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CO-amoxiclav

Natravox®




FORMULATION:
125mg/ 31.25 mg per 5mL powder for suspension - When reconstituted according to instructions, each 5mL of reconstituted suspension contains amoxicillin trihydrate equivalent to 125mg amoxicillin and potassium clavulanate equivalent to 31.25mg clavulanic acid.

200mg/28.5mg per 5mL powder for suspension - when reconstituted according to instructions, each 5mL of reconstituted oral suspension contains amoxicillin trihydrate equivalent to 200mg amoxicillin and potassium clavulanate equivalent to 28.5mg clavulanic acid.

250mg/62.5mg per 5mL powder for suspension - when reconstituted according to instructions, each 5mL of reconstituted oral suspension contains amoxicillin trihydrate equivalent to 250mg amoxicillin and potassium clavulanate equivalent to 62.5mg clavulanic acid.

400mg/57mg per 5mL powder for suspension - when reconstituted according to instructions, each 5mL of reconstituted oral suspension contains amoxicillin trihydrate equivalent to 400mg amoxicillin and potassium clavulanate equivalent to 57mg clavulanic acid.

250mg/125mg film-coated tablet: each tablet contains 250mg amoxicillin and 125mg clavulanic acid.

500mg/125mg film-coated tablet: each tablet contains 250mg amoxicillin and 125mg clavulanic acid.

500mg/100mg: each powder vial contains amoxicillin sodium equivalent to 500mg amoxicillin and potassium clavulanate equivalent to 100mg clavulanic acid.

1000mg/200mg: each powder vial contains amoxicillin sodium equivalent to 1000mg amoxicillin and potassium clavulanate equivalent to 200mg clavulanic acid.
INDICATIONS:
~ Upper respiratory tract infections (including ENT) - sinusitis, otitis media, recurrent tonsillitis. These infections are often caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes.

~Lower respiratory tract infections-acute exacerbations of chronic bronchitis, bronchopneumonia, urinary-tract infections often caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

~Genito-urinary tract and abdominal infections in particular cystitis (especially when recurrent or complicated, but not 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 tissues infections in particular, cellulites, animal bites, and severe dental abscess with spreading cellulites caused by Staphyloccocus aureus, Streptococcus pyogenes and Bacteriodes species.

ANTIMICROBIAL ACTIONS:
Co-amoxiclav is an antibacterial combination consisting of amoxicillin (as sodium) and the beta-lactamase inhibitor, clavulanic acid (as potassium clavulanate). Amoxicillin is the 4-hydroxy analogue of ampicillin.  Amoxicillin hinders the cell wall synthesis of sensitive bacteria and is bactericidal against many Gram-positive and Gram-negative bacteria.  It is active against all penicillin-sensitive bacteria: streptococci, and most strains of pneumococci, gonococci and meningococci are sensitive. Bacteria that produce beta-lactamase (e.g. most of the staphylococci) are resistant.  Amoxicillin is also active against strains of haemophilus influenza that do not produce beta-lactamase.

Clavulanic acid has a beta-lactam structure resembling that of penicillin nucleus, except that the fused thiazolidine ring of the penicillins is replaced by an oxazolidine ring.  In general, clavulanic acid has only weak antibacterial activity.  It is potent progressive inhibitor of plasmid-mediated and some chromosomal beta-lactamases produced by Gram-negative bacteria including Haemophilus ducreyi, H.influenzae, Neisseria gonorrhoeae, Moraxella catarrhalis (Branhamella catarrhalis), Bacteroides fragilis and some Enterobacteriacese.  It is also an inhibitor of the beta-lactamases produced by Staphylococcus aureus.  Clavulanic acid can permeate bacterial cell walls and can therefore inactivate both extracellular enzymes and those that are bound to the cell.  Its mode of action depends on the particular enzyme inhibited, but it generally acts as a competitive, and often, irreversible, inhibitor.  Clavulanic acid consequently enhances the activity of penicillin and cephalosporin antibacterials against many resistant strains of bacteria.  However, it is generally less effective against chromosomally medicated type 1 beta-lactamases: therefore, many Citrobacter, Enterobacter, Morganells and Serratia spp. and Pseudomonas aeruginosa remain resistant.  Some plasmid-mediated extended release spectrum beta lactamases in Klebsiella pneumoniae, some other Enterobactriaceae, and Ps. aeruginosa are also not inhibited by beta-lactamases inhibitors.

Co-amoxiclav 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, Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pasteurella multocida

Anaerobes:  Bacteroides species, including B.fragilis

DRUG INTERACTIONS
Probenicid decreases the renal tubular secretion of amoxicillin but does not affect clavulanic acid excretion.  Concurrent use with co-amoxiclav may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

Co-amoxiclav may reduce the efficacy of oral contraceptives and patients should be warned accordingly.

Penicillins such as co-amoxiclav may decrease the removal of methotrexate from the body increasing the risk of toxicity.

Antibiotics such as co-amoxiclav may alter the effect of anticoagulants such as warfarin.

Intravenous administration can cause local irritation, induration and phlebitis at the injection site.

CONTRAINDICATIONS
Co-amoxiclav is contraindicated in patients with a history of allergic reactions to any penicillin.  It is also contraindicated in patients with a previous history of amoxicillin-potassium clavulanate-associated cholestatic jaundice/ hepatic dysfunction.

SPECIAL WARNING AND SPECIAL PRECAUTIONS FOR USE
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.

If the parenteral administration of high dosage is necessary, the sodium content must be taken into account in patients on a sodium restricted diet.

