AMOXICILLIN/CLAVULANIC ACID CRISTERS 100 mg/12,5 mg/ml Child oral suspension powder in bottle Bottle/14g

Powder for oral suspension.

Amoxicillin …..........................................................................................................................100,00 mg

As amoxicillin trihydrate

Clavulanic acid...................................................................................................................................12,50 mg

As potassium clavulanate

For 1 mL of reconstituted suspension.

One bottle of 14 g of powder corresponds to 60 mL of reconstituted oral suspension, i.e. 224 dose-graduations (1 dose = 1 kg).

Excipients with known effect : maltodextrin (source of glucose), sodium and potassium. This medicine contains:

• 2,01 mg of glucose per dose graduation, i.e. 7,52 mg per mL of suspension

• 1,23 mg of sodium per dose graduation, i.e. 4,6 mg per mL of oral suspension.

• 0,61 mg of potassium per dose-graduation, i.e. 2,28 mg per mL of oral suspension.

Excipients:

AMOXICILLIN/CLAVULANIC ACID CRISTERS is indicated for the treatment of the following infections in adults and children (see sections Dosage and administration, Warnings and precautions and Pharmacodynamics) :

• acute bacterial sinusitis (appropriately diagnosed),

• acute otitis media,

• acute exacerbations of chronic bronchitis (appropriately diagnosed),

• community-acquired acute 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.

Official recommendations concerning the appropriate use of antibacterial agents should be taken into account.

Dosage

Doses are expressed as the quantity of amoxicillin/clavulanic acid, except where indicated by reference to an individual component.

The dose of AMOXICILLIN/CLAVULANIC ACID CRISTERS chosen to treat a particular infection must take into account:

• the expected pathogens and their probable susceptibility to antibacterial agents (see section Warnings and precautions),

• the severity and site of the infection,

• the patient's age, weight and renal function (see below).

The use of other formulations of AMOXICILLIN/CLAVULANIC ACID CRISTERS (e.g., providing higher doses of amoxicillin and/or different amoxicillin/clavulanic acid ratios) should be considered, if necessary (see sections Warnings and precautions and Pharmacodynamics).

For children weighing < 40 kg, this formulation of AMOXICILLIN/CLAVULANIC ACID CRISTERS provides a maximum daily dose of 1600-3000 mg of amoxicillin/200-400 mg of clavulanic acid when administered in accordance with the recommendations below.

If a higher daily dose of amoxicillin is deemed necessary, it is recommended to choose another formulation of AMOXICILLIN/CLAVULANIC ACID CRISTERS in order to avoid unnecessary administration of high daily doses of clavulanic acid (see sections Warnings and precautions and Pharmacodynamics).

The duration of treatment will depend on the patient's response to treatment. Certain infections (e.g., osteomyelitis) require prolonged treatment. Treatment should not be extended beyond 14 days without medical advice (see section Warnings and precautions on prolonged treatment).

Adults and children ≥ 40 kg should be treated with the formulations used in adults.

Children < 40 kg

In children, use amoxicillin/clavulanic acid in tablet, suspension or pediatric sachet form.

Recommended dose:

• from 40 mg/5 mg/kg/day to 80 mg/10 mg/kg/day (not exceeding 3000 mg/375 mg per day) in three doses, depending on the severity of the infection.

 

There are no clinical data for the 8/1 formulation in patients aged less than 1 month.

 

Elderly patients

No dose adjustment is considered necessary.

Patients with renal impairment

No dose adjustment is necessary in patients with a creatinine clearance (CrCl) greater than 30 ml/min.

In patients whose creatinine clearance is less than 30 ml/min, the use of AMOXICILLIN/CLAVULANIC ACID CRISTERS formulations with an amoxicillin to clavulanic acid ratio of 8/1 is not recommended, as no dose adjustment recommendations are available.

Patients with hepatic impairment

Use with caution and monitor liver function regularly (see sections Contraindications and Warnings and precautions).

Method of administration

AMOXICILLIN/CLAVULANIC ACID CRISTERS is intended for oral administration.

AMOXICILLIN/CLAVULANIC ACID CRISTERS should be taken during a meal, in order to minimize the risk of gastrointestinal intolerance.

Treatment may be initiated parenterally according to the SmPC of the IV formulation and continued with a formulation for oral administration.

Shake to loosen the powder, add water according to the instructions, invert and shake.

Shake the bottle before each use (see section Disposal and handling).

See section Disposal and handling for instructions on reconstituting the medicine before administration.

