiclav is contraindicated in patients with a previous history of hypersensitivity to amoxicillin, clavulanic acid or any of the excipients.

Co-amoxiclav suspension must not be administered to patients with verified hypersensitivity to P-lactams (eg; penicillins, cephalosporins) owing to the danger of anaphylactic shock. Consequently, a careful history should be taken in regard to any allergic reactions (eg; following previous administration of penicillins or cephalosporins) before commencing treatment.

Co-amoxiclav suspension must not be used in patients with high-grade hepatic functional impairment and in patients in whom hepatic functional impairment has occurred during previous treatment with Co-amoxiclav, for example cholestatic jaundice induced by Co-amoxiclav or penicillin.

Patients with infectious mononucleosis (glandular fever) and patients with lymphatic leukaemia have a higher risk of exanthema and consequently Co-amoxiclav suspension should not be administered in these diseases for concomitantly occurring bacterial infections.

4.4 Special warnings and precautions for use

Therapy should only be used with caution in patients with pre-existing hepatic impairment and with care in patients with renal dysfunction. The functional state of the liver and kidney should be established in such patients and monitored regularly. Discontinuation of therapy should be considered if these parameters worsen during treatment.

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. Liver function parameters should be checked at regular intervals in patients with signs of hepatic lesions and discontinuation of therapy should be considered if these parameters exacerbate during treatment.

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.

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 4.3). Erythematous rashes have been associated with glandular fever in patients receiving amoxycillin. Careful screening is recommended for P-lactam allergy (hypersensitivity reactions).

Therapy should not be administered to patients with suspected infectious mononucleosis (glandular fever) since they are at a higher risk of morbiliform rash due to amoxicillin.

Patients with severe gastrointestinal disturbances with vomiting and/or diarrhoea should not be treated with Co-amoxiclav suspension since adequate absorption cannot be guaranteed. Parenteral therapy is recommended in such cases.

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

Regular checks on haematological studies are indicated during long-term treatment.

With long-term use and/or in immunocompromised patients - the same as with the other broad-spectrum antibiotics - superinfections with resistant bacteria or yeasts are possible.

The following undesirable effects, which are extremely rare can in certain cases be acutely life-threatening. Consequently the physician should be consulted without delay if such side effects occur or are unexpectedly severe. Pseudomembranous colitis: in such cases the physician must consider discontinuing therapy with Co-amoxiclav depending on the indication and, if necessary, initiate suitable treatment at once (e.g. oral vancomycin, 250 mg q.i.d. daily in adults). Antiperistaltics are contraindicated. Severe acute hypersensitivity reactions: in such cases treatment with Co-amoxiclav must be discontinued at once and the usual corresponding emergency measures must be taken (e.g. adrenalin (epinephrine) 1/1000 (0.3-0.5 ml SC or IM in adults and 0.01 ml/kg SC or IM in children) is the first choice), antihistaminics, corticosteroids, sympathomimetics and, if necessary, artificial respiration).

Since amoxicillin at room temperature in high urinary concentrations can precipitate in the bladder catheter the patency of such a catheter should be checked at regular intervals.

Occurrence of (epileptiform) convulsions: the usual corresponding emergency measures are indicated (e.g. keep air-passages patent, anticonvulsants such as diazepam or barbiturates).

Cross allergy with cephalosporin is frequent (10-15%).

Co-amoxiclav 250/62 Oral Suspension Sugar-Free contains 6.7 mg aspartame per 5 ml dose and therefore care should be taken in phenylketonuria.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants

Prolongation of bleeding time and prothrombin time have been reported in some patients receiving Co-amoxiclav. A tendency to bleed can be potentiated due to concomitant administration of co-amoxiclav and anticoagulants of the coumarin class (e.g. dihydrocoumarol). Interaction of co-amoxiclav with indanedione-derivative anticoagulants, heparin, nonsteroidal anti-inflammatory drugs (NSAIDs) especially aspirin, other platelet aggregation inhibitors, or thrombolytic agents may be clinically significant. Co-amoxiclav should be used with care in patients on anti-coagulant therapy.

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.

Disulfiram

Co-amoxiclav should not be used concomitantly with disulfiram.

Methotrexate

The excretion of methotrexate is reduced with a resultant increased risk of toxicity.

Hormonal contraceptives

Co-amoxiclav may reduce the efficacy of hormonal contraceptives. Additional non-hormonal contraceptive precautions may need to be taken during and up to 7 days after taking co-amoxiclav.

