INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
RANCLAV Suspension
RANCLAV Forte Suspension

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

RANCLAV Suspension
RANCLAV Forte Suspension

COMPOSITION:
Ranclav Suspension: Each 5 mL of reconstituted suspension contains:

Amoxicillin Trihydrate equivalent to amoxicillin	125 mg
and Clavulanate potassium equivalent to clavulanic acid	31,25 mg
Sodium benzoate (as preservative)	0,2%m/v
Butylated hydroxy toluene(as antioxidant)	0,006% m/v

Ranclav Forte Suspension: Each 5 mL of reconstituted suspension contains:

Amoxicillin Trihydrate equivalent to amoxicillin	250 mg
and Clavulanate potassium equivalent to clavulanic acid	62,5 mg
Sodium benzoate (as preservative)	0,2%m/v
Butylated hydroxy toluene (as antioxidant)	0,006% m/v

PHARMACOLOGICAL CLASSIFICATION:
A20.1.2 Penicillins

PHARMACOLOGICAL ACTION
Mechanism of action:
Ranclav is a combination of amoxicillin and potassium clavulanate. The amoxicillin component of the formulation exerts a bactericidal action against many strains of Gram positive and Gram-negative organisms. The clavulanic acid component has little or no antimicrobial action. It does, however, by inactivation of susceptible beta-lactamase protect amoxicillin from degradation by beta-lactamase enzymes produced by penicillin resistant strains of organisms.
Antibacterial Activity
Clavulanic acid is an irreversible inhibitor of beta-lactamases produced by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris , H. influenzae, N. gonorrhoeae and B. fragilis (In-vitro activity does not necessarily imply in-vivo efficacy). 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.
Pharmacokinetics:
The pharmacokinetics of amoxicillin and clavulanic acid are closely allied and neither are adversely affected by the presence of food in the stomach, and are stable in the presence of gastric acid. The oral bioavailability of amoxicillin and potassium clavulante is approximately 90% and 75% respectively.
Peak serum levels of both occur about 1-2 hour after oral administration. Clavulanic acid has about the same plasma elimination half-life (1 hour) as that of amoxicillin (1,3 hours). Ranclav Suspension is eliminated primarily unchanged through the renal route(glomerular filtration and tubular secretion). Approximately 50-78% of amoxicillin and 25-40% of clavulanic acid are excreted unchanged in urine within the first 6 hrs. after administration.

INDICATIONS:
Ranclav is indicated for the treatment of infections caused by amoxicillin resistant organisms producing beta-lactamases sensitive to clavulanic acid:
Upper respiratory tract infections: Otitis media, tonsillitis, sinusitis.
Lower respiratory tract infections : Bronchitis (caused by amoxicillin resistant Beta-lactamases producing E. coli, H. influenzae and Haemophilus parainfluenzae), pneumonia.
Urinary tract infections: Cystitis, urethritis, pyelonephritis.
Skin and soft tissue infections.
Ranclav formulations 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:
Allergy to penicillins and cephalosporins. Safety in pregnancy has not been established. Safety in children under the age of 6 months has not been established. Ranclav is contra-indicated in patients with a previous history of amoxicillin and potassium clavulanate associated jaundice/hepatic dysfunction. Ranclav is also contraindicated in infectious mononucleosis. Patients with lymphatic leukemia and patients with hyperuricaemia having been treated with allopurinol may also be at an increased risk of developing skin rashes.

WARNINGS:
Transient hepatitis and cholestatic jaundice has been reported, hence, Ranclav should be used with caution in patients with evidence of hepatic dysfunction.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on Ranclav 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 Ranclav, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs, Ranclav should be discontinued and the appropriate therapy instituted: Adrenaline, corticosteroids and antihistamines.

DOSAGE AND DIRECTIONS FOR USE:
Ranclav suspension may be taken immediately before a meal.
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.
Children: The dose of Ranclav in children is 25-50 mg/kg/day of the 4 parts amoxicillin, 1 part clavulanic acid preparations (which corresponds to a daily dosage of the equivalent of 20-40 mg/kg of amoxicillin 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:
Amoxicillin sensitive organisms

Product	Upper respiratory tract infections	Lower respiratory tract infections	Urinary tract infections	Skin and soft tissue infections
(Children)
Ranclav (9 - 18 kg)	5-10 mL* 8 hourly	5-10 mL* 8 hourly	5-10 mL* 8 hourly	5-10 mL* 8 hourly
Ranclav Forte (18-37 kg)	5 mL* 8 hourly	5 mL* 8 hourly	5 mL* 8 hourly	5 mL* 8 hourly

Amoxicillin 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 pneumonia	Skin and soft tissue infections Staphylococcus aureus
(Children)
Ranclav (9-18 kg)	5-10 mL** 8 hourly	5-10 mL** 8 hourly	5-10 mL** 8 hourly	5-10 mL** 8 hourly
Ranclav Forte (18-37 kg)	5-10 mL** 8 hourly	5-10 mL** 8 hourly	5-10 mL** 8 hourly	5-10 mL** 8 hourly

