Augmentin 875/125mg Film Coated tablets

  • Name:

    Augmentin 875/125mg Film Coated tablets

  • Company:
    info
  • Active Ingredients:

    Amoxicillin trihydrate, Clavulanic Acid

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 06/03/18

files-icon(Click to Download)
Summary of Product Characteristics last updated on medicines.ie: 7/3/2018
print

Print ViewKeyword Search SmPC

GlaxoSmithKline (Ireland) Ltd

GlaxoSmithKline (Ireland) Ltd

Company Products

Medicine NameActive Ingredients
Medicine Name Amoxil Paediatric Suspension Active Ingredients Amoxicillin trihydrate
Medicine Name Amoxil Vial for Injection 500mg Active Ingredients Amoxicillin sodium
Medicine Name ANORO ELLIPTA 55 micrograms/22 micrograms inhalation powder, pre-dispensed Active Ingredients Umeclidinium bromide, Vilanterol trifenatate
Medicine Name Augmentin 250 mg/125 mg film-coated tablets Active Ingredients Amoxicillin trihydrate, Potassium clavulanate
Medicine Name Augmentin 500mg/125mg Film-coated Tablets Active Ingredients Amoxicillin trihydrate, Potassium clavulanate
Medicine Name Augmentin 875/125mg Film Coated tablets Active Ingredients Amoxicillin trihydrate, Clavulanic Acid
Medicine Name Augmentin Duo Mixed Fruit 400 mg/57 mg /5 ml Powder for Oral Suspension Active Ingredients Amoxicillin trihydrate, Clavulanic Acid
Medicine Name Augmentin DUO Suspension 400/57mg Active Ingredients Amoxicillin trihydrate, Potassium clavulanate
Medicine Name Augmentin Intravenous 1.2g Active Ingredients Amoxicillin sodium, Potassium clavulanate
Medicine Name Augmentin Paediatric 125mg/31.25mg per 5ml Powder for Oral Suspension Active Ingredients Amoxicillin trihydrate, Potassium clavulanate
Medicine Name AVAMYS 27.5 micrograms/spray nasal spray suspension Active Ingredients Fluticasone furoate
Medicine Name Avodart Soft Capsules 0.5mg Active Ingredients Dutasteride
Medicine Name Babyhaler Active Ingredients No Active Ingredients
Medicine Name Bactroban Nasal Ointment Active Ingredients Mupirocin calcium
Medicine Name Bactroban Ointment Active Ingredients Mupirocin
Medicine Name Becotide Evohaler 100 Active Ingredients Beclometasone Dipropionate
Medicine Name Becotide Evohaler 250 Active Ingredients Beclometasone Dipropionate
Medicine Name Becotide Evohaler 50 Active Ingredients Beclometasone Dipropionate
Medicine Name Benlysta 120 mg and 400 mg powder for concentrate for solution for infusion Active Ingredients Belimumab
Medicine Name Betnovate C 0.1% / 3% w/w Cream Active Ingredients Betamethasone Valerate, Clioquinol
Medicine Name Betnovate Cream 0.1% w/w Active Ingredients Betamethasone Valerate
Medicine Name Betnovate Ointment 0.1% w/w Active Ingredients Betamethasone Valerate
Medicine Name Betnovate RD Cream Active Ingredients Betamethasone Valerate
Medicine Name Betnovate RD Ointment Active Ingredients Betamethasone Valerate
Medicine Name Betnovate Scalp Application 0.1% w/v Cutaneous Solution Active Ingredients Betamethasone Valerate
1 - 0 of 136 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 7 March 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 7 March 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Addition of the agreed wording from a PRAC recommendation on Drug Reaction with eosinophilia and systemic symptoms (DRESS) syndrome to:

 

SmPC Sections 4.4 Special warnings and precautions for use - change to statement: "Serious and occasionally fatal hypersensitivity reactions (including anaphylaxisctoid and severe cutaneous adverse reactions) (including anaphylactoid) reactions have been reported in patients on penicillin therapy."
SmPC 4.8 Undesirable effects: added new adverse effect: drug reaction with eosinophilia and systemic symptoms (DRESS) with a frequency of 'Not known'.

 

Updated on 6 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 6 March 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 7 June 2017 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Update to absorption statements in SmPC section 4.2, 4.8, 5.2.

Updated on 6 June 2017 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 4 March 2016 SmPC

Reasons for updating

  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 8 – new PA Number
Section 10 – update to date

 


Updated on 4 March 2016 PIL

Reasons for updating

  • Change to date of revision
  • Change to marketing authorisation holder

Updated on 4 January 2016 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

QRD and minor administrative updates.
Section 4.8 - AE reporting details added
Section 5.1 - Update to include staphylococcus spp. resistance category

Updated on 23 December 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to improve clarity and readability
  • Addition of information on reporting a side effect.

