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Logo AUGMENTIN IV 0,6 (Vials)
AUGMENTIN IV 1,2 (Vials)
SCHEDULING STATUS:
S4

PROPRIETARY NAMES
(and dosage form):

AUGMENTIN IV 0,6 (Vials)
AUGMENTIN IV 1,2 (Vials)

COMPOSITION:
Augmentin IV 0,6: powder vials for intravenous injection containing amoxycillin sodium equivalent to 500 mg of amoxycillin and potassium clavulanate equivalent to 100 mg clavulanic acid.
Augmentin IV 1,2: powder vials for intravenous injection containing amoxycillin sodium equivalent to 1 000 mg of amoxycillin and potassium clavulanate equivalent to 200 mg clavulanic acid.

PHARMACOLOGICAL CLASSIFICATION:
A.20.1.2 Penicillins

PHARMACOLOGICAL ACTION:
(a) Bacteriology
  (i) Spectrum 
    Augmentin is the group name for formulations containing 2, 4 and 5 parts of a broad spectrum penicillin, amoxycillin and 1 part of potassium clavulanate. Potassium clavulanate has been shown in vitro to be an irreversible inhibitor of ß-lactamase produced by: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Haemophilus influenzae, Neisseria gonorrhoea and Bacteroides fragilis. Potassium clavulanate does not inactivate the chromosomally mediated (Sykes Type 1 Cephalosporinase) ß-lactamases produced by Acinetobacter species, Citrobacter species, Enterobacter, Indole positive Proteus, Providencia species and Serratia marcescens. In vitro the formulation showed synergism against amoxycillin-resistant organisms, with no evidence of antagonism and the activity was not reduced in the presence of serum. 
    (In vitro activity does not necessarily imply in vivo efficacy). 
  (ii) Bactericidal action 
    The amoxycillin component of the formulations exert a bactericidal action against many strains of Gram-positive and Gram-negative organisms. The clavulanic acid component has very little bactericidal action. It does however, by inactivation of susceptible ß-lactamases, protect amoxycillin from degradation by a large number of ß-lactamase enzymes produced by penicillin resistant strains of organisms. 
(b) Absorption
  The pharmacokinetics of amoxycillin and clavulanic acid are closely allied. Doubling the dose virtually doubles the peak serum level.
(c) Excretion
  Co-administration of probenecid has little effect on the excretion of the clavulanic acid component of the formulation.
(d) Stability
  The 5 parts amoxycillin and 1 part clavulanic acid Augmentin IV 0,6 and Augmentin IV 1,2 powder vials for injection are stable at room temperature (below 25°C) for two years. When reconstituted it must be used within 20 minutes.

INDICATIONS:
Augmentin formulations are indicated for the treatment of infections caused by amoxycillin resistant organisms producing ß-lactamases sensitive to clavulanic acid:
Upper respiratory tract, such as sinusitis, otitis media, tonsillitis.
Lower respiratory tract, such as bronchitis (caused by amoxycillin resistant ß-lactamase producing Escherichia coli, Haemophilus influenzae and Haemophilus para-influenzae) pneumonia.
Urinary tract infections, such as cystitis, urethritis, pyelonephritis.
Skin and soft tissues.
Augmentin formulations will also be effective in the treatment of infections caused by amoxycillin sensitive organisms at the appropriate amoxycillin dosage since in this situation the clavulanic acid component does not contribute to the therapeutic effect.

CONTRA-INDICATIONS:
Allergy to penicillins and cephalosporins.
Safety in pregnancy has not been established.
Augmentin is contra-indicated in patients with a previous history of Augmentin-associated jaundice/hepatic dysfunction.
Safety and efficacy in children has not been established with the parenteral forms of Augmentin.

WARNINGS:
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy.
Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.
There have been reports of individuals with a history of penicillin hypersensitivity, who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with any penicillin careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other allergens. If an allergic reaction occurs, Augmentin should be discontinued and the appropriate therapy instituted: adrenaline corticosteroids and antihistamines.
Transient hepatitis and cholestatic jaundice has been reported. Augmentin should be used with caution in patients with evidence of hepatic dysfunction.
Augmentin IV formulations should not be given intramuscularly or subcutaneously.
Augmentin IV formulations, as with other penicillins and cephalosporins, should not be mixed with aminoglycosides in the same syringe or giving set, as substantial inactivation of the aminoglycosides can result.

