 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'.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains Amoxicillin sodium amoxicillin equivalent to 500  mg of Amoxicillinamoxicillin and potassium

 clavulanate equivalent to 100  mg of clavulanic acid.

For athe full list of excipients, see section 6.1.

4.3       Contraindications

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in section 6.1.

6.2     Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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

 If Augmentin is prescribed concurrentlyconcomitantly 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 can occur under these conditions.

Augmentin issolutions should not stable inbe mixed with infusions containing glucose, dextran or bicarbonate.  Reconstituted solutions of Augmentin should therefore not be added to such infusions but may be injected into the drip tubing over a period of three to four minutes.

This medicinal product must not be mixed with other medicinal products except those listed in section 6.6.

6.3     Shelf life

Unopened: Powder in vials

2 years

OnceReconstituted vials (for intravenous injection or before dilution for infusion)

The reconstituted and added to infusions:

            Intravenous Infusion                                                           Stability period at 25°C

            solution (1 vial with 10 ml of Water for Injections BP                4 hrPh.Eur.) should be used or diluted immediately, within 20 minutes.

            Sodium Chloride Intravenous

Diluted for intravenous infusion BP (0.9% w/v)             4 hr

            Sodium Lactate Intravenous infusion BP (M/6)                                     4 hr

            Compound Sodium Chloride Injection BPC 1959 (Ringer’s)                   3 hr

            Compound Sodium Lactate Intravenous

            Infusion BP (Ringer-Lactate: Hartmann’s)                                             3 hr

            Potassium Chloride and Sodium Chloride Intravenous infusion BP        3 hr

Chemical and physical in-use stability has been demonstrated for 2-3 hours at 25°C, or 8 hours at 5 C.  From a microbiological point of view, the reconstituted and diluted solution (1 reconstituted vial in a minimum volume of 50 ml of infusion fluid) should be used immediately. 

Intravenous infusions of amoxicillin/clavulanic acid 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 (25°C), infusions should be completed within the times stated in the table below.

For storage at 5°C, the reconstituted solution shouldsolutions of Augmentin IV may be added to pre-refrigerated infusion bags containing either Water for Injection Ph. Eur. or sodium chloride BP (0.9% w/v), which may be stored for up to 8 hours.  Thereafter, the infusion should be administered immediately after reaching room temperature.

            Intravenous Infusion                                                     Storage period 5°C

            Water for Injections BP                                                             8 hr

            Sodium Chloride Intravenous infusion BP (0.9% w/v)                8 hr

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

Augmentin IV is less stable in infusions containing glucose, dextran or bicarbonate.  Reconstituted solutions of amoxicillin/clavulanic acid may be injected into the drip tubing over a period of 3 to 4 min.

Any residual antibiotic solution should be discarded.

6.4       Special precautions for storage

Vials: Do not store above 25°C.  Keep the container tightly closed.

Store in a dry placethe original package in order to protect from moisture.

For storage detailsconditions after reconstitution of reconstituted solutionsthe medicinal product, see section 6.3.

6.5       Nature and contents of container

10 mL, clear, Type IClear glass 10 ml or 25 mL, Ph.Eur. ml vials (Type I or Type III glass vials) with chlorobutyl rubber stopper and sealing ring

PackPacks of 1, 5 or 10 in a carton.vials

Not all pack sizes may be marketed.

6.6       Special precautions for disposal and other handling

For single use only. Discard any unused solution.

The reconstitution/dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation of solutions for intravenous injection

Water for Injection Ph. Eur. is the normal solvent.  Augmentin 500/100 mg should be dissolved in 10  ml of solvent.  This yields approximately 10.5 ml of solution for single-dose use.  A transient pink colouration may or may not develop during reconstitution.  Reconstituted solutions are normally colourless or a pale straw colour. 

Augmentin should be administered within 20 min of reconstitution.

Preparation of solutions for intravenous infusion

Augmentin vials are not suitable for multi-dose use.

Augmentin should be reconstituted as described above for injection.  Without delay the reconstituted solution should be added to 50 ml of infusion fluid using a minibag or in-line burette. 

(New text marked in red)

6.6       Instructions for Use/Handling

To reconstitute dissolve in 10 ml Water for Injections (final volume 10.5 ml). Reconstituted solutions are normally colourless; however a transient pink colour may appear during reconstitution.

Section 4.4     

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 (see Overdosage).

Section 4.8 (whole section rearranged & just crystalluria added)     

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 Section 4.4 Special warnings and special precautions for use)

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.

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). 

Hepatobiliary disorders

Uncommon       A moderate rise in AST and/or ALT and Alkaline Phosphatases 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.

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.

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)

Section 4.9

Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4 Special warnings and special precautions for use).

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