• Hypersensitivity to the active substances, to penicillins or to any of the excipients listed in section Composition.

• History of severe immediate hypersensitivity reaction (e.g., anaphylaxis) to another beta-lactam (e.g., a cephalosporin, a carbapenem or a monobactam).

• History of jaundice/hepatic disorders associated with amoxicillin/clavulanic acid (see section Adverse effects).

Before starting treatment with amoxicillin/clavulanic acid, a thorough history is necessary to look for previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactams (see sections Contraindications and Adverse effects).

Serious and sometimes fatal hypersensitivity reactions (including anaphylactoid reactions and severe cutaneous adverse reactions) have been observed in patients treated with penicillins. Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that can lead to myocardial infarction (see section Adverse effects).

The occurrence of such reactions is more likely in patients with a history of penicillin hypersensitivity and in individuals with atopy. Drug-induced enterocolitis syndrome (DIES) has been reported mainly in children receiving amoxicillin/clavulanic acid (see section Adverse effects). SEIM is an allergic reaction whose main symptom is prolonged vomiting (1 to 4 hours after drug administration) in the absence of cutaneous or respiratory allergic symptoms. Other symptoms may include abdominal pain, diarrhoea, hypotension or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock. The occurrence of any allergic manifestation requires discontinuation of treatment with amoxicillin/clavulanic acid and initiation of another appropriate treatment.

In case of infection proven to be caused by organisms sensitive to amoxicillin, consideration should be given to replacing the amoxicillin/clavulanic acid combination with amoxicillin alone, according to official recommendations.

This presentation of AMOXICILLIN/CLAVULANIC ACID CRISTERS may not be suitable when there is a significant risk that the expected pathogens have reduced susceptibility or are resistant to beta-lactams, without mediation by beta-lactamases sensitive to inhibition by clavulanic acid. This formulation may not be suitable for treating S. pneumoniae penicillin-resistant.

Convulsions are possible in patients with renal impairment or in patients receiving high doses (see section Adverse effects).

The amoxicillin/clavulanic acid combination should be avoided in case of suspected infectious mononucleosis, as the occurrence of a morbilliform rash has been associated with this condition after the use of amoxicillin.

Concomitant use of allopurinol during treatment with amoxicillin may increase the likelihood of allergic skin reactions.

Prolonged use of AMOXICILLIN/CLAVULANIC ACID CRISTERS may in some cases lead to excessive growth of non-susceptible organisms.

The occurrence at the beginning of treatment of a generalised febrile erythema associated with pustules may be a symptom of acute generalised exanthematous pustulosis (AGEP) (see section Adverse effects). This reaction requires discontinuation of treatment with AMOXICILLIN/CLAVULANIC ACID CRISTERS and contraindicates any future use of amoxicillin in the patient.

The amoxicillin/clavulanic acid combination should be used with caution in patients showing signs of hepatic impairment (see sections Dosage and administration, Contraindications and Adverse effects).

Hepatic effects have been reported mainly in men and elderly patients and may be associated with prolonged treatment. These effects have very rarely been reported in children. In all populations, signs and symptoms generally appear during or shortly after treatment but, in some cases, may only appear several weeks after treatment has stopped. They are generally reversible. Hepatic effects can be severe and deaths have been reported in extremely rare circumstances.

They have almost always occurred in patients with a serious underlying disease or taking concomitant medicinal products known for their potential to induce hepatic effects (see section Adverse effects).

Antibiotic-associated colitis has been observed with virtually all antibacterial agents, including amoxicillin; its severity varies, from mild to life-threatening (see section Adverse effects). Therefore, it is important to consider this diagnosis if diarrhoea occurs during or after administration of any antibiotic. If antibiotic-associated colitis occurs, the amoxicillin/clavulanic acid combination must be stopped immediately; a physician should be consulted and appropriate treatment initiated. Medicinal products that inhibit peristalsis are contraindicated in this situation.

In case of prolonged treatment, it is recommended to regularly monitor organ function, in particular renal, hepatic and haematopoietic function.

Rare cases of prolonged prothrombin time (Quick time) have been reported in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be put in place when anticoagulants are prescribed concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections Interactions and Adverse effects).

In patients with renal impairment, the dose should be adjusted to the severity of the impairment (see section Dosage and administration).

