AUGMENTIN® 375 tablets; AUGMENTIN® 625 tablets; AUGMENTIN® BD tablets

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

AUGMENTIN® 375 tablets
AUGMENTIN® 625 tablets
AUGMENTIN® BD tablets

10714.062.1

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

AUGMENTIN^® 375 tablets
AUGMENTIN^® 625 tablets
AUGMENTIN^® BD tablets

COMPOSITION:

AUGMENTIN 375:	White/off-white, oval, film coated tablets containing amoxycillin trihydrate equivalent to 250 mg amoxycillin and potassium clavulanate equivalent to 125 mg clavulanic acid.
AUGMENTIN 625:	White/off-white, oval, film coated tablets containing amoxycillin trihydrate equivalent to 500 mg amoxycillin and potassium clavulanate equivalent to 125 mg clavulanic acid.
AUGMENTIN BD	White/off-white, capsule-shaped, film coated tablets containing amoxycillin trihydrate equivalent to 875 mg amoxycillin and potassium clavulanate equivalent to 125 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 7 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 beta-lactamases 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) beta-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 beta-lactamases, protect amoxycillin from degradation by a large number of beta-lactamase enzymes produced by penicillin resistant strains of organisms.

(b) Absorption
The pharmacokinetics of amoxycillin and clavulanic acid are closely allied and neither are adversely affected by the presence of food in the stomach. After an oral dose of the 2 parts amoxycillin and 1 part clavulanic acid AUGMENTIN 375 tablet, taken at the start of a meal, a mean peak serum level of 5,7 micrograms amoxycillin and 3,8 micrograms clavulanic acid per millilitre was achieved within one hour in healthy volunteers. Doubling the dose virtually doubles the peak serum level.
(c) Excretion
64,9% of amoxycillin and 37,5% of clavulanic acid are excreted unchanged in the urine in the first 6 hours after an oral dose of 2 to 1 AUGMENTIN 375 tablet. Co-administration of probenecid has little effect on the excretion of the clavulanic acid component of the formulation.

INDICATIONS:
AUGMENTIN formulations are indicated for the treatment of infections caused by amoxycillin resistant organisms producing beta-lactamases sensitive to clavulanic acid:
Upper respiratory tract infections, such as sinusitis, recurrent otitis media, tonsillitis.
Lower respiratory tract infections, such as bronchitis (caused by amoxycillin resistant beta-lactamase producing Escherichia coli, Haemophilus influenzae andHaemophilus para-influenzae), bronchopneumonia.
Genito-urinary tract infections, such as cystitis, urethritis, pyelonephritis.
Skin and soft tissue infections.
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:
In patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and cephalosporins.
Safety in pregnancy has not been established. There is limited information on the use of AUGMENTIN in human pregnancy.
Use should be avoided in pregnancy unless considered essential by the physician.
AUGMENTIN is contra-indicated in patients with a previous history of AUGMENTIN-associated jaundice/hepatic dysfunction.

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 or other allergens. If an allergic reaction occurs, AUGMENTIN should be discontinued and the appropriate therapy instituted: adrenaline, corticosteroids and antihistamines.
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.
Transient hepatitis and cholestatic jaundice has been reported. 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. AUGMENTIN BD should not be used in patients with a glomerular filtration rate of less than 30 mL/minute. Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

DOSAGE AND DIRECTIONS FOR USE:
Tablets should be taken immediately before a meal.

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:
The adult dose for AUGMENTIN is one or two AUGMENTIN 375 tablet(s) every eight hours at the start of a meal. For more severe infections and infection of the respiratory tract, the dose should be one AUGMENTIN 625 tablet every eight hours at the start of a meal, or one AUGMENTIN BD tablet every 12 hours at the start of a meal.
Since AUGMENTIN 375, 625 and BD tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), two AUGMENTIN 375 tablets are not equivalent to one AUGMENTIN 625 tablet, and two AUGMENTIN 625 tablets are not equivalent to one AUGMENTIN BD. Therefore, two AUGMENTIN 375 tablets should not be substituted for one AUGMENTIN 625 tablet or two AUGMENTIN 625 tablets for one AUGMENTIN BD tablet for the treatment of more severe infections.

Impaired renal function:
Both amoxycillin and clavulanic acid are excreted by the kidneys and the serum half-life of each increases in patients with renal failure. Therefore, the dose may need to be reduced or the interval extended. Dosage adjustments are based on the maximum recommended level of amoxycillin. The following schedule is proposed:
AUGMENTIN 375, 625:
Mild impairment (creatinine clearance greater than 30 mL/minute) : no change in dosage.
Moderate impairment (creatinine clearance 10 to 30 mL/minute) : 1 tablet every twelve hours.
Severe impairment (creatinine clearance less than 10 mL/minute) : half a tablet every twelve hours.
AUGMENTIN BD should not be used in patients with a glomerular filtration rate of less than 30 mL/minute.
Haemodialysis decreases serum concentrations of both amoxycillin and clavulanic acid and an additional dose should be administered at the end of dialysis.

