Summary of medicine characteristics - CO-AMOXICLAV 125 MG / 31.25 MG / 5 ML POWDER FOR ORAL SUSPENSION
1 NAME OF THE MEDICINAL PRODUCT
Co-amoxiclav 125 mg/31.25 mg/5 ml Powder for Oral Suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
2. QUALITATIVE AND QUANTITATIVE COMPOSITION5 ml reconstituted suspension contains:
Amoxicillin trihydrate 143.50 mg corresponding to 125 mg amoxicillin
Potassium clavulanate 37.2 mg corresponding to 31.25 mg clavulanic acid
Excipients with known effect:
Each 5 ml reconstituted suspension contains 8.5 mg aspartame (E951), small amounts of sorbitol (E420), dextrose and maltodextrin (glucose).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for oral suspension
Off-white powder or off-white suspension once reconstituted.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Co-amoxiclav is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1).
Acute bacterial sinusitis (adequately diagnosed)
Acute otitis media
Acute exacerbations of chronic bronchitis (adequately diagnosed)
Community acquired pneumonia
Cystitis
Pyelonephritis
Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with
spreading cellulitis.
Bone and joint infections, in particular osteomyelitis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Posology
Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.
The dose of Co-amoxiclav that is selected to treat an individual infection should take into account:
The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)
The severity and the site of the infection
The age, weight and renal function of the patient as shown below.
The use of alternative presentations of Co-amoxiclav (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1).
For adults and children > 40 kg, this formulation of Co-amoxiclav provides a total daily dose of 1500 mg amoxicillin/375 mg clavulanic acid, when administered as recommended below. For children < 40 kg, this formulation of Co-amoxiclav provides a maximum daily dose of 2400 mg amoxicillin/600 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Co-amoxiclav is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1).
The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy).
Adults and children > 40 kg
One 500 mg/125 mg dose taken three times a day.
Children < 40 kg
20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses.
Children may be treated with Co-amoxiclav tablets or suspensions. Children aged 6 years and below should preferably be treated with Co-amoxiclav suspension.
No clinical data are available on doses of amoxicillin and clavulanic acid 4:1 formulations higher than 40 mg/10 mg/kg per day in children under 2 years.
Elderly
No dose adjustment is considered necessary.
Renal impairment
Dose adjustments are based on the maximum recommended level of amoxicillin.
No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.
Adults and children > 40 kg
| CrCl: 10–30 ml/min | 500 mg/125 mg twice daily |
| CrCl < 10 ml/min | 500 mg/125 mg once daily |
| Haemodialysis | 500 mg/125 mg every 24 hours, plus 500 mg/125 mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased) |
Children < 40 kg
| CrCl: 10–30 ml/min | 15 mg/3.75 mg/kg twice daily (maximum 500 mg/125 mg twice daily) |
| CrCl < 10 ml /min | 15 mg/3.75 mg/kg as a single daily dose (maximum 500 mg/125 mg) |
| Haemodialysis | 15 mg/3.75 mg/kg per day once daily. Prior to haemodialysis 15 mg/3.75 mg/kg. In order to restore circulating drug levels, 15 mg/3.75 mg per kg should be administered after haemodialysis. |
Hepatic impairment
Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).
Method of administration
Co-amoxiclav is for oral use.
Co-Amoxiclav should be administered with a meal to minimise potential gastrointestinal intolerance.
Therapy can be started parenterally according to the SmPC of the IV-formulation and continued with an oral preparation.
Shake to loosen powder, add water as directed, invert and shake.
Shake the bottle before each dose.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in section 6.1.
History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).
4.4 Special warnings and precautions for use
Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).
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 and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.
In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.
This presentation of Co-amoxiclav is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae.
Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).
Amoxicillin/clavulanic acid 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.
Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
Prolonged use may occasionally result in overgrowth of non-susceptible organisms.
The occurrence at the treatment initiation of a feverish generalised erythema associated with pustule may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see section 4.8). This reaction requires Co-amoxiclav discontinuation and contraindicates any subsequent administration of amoxicillin.
Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see section 4.2).
Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, 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. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8).
Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Antiperistaltic medicinal products are contraindicated in this situation.
Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.
Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).
In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).
In patients with reduced urine output, crystalluria 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 (see section 4.9).
During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.
The presence of clavulanic acid in Co-amoxiclav may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with nonAspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.
Co-amoxiclav contains aspartame (E951), which is a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks
of age.
This medicinal product contains dextrose and maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine.
Co-amoxiclav contains sorbitol (E420). This medicine contains 328 mg sorbitol in each 5ml
dose. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
This medicine contains less than 1 mmol sodium (23mg) per 5ml dose, that is to say essentially “sodium free”.
