INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
RANCLAV 1 g Tablets

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

RANCLAV 1 g Tablets

COMPOSITION
Each film-coated tablet contains
Amoxicillin trihydrate
equivalent to amoxicillin        875 mg
Clavulanate potassium
equivalent to clavulanic acid        125 mg
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A 20.1.2 Penicillins

PHARMACOLOGICAL ACTION
Ranclav 1 g is a combination of amoxicillin and clavulanic acid.
Amoxicillin is a semi-synthetic beta-lactamase-susceptible penicillin which has in vitro bactericidal activity against a broad spectrum of non beta-lactamase-producing Gram-positive and Gram-negative organisms. The spectrum of activity does not include those organisms which produce beta-lactamases, namely resistant staphylococci and all strains of Pseudomonas, Klebsiella and Enterobacter.
Clavulanic acid has been shown 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. Clavulanic acid 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 amoxicillin-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). The clavulanic acid component has very little bactericidal action.
Pharmacokinetics
Absorption
Amoxicillin is stable in the presence of acidic gastric secretions. Peak blood levels are achieved 1-2 hours after administration. There is a linear dose response in peak serum levels.
The pharmacokinetics of amoxicillin and clavulanic acid are closely allied and neither is adversely affected by the presence of food in the stomach.
Distribution
Approximately 18% of the total amoxicillin content is protein bound. Amoxicillin diffuses readily into most body tissues with the exception of the brain and spinal fluid. Inflammation generally increases the permeability of the meninges to penicillin and this may apply to amoxicillin.
Excretion
The elimination half-life of amoxicillin is approximately 1 hour. Co-administration of probenecid has little effect on the excretion of the clavulanic acid component of the formulation. Small amounts of amoxicillin are also excreted in the faeces and bile.

INDICATIONS
Ranclav 1 g is indicated for the treatment of infections caused by amoxicillin 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 and bronchopneumonia.
	Genito-urinary tract infections such as cystitis, urethritis, pyelonephritis.
	Skin and soft tissue infections.

Ranclav 1 g will also be effective in the treatment of infections caused by amoxicillin sensitive organisms at the appropriate amoxicillin dosage since in this situation the clavulanic acid component does not contribute to the therapeutic effect.

CONTRA-INDICATIONS
Hypersensitivity to penicillins and cephalosporins. Cross-sensitivity between penicillins and cephalosporins is well documented.
Ranclav 1 g is contra-indicated in patients with a previous history of amoxicillin/clavulanic acid associated jaundice/hepatic dysfunction.

WARNINGS
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Before initiating therapy with Ranclav 1 g, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. 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.
If an allergic reaction occurs, Ranclav 1 g should be discontinued and the appropriate therapy instituted. Serious anaphylactic reactions may require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation may also be required.
Ranclav 1 g 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.
Prolonged use may result in overgrowth of non-susceptible organisms. Pseudomembranous enterocolitis has been reported.
Prolongation of prothrombin time has been reported rarely in patients receiving Ranclav 1 g. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently.
Periodic assessment of organ function, including renal, hepatic and haemopoietic functions, is advisable during prolonged therapy.
Transient hepatitis and cholestatic jaundice has been reported. Ranclav 1 g should be used with caution in patients with evidence of hepatic dysfunction.
Ranclav 1 g should not be used in patients with a glomerular filtration rate of less than 30 mL/minute.

INTERACTIONS
Probenecid decreases the renal tubular secretion of amoxicillin, but does not affect clavulanic acid excretion. Concurrent use with Ranlav 1 g may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.
Ranclav 1 g may reduce the efficacy of oral contraceptives and patients should be warned accordingly.
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.
Tetracyclines and other bacteriostatic medicines may interfere with the bactericidal effects of amoxicillin.
Interaction with laboratory tests
It is recommended that when testing for the presence of glucose in urine during Ranclav 1 g treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.

PREGNANCY AND LACTATION
Use in pregnancy
The safety of Ranclav 1 g in pregnancy has not been established.
Use in lactation
Amoxicillin is distributed in breast milk. Although significant problems in humans have not been documented, the use of amoxicillin by nursing mothers may lead to sensitisation, diarrhoea, candidiasis and skin rash in the infant.

DOSAGE AND DIRECTIONS FOR USE
Tablets should be taken immediately before a meal.
Dosages
General Information: For infections caused by amoxicillin sensitive organisms the dosage is that approved for amoxicillin as the clavulanic acid component does not contribute to the therapeutic effect.
Adults
The adult dose for Ranclav 1 g is one Ranclav 1 g tablet every 12 hours at the start of a meal.
Since Ranclav 375, 625 and 1 g tablets contain the same amount of clavulanic acid (125 g as the potassium salt), two Ranclav 375 tablets are not equivalent to one Ranclav 625 tablet and two Ranclav 625 tablets are not equivalent to one Ranclav 1 g. Therefore two Ranclav 375 tablets should not be substituted for one Ranclav 625 tablet or two Ranclav 625 tablets for one Ranclav 1 g tablet for the treatment of more severe infections.