Updated on 16 July 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 16 July 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to address of the MA Holder

Updated on 23 April 2015 SmPC

Reasons for updating

  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

9. Common MR Renewal Date of 19 October 2014
10. Date of revision of text

Updated on 2 January 2014 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Changes to:

Section 4.5 - Interaction with other medicinal products and other forms of interaction,
Section 4.8 - Undesirable effects

Updated on 23 December 2013 PIL

Reasons for updating

  • Change to side-effects

Updated on 22 August 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

2 Update qualitative and quantative statement to QRD format
3 Description of tablet amended
4.2 Add information on children weighing less than 25 kg
6.1 name of excipients - update Macrogol to Macrogol (4000,6000)
6.3 Update infromation on desiccated pouch packs
6.4 Harmonise information non storage - delete information on dessicant    
6.5 Harmonise description of packs - re-arrange informatno
10  Revision date changed

Updated on 21 August 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to storage instructions
  • Change to date of revision
  • Change to appearance of the medicine

Updated on 18 February 2011 PIL

Reasons for updating

  • Change due to harmonisation of patient information leaflet

Updated on 6 January 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Augmentin 875/125mg Film Coated tablets contain Amoxicillin trihydrate equivalent to 875mg amoxicillin and potassium clavulanate equivalent to 125mg clavulanic acid

 

For a full list of excipients see section 6.1

 

 

3.       PHARMACEUTICAL form

 

Film coated tablet.

 

White to off white oval film coated tablet engraved ‘Augmentin’ on one side

 

White to off white oval film coated tablet debossed with the letters AC on both sides and with a score line on one side. The purpose of the score line is to aid swallowing and not to enable the tablet to be divided into two equal halves

 

4.       Clinical particulars

 

4.1     Therapeutic indications

 

Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1):

 

·                Acute bacterial sinusitis (adequately diagnosed)

·                Acute otitis media

·                Acute exacerbations of chronic bronchitis (adequately diagnosed)

·                Community acquired pneumonia

·                Cystitis

·                Pyelonephritis

·                Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis.

·                Bone and joint infections, in particular osteomyelitis.

 

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

 

4.2       Posology and method of administration

 

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.

 

The dose of Augmentin that is selected to treat an individual infection should take into account:

 

·                The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)

·                The severity and the site of the infection

·                The age, weight and renal function of the patient as shown below.

 

The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1).

 

For adults and children ³ 40 kg, this formulation of Augmentin provides a total daily dose of 1750 mg amoxicillin/ 250 mg clavulanic acid with twice daily dosing and 2625 mg amoxicillin/375 mg clavulanic acid with three times daily dosing, when administered as recommended below.  For children < 40 kg, this formulation of Augmentin provides a maximum daily dose of 1000-2800 mg amoxicillin/143-400 mg clavulanic acid, when administered as recommended below.  If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Augmentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1).

 

The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy).

 

Adults and children ³ 40 kg

 

Recommended doses:

 

·                                   standard dose: (for all indications) 875 mg/125 mg two times a day;

 

·                higher dose - (particularly for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections): 875 mg/125 mg three times a day.

 

Children < 40 kg

 

Children may be treated with Augmentin tablets, suspensions or paediatric sachets.

 

Recommended doses:

 

·                                   25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses;

 

·                up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some infections (such as otitis media, sinusitis and lower respiratory tract infections).

 

No clinical data are available for Augmentin 7:1 formulations regarding doses higher than 45 mg/6.4 mg per kg per day in children under 2 years

 

There are no clinical data for Augmentin 7:1 formulations for patients under 2 months of age.  Dosing recommendations in this population therefore cannot be made.

 

Elderly

 

No dose adjustment is considered necessary.

 

Renal impairment

 

No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

 

In patients with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available.

 

Hepatic impairment

 

Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4). 

 

Method of administration

 

Augmentin 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 to the SmPC of the IV-formulation and continued with an oral preparation.

 

4.3       Contraindications

 

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.

 

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

 

History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

 

4.4     Special warnings and precautions for use

 

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).

 

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 and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.

 

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.

 

This presentation of Augmentin is not suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid.  This presentation should not be used to treat penicillin-resistant S. pneumoniae.

 

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see 4.8).

 

Amoxicillin/clavulanic acid 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.

 

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

 

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

 

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin.

 

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8).

 

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.  In all populations, 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 (see section 4.8). 

 

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8).  Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, Augmentin should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation.

 

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 amoxicillin/clavulanic acid.  Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly.  Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8).

 

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

 

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy.  During the 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.  In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9). 

 

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.

 

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.

 

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection.  Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.  Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Oral anticoagulants

 

Oral 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).

 

Methotrexate

 

Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

 

Probenecid

 

Concomitant 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.

 

4.6       Pregnancy and lactation

 

Pregnancy

 

Animal 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.

 

Lactation

 

Both 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.

 

4.7     Effects on ability to drive and use machines

 

No studies on the effects on the ability to drive and use machines have been performed.  However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

 

4.8       Undesirable effects

 

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.

 

The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below.

 

The following terminologies have been used in order to classify the occurrence of undesirable effects.