Very rare cases of crystalluria (including acute renal injury) have been observed in patients with low urine output, mainly during parenteral administration. In case of administration of high doses of amoxicillin, it is advised to maintain adequate fluid intake and urine output to reduce the risk of crystalluria. In patients with urinary catheters, the patency of the catheter should be checked regularly (see sections Adverse effects and Overdose).

During treatment with amoxicillin, the enzymatic method with glucose oxidase should be used when testing for the presence of glucose in urine, as non-enzymatic methods may lead to false-positive results.

The presence of clavulanic acid in AMOXICILLIN/CLAVULANIC ACID CRISTERS may cause non-specific binding of IgG and albumin to red blood cell membranes, leading to a falsely positive Coombs test.

A positive result of the enzyme immunoassay test Aspergillus Platelia from Bio-Rad laboratories have been reported in patients receiving amoxicillin/clavulanic acid. However, these patients were not infected with Aspergillus. Cross-reactions with non- Aspergillus polysaccharides and polyfuranoses have been reported during the enzyme immunoassay test Aspergillus Platelia from Bio-Rad laboratories. Therefore, positive analytical results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Related to excipients

This medicine contains maltodextrin (glucose). Patients with glucose-galactose malabsorption syndrome (a rare hereditary disease) must not take this medicine.

This medicine contains 1,23 mg of sodium per dose graduation, i.e. 4,6 mg per mL of oral suspension: this should be taken into account in people following a strict low-sodium diet.

This medicine contains 0,61 mg of potassium per dose graduation, i.e. 2,28 mg per mL of oral suspension. To be taken into account in patients with renal impairment or in patients monitoring their dietary potassium intake.

Oral anticoagulants

Oral anticoagulants are often administered concomitantly with antibiotics of the penicillin family and no interaction has been reported. However, cases of increased INR have been reported in patients maintained on acenocoumarol or warfarin during amoxicillin administration. If co-administration is necessary, prothrombin time or INR should be closely monitored when amoxicillin is added or discontinued. In addition, a dose adjustment of oral anticoagulants may be necessary (see sections Warnings and precautions and Adverse effects).

Methotrexate

Penicillins may reduce the excretion of methotrexate and thus increase its toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may lead to a prolonged increase in the blood concentration of amoxicillin, but not of clavulanic acid.

Mycophenolate mofetil

In patients treated with mycophenolate mofetil, a decrease of approximately 50 % in the trough concentrations of the active metabolite, mycophenolic acid (MPA), has been reported in the days following the start of oral treatment combining amoxicillin and clavulanic acid. The change in trough concentration does not necessarily imply a change in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should normally not prove necessary in the absence of clinical signs of graft dysfunction. However, close clinical monitoring is required during administration of the combination, as well as shortly after the end of the antibiotic treatment.

Pregnancy

Animal studies have shown no direct or indirect harmful effects on pregnancy and/or embryonic/fetal development and/or parturition and/or postnatal development (see section Preclinical safety). Limited data on the use of amoxicillin/clavulanic acid in pregnant women do not indicate an increased risk of congenital malformations. A single study conducted in women with premature rupture of the foetal membranes before term indicated that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in newborns. Use should be avoided during pregnancy unless the physician considers it necessary.

Breast-feeding

Both substances are excreted in breast milk (the effects of clavulanic acid on the breastfed infant are not known). Therefore, diarrhoea and fungal infection of the mucous membranes are possible in the breastfed infant and may require discontinuation of breastfeeding.

The possibility of sensitisation must be taken into account. The amoxicillin-clavulanic acid combination may only be used during breast-feeding after the treating physician has assessed the benefit/risk ratio.

Effects on the ability to drive vehicles or use machines have not been studied.

However, the occurrence of adverse reactions (e.g., allergic reactions, dizziness, convulsions) that may affect the ability to drive vehicles or use machines is possible (see section Adverse effects).

The most frequent adverse reactions are diarrhoea, nausea and vomiting.

The adverse reactions identified in clinical studies and since the marketing of amoxicillin/clavulanic acid are listed below by system organ class according to MedDRA classification.