DOSAGE AND DIRECTIONS FOR USE:
Directions for use:
Augmentin IV 0,6 powder vials for injection can be reconstituted by dissolving in 10 mL Water for Injections B.P.
Augmentin IV 1,2 powder vials for injection can be reconstituted by dissolving in 20 mL Water for Injections B.P.
When a diluent is added a transient pink colouration or slight opalescence will be observed whereafter, a pale yellow fluid.
For intravenous infusion, the reconstituted vial should be further diluted with the desired volume of a suitable infusion fluid (see compatibility and stability below).

Compatibility and stability:
The period of stability of Augmentin IV infusion fluids after reconstitution and dilution are as follows:

STRENGTH INFUSION FLUID VOLUME OF FLUID INFUSION (mL) STABILITY (hours)
    AUGMENTIN IV 0,6 AUGMENTIN IV 1,2 *5°C 25°C
AUGMENTIN IV 0,6 Water for Injections 50 100 8 4
600 mg reconstituted with 10 mL Water for Injections Sodium Chloride Intravenous Infusion B.P. (0,9% m/v) 50 100 8 4
  Sodium Lactate Intravenous Infusion. (M/6) 50 100 – 4
  Compound Sodium Chloride Injection. (Ringers Solution) 50 100 – 3
AUGMENTIN IV 1,2
1,2 g reconstituted with 20 mL Water for Injections		 Compound Sodium Lactate Intravenous Infusion B.P. (Hartmann’s Solution; Ringer-Lactate Solution) 50 100 – 3
  Potassium Chloride and Sodium Chloride Intravenous Infusion B.P. 50 100 – 3
*For storage at 5°C, the reconstituted solutions should be added to a pre-refrigerated bag of infusion fluid. In use, the solution should be allowed to reach room temperature and then administered without delay.
Alternatively, if minibags of sodium chloride 0,9% m/v are to be used the stability results obtained with Augmentin indicated that 600 mg per 50 mL or 1,2g per 100 mL bag is suitable. Using a MINI-BAG™ PLUS unit containing 50 mL or 100 mL physiological saline, the appropriate volume of sodium chloride solution may be transferred from the MINI-BAG™ PLUS unit bag into an Augmentin IV 0,6 or Augmentin IV 1,2 vial respectively, and then back into the bag after dissolution. When the latter method is used the permissible time between preparation of the solution and completion of the infusion is reduced from 4 hours to 3 hours.
Augmentin IV vials should not be reconstituted or mixed with:
  dextrose solution
  sodium bicarbonate solution for injection
  protein hydrolysates or other proteinaceous fluids
  blood or plasma
  intravenous lipids
However, the reconstituted solution may be injected into the drip tubing of infusion fluids containing glucose, bicarbonate and dextran over a period of 3-4 minutes.

ADMINISTRATION:
Note: Augmentin IV vials are not suitable for intramuscular or subcutaneous administration.
The reconstituted vials can be administered intravenously by injection (2 minutes) or slow intravenous infusion (30 minutes). Infusion should be completed within the period of stability of Augmentin IV infusions after reconstitution and dilution as reflected in the table under the section “Compatibility and Stability”presented above. The contents of the vials must be used within 20 minutes and thereafter any unused material discarded.

DOSAGES:
General information:
For infections caused by amoxycillin sensitive organisms the dosage is that approved for amoxycillin as the clavulanic acid component does not contribute to the therapeutic effect.
Adult (Intravenous):
For severe infections of the respiratory tract, urinary tract and skin and soft tissue requiring parenteral therapy initially 1 Augmentin IV 1,2 vial containing the equivalent of 1 000 mg amoxycillin and 200 mg clavulanic acid can be administered intravenously 6 to 8 hourly by intravenous injection (2 minutes) or intravenous infusion (30 minutes) until condition settles followed by oral therapy with Augmentin 375 tablets at the recommended dose. If no response has occurred within 48 hours therapy must be reviewed.
Intravenous treatment with Augmentin should not extend beyond 10 days without review and the total daily administration of clavulanic acid should not exceed 800 mg. Treatment can be continued with Augmentin 375 tablets orally where appropriate after a satisfactory therapeutic response has been obtained.