Allopurinol

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.

Other antibiotics

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

Sulfasalazine

Aminopenicillins may reduce the serum levels of sulfasalazine.

Digoxin

An increase in absorption of digoxin is possible on concurrent administration with co-amoxiclav.

Other forms of interaction

Co-amoxiclav has been reported to influence results of diagnostic laboratory tests. Nonenzymatic methods for determining urinary sugar can yield falsely positive results. Likewise the urobilinogen test can be affected.

The occurrence of diarrhoea may impair the absorption of other medicaments and consequently adversely affect their efficacy.

Forced diuresis leads to a reduction in serum concentrations owing to increased elimination of amoxicillin.

4.6 Fertility, pregnancy and lactation

Animal studies with orally and parenterally administered co-amoxiclav have shown no teratogenic effects. There is limited experience of the use of co-amoxiclav in human pregnancy. Use of co-amoxiclav suspension in pregnancy, especially during the first trimester, is not recommended unless considered essential by the physician.

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 children.

4.7 Effects on ability to drive and use machines

Co-amoxiclav 250/125 mg tablets have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Undesirable effects are mainly of a mild and transitory nature.

The most commonly reported adverse drug reactions are hypersensitivity reactions.

Hypersensitivity reactions:

Common(> 1%-< 10%):

Cutaneous reactions e.g., exanthema, pruritus, urticaria; the typical morbilliform exanthema occurs 5-11 days after start of therapy. The immediate appearance of urticaria indicates an allergic reaction to amoxicillin and the therapy should be discontinued.

Rare (>0.01%-<0.1%) (See 4.4):

Angioneurotic oedema (Quincke’s oedema), erythema multiforme exudatum, Stevens-Johnson syndrome, eosinophilia, drug fever, laryngeal oedema, Serum Sickness, haemolytic anaemia, allergic vasculitis, interstitial nephritis, anaphylactic shock.

Haematological effects:

Rare reports of leucopenia, granulocytopenia, thrombocytopenia, pancytopenia, anaemia (may be haemolytic), myelosuppression, agranulocytosis, prolongation of bleeding time and prolongation of prothrombin time.

Gastrointestinal reactions:

Common (>1%-<10%):

Gastric complaints, nausea, loss of appetite, indigestion, vomiting, flatulence, soft stools, diarrhoea, enanthemas (particularly in the mouth), dry mouth, taste disturbances. These effects on the gastrointestinal tract are mostly mild and frequently disappear during treatment or after completion of therapy.

If severe or persistent diarrhoea occurs, the very rare possibility of pseudomembranous colitis should be considered.

As with other antibiotics, children under two years may show a higher incidence of gastrointestinal side effects.

Superficial tooth discolouration may occur rarely; it can usually be removed by brushing.

Very Rare (>0.001%-<0.01%):

Development of black tongue.

Hepatic effects:

Uncommon (>0.1%-<1%):

Moderate and transient increase of liver enzymes, rare reports of hepatitis and cholestatic jaundice. Signs and symptoms usually occur during and shortly after treatment but may be delayed until several weeks after therapy.

Hepatic reactions are usually reversible but may be severe and very rarely fatal. Hepatic effects have been reported more commonly in males and in elderly patients but very rarely in children. The risk also increases when therapy is prolonged beyond 14 days.

Renal effects:

Rare (>0.01%-<0.1%):

Acute interstitial nephritis may occur in rare cases.

Disturbances of the central nervous system:

CNS effects have been seen rarely. They include hyperkinesias, dizziness, headache and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Genito-urinary effects:

Vaginal itching, soreness and discharge may occur.

Other side effects:

Prolonged and repeated use of the preparation can result in superinfections and colonisation with resistant organisms or yeasts such as oral or vaginal candidiasis.

The following undesirable effects, which are extremely rare (for detailed information on these side effects see above), can in certain cases be acutely life-threatening. Consequently the physician should be consulted without delay if such side effects occur unawares or are unexpectedly severe.

Pseudomembranous colitis:

In such cases the physician must consider discontinuing therapy with Co-amoxiclav depending on the indication and, if necessary, initiate suitable treatment at once (eg: oral vancomycin 250 mg qid. daily in adults). Antiperistaltics are contraindicated.

