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AUGMENTIN Syrup 125: Glass bottles of off-white powder for the preparation of 100mL suspension. When reconstituted each 5mL contains potassium clavulanate equivalent to 31.25mg clavulanic acid with amoxycillin trihydrate equivalent to 125mg amoxycillin. When reconstituted the suspension is white/cream in colour.
AUGMENTIN Forte Syrup 250: Glass bottles of off-white powder for the preparation of 100mL suspension. When reconstituted each 5mL contains potassium clavulanate equivalent to 62.5mg clavulanic acid with amoxycillin trihydrate equivalent to 250mg amoxycillin. When reconstituted the suspension is white/cream in colour.
AUGMENTIN 500 Tablets: White to off white oval shaped, film coated tablets approximately 20mm x 9.5mm engraved 'AC' with score line on one side and plain on the other side. Each tablet contains potassium clavulanate equivalent to 125mg clavulanic acid with amoxycillin trihydrate equivalent to 500mg amoxycillin.
Syrup and tablets.
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 amoxycillin to embrace a wider range of organisms, including many resistant to other beta-lactam antibiotics.
Microbiology: Amoxycillin is a semisynthetic antibiotic with a broad spectrum of antibacterial activity against many gram-positive and gram-negative micro-organisms. Amoxycillin is, however susceptible to degradation by beta-lactamases and therefore the spectrum of activity of amoxycillin 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 amoxycillin from degradation by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxycillin to include many bacteria normally resistant to amoxycillin 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:
*Some members of these species of bacteria produce beta-lactamase, rendering them insensitive to amoxycillin alone.
Absorption: The two components of AUGMENTIN, amoxycillin 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 AUGMENTIN is optimised when taken at the start of a meal.
The pharmacokinetic results for two separate studies, in which AUGMENTIN 500/125 (625mg) tablets (in comparison with the two components given separately) were administered in the fasting state to groups of healthy volunteers, are presented below.
| Mean Pharmacokinetic Parameters | |||||
|---|---|---|---|---|---|
| Drug Administration | Dose (mg) |
C max (mg/L) |
T max (hours) |
AUC (mg.h/L) |
T½ (hours) |
| Amoxycillin | |||||
| AUGMENTIN 500/125mg | 500 | 6.5 | 1.5 | 23.2 | 1.3 |
| Amoxycillin 500mg | 500 | 6.5 | 1.3 | 19.5 | 1.1 |
| Clavulanic Acid | |||||
| AUGMENTIN 500/125mg | 125 | 2.8 | 1.3 | 7.3 | 0.8 |
| Clavulanic acid 125mg | 125 | 3.4 | 0.9 | 7.8 | 0.7 |
Amoxycillin serum concentrations achieved with AUGMENTIN are similar to those
produced by the oral administration of equivalent doses of amoxycillin alone.
Concomitant use of probenecid delays amoxycillin excretion but does not delay renal excretion of clavulanic acid (see Interactions).
Distribution: Following intravenous administration therapeutic concentrations of both amoxycillin 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 amoxycillin 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.
Amoxycillin, 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 amoxycillin 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 amoxycillin is via the kidney, whereas for clavulanate it is by both renal and non-renal mechanisms. Approximately 60-70% of the amoxycillin 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.
Amoxycillin 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.
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 amoxycillin susceptible organisms are amenable to AUGMENTIN treatment due to its amoxycillin content. Mixed infections caused by amoxycillin susceptible organism in conjunction with AUGMENTIN-susceptible beta-lactamase-producing organisms may therefore be treated by AUGMENTIN.
Premature: No dosage recommendations can be made for this category.
Children 3-9 months: 1.25mL of AUGMENTIN Syrup 125 three times a day.
Children 9 months - 2 years: 2.5mL of AUGMENTIN Syrup 125 three times a day.
Children 2-6 years: 5mL of AUGMENTIN Syrup 125 three times a day. In severe infections this may be increased to 10mL AUGMENTIN Syrup 125 three times a day.
Children 7-12 years: 5mL of AUGMENTIN Syrup 250 three times daily. In severe infections this may be increased to 10mL of AUGMENTIN Syrup 250 three times a day.
Adults and Children 40kg and over: 1 AUGMENTIN 500 Tablet twice daily for mild to moderate infections. For lower respiratory tract infections, complicated urinary tract infections or severe infections at other sites, 1-2 AUGMENTIN 500 Tablet three times daily.
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 amoxycillin.
| Mild Impairment (creatinine clearance >30mL/min) | Moderate Impairment (creatinine clearance 10-30mL/min) | Severe Impairment (creatinine clearance <10mL/min) |
|
|---|---|---|---|
| Tablet | No change in dosage | 1 tablet 12 hourly | 1 tablet once daily Dialysis decreases serum concentrations of AUGMENTIN. An additional dose may need to be supplemented at the of dialysis |
Children: Dosing adjustments are based on the
maximum recommended level of amoxycillin.
| Mild Impairment (creatinine clearance >30mL/min) | Moderate Impairment (creatinine clearance 10-30mL/min) | Severe Impairment (creatinine clearance <10mL/min) |
|
|---|---|---|---|
| Oral Solution (in the majority of cases, parenteral therapy, where available, may be preferred). |
No change in dosage | 15/3.75 mg/kg given 12 hourly (maximum 500/125mg twice daily). | 15/3.75mg/kg given as a single daily dose. (maximum 500/125 mg). Dialysis decreases serum concentrations of AUGMENTIN. Prior to haemodialysis one additional dose of 15/3.75 mg/kg should be administered. In order to restore circulating drug levels, another dose of 15/3.75 mg/kg should be administered after haemodialysis |
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).