The following terminology is used to classify adverse reactions according to their frequency:

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 (frequency cannot be estimated from the available data)

Infections and infestations
Mucocutaneous candidiasis	Common
Excessive development of non-susceptible organisms	Frequency not known
Blood and lymphatic system disorders
Reversible leucopenia (including neutropenia)	Rare
Thrombocytopenia	Rare
Reversible agranulocytosis	Frequency not known
Haemolytic anaemia	Frequency not known
Prolongation of bleeding time and prothrombin time (Quick test)1	Frequency not known
Immune system disorders8
Quincke's oedema	Frequency not known
Anaphylaxis	Frequency not known
Serum sickness	Frequency not known
Hypersensitivity vasculitis	Frequency not known
Nervous system disorders
Dizziness	Uncommon
Headache	Uncommon
Reversible hyperactivity	Frequency not known
Convulsions1	Frequency not known
Aseptic meningitis	Frequency not known
Cardiac disorders
Kounis syndrome	Frequency not known
Gastrointestinal disorders
Diarrhoea	Common
Nausea2	Common
Vomiting	Common
Indigestion	Uncommon
Antibiotic-associated colitis3	Frequency not known
Drug-induced enterocolitis syndrome	Frequency not known
Acute pancreatitis	Frequency not known
Glossophytia	Frequency not known
Dental discolorations9	Frequency not known
Hepatobiliary disorders
Elevations of AST and/or ALT levels4	Uncommon
Hepatitis5	Frequency not known
Cholestatic jaundice5	Frequency not known
Skin and subcutaneous tissue disorders5
Skin rash	Uncommon
Pruritus	Uncommon
Urticaria	Uncommon
Erythema multiforme	Rare
Stevens-Johnson syndrome	Frequency not known
Toxic epidermal necrolysis	Frequency not known
Bullous or exfoliative dermatitis	Frequency not known
Acute generalised exanthematous pustulosis (AGEP)1	Frequency not known
Drug hypersensitivity syndrome (DRESS)	Frequency not known
Linear IgA dermatosis	Frequency not known
Renal and urinary disorders
Interstitial nephritis	Frequency not known
Crystalluria (including acute kidney injury)7	Frequency not known
1 See section Warnings and precautions 2 Nausea is more often associated with high oral doses. Gastrointestinal effects may be lessened by taking AMOXICILLIN/CLAVULANIC ACID CRISTERS during a meal. 3 Including pseudomembranous colitis and haemorrhagic colitis (see section Warnings and precautions) 4 A moderate increase in AST and/or ALT levels has been noted in patients treated with beta-lactam antibiotics, but the significance of these increases is unknown. 5 These effects have been observed with other penicillins and cephalosporins (see section Warnings and precautions). 6 If hypersensitivity dermatitis occurs, treatment must be discontinued (see section Warnings and precautions). 7 See section Overdose 8 See sections Contraindications and Warnings and precautions 9 Superficial dental discolorations have very rarely been observed in children. Good oral hygiene helps prevent dental discolorations, as these can generally be removed by brushing.

Reporting of suspected adverse reactions

The reporting of suspected adverse effects after marketing authorisation of the medicine is important. It allows continuous monitoring of the benefit/risk balance of the medicine. Healthcare professionals report any suspected adverse effect via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

Signs and symptoms of overdose

Gastrointestinal symptoms and disturbances of fluid and electrolyte balance are possible.

Cases of crystalluria leading in some cases to renal failure have been observed with amoxicillin (see section Warnings and precautions).

Convulsions are possible in patients with renal impairment or those receiving high doses.

Precipitation of amoxicillin has been observed in urinary catheters, particularly after intravenous administration of high doses. The patency of the catheter should be checked regularly (see section Warnings and precautions).

Management of intoxication

Treatment of gastrointestinal signs is symptomatic and involves particular monitoring of fluid and electrolyte balance.

Amoxicillin and clavulanic acid can be removed from the blood circulation by haemodialysis.

Pharmacotherapeutic class: Association of penicillins, including beta-lactamase inhibitors, ATC code: J01CR02.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (an antibiotic of the beta-lactam family), which inhibits one or more enzymes (often referred to as penicillin-binding proteins or PBPs) in the biosynthetic pathway of bacterial peptidoglycans, structural components of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to a weakening of the cell wall, often followed by cell lysis and death.

As amoxicillin is subject to degradation by beta-lactamases produced by resistant bacteria, its spectrum of activity when administered alone does not include organisms producing these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inhibits certain beta-lactamase enzymes and thus prevents the inactivation of amoxicillin. Clavulanic acid alone does not have a clinically relevant antibacterial effect.

Pharmacokinetic/pharmacodynamic relationship

The time above the minimum inhibitory concentration (T > MIC) is considered the main parameter of the efficacy of amoxicillin.