Very common (³1/10)

Common (³1/100 to <1/10)

Uncommon (³1/1,000 to <1/100)

Rare (³1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

 

Infections and infestations

Mucocutaneous candidosis

 

Common

Overgrowth of non-susceptible organisms

Not known

Blood and lymphatic system disorders

Reversible leucopenia (including neutropenia)

Rare

Thrombocytopenia

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

Anaphylaxis

Not known

Serum sickness-like syndrome

Not known

Hypersensitivity vasculitis

 

Not known

Nervous system disorders

Dizziness

Uncommon

Headache

Uncommon

Reversible hyperactivity

Not known

Convulsions2

 

Not known

Gastrointestinal disorders

Diarrhoea

Very common

Nausea3

Common

Vomiting

Common

Indigestion

Uncommon

Antibiotic-associated colitis4

Not known

Black hairy tongue

Not known

Hepatobiliary disorders

Rises in AST and/or ALT5

Uncommon

Hepatitis6

Not known

Cholestatic jaundice6

 

Not known

Skin and subcutaneous tissue disorders 7

Skin rash

Uncommon

Pruritus

Uncommon

Urticaria

Uncommon

Erythema multiforme

Rare

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

Crystalluria8

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.

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 4.3

10 See section 4.4

 

 

4.9     Overdose

 

Symptoms and signs of overdose

 

Gastrointestinal 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 intoxication

 

Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.

 

Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

 

Mode of action

 

Amoxicillin 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 relationship

 

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.

 

Mechanisms of resistance

 

The 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.

 

Breakpoints

 

MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

 

Organism

Susceptibility Breakpoints (mg/ml)

 

Susceptible

Intermediate

Resistant

 

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

Enterobacteriaceae1,4

-

-

> 8

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.

 

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

 

Commonly susceptible species

Aerobic Gram-positive micro-organisms

Enterococcus faecalis

Gardnerella vaginalis

Staphylococcus aureus (methicillin-susceptible)

Streptococcus agalactiae

Streptococcus pneumoniae1

Streptococcus pyogenes and other beta-haemolytic streptococci

Streptococcus viridans group

 

Aerobic Gram-negative micro-organisms

Capnocytophaga spp.

Eikenella corrodens

Haemophilus influenzae2

Moraxella catarrhalis

Pasteurella multocida

 

Anaerobic micro-organisms

Bacteroides fragilis

Fusobacterium nucleatum

Prevotella spp.

 

Species for which acquired resistance may be a problem

Aerobic Gram-positive micro-organisms

Enterococcus faecium $

 

Aerobic Gram-negative micro-organisms

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Proteus vulgaris

 

Inherently resistant organisms

Aerobic Gram-negative micro-organisms

Acinetobacter sp.

Citrobacter freundii

Enterobacter sp.

Legionella pneumophila

Morganella morganii

Providencia spp.

Pseudomonas sp.

Serratia sp.

Stenotrophomonas maltophilia

 

Other micro-organisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetti

Mycoplasma pneumoniae

$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance.

£ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid

1 Streptococcus 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%.

 

5.2       Pharmacokinetic properties

 

Absorption

 

Amoxicillin 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 (875 mg/125 mg tablets given twice 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

(mg)

(mg/ml)

(h)

((mg.h/ml)

(h)

Amoxicillin

AMX/CA

875 mg/125 mg

875

11.64

± 2.78

1.50
(1.0-2.5)

53.52

± 12.31

1.19

± 0.21

Clavulanic acid

AMX/CA

875 mg/125 mg

125

2.18

± 0.99

1.25
(1.0-2.0)

10.16

± 3.04

0.96

± 0.12

AMX – amoxicillin, CA – clavulanic acid

* Median (range)

 

Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

 

Distribution

 

About 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).

 

Biotransformation

 

Amoxicillin 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.

 

Elimination

 

The 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).

 

Age

 

The 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.

 

Gender

 

Following 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 impairment

 

The 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 impairment

 

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

 

5.3     Preclinical safety data

 

Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction.

 

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.

 

Carcinogenicity studies have not been conducted with Augmentin or its components.

 

6.4       Special precautions for storage

 

Do not store above 25oC

Store in the original package in order to protect from moisture. Do not remove the desiccant. Keep blister in the outer carton in order to protect from light.

6.5       Nature and contents of container

 

Aluminium/PVC/PvDC blister in a desiccated aluminium pouch or Aluminium/PVC/PVdC blister enclosed in a cold formed laminate overwrap consisting of Aluminium and polyamide with a PVC lacquer.

 

Packs containing 4 or 14 tablets

 

Not all pack sizes may be marketed.

 

Updated on 26 August 2008 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 10:
 
Revision Date change to September 2006

Updated on 20 December 2006 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.5...............

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 amoxicillin-clavulanate and allopurinol.

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

4.8...................

Gastrointestinal disorders

Very common Diarrhoea

Common Nausea, vomiting

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.

Uncommon Indigestion

Very Rare Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis).

Black hairy tongue

............................

Updated on 26 October 2006 PIL

Reasons for updating

  • Change to side-effects

Updated on 19 May 2005 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 18 February 2005 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)