Oral Route (Suspensions):
Augmentin Syrup 125: To make up to 100mL, first shake bottle to loosen powder. Then add 92mL water and shake well. When reconstituted, each 5mL contains amoxycillin trihydrate equivalent to 125mg amoxycillin and potassium clavulanate equivalent to 31.25mg clavulanic acid.
Augmentin Syrup 250: To make up to 100mL, first shake bottle to loosen powder. Then add 90mL water and shake well. When reconstituted, each 5mL contains amoxycillin trihydrate equivalent to 250mg amoxycillin and potassium clavulanate equivalent to 62.5mg clavulanic acid.
When first reconstituted, allow to stand for 5 minutes to ensure full dispersion.
Once reconstituted , the suspension must be stored in a refrigerator (at 2°C to 8°C) and used within 10 days.
Shake well before taking each dose.
To minimise potential gastrointestinal intolerance, administer at the start of a meal.
The absorption of AUGMENTIN 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.
For administrations of suspensions to children below 3 months, a syringe graduated to permit accurate and reproducible volumes to be dispensed, should be used.
For administration to children up to 2 years old, AUGMENTIN suspensions may be diluted to half-strength using water.
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.
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 amoxycillin.
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).
AUGMENTIN Suspensions contain aspartame, which is a source of phenylalanine and should be used with caution in patients with phenylketonuria.
In patients with reduced urine output crystalluria has been observed very rarely, predominantly with parenteral therapy. During administration of high doses of amoxycillin it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxycillin crystalluria (see Overdosage).
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.
Adverse effects on the ability to drive or operate machinery have not been observed.
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.
| 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 Warnings and Precautions) |
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. |
Vascular disorders: |
|
| Rare | Thrombophlebitis at the site of injection |
Gastrointestinal disorders following intravenous administration: |
|
| Common | Diarrhoea |
| Uncommon | Nausea, vomiting, indigestion |
| Very Rare | Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis) are less likely to occur after parenteral administration. |
Gastrointestinal disorders following oral administration to adults: |
|
| Very common | Diarhoea |
| Common | Nausea, vomiting |
| Uncommon | Indigestion |
| Very Rare | Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis). Black hairy tongue. Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. |
Gastrointestinal disorders following oral administration to paediatrics: |
|
| Common | Diarrhoea, nausea, vomiting |
| Uncommon | Indigestion |
| Very Rare | Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis). Black hairy tongue. Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. |
In all populations nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking AUGMENTIN at the start of a meal. |
|
Hepatobiliary disorders: |
|
| Uncommon | A moderate rise in AST and/or ALT 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. These events have been very 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. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects. |
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 Overdosage) |
Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxycillin. Concomitant use with AUGMENTIN may result in increased and prolonged blood levels of amoxycillin, but not of clavulanic acid.
Concomitant use of allopurinol during treatment with amoxycillin 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.
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.
Amoxycillin crystalluria, in some cases leading to renal failure, has been observed (see Warnings and Precautions).
When present at high concentrations in urine at room temperature, amoxycillin may precipitate in bladder catheters. A regular check of potency 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 amoxycillin 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.
None known for tablets and syrups.
Tablets: 36 months when stored below 25°C.
Syrup (Dry powder): 24 months when stored below 25°C.
Syrup (Reconstituted powder): 10 days when stored at 2°C to 8°C.
Special storage precautions
All AUGMENTIN preparations should be stored in a dry place at less than 25°C.
AUGMENTIN (dry powder): store below 25°C and protect from moisture using a well-sealed container.
Once reconstituted, AUGMENTIN Syrup 125 and AUGMENTIN Syrup 250 should be stored in a refrigerator (at 2°C to 8°C) (but not frozen) and used within 10 days.
AUGMENTIN Tablets, 10 tablet blister strips, are packed in sealed desiccant-containing foil pouches . The tablets should be used within 30 days of the foil pouch being opened.
For administration of suspensions to children below 3 months, a syringe graduated to permit accurate and reproducible volumes to be dispensed, should be used.
For administration to children up to 2 years old, AUGMENTIN suspensions may be diluted to half-strength using water.
Prescription Medicine.
AUGMENTIN 500 Tablets: Two 10-tablet blister strips (total of 20 tablets)
AUGMENTIN Syrup 125: Glass bottles of powder for 100mL suspension
AUGMENTIN Syrup 250: Glass bottles of powder for 100mL suspension
GlaxoSmithKline NZ Limited
AMP Centre
Cnr Albert & Customs Streets
Private Bag 106600
Downtown
Auckland
NEW ZEALAND
Phone: (09) 367 2900
Fax: (09) 367 2506
Issue date: 19 March 2008
Issue number: 10
Augmentin® is a registered trade mark of the GlaxoSmithKline group of companies.
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