DOSAGE GUIDE:
AMOXYCILLIN SENSITIVE ORGANISMS

PRODUCT	UPPER RESPIRATORY TRACT INFECTIONS	LOWER RESPIRATORY TRACT INFECTIONS	URINARY TRACT INFECTIONS	SKIN AND SOFT TISSUE INFECTIONS
ADULTS:
AUGMENTIN 375	1 - 2 tablets 8 hourly	1 - 2 tablets 8 hourly	1 - 2 tablets 8 hourly	1 - 2 tablets 8 hourly
AUGMENTIN 625	1 tablet 8 hourly	1 tablet 8 hourly	1 tablet 8 hourly	1 tablet 8 hourly
AUGMENTIN BD	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly

AMOXYCILLIN RESISTANT ORGANISMS

PRODUCT	UPPER RESPIRATORY TRACT INFECTIONS (otitis media) H. influenzae H. para influenzae	LOWER RESPIRATORY TRACT INFECTIONS (bronchitis) H. influenzae H. para influenzae	URINARY TRACT INFECTIONS E. coli Klebsiella pneumoniae	SKIN AND SOFT TISSUE INFECTIONS Staphylococcus aureus
ADULTS:
AUGMENTIN 375	2 tablets 8 hourly	2 tablets 8 hourly	1 - 2 tablets 8 hourly	1 - 2 tablets 8 hourly
AUGMENTIN 625	1 tablet 8 hourly	1 tablet 8 hourly	1 tablet 8 hourly	1 tablet 8 hourly
AUGMENTIN BD	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most frequently reported adverse effects are diarrhoea, nausea, vomiting, indigestion, 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 gastrointestinal symptoms occur - and a higher concentration of amoxycillin is required, consideration should be given to administering the additional amoxycillin separately.
The following adverse reactions have been reported for ampicillin class antibiotics and may occur with AUGMENTIN:
Hypersensitivity reactions:
Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome and hypersensitivity vasculitis have been observed. Skin rashes, pruritis and urticaria have been occasionally reported. Erythema multiforme, Stevens-Johnson syndrome, and less frequently bullous exfoliative dermatitis, toxic epidermal necrolysis and acute generalised exanthematous pustulosis (AGEP) 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). Interstitial nephritis can occur rarely.
Gastrointestinal reactions:
Effects include gastritis, stomatitis, glossitis, black `hairy' tongue and enterocolitis. Mucocutaneous candidiasis and antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis) have been reported. If gastrointestinal reactions are evident, they may be reduced by taking AUGMENTIN at the start of a meal.
Hepatic effects:
A moderate rise in aspartate transaminase (AST) and/or alanine transaminase (ALT) has been noted in patients treated with AUGMENTIN, but the significance of these findings is unknown.
Hepatitis and cholestatic jaundice have been reported.
Hepatic events have been reported predominantly in males or 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, death has been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications.
Haematologic effects:
Haemolytic anaemia, reversible thrombocytopaenia, thrombocytopaenic purpura, eosinophilia, reversible leucopaenia (including neutropaenia or 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. Prolongations of bleeding time and prothrombin time have also been reported less frequently. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly.
Central Nervous System effects:
CNS effects have been seen rarely. These include reversible hyperactivity, dizziness, headache and convulsions. Convulsions may occur with impaired renal function or in those receiving high doses.
Miscellaneous:
Superficial tooth discolouration has been reported rarely. It usually can be removed by brushing.
Special 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 the AUGMENTIN dosage should be adjusted. (see DOSAGE AND DIRECTIONS FOR USE.)
Use in lactation:
Amoxycillin is excreted in breast milk; there is no data on the excretion of clavulanic acid in human milk. Trace quantities of clavulanate can 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 breast-fed infant.
Interactions:
Probenecid decreases the renal tubular secretion of amoxycillin, but does not affect clavulanic acid excretion. Concomitant use with AUGMENTIN may result in increased and prolonged blood levels of amoxycillin but not of clavulanic acid.
The concomitant administration of allopurinol and ampicillin substantially increases the incidence of skin 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 concomitantly.
No information is available about the concurrent use of AUGMENTIN and alcohol. However, the ingestion of alcohol whilst being treated with some other beta-lactam antibiotics has precipitated a disulfiram (Antabuse®)-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 woman 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.

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 375: White/off-white, oval, film coated tablets engraved AUGMENTIN on one side.
AUGMENTIN 625: White/off-white, oval, film coated tablets engraved AUGMENTIN on one side.
AUGMENTIN BD: White/off-white, capsule shaped, scored, film-coated tablet, embossed ‘A’and ‘C’on both sides with a breakline on one side.

PRESENTATION:
AUGMENTIN 375: Amber glass bottle containing 15 AUGMENTIN 375 tablets.
AUGMENTIN 625: Amber glass bottle containing 15 AUGMENTIN 625 tablets.
AUGMENTIN BD: Amber glass bottle containing 10 AUGMENTIN BD tablets.

STORAGE INSTRUCTIONS:
AUGMENTIN preparations should be stored in a cool, dry place below 25°C and protected from light.
AUGMENTIN 375, 625 and BD tablets: Bottles should be kept tightly closed and the tablets should be dispensed in their original containers or in moisture-proof containers.
DO NOT REMOVE DESICCANT.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:

AUGMENTIN 375tablets	:	N/20.1.2/192
AUGMENTIN 625tablets	:	28/20.1.2/0494
AUGMENTIN BDtablets	:	32/20.1.2/0239

Zimbabwe:
AUGMENTIN 375tablets : 83/7.1.2/1732 PP
AUGMENTIN 625tablets : 95/7.1.2/3014 PP
AUGMENTIN BD tablets : 2001/7.1.2/3960 PP

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
GlaxoSmithKline South Africa (Pty) Limited
57 Sloane Street
Bryanston
2012

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
03 May 1999

Augmentin and the GSK logo are trademarks of the GlaxoSmithKline group of companies.

In-line with MDS-007