For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only.
Prescribing Information
1.0 Generic Name
Amoxycillin and Potassium Clavulanate for Oral Suspension IP
2.0 Qualitative and Quantitative Composition
Each combi pack contains (A) Amoxycillin and Potassium Clavulanate for Oral Suspension IP Each 5 ml of reconstituted suspension contains Amoxycillin Trihydrate IP equivalent to Amoxycillin...........600 mg Potassium Clavulanate Diluted IP equivalent to Clavulanic Acid...42.9 mg Excipients...............................................q.s. (B) 2 Ampoules of Sterile Water for Reconstitution of Dry Syrup Each ampoule contains Sterile Water for Reconstitution...........................................................25 ml
3.0 Dosage Form and Strength
Amoxycillin and Potassium Clavulanate Oral Suspension IP is an off-white powder which, when constituted, yields an off-white to tan coloured, Orange flavored suspension. Amoxycillin and Potassium Clavulanate (600 mg and 125 mg)
4.0 Clinical Particulars
4.1 Therapeutic Indications
Amoxycillin -Clavulanate should be used in accordance with local official antibiotic-prescribing guidelines and local susceptibility data. Amoxycillin and Potassium Clavulanate Oral Suspension IP is indicated for short term treatment of paediatric patients with bacterial infections at the following sites when caused by amoxycillin-clavulanate-susceptible organisms:
Upper Respiratory Tract Infections (including ENT) e.g. Acute otitis media (AOM), persistent AOM, or recurrent AOM, typically caused by Streptococcus pneumoniae*, Haemophilus influenzae# and Moraxella catarrhalis#
Tonsillo-pharyngitis and sinusitis, typically caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes.
Lower Respiratory Tract Infections e.g. lobar and bronchopneumonia typically caused by Streptococcus pneumoniae*, Haemophilus influenzae# and Moraxella catarrhalis#
*Penicillin minimum inhibitory concentration (MIC) less than or equal to 4 micrograms/mL. # Some members of these species of bacteria produce beta-lactamase, rendering them insensitive to amoxycillin alone.
Susceptibility to amoxycillin-clavulanate will vary with geography and time. Local susceptibility data should be consulted where available, and microbiological sampling and susceptibility testing performed where necessary.
Infections caused by amoxycillin-susceptible organisms are amenable to amoxycillin-clavulanate treatment due to its amoxycillin content. Mixed infections caused by amoxycillin-susceptible organisms in conjunction with amoxycillin-clavulanate- susceptible beta-lactamase-producing organisms may therefore be treated by amoxycillin clavulanate.
4.2 Posology and Method of Administration
Dosage should be expressed in terms of the age of the child and either in mg/kg/day or mL of suspension per dose.
Dosages are expressed throughout in terms of amoxycillin/clavulanate content except when doses are stated in terms of an individual component.
To minimize potential gastrointestinal intolerance, administer at the start of a meal.
The absorption of amoxycillin-clavulanate is optimized when taken at the start of a meal.
Therapy can be started parenterally and continued with an oral preparation.
Treatment should not be extended beyond 14 days without review.
Populations Amoxycillin and Potassium Clavulanate Oral Suspension IP is recommended for use in children aged 3 months and older.
Adults There is no experience with Amoxycillin and Potassium Clavulanate Oral Suspension IP in adults.
Children (3 months and older) Amoxycillin and Potassium Clavulanate Oral Suspension IP is recommended for dosing at 90/6.4 mg/kg/day in 2 divided doses at 12-hourly intervals for 10 days.
There is no experience in paediatric patients weighing more than 40 kg.
There are no clinical data on amoxycillin-clavulanate in children under 3 months of age.
Body Weight (kg)
Volume providing 90/6.4 mg/kg/day
8
3.0 mL twice daily
12
4.5 mL twice daily
16
6.0 mL twice daily
20
7.5 mL twice daily
24
9.0 mL twice daily
28
10.5 mL twice daily
32
12.0 mL twice daily
36
13.5 mL twice daily
Amoxycillin and Potassium Clavulanate Oral Suspension IP (Amoxycillin 600 mg/Clavulanic Acid 42.9 mg per 5 mL), does not contain the same amount of clavulanic acid (as the potassium salt) as any of the other Amoxycillin and Potassium Clavulanate Oral Suspension IP suspensions.
