Data Sheet

AUGMENTIN®™

Amoxicillin sodium/potassium clavulanate (injections)

Presentation

AUGMENTIN 600mg Intravenous: Vials of sterile white to off-white powder providing potassium clavulanate equivalent to 100mg clavulanic acid with amoxicillin sodium equivalent to 500mg amoxicillin. For reconstitution as an intravenous injection or infusion.

AUGMENTIN 1.2g Intravenous: Vials of sterile white to off-white powder providing potassium clavulanate equivalent to 200mg clavulanic acid with amoxicillin sodium equivalent to 1g amoxicillin. For reconstitution as an intravenous injection or infusion.

Pharmaceutical forms

Injection.

Uses

Actions

AUGMENTIN (beta-lactam antibacterial penicillin co-formulated with a beta-lactamase inhibitor) is an antibiotic agent with a notably broad spectrum of activity against the commonly occurring bacterial pathogens in general practice and hospital. The beta-lactamase inhibitory action of clavulanate extends the spectrum of amoxicillin to embrace a wider range of organisms, including many resistant to other beta-lactam antibiotics.

Pharmacodynamic properties

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

Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta-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 beta-lactamases.

The presence of clavulanic acid in AUGMENTIN formulations protects amoxicillin from degradation by beta-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 possesses the distinctive properties of a broad spectrum antibiotic and a beta-lactamase inhibitor. AUGMENTIN 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-positive anaerobes:
  Clostridium species
  Peptococcus species
  Peptostreptococcus species
• 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-negative anaerobes:
  Bacteroides species* (including Bacteroides fragilis)
  Fusobacterium species*
• Others:
  Borrelia burgdorferi
  Chlamydiae
  Leptospira icterohaemorrhagiae
  Treponema pallidum

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

Pharmacokinetic properties

Absorption: The two components of AUGMENTIN, amoxicillin and clavulanic acid are fully dissociated in aqueous solution at physiological pH. The pharmacokinetic results for studies in which AUGMENTIN was administered to groups of healthy volunteers as either 500/100 (600mg) or 1000/200mg (1.2g) given as a bolus intravenous injection are presented below.

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

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 medicines 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 13%-25% of total plasma drug content of each compound 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. 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 breastfed 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.

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 60-70% 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 500/125mg tablet or a single 500/100mg or a single 1000/200mg bolus intravenous injection.

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 as carbon dioxide in expired air.

Therapeutic indications

AUGMENTIN is indicated for the short term treatment of common bacterial infections such as:

Upper Respiratory Tract Infections (including ENT): e.g. tonsillitis, sinusitis, otitis media

Lower Respiratory Tract Infections: e.g. acute exacerbations of chronic bronchitis, lobar and broncho-pneumonia

Genito-urinary Tract Infections: e.g. cystitis, urethritis, pyelonephritis, female genital infections

Skin and Soft Tissue Infections

Bone and Joint Infections: e.g. osteomyelitis

Other Infections: e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis, septicaemia, peritonitis, post-surgical infections

AUGMENTIN is indicated for prophylaxis against infection which may be associated with major surgical procedures such as gastro-intestinal, pelvic, head and neck, cardiac, renal, joint replacement and biliary tract surgery.

Infections caused by amoxicillin susceptible organisms are amenable to AUGMENTIN treatment due to its amoxicillin content. Mixed infections caused by amoxicillin susceptible organism in conjunction with AUGMENTIN-susceptible beta-lactamase-producing organisms may therefore be treated by AUGMENTIN.

Dosage and Administration

Dosage

Children 0-3 months: 30mg/kg* AUGMENTIN every 12 hours in infants < 4kg and 30mg/kg* AUGMENTIN every 8 hours in infants >4kg

Children 3 months - 12 years: Usually 30mg/kg* AUGMENTIN 8 hourly. In more serious infections, increase frequency to 6 hourly intervals.

Adults and Children 40kg and over: Usually 1.2g 8 hourly. In more serious infections, increase frequency to 6 hourly intervals.

*Each 30mg AUGMENTIN provides 5mg clavulanic acid with 25mg amoxicillin.

Dosage for surgical prophylaxis: Surgical prophylaxis with AUGMENTIN should aim to protect the patient for the period of risk of infection. Accordingly, procedures in adults lasting for less than 1 hour are successfully covered by 1.2g AUGMENTIN Intravenous given at induction of anaesthesia. Longer operations require subsequent doses of 1.2g AUGMENTIN IV (up to 4 doses in 24 hours), and this regime can be continued for several days if the procedure has significantly increased the risk of infection. Clear clinical signs of infection at operation will require a normal course of IV or oral AUGMENTIN therapy post-operatively.

Dosage in renal impairment:

Adults: Dosing adjustments are based on the maximum recommended level of amoxicillin.

Each 1.2g vial of AUGMENTIN contains 1.0mmoL of potassium and 3.1mmoL of sodium (approx.).

Children: Dosing adjustments are based on the maximum recommended level of amoxicillin.

Dosage in hepatic impairment: Dose with caution; monitor hepatic function at regular intervals for both adults and children.

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

Dosage in elderly: No adjustment needed, dose as for adults. If there is evidence of renal impairment, dose should be adjusted as for renally impaired adults (see above).

Administration

AUGMENTIN intravenous may be administered either by intravenous injection or by intermittent infusion. It is not suitable for intramuscular administration.

600mg Vial: To reconstitute dissolve in 10mL of Water for Injections B.P. (Final volume 10.5mL).