4.5 Interaction with other medicinal products and other forms of interaction
Oral anticoagulants
Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).
Methotrexate
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
Probenecid
Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.
Mycophenolate mofetil
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 amoxicillin plus clavulanic acid. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
4.6 Fertility, pregnancy and lactation
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.
Breast-feeding
Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility of sensitisation should be taken into account.
Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).
4.8 Undesirable effects
The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.
The ADRs derived from clinical studies and post-marketing surveillance with Co-amoxiclav, sorted by MedDRA System Organ Class are listed below.
The following terminologies have been used in order to classify the occurrence of undesirable effects.
Very common (>1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1,000 to <1/100)
Rare (>1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Infections and infestations
| Mucocutaneous candidosis | Common |
| Overgrowth of non-susceptible organisms | Not known |
| Blood and lymphatic system disorders | |
| Reversible leucopenia (including neutropenia) | Rare |
| Thrombocytopenia | Rare |
| Reversible agranulocytosis | Not known |
| Haemolytic anaemia | Not known |
| Prolongation of bleeding time and prothrombin time1 | Not known |
| Immune system disorders10 | |
| Angioneurotic oedema | Not known |
| Anaphylaxis | Not known |
| Serum sickness-like syndrome | Not known |
| Hypersensitivity vasculitis | Not known |
| Nervous system disorders | |
| Dizziness | Uncommon |
| Headache | Uncommon |
| Reversible hyperactivity | Not known |
| 2 2 Convulsions | Not known |
| Aseptic meningitis | Not known |
| Gastrointestinal disorders | |
| Diarrhoea | Common |
| Nausea3 | Common |
| Vomiting | Common |
| Indigestion | Uncommon |
| Antibiotic-associated colitis4 | Not known |
| Black hairy tongue | Not known |
| Tooth discolouration11 | Not known |
| Hepatobiliary disorders | |
| Rises in AST and/or ALT5 | Uncommon |
| Hepatitis6 | Not known |
| Cholestatic jaundice6 | Not known |
| Skin and subcutaneous tissue disorders 7 |
| Skin rash | Uncommon |
| Pruritus | Uncommon |
| Urticaria | Uncommon |
| Erythema multiforme | Rare |
| Stevens-Johnson syndrome | Not known |
| Toxic epidermal necrolysis | Not known |
| Bullous exfoliative-dermatitis | Not known |
| Acute generalised exanthemous pustulosis (AGEP)9 | Not known |
| Drug reaction with eosinophilia and systemic symptoms (DRESS) | Not known |
| Renal and urinary disorders | |
| Interstitial nephritis | Not known |
| 8 ‘8 Crystalluria | Not known |
| 1 See section 4.4 2 See section 4.4. 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid with a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 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. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 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. | |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
Symptoms and signs of overdose
Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident.
Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).
Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4).
Treatment of intoxication
Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of penicillins, incl. betalactamase inhibitors; ATC code: J01CR02.
Mechanism of action
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall.
Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.
Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
PK/PD relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
Mechanisms of resistance
The two main mechanisms of resistance to amoxicillin/clavulanic acid are:
Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.
Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Breakpoints
MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).
| Organism | Susceptibility Breakpoints (^g/ml) | ||
| Susceptible | Resistant | ||
| Haemophilus influenzae | < 21 | > 21 | |
| Moraxella catarrhalis | < 11 | > 11 | |
| Staphylococcus spp | < 0.1252,3,4 | > 0.1252,3,4 | |
| Enterococcus | < 41 | > 81 | |
| Streptococcus A, B, C, G | < 0.252 | > 0.252 | |
| Streptococcus pneumoniae | < 0.51,5 | > 11,5 | |
| Enterobacterales | < 81,6 | > 86 | |
| Enterobacterales in uncomplicated UTIs | <321,6 | > 326 | |
| Gram-negative Anaerobes | < 41 | > 81 | |
| Gram-positive Anaerobes (except Clostridioides difficile) | < 41 | > 81 | |
| Non-species related breakpoints | < 21 | > 81 |
1 The reported values are for amoxicillin concentrations. For susceptibility testing purposes, the concentration of clavulanic acid is fixed at 2 mg/l.
2
Breakpoint values in the table are based on benzylpenicillin breakpoints.
3
Most staphylococci are penicillinase producers, which make them resistant to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. When staphylococci test as susceptible to benzylpenicillin and cefoxitin they can be reported as susceptible to the above agents. However, the efficacy of oral formulations, particularly phenoxymethylpenicillin, is uncertain. Isolates that test as resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to P-lactamase inhibitor combinations, the isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin), nafcillin and many cephalosporins. With the exception of ceftaroline and ceftobiprole, cefoxitin-resistant isolates are resistant to all beta-lactam agents.