Severe acute hypersensitivity reactions (e.g. anaphylaxis):

In such cases treatment with Co-amoxiclav must be discontinued at once and the usual corresponding emergency measures must be taken (e.g. adrenalin epinephrine) 1/1000 (0.3-0.5 ml SC or IM in adults and 0.01 ml/kg SC or IM in children) is the first choice), antihistaminics, corticosteroids, sympathomimetics and, if necessary, artificial respiration).

Occurrence of (epileptiform) convulsions:

The usual corresponding emergency measures are indicated (e.g. keep air-passages patent, anticonvulsants such as diazepam or barbiturates).

4.9 Overdose

Symptoms of overdosage:

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

Management of overdosage:

There is no specific antidote for overdose. Treatment consists of haemodialysis and symptomatic measures paying particular attention to the water and electrolyte balance, especially if there are any gastro-intestinal symptoms. Administration of medicinal charcoal and gastric lavage are useful only in cases of very high overdose (> 250 mg/kg). In case of severe renal insufficiency, Co-amoxiclav can be eliminated from the circulation via haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: J01C R Mechanism of Action

Amoxicillin acts through inhibition of biosynthesis of the bacterial cell wall mucopeptide. It is bactericidal against many Gram-positive and Gramnegative organisms during the stage of active multiplication. However, it is susceptible to degradation by beta-lactamases and therefore its spectrum does not include lactamase producing bacteria. Clavulanic acid is a beta-lactam structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta-lactamases commonly found in bacteria resistant to beta-lactam antibiotics.

The formulation of amoxicillin with clavulanic acid protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin.

Break points

The British Society for Antimicrobial Chemotherapy (BSAC) recommended breakpoints for amoxicillin/clavulanic acid (expressed as the concentration of amoxicillin) are: susceptible (S) < 8, resistant (R) > 16 mg/l. However, for organisms causing urinary tract infection the general breakpoints are S < 32, R >64 mg/l.

For Haemophilus influenzae and Moraxella catarrhalis, S < 1, R > 2 mg/l.

Antibacterial Spectrum

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

Aerobes: Enterococcus faecalis*, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Staphylococcus aureus*

Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus.

Gram-negative

Aerobes: Escherichia coli*, Haemophilus influenzae*, Klebsiella species*, Moraxella catarrhalis*, Neisseria gonorrhoeae*, Proteus mirabilis*, Proteus vulgaris* and Pasteurella multocida.

Anaerobes: Bacteroides species* including B. fragilis.

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

5.2 Pharmacokinetic properties

The pharmacokinetics of the two components of Co-amoxiclav are closely matched.

Amoxicillin and clavulanate are both well absorbed after oral administration and are stable in the presence of gastric acid. Food does not affect the absorption and this combination product may be given without regard to meals. The oral bioavailability of amoxicillin and potassium clavulanate is approximately 90% and 75% respectively.

Peak serum levels of both occur about 1 hour after oral administration. Both clavulanate and amoxicillin have low levels of serum binding; about 70% remains free in the serum.

Amoxicillin is bound to serum proteins to an extent of 17-20% while clavulanic acid is 20-30% bound to serum proteins. Approximately 10% of the dose of amoxicillin and less than 50% of dose of clavulanate are metabolised.

Clavulanic acid has about the same plasma elimination half-life (1hr) as that of amoxicillin (1.3 hrs.). Co-amoxiclav is eliminated primarily unchanged through the renal route (glomerular filtration and tubular secretion). Approximately 50-78% of amoxicillin and 25-40% of clavulanic acid are excreted unchanged in urine within the first 6 hrs. after administration.

5.3 Preclinical safety data

The pharmacological and toxicological properties of amoxicillin and clavulanic acid are well established. There are no additional relevant data beyond the comments in section 4.6

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Colloidal anhydrous silica, sorbitol (E420), sodium benzoate (E211), sodium citrate, aspartame (E951), butyl hydroxyl toluene (E321), xanthan gum, monosodium citrate, passion fruit flavour.

6.2 Incompatibilities

None reported.

6.3 Shelf life

Shelf life as packaged for sale: 18 Months Shelf life following constitution: 7 days

6.4 Special precautions for storage

Keep the container tightly closed. Before constitution, do not store above 25°C. After constitution, the suspension should be stored in a refrigerator (at 2°C-8°C). Do not freeze.

6.5 Nature and contents of container

Natural translucent high density polyethylene bottle with white, opaque polypropylene child resistant closure contained in a cardboard carton. Each bottle contains 100 ml upon constitution.