- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- Administrative data
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal status
Adults and children ≥ 40 kgOne 500 mg/125 mg dose taken three times a day.
Children < 40 kg20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses.Children may be treated with Augmentin tablets, suspensions or paediatric sachets. As the tablets cannot be divided, children weighing less than 25 kg must not be treated with Augmentin tablets.The table below presents the received dose (mg/kg body weight) in children weighing 25 kg to 40 kg upon administering a single 500/125 mg tablet.
|Body weight [kg]||40||35||30||25||Single dose recommended [mg/kg body weight] (see above)|
|Amoxicillin [mg/kg body weight] per single dose (1 film-coated tablet)||12.5||14.3||16.7||20.0||6.67 20|
|Clavulanic acid [mg/kg body weight] per single dose (1 film-coated tablet)||3.1||3.6||4.2||5.0||1.67 - 5|
ElderlyNo dose adjustment is considered necessary.
Renal impairmentDose adjustments are based on the maximum recommended level of amoxicillin.No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.
Adults and children ≥ 40 kg
|CrCl: 10-30 ml/min||500 mg/125 mg twice daily|
|CrCl < 10 ml /min||500 mg/125 mg once daily|
|Haemodialysis||500 mg/125 mg every 24 hours, plus 500 mg/125 mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)|
Children < 40 kg
|CrCl: 10-30 ml/min||15 mg/3.75 mg/kg twice daily (maximum 500 mg/125 mg twice daily).|
|CrCl < 10 ml /min||15 mg/3.75 mg/kg as a single daily dose (maximum 500 mg/125 mg).|
|Haemodialysis||15 mg/3.75 mg/kg per day once daily. Prior to haemodialysis 15 mg/3.75 mg/kg. In order to restore circulating drug levels, 15 mg/3.75 mg per kg should be administered after haemodialysis.|
Hepatic impairmentDose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).
Method of administrationAugmentin is for oral use.Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. Therapy can be started parenterally according the SPC of the IV-formulation and continued with an oral preparation.
Oral anticoagulantsOral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).
MethotrexatePenicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
ProbenecidConcomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.Mycophenolate mofetil In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50% has been reported following commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
PregnancyAnimal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.
LactationBoth substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.
|Infections and infestations|
|Overgrowth of non-susceptible organisms||Not known|
|Blood and lymphatic system disorders|
|Reversible leucopenia (including neutropenia)||Rare|
|Reversible agranulocytosis||Not known|
|Haemolytic anaemia||Not known|
|Prolongation of bleeding time and prothrombin time1||Not known|
|Immune system disorders10|
|Angioneurotic oedema||Not known|
|Serum sickness-like syndrome||Not known|
|Hypersensitivity vasculitis||Not known|
|Nervous system disorders|
|Reversible hyperactivity||Not known|
|Aeseptic meningitis||Not known|
|Antibiotic-associated colitis4||Not known|
|Black hairy tongue||Not known|
|Rises in AST and/or ALT5||Uncommon|
|Cholestatic jaundice6||Not known|
|Skin and subcutaneous tissue disorders 7|
|Stevens-Johnson syndrome||Not known|
|Toxic epidermal necrolysis||Not known|
|Bullous exfoliative-dermatitis||Not known|
|Acute generalised exanthemous pustulosis (AGEP)9||Not known|
|Renal and urinary disorders|
|Interstitial nephritis||Not known|
|1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 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. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4|
Symptoms and signs of overdoseGastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).Convulsions may occur in patients with impaired renal function or in those receiving high doses.Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4).
Treatment of intoxicationGastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.
Mode of actionAmoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that 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, which is usually followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria 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 penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
PK/PD relationshipThe time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
Mechanisms of resistanceThe two main mechanisms of resistance to amoxicillin/clavulanic acid are:• Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
BreakpointsMIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)
|Organism||Susceptibility Breakpoints (μg/ml)|
|Haemophilus influenzae1||≤ 1||-||> 1|
|Moraxella catarrhalis1||≤ 1||-||> 1|
|Staphylococcus aureus 2||≤ 2||-||> 2|
|Coagulase-negative staphylococci 2||≤ 0.25||> 0.25|
|Enterococcus1||≤ 4||8||> 8|
|Streptococcus A, B, C, G5||≤ 0.25||-||> 0.25|
|Streptococcus pneumoniae3||≤ 0.5||1-2||> 2|
|Gram-negative Anaerobes1||≤ 4||8||> 8|
|Gram-positive Anaerobes1||≤ 4||8||> 8|
|Non-species related breakpoints1||≤ 2||4-8||> 8|
|1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l. 2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.|
|Commonly susceptible species|
|Aerobic Gram-positive micro-organisms Enterococcus faecalisGardnerella vaginalisStaphylococcus aureus (methicillin-susceptible)£Coagulase-negative staphylococci (methicillin-susceptible) Streptococcus agalactiaeStreptococcus pneumoniae1Streptococcus pyogenes and other beta-haemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organismsCapnocytophaga spp. Eikenella corrodensHaemophilus influenzae2Moraxella catarrhalisPasteurella multocidaAnaerobic micro-organismsBacteroides fragilisFusobacterium nucleatumPrevotella spp.|
|Species for which acquired resistance may be a problem|
|Aerobic Gram-positive micro-organismsEnterococcus faecium $ Aerobic Gram-negative micro-organismsEscherichia coli Klebsiella oxytoca Klebsiella pneumoniaeProteus mirabilisProteus vulgaris|
|Inherently resistant organisms|
|Aerobic Gram-negative micro-organismsAcinetobacter sp. Citrobacter freundiiEnterobacter sp. Legionella pneumophila Morganella morganiiProvidencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophiliaOther micro-organismsChlamydophila pneumoniaeChlamydophila psittaciCoxiella burnetti Mycoplasma pneumoniae|
|$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1Streptococcus pneumoniae that are resistant to penicillin should not be treated with this presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.|
AbsorptionAmoxicillin 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/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour. The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (500 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below.
|Mean (± SD) pharmacokinetic parameters|
|Active substance(s) administered||Dose||Cmax||Tmax *||AUC (0-24h)||T 1/2|
|AMX/CA 500/125 mg||500||7.19 ± 2.26||1.5 (1.0-2.5)||53.5 ± 8.87||1.15 ± 0.20|
|AMX/CA 500 mg/125 mg||125||2.40 ± 0.83||1.5 (1.0-2.0)||15.72± 3.86||0.98± 0.12|
|AMX amoxicillin, CA clavulanic acid * Median (range)|
DistributionAbout 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).
BiotransformationAmoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air.
EliminationThe major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. 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 single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).
AgeThe elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
GenderFollowing oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.
Renal impairmentThe total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).
Hepatic impairmentHepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
Tablet coreMagnesium stearateSodium starch glycolate, Type AColloidal anhydrous silicaMicrocrystalline cellulose
Tablet film-coatTitanium dioxide (E171)HypromelloseMacrogol (4000, 6000)Dimeticone
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