In patients with reduced urine output crystalluria has been observed very rarely, predominantly with parenteral therapy.  During 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.  Amoxicillin has been reported to precipitate in bladder catheters after intravenous administration of large doses.  A regular check of potency should be maintained.

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.

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

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

 

PREGNANCY AND LACTATION
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 co-amoxiclav 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.

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 REACTIONS
Adverse reactions are uncommon and mainly of a mild and transitory nature.

Gastrointestinal reactions:
Diarrhea, indigestion, nausea, vomiting, and mucocutaneous candidiasis have been reported.  Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis) has been reported rarely.  Nausea, although uncommon, is more often associated with higher oral dosages.  If gastrointestinal side effects occur with oral therapy they may be reduced by taking Co-amoxiclav at the start of meals.

Superficial tooth discolouration has been reported rarely, mostly with the suspension.  It can usually be removed by brushing.

Renal and urinary tract disorders:

Crystalluria has been reported very rarely.

Genito-urinary effects:
Vaginal itching, soreness and discharge may occur.

Hepatic effects:
Moderate and asymptomatic rises in AST and/ or ALT and alkaline phosphatases have been reported occasionally.  Hepatitis and cholestatic jaundice have been reported rarely.  These hepatic reactions have been reported more commonly with Co-amoxiclav than with other penicillins.

After Co-amoxiclav hepatic reactions have been reported more frequently in males and elderly patients, particularly those over 65 years.  The risk increases with duration of treatment longer than 14days.  These reactions have been very rarely reported in children.  Signs and symptoms usually occur during or shortly after treatment but in some cases may not occur until several weeks after treatment has ended.  Hepatic reactions are usually reversible but they may be severe, and, very rarely, deaths have been reported.

Hypersensitivity reactions:
Urticarial and erythematous skin rashes sometimes occur.  Rarely, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), serum sickness-like syndrome and hypersensitivity vasculitis have been reported.  Treatment should be discontinued if one of these disorders occurs.  In common with other Beta-lactams antibiotics angioedema and anaphylaxis have been reported.  Interstitial nephritis can occur rarely.

Haematological effects:
As with other Beta-lactams transient leucopenia (including neutropenia and agranulocytosis), thrombocytopenia and haemolytic anaemia have been reported rarely.  Prolongation of bleeding time and prothrombin time has also been reported rarely.

CNS effects:
CNS effects have been seen very rarely.  These include reversible hyperactivity, dizziness, headache and convulsions.  Convulsions may occur with impaired renal function or in those receiving high doses.



Local:
Thrombophlebitis at the site of the injection has been reported occasionally.

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.

INCOMPATIBILITIES:
Co-amoxiclav injection should NOT be mixed or reconstituted with dextrose solution, sodium bicarbonate solution for injection, protein hydrolysates and other proteinaceous fluids, blood or plasma or withintravenous lipid emulsions.

If co-amoxiclav is prescribed concurrently with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions.

CAUTION:
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

DOSAGES FOR TREATMENT OF INFECTIONS:
Direction for reconstitution:

Co-amoxiclav (Natravox) 500mg/ 100mg IV: Dissolve the powder in 10mL water for injection
Co-amoxiclav (Natravox) 1000mg/ 200mg IV: Dissolve the powder in 2mL water for injection

For intravenous infusion: the reconstituted vial should be further diluted with the desired volume of a suitable infusion liquid.

Co-amoxiclav (Natravox) IV is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solution should, therefore, not be added to such infusions but may be injected into the drip tubing over a period of three to four minutes.

Note: Co-amoxiclav (Natravox) IV vials are not suitable for intramuscular or subcutaneous administration.
Co-amoxiclav (Natravox) IV vials should be given by slow intravenous injection over a period of three to four minutes. It may be injected directly into a vein or via a drip tube.

USE RECONSTITUTED SOLUTION WITHIN 20 MINUTES.
DISCARD ANY UNUSED SOLUTION.


Duration of therapy should be appropriate to the indication and should not exceed 14days without review.

Dosages for the treatment of infection

Adults and children over 12 years: usually 1.2g every eight hours. By intravenous injection (3-4 minutes) or intravenous infusion (30 minutes). In more serious infections, increase frequency to six-hour intervals.

Adult dosage for surgical prophylaxis

The usual dose is 1.2g Co-amoxiclav (Natravox) IV given at the induction of anaesthesia. Operations where there is a high risk of infection, e.g. colorectal surgery, may require three, and, up to four, doses of 1.2g Co-amoxiclav (Natravox) IV in a 24-hour period. These doses are usually given at 0, 8, 16 (and 24) hours. This regimen can be continued for several days if the procedure has a significantly increased risk of infection.

Clear clinical signs of infection at operation will require a normal course of intravenous or oral Co-amoxiclav (Natravox) therapy post-operatively.

Dosage in renal impairment

Adults

Mild impairment
(creatinine clearance>30mL/min)
Moderate impairment (creatinine clearance 10 to 30mL/ min)

Severe impairment
(creatinine clearance <10mL/min)
No change in dosage 1.2g IV stat., followed by 600mg IV 12 hourly 1.2g IV stat., followed by 600 mg IV 24 hourly.

Dialysis decreases serum concentrations of Natravox and an additional 600mg IV dose may need to be given during dialysis and at the end of dialysis.


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. Each 1.2g vial of co-amoxiclav (Natravox) IV contains 1.0mmol of potassium and 2.7mmol of sodium (approx.)

STORE THE DRY POWDER IN COOL DRY PLACE STORE BELOW 25OC
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