Impaired renal function
Both amoxicillin 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 amoxicillin. The following schedule is proposed.
Ranclav 1 g should not be used in patients with a glomerular filtration rate of <30 mL/minute.
Haemodialysis decreases serum concentrations of both amoxicillin and clavulanic acid and an additional dose should be administered at the end of dialysis.

Dosage guide

Amoxicillin-Sensitive Organisms
Product	Upper Respiratory Tract Infection	Lower Respiratory Tract Infection	Urinary Tract Infection	Skin & Soft Tissue Infections
Ranclav 1 g	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly

Amoxicillin-Resistant Organisms
Product	Upper Respiratory Tract Infection (Otitis media)	Lower Respiratory Tract Infection (bronchitis)	Urinary Tract Infection	Skin & Soft Tissue Infections
Ranclav 1 g	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly	1 tablet 12 hourly

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The side-effects considered at least possibly related to the treatment are listed below by body system, organ class and frequency (wherever applicable). Frequencies are defined as very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000) or frequency unknown.
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 Ranclav 1 g 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 amoxicillin is required, consideration should be given to administering amoxicillin separately.

The following adverse reactions have been reported and may occur with Ranclav 1 g:
Hypersensitivity reactions
Skin rashes, pruritus and urticaria, serum-sickness-like syndrome, erythema multiforme, rare cases of Stevens-Johnson syndrome, hypersensitivity vasculitis and less frequently bullous exfoliative dermatitis and toxic epidermal necrolysis have been reported. Whenever such reactions occur, Ranclav 1 g 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.
Gastro-intestinal reactions
Nausea, vomiting, diarrhoea, gastritis, stomatitis, glossitis, black ‘hairy’tongue, enterocolitis, mucocutaneous candidiasis and antibiotic associated colitis (including pseudomembranous colitis and haemorrhagic colitis). If gastro-intestinal reactions are evident, they may be reduced by taking Ranclav 1 g at the start of a meal.
Hepato-biliary disorders
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 (AST) and/or alanine transaminase (ALT) has been noted in patients treated with Ranclav 1 g, but the significance of these findings is unknown.
Renal effects
Crystalluria has been reported.
Haematological effects
Haemolytic anaemia, reversible thrombocytopenia, thrombocytopenic purpura, eosinophilia, reversible leucopenia and agranulocytosis have been reported. 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 Ranclav 1 g. Prolongation of bleeding time and prothrombin time has also been reported less frequently.
Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly.
CNS 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.

Special Precautions
Caution is needed when administering amoxicillin to patients with syphilis as the Jarisch-Herxheimer reaction may occur in these patients.
When high doses are administered, adequate fluid intake and urinary output must be maintained.
The sodium content must be taken into account in patients on a sodium-restricted diet if the administration of high doses is necessary.
Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function, is advisable during prolonged therapy. Since Ranclav 1 g contains amoxicillin, 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 amoxicillin is used. Ranclav 1 g should be given with caution to patients with lymphatic leukaemia since they are especially susceptible to amoxicillin 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 Ranclav 1 g. 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 Ranclav 1 g dosage should be adjusted (See Dosage and Directions for Use).
Use in lactation
Amoxicillin is excreted in breast milk; there are no data on the excretion of clavulanic acid in human milk. Therefore, caution should be exercised when Ranclav 1 g is administered to a nursing woman.
The use of Ranclav 1 g 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
Overdosage with amoxicillin is usually asymptomatic. However, gastro-intestinal effects such as nausea, vomiting and diarrhoea may be evident and symptoms of water and electrolyte imbalance should be treated symptomatically.
Adequate fluid intake and urinary output must be maintained to minimize the possibility of crystalluria.
Amoxicillin may be removed from the 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
White, film-coated, capsule shaped tablets debossed with ‘RX509’ on one side and a scoreline on the other.

PRESENTATION
Cartons containing 10 or 12 tablets packed in aluminium strips comprised of plain aluminium foil laminated with LDPE.

STORAGE INSTRUCTIONS
Store below 25°C in the original package, protected from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
40/20.1.2/0568

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
Centurion.

DATE OF PUBLICATION OF THE PACKAGE INSERT
August 2007

New addition to this site: December 2007
Source: Pharmaceutical Industry

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