Amoxycillin and Potassium Clavulanate Oral Suspension IP contains 42.9 mg of clavulanic acid per 5 mL whereas Amoxycillin and Potassium Clavulanate Oral Suspension IP Dry syrup (Amoxycillin 200 mg/Clavulanic Acid 28.5 mg per 5 mL) suspension contains 28.5 mg of clavulanic acid per 5 mL and Amoxycillin and Potassium Clavulanate Oral Suspension IP (Amoxycillin 400 mg/Clavulanic Acid 57 mg per 5 mL) suspension contains 57 mg of clavulanic acid per 5 mL. Therefore, other Amoxycillin and Potassium Clavulanate Oral Suspension IP preparations should not be substituted for Amoxycillin and Potassium Clavulanate Oral Suspension IP, As they are not interchangeable.
Renal impairment No dosage adjustment is necessary in patients with creatinine clearance of greater than or equal to 30 mL/min. There are no dosage recommendations available for Amoxycillin and Potassium Clavulanate Oral Suspension IP in patients with creatinine clearance of less than 30 mL/min.
Hepatic impairment Dose with caution; monitor hepatic function at regular intervals. There are insufficient data on which to base a dosage recommendation.
4.3 Contraindications
in patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and cephalosporins.
in patients with a previous history of amoxycillin-clavulanate-associated jaundice/hepatic dysfunction.
4.4 Special Warnings and Precautions for use
Before initiating therapy with amoxycillin-clavulanate, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.
Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy.
These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity. If an allergic reaction occurs, amoxycillin-clavulanate therapy should be discontinued and appropriate alternative therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous (i.v.) steroids and airway management, including intubation may also be required.
Amoxycillin-clavulanate 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.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further.
In general, amoxycillin-clavulanate is well tolerated and possesses the characteristic low toxicity of the penicillin group of antibiotics. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.
Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxycillin-clavulanate and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.
Amoxycillin-clavulanate should be used with caution in patients with evidence of hepatic dysfunction.
In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxycillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxycillin crystalluria.
4.5 Drug Interactions
Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxycillin. Concomitant use with amoxycillin-clavulanate may result in increased and prolonged blood levels of amoxycillin but not of clavulanic acid. Concomitant use of allopurinol during treatment with amoxycillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of amoxycillin clavulanate and allopurinol. In common with other antibiotics, amoxycillin-clavulanate may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. In the literature there are rare cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxycillin. If co administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxycillin In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid of approximately 50% has been reported following commencement of oral amoxycillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure.
4.6 Use in Special Population
Pregnancy Use should be avoided in pregnancy, unless considered essential by the physician.
Lactation Amoxycillin-clavulanate may be administered during the period of lactation. With the exception of the risk of sensitization, associated with the excretion of trace quantities in breast milk, there are no known detrimental effects for the breast-fed infant.
Hepatic Impairment Dose with caution; monitor hepatic function at regular intervals. There are insufficient data on which to base a dosage recommendation.
Renal Impairment No dosage adjustment is necessary in patients with creatinine clearance of greater than or equal to 30 mL/min. There are no dosage recommendations available for Amoxycillin and Potassium Clavulanate Oral Suspension IP in patients with creatinine clearance of less than 30 mL/min.
4.7 Effects on Ability to Drive and Use Machines
Adverse effects on the ability to drive or operate machinery have not been observed.
4.8 Undesirable Effects
Data from large clinical trials were used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e. those occurring at < 1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency.
Infections and infestations Common: Mucocutaneous candidiasis
Blood and lymphatic system disorders: Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia Very rare: Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time
Immune system disorders Very rare: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis
Nervous system disorders: Uncommon: Dizziness, headache Very rare: Reversible hyperactivity, aseptic meningitis, convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Gastrointestinal disorders: Common: Diarrhoea, nausea, vomiting Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking amoxycillin-clavulanate at the start of a meal. Uncommon: Indigestion Very rare: Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis, Black hairy tongue. Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.