DOSAGE GUIDE:
AMOXYCILLIN SENSITIVE ORGANISMS
PRODUCT Upper Respiratory Tract Infections Lower Respiratory Tract Infections Urinary Tract Infections Skin and Soft Tissue Infections 
Adults:
AUGMENTIN IV 1,2 1 Vial 1) 6 - 8 hourly 1 Vial 1) 6 - 8 hourly 1 Vial 1) 6 - 8 hourly 1 Vial 1) 6 - 8 hourly 
AUGMENTIN IV 0,6 2 Vials 1) 6 - 8 hourly 2 Vials 1) 6 - 8 hourly 2 Vials 1) 6 - 8 hourly 2 Vials 1) 6 - 8 hourly 

AMOXYCILLIN RESISTANT ORGANISMS
PRODUCT Upper Respiratory Tract Infections
(Otitis Media)
H. influenzae
H. parainfluenzae		 Lower Respiratory Tract Infections
(Bronchitis)
H. influenzae
H. parainfluenzae		 Urinary Tract Infections
E. coli
Klebsiella pneumoniae		 Skin and Soft Tissue Infections
Staphylococcus
aureus		 
Adults:
AUGMENTIN IV 1.2 1 Vial 1) 6 - 8 hourly 1 Vial 1) 6 - 8 hourly 1 Vial 1) 6 - 8 hourly 1 Vial 1) 6 - 8 hourly 
AUGMENTIN IV 0,6 2 Vials 1) 6 - 8 hourly 2 Vials 1) 6 - 8 hourly 2 Vials 1) 6 - 8 hourly 2 Vials 1) 6 - 8 hourly 
1) Intravenous therapy should not be continued for longer than 10 days.

NOTE:
1. Insufficient evidence exists at present to recommend an intravenous dosage in children.
2. Patients with renal impairment:
  Each Augmentin IV 0,6 vial contains 0,5 mmol of potassium and 1,4 mmol of sodium.
  Each Augmentin IV 1,2 vial contains 1,0 mmol of potassium and 2,8 mmol of sodium.
As both the amoxycillin and clavulanic acid components of Augmentin are excreted by the kidneys, accumulation of both may occur in patients with renal insufficiency. In these cases monitoring of the serum levels and a reduction in the number of administrations of the suggested dosage may be required.
Experiences in a limited number of patients with varying degrees in renal insufficiency suggests that the following schedule of dosage based on the creatinine clearance of the patient, may be used as a guideline:

Creatinine Clearance Dosage
> 70 mL/min no dosage adjustment
10 - 30 mL/min 1,2 g Augmentin stat and 600 mg 12 hourly
< 10 mL/min 1,2 g Augmentin stat and 600 mg daily

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most frequently reported adverse effects are diarrhoea, nausea, vomiting, abdominal pain, skin rashes, urticaria, and erythema multiforme, vaginitis, abnormal taste, headache, dizziness, tiredness and hot flushes.
The incidence and severity of adverse effects, particularly nausea and diarrhoea, increased with the higher recommended dose and can be minimised by administering the agent at the start of a meal. In addition, as these symptoms are especially related to the potassium clavulanate component, where these gastro-intestinal symptoms occur and a higher concentration of amoxycillin is required, consideration should be given to administering the additional amoxycillin separately.
Hepatitis and cholestatic jaundice have been reported. The events may be severe, and occur predominantly in adult or elderly patients. 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. The hepatic events are usually reversible. However, in extremely rare circumstances, death has been reported. These have almost always been cases associated with serious underlying disease or concomitant medication.
A moderate rise in Aspartate transaminase and/or Alanine transaminase has been noted in patients treated with Augmentin. The following adverse reactions have been reported for ampicillin class antibiotics and may occur with Augmentin.
Gastro-Intestinal - gastritis, stomatitis, glossitis, black ‘hairy’tongue, enterocolitis and pseudomembranous colitis. If gastro-intestinal reactions are evident, they may be reduced by taking Augmentin at the start of a meal.
Hypersensitivity - skin rashes, urticaria, erythema multiforme, rare cases of Stevens-Johnson syndrome and less frequently exfoliative dermatitis and toxic epidermal necrolysis have been reported. Whenever such reactions occur, Augmentin should be discontinued. Serious and occasional fatal hypersensitivity (anaphylactic) reactions and angioneurotic oedema can occur with oral penicillin (see warnings).
Haematopoietic and lymphatic - Anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leucopenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with Augmentin. Prolongation of bleeding time and prothrombin time have also been reported less frequently.

