CLAVUMOX S (Powder for Suspension); CLAVUMOX SF (Powder for Suspension Forte)

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

CLAVUMOX S (Powder for Suspension)
CLAVUMOX SF (Powder for Suspension Forte)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CLAVUMOX S (Powder for Suspension)
CLAVUMOX SF (Powder for Suspension Forte)

COMPOSITION:

CLAVUMOX S:	Powder for suspension, when reconstituted according to instructions each 5 mL contains amoxycillin trihydrate equivalent to 125 mg amoxycillin and potassium clavulanate equivalent to 31,25 mg clavulanic acid.
CLAVUMOX SF:	Powder for suspension forte, when reconstituted according to instructions each 5 mL contains amoxycillin trihydrate equivalent to 250 mg amoxycillin and potassium clavulanate equivalent to 62,5 mg clavulanic acid.

PHARMACOLOGICAL CLASSIFICATION:
A.20.1.2 Penicillins

PHARMACOLOGICAL ACTION:
(a) Bacteriology

(i)

Spectrum - 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 gonorrhoeae 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. 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.

INDICATIONS:
CLAVUMOX formulations are indicated for the treatment of infections caused by amoxycillin resistant organisms producing beta-lactamases sensitive to clavulanic acid:
Upper respiratory tract, such as sinusitis, otitis media, tonsillitis.
Lower respiratory tract, such as bronchitis (caused by amoxycillin resistant beta-lactamase producing Escherichia coli, Haemophilus influenzae and Haemophilus para-influenzae), pneumonia.
Urinary tract infections, such as cystitis, urethritis, pyelonephritis.
Skin and soft tissues.
CLAVUMOX 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.
Safety in children under 6 months of age has not been established.
CLAVUMOX is contra-indicated in patients with a previous history of CLAVUMOX-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, CLAVUMOX should be discontinued and the appropriate therapy instituted: adrenaline, corticosteroids and antihistamines. Transient hepatitis and cholestatic jaundice has been reported. CLAVUMOX should be used with caution in patients with evidence of hepatic dysfunction.

DOSAGE AND DIRECTIONS FOR USE:
Suspensions should be taken immediately before a meal.
Reconstitution:
CLAVUMOX S:
For reconstitution to 100 mL, add 92 mL water, invert the bottle and shake well until all the powder is dispersed.
CLAVUMOX SF:
For reconstitution to 100 mL, add 90 mL water, invert the bottle and shake well until all the powder is dispersed.
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.
Children:
The dose of CLAVUMOX in children is 25 - 50 mg/kg/day of the 4 parts amoxycillin, 1 part clavulanic acid preparations (which corresponds to a daily dosage of the equivalent of 20 - 40 mg/kg of amoxycillin and 5 -10 mg/kg of clavulanic acid) to be taken in divided doses every eight hours, at the start of a meal.
Dosage Guide:
AMOXYCILLIN-SENSITIVE ORGANISMS

PRODUCT	UPPER RESPIRATORY TRACT INFECTIONS	LOWER RESPIRATORY TRACT INFECTIONS	URINARY TRACT INFECTIONS	SKIN AND SOFT TISSUE INFECTIONS
CHILDREN:
CLAVUMOX S (9-18 KG)	5-10 mL ¹⁾8hourly	5-10 mL ¹⁾8hourly	5-10 mL ¹⁾8hourly	5-10 mL ¹⁾8hourly
CLAVUMOX SF (18-37 KG)	5 mL ¹⁾8hourly	5 mL ¹⁾8hourly	5 mL ¹⁾8hourly	5 mL ¹⁾8hourly

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
CHILDREN:
CLAVUMOX S (9-18 KG)	5-10 mL ²⁾8hourly	5-10 mL ¹⁾8hourly	5-10 mL ¹⁾8hourly	5-10 mL ¹⁾8hourly
CLAVUMOX SF (18-37 KG)	5-10 mL ²⁾8hourly	5-10 mL ¹⁾⁾8hourly	5-10 mL ¹⁾8hourly	5-10 mL ¹⁾8hourly

1) To correspond to a dosage of 25-50 mg/kg/day.
2) To correspond to a dosage of 50 mg/kg/day.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most frequently reported adverse effects were 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 associated with CLAVUMOX 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 CLAVUMOX, the significance of these findings is unknown.
The following adverse reactions have been reported for ampicillin class antibiotics and may occur with CLAVUMOX:
Gastro-intestinal - Gastritis, stomatitis, glossitis black 'hairy' tongue enterocolitis and pseudomembranous colitis. If gastro-intestinal reactions are evident, they may be reduced by taking CLAVUMOX 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, CLAVUMOX 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 patients treated with CLAVUMOX.
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 CLAVUMOX 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. CLAVUMOX 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 orCandida), 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 CLAVUMOX. 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 CLAVUMOX dosage should be adjusted. (See Dosage and Administration.)
Care should be taken when treating patients with syphilis, as the Jarisch-Herxheimer reaction may occur shortly after starting treatment. This reaction, manifesting as fever, chills, headache and reactions at the site of the lesion, can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as with optic atrophy.
Use in lactation - Amoxycillin is excreted in the milk; there are no data on the excretion of clavulanic acid in human milk. Therefore, caution should be exercised when CLAVUMOX 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 CLAVUMOX may result in increased and prolonged blood levels of amoxycillin but not of clavulanic acid.
The concurrent administration of allopurinol and ampicillin increases substantially 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 CLAVUMOX and allopurinol administered concurrently.
No information is available about the concurrent use of CLAVUMOX 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 CLAVUMOX.
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 CLAVUMOX. CLAVUMOX 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:

CLAVUMOX S:	Off-white powder with a characteristic odour for reconstitution to an off-white suspension.
CLAVUMOX SF:	Off-white powder with a characteristic odour for reconstitution to an off-white suspension forte.

PRESENTATION:

CLAVUMOX S:	150 mL clear glass bottles containing powder for reconstitution to 100 mL CLAVUMOX suspension.
CLAVUMOX SF:	150 mL clear glass bottles containing powder for reconstitution to 100 mL CLAVUMOX suspension forte.

STORAGE INSTRUCTIONS:
Stability:
The 4 parts amoxycillin and 1 part clavulanic acid CLAVUMOX S and SF powder for suspension and suspension forte are stable at room temperature (25°C) as indicated by expiry date.
When reconstituted the suspensions are stable for 7 days it kept in a refrigerator (2-8°C) and should be used within 7 days.
KEEP OUT OF REACH OF CHILDREN.
CLAVUMOX S & SF dry powder should be stored in a cool, dry place below 25°C.
CLAVUMOX S & SF suspensions, once reconstituted, should be kept in a refrigerator (2-8°C). Do not freeze. Discard any unused suspension after 7 days.

REGISTRATION NUMBERS:

CLAVUMOX S (suspension) :	30/20.1.2/0317
CLAVUMOX SF (suspension forte) :	30/20.1.2/0318

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Group Laboratories SA (Pty) Limited
39 Hawkins Avenue, Epping Industria 1,
Cape Town, 7460

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
19 April 1996

Marketed and Distributed by Aspen Pharmacare
Healthcare Park
Woodlands Drive
Woodmead, 2052

P2635/1

Current: February 2004
Source: Community Pharmacy

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