*        To correspond to a dosage of 25-50 mg/kg/day
**        To corespond to a dosage of 50 mg/kg/day
Directions for mixing: Add 83 mL and 80 mL water for Ranclav Suspension and Ranclav Forte Suspension respectively in 2 portions to dry mixture in the bottle. Shake well after each addition.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Amoxicillin
Sensitivity reactions are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever or urticaria. The hypersensitivity reactions reported are erythematous maculopapular rashes, urticaria, fever and joint pains. Anaphylactic shock may occur.
Gastro-intestinal
Nausea, heartburn, vomiting and diarrhoea.
Pseudomembranous colitis has been reported.
Liver
Hepatotoxicity, hepatitis, cholestatic jaundice may occur. A moderate rise in serum glutamic oxalacetic transaminase (SGOT) has been noted, but the significance of this finding is unknown.
Hemic and Lymphatic Systems
Anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and granulocytopenia have been reported during therapy with Ranclav. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.
Central Nervous System
Reversible hyperactivity, agitation, anxiety, insomnia, confusion, behavioural changes, and/or dizziness have also been reported. Depression, seizures, or hallucinations.
Other
A sore mouth or tongue and a black hairy tongue have been reported.
Allergic reactions which may include exfoliative dermatitis, other skin rashes, interstitial nephritis and vasculitis, may occur. Erythema multiforme (including Stevens Johnson syndrome), toxic episodes of necrolysis.

Clavulanic acid:
Gastrointestinal: Nausea and diarrhoea
Liver: Cholestatic jaundice and hepatitis

Precautions
Allergic reactions may occur, usually manifesting as pruritic skin rash, an erythematous skin reaction, urticaria, angiodema, anaphylaxis or eosinophilia –Coomb’s test may become positive. In this event, withdrawal of Ranclav and the administration of antihistamine will suffice in most cases. Should a serious anaphylactic reaction occur, Ranclav should be discontinued and the patient treated with the usual agents: adrenalin, corticosteroids and antihistamines.
Treatment with Ranclav may give rise to a maculopapular rash during therapy or within a few days after completion. The incidence of maculopapular rash is especially high in patients suffering from infectious mononucleosis and hence should be avoided.
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. Monilial overgrowth such as vaginitis and thrush have been reported.
Treatment with Ranclav can cause gastrointestinal symptoms such as diarrhoea, nausea and vomiting which can be minimised by administering the medicine 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 the additional amoxicillin separately.
Caution must be exercised in patients with syphilis as some patients may experience a Jarisch - Herxheimer reaction shortly after starting the treatment. Symptoms include fever, chills, headache and reactions at the site of the lesions. The reactions can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as optic atrophy.
A moderate rise in aspartame transaminase/alanine transaminase has been observed in patients treated with this combination.
Impaired renal function
Renal function should be monitored in patients with moderate to severe renal impairment and Ranclav dosage should be adjusted (See Dosage and Directions for use). High dose should be avoided in patients with impaired renal function/heart failure and in patients receiving potassium sparing diuretics.
Impaired hepatic function
Ranclav should be used with caution in patients with underlying hepatic disease as hepatic and cholestatic jaundice have been reported with this combination. The condition is more predominant in adult and eldery patients.
Use in lactation
Amoxicillin is excreted in human milk but the excretion of clavulanic acid has not been studied conclusively therefore caution should be exercised when Ranclav is administered to nursing mothers.
Interactions:
Concurrent use of Ranclav with probenecid may result in increased and prolonged blood levels of amoxicillin but since the excretion of clavulanic acid is unchanged by probenecid, its blood level remains unaffected.
Interaction of Ranclav with coumarin or indandione - derivative anticoagulants, heparin, non-steroidal anti-inflammatory drugs (NSAIDs) especially, aspirin, other platelet aggregation inhibitors or thrombolytic agents may be clinically significant. Ranclav may decrease the efficacy of oestrogen-containing oral contraceptives.
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 hyperuriceamia present in these patients. There are no data on amoxicillin/clavulanate combination and allopurinol administered concurrently.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Nausea, vomiting and diarrhoea may occur with overdosing. Treatment is symptomatic and supportive.
Amoxicillin and clavulanic acid may be removed from the circulation by haemodialysis.

IDENTIFICATION:
Ranclav Suspension:
White to off-white powder forming a white to pale yellow suspension on constitution with water. The resulting suspension has a fruity flavour.
Ranclav Forte Suspension:
White to off-white powder forming a white to pale yellow suspension on constitution with water. The resulting suspension has a fruity flavour.

PRESENTATION:
Ranclav Suspension: Natural transluscent HDPE bottle of 100 mL
Ranclav Forte Suspension: Natural transluscent HDPE bottle of 100 mL

STORAGE INSTRUCTIONS:
Store below 25°C, protected from moisture.
After reconstitution the product must be stored at 2-8°C in a refrigerator. In order to maintain stability, the prepared suspension must under no circumstances be stored outside the fridge. The prepared suspension should be consumed within 7 days of preparation.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
Ranclav Suspension:        34/20.1.2/0251
Ranclav Forte Suspension:        34/20.1.2/0252

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
RANBAXY (SA) (PTY) LTD
3^rd Floor
Outspan House
1006 Lenchen Avenue North
CENTURION

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
October 2001

New addition to this site: March 2002
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