Precautions:
Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function, is advisable during prolonged therapy.
Since Augmentin contains amoxycillin, an aminopenicillin, it is not the treatment of choice in patients presenting with sore throat or pharyngitis because of the possibility that the underlying cause is infectious mononucleosis, in the presence of which there is a high incidence of rash if amoxycillin is used. Augmentin should be given with caution to patients with lymphatic leukaemia since they are especially susceptible to amoxycillin induced skin rashes.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Aerobacter, Pseudomonas or Candida), the agent should be discontinued and/or appropriate therapy instituted.
Impaired hepatic function - Changes in liver function tests have been observed in some patients receiving Augmentin. It should be used with care in patients with evidence of severe hepatic dysfunction.
Impaired renal function - In patients with moderate or severe renal impairment Augmentin dosage should be adjusted. (See Dosage and Administration).
Use in lactation - amoxycillin is excreted in the milk; there is no data on the excretion of clavulanic acid in human milk. Therefore, caution should be exercised when Augmentin is administered to a nursing woman.

Interactions:
Probenecid decreases the renal tubular secretion of amoxycillin, but does not affect clavulanic acid excretion. Concurrent use with Augmentin may result in increased and prolonged blood levels of amoxycillin but not of clavulanic acid.
The concurrent administration of allopurinol and ampicillin substantially increases the incidence of rashes in patients receiving both agents as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricaemia present in these patients. There is no data on Augmentin and allopurinol administered concurrently.
No information is available about the concurrent use of Augmentin and. alcohol. However, the ingestion of alcohol whilst being treated with some other ß-lactam antibiotics has precipitated a disulfiram (antibuse) like reaction in some patients. Therefore, the ingestion of alcohol should be avoided during and for several days after treatment with Augmentin.
Following administration of ampicillin to pregnant women a transient decrease in plasma concentration of total conjugate oestriol, oestriol-glucuronide, conjugated oestrone and oestradiol has been noted. This effect may also occur with amoxycillin and therefore Augmentin. Augmentin may reduce the efficacy of oral contraceptives and patients should be warned accordingly. The use of this antibiotic may lead to the selection of resistant strains of organisms and sensitivity testing should, therefore, be carried out whenever possible, to demonstrate the appropriateness of therapy.
Intravenous administration can cause local irritation, induration and phlebitis at the injection site.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Nausea, vomiting and diarrhoea may occur with overdosing. Treatment is symptomatic and supportive.
Amoxycillin may be removed from circulation by haemodialysis. The molecular/weight, degree of protein binding and pharmacokinetic profile of clavulanic acid together with information from a single patient with renal insufficiency all suggest that this compound may also be removed by haemodialysis.

IDENTIFICATION:
Augmentin IV 0,6: white to pale yellow powder in vials when reconstituted a clear pale yellow solution.
Augmentin IV 1,2: white to pale yellow powder in vials when reconstituted a clear pale yellow solution.

PRESENTATION:
Augmentin IV 0,6: Clear glass vials containing powder for injection in cartons of 5 vials or a single vial packed with a 50 mL Mini-Bag™ Plus (SABAX) Sodium Chloride 0,9% (registration number D/24/106).
Augmentin IV 1,2: Clear glass vials containing powder for injection in cartons of 5 vials or a single vial packed with a 100 mL Mini-Bag™ Plus (SABAX) Sodium Chloride 0,9% (registration number D/24/106).

STORAGE INSTRUCTIONS:
Keep out of reach of children.
Augmentin preparations should be stored in a cool, dry place below 25°C.
Augmentin IV vials: IV Injection: once reconstituted, vials must be used within 20 minutes.
  IV Infusion: Infusions must be used within 2 hours of reconstitution.

REGISTRATION NUMBERS:
Augmentin IV 0,6 (vials) –U/20.1.2/45
Augmentin IV 1,2 (vials) –U/20.1.2/46

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
SmithKline Beecham Pharmaceuticals (Pty) Ltd
6 Carey Street, Wynberg Ext. 6, Johannesburg 2090.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
09.09.1991

Augmentin and the SB logo are trade marks.

        P1391

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