Ranclav 1 g Film-coated tablets

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.

Posology

Tablets should be taken immediately before a meal. During the administration of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to prevent any possibility of amoxicillin crystalluria.

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

For severe infections and infection of the respiratory tract, 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.

Special populations

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

Adults: 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 H. influenzae, H. parainfluenzae H. influenzae, H. parainfluenzae E. coli, Klebsiella pneumoniae Staphylococcus aureus

Adults: Ranclav 1 g 1 tablet 12 hourly 1 tablet 12 hourly 1 tablet 12 hourly 1 tablet 12 hourly

Paediatric population

Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

Method of administration

Oral use. Tablets should be taken immediately before a meal.

Hypersensitivity to penicillins and cephalosporins or to any of the excipients listed in Section 6.1. Cross-sensitivity between penicillins and cephalosporins is well documented. RANCLAV 1 g is contraindicated in patients with a previous history of amoxicillin/clavulanic acid associated jaundice/hepatic dysfunction.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). 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 a hypersensitivity 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.

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 morbilliform rash if amoxicillin is used. RANCLAV 1 g should be avoided if infectious mononucleosis is suspected. RANCLAV 1 g should be given with caution to patients with lymphatic leukaemia since they are especially susceptible to amoxicillin induced skin rashes.

Prolonged may result in overgrowth of non-susceptible organisms. Pseudomembranous enterocolitis has been reported. 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. 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.

Impaired hepatic function

Changes in liver function tests have been observed in some patients receiving RANCLAV 1 g. Transient hepatitis and cholestatic jaundice has been reported. RANCLAV 1 g should be used with caution in patients with evidence of hepatic dysfunction.

Impaired renal function

In patients with moderate or severe renal impairment RANCLAV 1 g dosage should be adjusted (See section 4.2). RANCLAV 1 g should not be used in patients with a glomerular filtration rate of less than 30 mL/minute. Caution is needed when administering amoxicillin to patients with syphilis as the Jarisch-Herxheimer reaction may occur in these patients. In patients with reduced urine output, crystalluria (including acute renal injury) has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should 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.

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. Drug-induced enterocolitis syndrome (DIES) has been reported mainly in children receiving amoxicillin/clavulanate (see section 4.8). DIES is an allergic reaction with the leading symptom of protracted vomiting (1-4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Further symptoms could comprise abdominal pain, diarrhoea, hypotension or leucocytosis with neutrophilia. There have been severe cases including progression to shock.

Concomitant use of Probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin but does not affect clavulanic acid excretion. Concurrent use of probenecid with RANCLAV 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. Methotrexate: Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

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

The safety of RANCLAV 1 g in pregnancy has not been established.

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. 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.

Fertility

There is no fertility data available.

Patients should be made aware of the symptoms of dizziness or convulsions (when high doses are used), and should be careful when driving, or operating machinery.

a. Summary of the safety profile

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 gastrointestinal symptoms occur and a higher concentration of amoxicillin is required, consideration should be given to administering amoxicillin separately.

b. Tabulated list of adverse reactions

MedDRA System organ class Frequency Adverse reactions Infections and Infestations Frequent Vaginitis

Frequency Unknown Mucocutaneous candidiasis. Blood and lymphatic system disorders Less Frequent Prolongation of bleeding time and prothrombin time; thrombosis Frequency Unknown Haemolytic anaemia, reversible thrombocytopenia, thrombocytopenic purpura, eosinophilia, reversible leucopenia and agranulocytosis. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Immune system disorders Frequency Unknown Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis. 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 section 4.4).

Nervous system disorders Frequent Headache, dizziness, hot flushes Less Frequent Reversible hyperactivity, convulsions. Unknown Asceptic meningitis Convulsions may occur with impaired renal function or in those receiving high doses.

Gastrointestinal disorders Frequent Diarrhoea, nausea, vomiting, indigestion, abdominal pain Frequency Unknown Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis), black hairy tongue, gastritis, stomatitis, Drug-induced enterocolitis syndrome, pancreatitis acute (DIES) If gastrointestinal reactions are evident, they may be reduced by taking RANCLAV 1 g at the start of a meal.

Hepato-biliary disorders Frequency Unknown Hepatitis*, cholestatic jaundice*. Rises in AST and/or ALT. *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.

Skin and subcutaneous tissue disorders Frequent Skin rashes, urticaria, pruritus and erythema multiforme Less Frequent Stevens-Johnson syndrome, Toxic epidermal necrolysis, Bullous exfoliative-dermatitis Unknown Linear IgA disease Whenever such reactions occur, RANCLAV 1 g should be discontinued.

Renal and urinary disorders Frequency Unknown Interstitial nephritis, Crystalluria (including acute renal injury) General disorders and administration site conditions Frequent Abnormal taste; tiredness Cardiac disorders Unknown Kounis syndrome

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Symptoms and signs

Overdosage with amoxicillin is usually asymptomatic. However, gastro-intestinal effects such as nausea, vomiting and diarrhoea may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

Management: 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. In patients with bladder catheters, a regular check of patency should be maintained (see sections 4.8 and 4.9). 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.