Hepatobiliary disorders Uncommon: A moderate rise in AST and/or ALT has been noted in patients treated with betalactam class antibiotics, but the significance of these findings is unknown. Very rare: Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins.
Reporting of Suspected Adverse Reactions Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zorvia.com By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 Overdose
Symptoms and Signs Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxycillin crystalluria, in some cases leading to renal failure, has been observed.
Treatment GI symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxycillin-clavulanate can be removed from the circulation by haemodialysis.
Drug abuse and dependence Drug dependency, addiction and recreational abuse have not been reported as a problem with this compound
5.0 Pharmacological Properties
5.1 Mechanism of Action
Amoxycillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxycillin is however susceptible to degradation by beta-lactamase and therefore the spectrum of activity of amoxycillin alone does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta-lactamase enzymes commonly found in micro organisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance. It is generally less effective against chromosomally-mediated type 1 beta-lactamases. The presence of clavulanic acid in amoxycillin-clavulanate formulations protects amoxycillin from degradation by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxycillin to include many bacteria normally resistant to amoxycillin and other penicillins and cephalosporins. Thus amoxycillin-clavulanate possesses the distinctive properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor.
5.2 Pharmacodynamic Properties
Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors.
Species for which acquired resistance may be a problem Aerobic Gram-positive micro-organisms: Enterococcus faecium Aerobic Gram-negative micro-organisms: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris
$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £ All methicillin-resistant staphylococci are resistant to amoxycillin/clavulanic acid. 1 Streptococcus pneumoniae that are resistant to penicillin should not be treated with this presentation of amoxycillin/clavulanic acid.
5.3 Pharmacokinetic Properties
Absorption The two components, of amoxycillin-clavulanate, amoxycillin and clavulanic acid are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxycillin-clavulanate is optimized when taken at the start of a meal.
Distribution Following i.v. administration therapeutic concentrations of both amoxycillin and clavulanic acid maybe detected in the tissues and interstitial fluid. Therapeutic concentrations of both drugs have been found in gall bladder, abdominal tissue, skin, fat, and muscle tissues; fluids found to have therapeutic levels include synovial and peritoneal fluids, bile and pus. Neither amoxycillin nor clavulanic acid is highly protein bound, studies show that about 25% for clavulanic acid and 18% for amoxycillin of total plasma drug content is bound to protein. Amoxycillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanate can also 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. No evidence of impaired fertility or harm to the foetus was detected.
Metabolism Amoxycillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one and eliminated in urine and faeces as carbon dioxide in expired air.
Elimination As with other penicillins, the major route of elimination for amoxycillin is via the kidney, whereas for clavulanate it is by both renal and non-renal mechanisms. Approximately 60 to 70% of the amoxycillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250/125 mg or a single 500/125 mg tablet. Concomitant use of probenecid delays amoxycillin excretion but does not delay renal excretion of clavulanic acid.
6.0 Nonclinical Properties
6.1 Animal Toxicology or Pharmacology
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. Repeat dose toxicity studies performed in dogs with Amoxycillin/Clavulanic Acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Amoxycillin/Clavulanic Acid.
7.0 Description
Amoxycillin-clavulanate (beta-lactam antibacterial penicillin co-formulated with a beta-lactamase inhibitor) is an antibiotic agent with a notably broad spectrum of activity against the commonly occurring bacterial pathogens in general practice and hospital. The beta-lactamase inhibitory action of clavulanate extends the spectrum of amoxycillin to embrace a wider range of organisms, including many resistant to other beta-lactam antibiotics.
8. Pharmaceutical particulars
8.1 Incompatibilities
As per carton
8.2 Shelf-Life
As per carton
8.3 Packaging Information
As per carton
8.4 Storage and Handling Instructions
Store at a temperature not exceeding 25°C, protected from light and moisture.
9.0 Patient Counselling Information
Patients should be informed that Zormox-CV ES may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, including Zormox-CV ES, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Zormox-CV ES is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may : (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zormox-CV ES or other antibacterial drugs in the future.
Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician.
Patients should be aware that Zormox-CV ES contains a penicillin class drug product that can cause allergic reactions in some individuals.