1.2g Vial: To reconstitute dissolve in 20mL of Water for Injections B.P. (Final volume 20.9mL).

AUGMENTIN intravenous should be given by slow intravenous injection over a period of 3-4 minutes and within 20 minutes of reconstitution. It may be injected directly into the vein or via a drip tube.

To prepare AUGMENTIN for intravenous infusion, add without delay 600mg reconstituted solution to 50mL infusion fluid or 1.2g reconstituted solution to 100mL infusion fluid (e.g. using a mini-bag or in-line burette). Infuse over 30-40 minutes and complete within the times stated.

Satisfactory antibiotic concentrations are retained at 5°C and at room temperature (25°C) in the recommended volumes of the following infusion fluids. If reconstituted and maintained at room temperature, infusions should be completed within the time stated.

For storage at 5°C, the reconstituted solution should be added to pre-refrigerated infusion bags which may be stored for up to 8 hours. Thereafter, the infusion should be administered immediately after reaching room temperature.

Any residual antibiotic solutions should be discarded.

AUGMENTIN vials are not suitable for multi-dose use.

AUGMENTIN intravenous 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 3-4 minutes.

AUGMENTIN Intravenous should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.

Contraindications

In patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and cephalosporins.

AUGMENTIN is contraindicated in patients with a previous history of AUGMENTIN-associated jaundice/hepatic dysfunction.

Warnings and Precautions

Before initiating therapy with AUGMENTIN, 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. If an allergic reaction occurs, AUGMENTIN therapy should be discontinued and appropriate alternative therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation may also be required.

AUGMENTIN 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.

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

In general AUGMENTIN is well tolerated and possesses the characteristic low toxicity of the penicillin group of antibiotics. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.

Prolongation of prothrombin time has been reported rarely in patients receiving AUGMENTIN. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly.

AUGMENTIN should be used with caution in patients with evidence of hepatic dysfunction.

In patients with renal impairment, dosage should be adjusted according to the degree of impairment (Dosage and Administration).

The presence of clavulanic acid in AUGMENTIN may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

If the parenteral administration of high doses 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 (see Overdosage).

Use during pregnancy and lactation

Use in Pregnancy: Reproduction studies in animals (mice and rats at doses up to 10 times the human dose) with orally and parentally administered AUGMENTIN 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, unless considered essential by the physician.

Use in Lactation: AUGMENTIN 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 breastfed infant.

Effects on the ability to drive and operate machinery

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

Adverse Effects

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.

Interactions

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use with AUGMENTIN may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.

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 AUGMENTIN and allopurinol.

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

The presence of clavulanic acid in AUGMENTIN may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Overdosage

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.

Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Warnings and Precautions).

Amoxicillin has been reported to precipitate in bladder catheters after intravenous administration of large doses. A regular check of patency should be maintained.

AUGMENTIN can be removed from the circulation by haemodialysis.

A prospective study of 51 paediatric patients at a poison control centre suggested that overdosages of less than 250mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.

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

Pharmaceutical Precautions

Incompatibilities

AUGMENTIN Intravenous should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions. If prescribed concomitantly with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because of loss of activity of the aminoglycoside under these conditions.

AUGMENTIN solutions should not be mixed with infusions containing glucose, dextran or bicarbonate.

Shelf life

2 years when stored below 25°C.

Special storage precautions

All AUGMENTIN preparations should be stored in a dry place at less than 25°C.

For AUGMENTIN Intravenous, particulars of stability in solution and compatabilities are given under "Administration" and in the package enclosure leaflet.

Instructions for Use/Handling

Intravenous route:

Water for Injections B.P. is the normal diluent. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally a colourless or a pale straw colour.

AUGMENTIN should be administered within 20 minutes of reconstitution.

Preparation of intravenous infusions and stability: Add without delay the reconstituted solution of 500/100mg (as prepared above - this is a minimum volume) to 50mL of infusion fluid or of 1000/200 mg to 100mL infusion fluid (e.g. using a minibag or in-line burette).

Intravenous infusions of AUGMENTIN may be given in a range of different intravenous fluids. Satisfactory antibiotic concentrations are retained at 5°C and at room temperature 25°C in the recommended volumes of the following infusion fluids. If reconstituted and maintained at room temperature, infusions should be completed within the times stated.

The stability of AUGMENTIN intravenous solutions is concentration dependent. In the event that the use of more concentrated solutions is required, the stability period should be adjusted accordingly.

For storage at 5°C, the reconstituted solutions of 1000/200 mg and 500/100 mg may be added to pre-refrigerated infusion bags which may be stored for up to 8 hours. Thereafter, the infusion should be administered immediately after reaching room temperature.

 
AUGMENTIN is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solutions of AUGMENTIN may be injected into the drip tubing over a period of 3-4 minutes.

Any residual antibiotic solution should be discarded.

AUGMENTIN vials are not suitable for multi-dose use.

Medicine Classification

Prescription Medicine.

Package Quantities

AUGMENTIN Vials 600mg: Packs of 10
AUGMENTIN Vials 1.2g: Packs of 10

Name and Address

GlaxoSmithKline NZ Limited
AMP Centre
Cnr Albert & Customs Streets
Private Bag 106600
Downtown
Auckland
NEW ZEALAND

Phone: (09) 367 2900
Fax: (09) 367 2506

Date of Preparation

Issue date: 2 July 2008

Issue number: 9

Augmentin®™ is a registered trade mark of the GlaxoSmithKline group of companies.

© This data sheet is copyrighted to GlaxoSmithKline and may be reproduced but not altered in any way.