4 Ampicillin susceptible S. saprophyticus are mecA-negative and susceptible to ampicillin, amoxicillin and piperacillin (without or with a beta-lactamase inhibitor).
5 The oxacillin 1 unit disk screen test shall be used to exclude beta-lactam resistance mechanisms. When the screen is negative (inhibition zone >20 mm) all beta-lactam agents for which clinical breakpoints are available, can be reported susceptible without further testing.
6 Wild type Enterobacterales are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild-type isolates of E. coli and P. mirabilis as "Susceptible,
The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Gardnerella vaginalis
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Staphylococcus aureus (methicillin-susceptible)
Coagulase-negative staphylococci (methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae1
Streptococcus pyogenes and other beta-haemolytic streptococci
Streptococcus viridans group
Aerobic Gram-negative micro-organisms Capnocytophaga spp.
Eikenella corrodens
2
Haemophilus influenzae
Moraxella catarrhalis
Pasteurella multocida
Anaerobic micro-organisms
Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.
Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
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Enterococcus faecium
Aerobic Gram-negative micro-organisms
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris
Inherently resistant organisms
Aerobic Gram-negative micro-organisms
Acinetobacter sp.
Citrobacter freundii Enterobacter sp.
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas sp.
Serratia sp.
Stenotrophomonas maltophilia
Other micro-organisms
Chlamydophila pneumoniae
Chlamydophila psittaci
Coxiella burnetti
Mycoplasma pneumoniae
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Natural intermediate susceptibility in the absence of acquired mechanism of resistance.
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All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid
1Streptococcus pneumoniae that are resistant to penicillin should not be treated with this presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4).
2
Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.
5.2 Pharmacokinetic properties
Absorption
Amoxicillin 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. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour.
The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (500 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below.
| Mean (± SD) pharmacokinetic parameters | |||||
| Active substance(s) administered | Dose | Cmax | Tmax * | AUC (024h) | T 1/2 |
| (mg) | Wml) | (h) | (gg.h/ml) | (h) | |
| Amoxicillin | |||||
| AMX/CA 500 mg/125 mg | 500 | 7.19 ± 2.26 | 1.5 (1.0–2.5) | 53.5 ± 8.87 | 1.15 ± 0.20 |
| Clavulanic acid | |||||
| AMX/CA 500 mg/125 mg | 125 | 2.40 ± 0.83 | 1.5 (1.0–2.0) | 15.72 ± 3.86 | 0.98 ± 0.12 |
| AMX – amoxicillin, CA – clavulanic acid * Median (range) | |||||
Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone.
Distribution
About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3–0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.
Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.
From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).
Biotransformation
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air.
Elimination
The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.
Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single amoxicillin/clavulanic acid 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50–85% for amoxicillin and between 27–60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.
Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).
Age
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Gender
Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.
Renal impairment
The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).
Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
5.3 Preclinical safety data
5.3 Preclinical safety dataNon-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and toxicity to reproduction.
Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.
Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid anhydrous
Sodium citrate
Aspartame
Talc
Guar
Silica colloidal anhydrous
Flavouring agents (lemon containing dextrose and maltodextrin (glucose), peachapricot containing maltodextrin (glucose) and sorbitol (E420) and orange (containing essence of bergamot and maltodextrin (glucose)))
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Powder for oral suspension: 3 years
Reconstituted oral suspension: 7 days
6.4 Special precautions for storage
Powder for oral suspension: Do not store above 25°C. Store in the original container. Keep the container tightly closed in order to protect from moisture.
Oral Suspension: Store in a refrigerator (2°C to 8°C). Do not freeze. Keep the bottle tightly closed.
6.5 Nature and contents of container
Amber glass bottle with child resistant closure and polypropylene measuring spoon.
The powder in each bottle reconstitutes to form 100 ml of oral suspension.
6.6 Special precautions for disposal and other handling
Preparation of suspension formulation:
After opening of the screw cap, ensure that the bottle cap seal is intact and tightly attached to the bottle rim. Do not use if not intact. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well.
| Strength | Volume of water to be added after reconstitution (ml) | Final volume of reconstituted oral suspension (ml) |
| 125mg/31.25mg/5ml | 95 | 100 |
Alternatively fill the bottle with water to just below the mark on the bottle label, invert and shake well, then top up with water exactly to the mark, invert and again shake well.
Shake the bottle well before each dose.
After reconstitution the ready-for-use suspension is off-white.
This medicinal product should not be used if lumps of powder are visible in the bottle before reconstitution.
After reconstitution the product should not be used if the colour of the reconstituted product is different from the one described before.
No special requirements for disposal.