Mechanisms of resistance

The two main mechanisms of resistance to amoxicillin/clavulanic acid are:

• Inactivation by bacterial beta-lactamases not inhibited by clavulanic acid, including classes B, C and D;

• Modification of PLPs, which reduces the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may result in bacterial resistance, particularly in Gram-negative bacteria.

Critical values

The critical MIC values for amoxicillin/clavulanic acid are derived from EUCAST (European Committee on Antimicrobial Susceptibility Testing) version 12.

Organism	Critical MIC values (mg/L)
	Susceptible ≤	Resistant >
Enterobacterales associated with uncomplicated urinary tract infections	321	321
Staphylococcus spp. spp.	Note2,3,4	Note2,3,4
Enterococcus spp.5	41,6	81,6
Group A, B, C and G streptococci7	Note8	Note8
Streptococcus pneumoniae7	0,51	11
Viridans group streptococci7	Note9,10	Note9,10
Haemophilus influenzae	0,0011	21
Moraxella catarrhalis	11	11
Pasteurella multocida	11	11
Burkholderia pseudomallei	0,0011	81
Species-independent critical concentrations	21	81
1 For susceptibility testing, the concentration of clavulanic acid is fixed at 2 mg/L. 2 Most S. aureus are penicillinase producers and some are resistant to methicillin. These two mechanisms render them resistant to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. Isolates tested susceptible to benzylpenicillin and cefoxitin may be reported as susceptible to all penicillins. Isolates tested resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to beta-lactam/beta-lactamase inhibitor combinations, isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin) and nafcillin. For agents administered orally, care must be taken to obtain sufficient exposure at the site of infection. Isolates tested resistant to cefoxitin are resistant to all penicillins. 3 Most staphylococci are penicillinase producers and some are resistant to methicillin. These two mechanisms render them resistant to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. No currently available method can reliably detect penicillinase production by all staphylococcal species, but methicillin resistance can be detected with cefoxitin as mentioned. 4 The S. saprophyticus susceptible to ampicillin are mecA-negative and are susceptible to ampicillin, amoxicillin and piperacillin (without or with a beta-lactamase inhibitor). 5 The critical concentrations of aminopenicillin for enterococci are based on intravenous administration. Oral administration is only relevant for urinary tract infections. 6 Susceptibilities to ampicillin, amoxicillin and piperacillin (with and without beta-lactamase inhibitor) can be inferred from that of ampicillin. Resistance to ampicillin is uncommon in E. faecalis (to be confirmed according to the MIC) but frequent in E. faecium. 7 The addition of a beta-lactamase inhibitor does not provide any clinical benefit. 8 The susceptibility of group A, B, C and G streptococci to penicillins is inferred from the susceptibility to benzylpenicillin (indications other than meningitis), with the exception of phenoxymethylpenicillin and isoxazolylpenicillins for group B streptococci. group B. 9 Benzylpenicillin (MIC or disk diffusion) can be used to screen for beta-lactam resistance in viridans group streptococci. Isolates with a negative screening test may be reported as susceptible to the beta-lactams for which clinical critical concentrations are listed (including those that have a "Note"). Isolates with a positive screening test must be tested for susceptibility to individual agents or must be reported as resistant.   10 For isolates with a negative benzylpenicillin test (zone of inhibition ≥18 mm or MIC ≤ 0,25 mg/L), susceptibility can be inferred from that of benzylpenicillin or ampicillin. For isolates with a positive benzylpenicillin test (zone of inhibition <18 mm or MIC > 0,25 mg/L), susceptibility is inferred from that of ampicillin.

The prevalence of resistance may vary geographically and over time for some species, and local information on resistance prevalence is desirable, particularly for the treatment of severe infections. If necessary, specialist advice should be sought when the usefulness of the agent in certain types of infection may be questionable given the local prevalence of resistance.

Classes

Commonly susceptible species

Gram-positive aerobes

Enterococcus faecalis

Gardnerella vaginalis

Staphylococcus aureus (sensitive to methicillin)£ Coagulase-negative staphylococci (methicillin-sensitive)

Streptococcus agalactiae Streptococcus pneumoniae1

Streptococcus pyogenes and other beta-haemolytic streptococci

Group of Streptococcus viridans

Gram-negative aerobes

Capnocytophaga spp.

Eikenella corrodens

Haemophilus influenzae2

Moraxella catarrhalis

Pasteurella multocida Anaerobes

Bacteroides fragilis

Fusobacterium nucleatum

Prevotella spp.

Species with potentially problematic acquired resistance

Gram-positive aerobes

Enterococcus faecium$

Gram-negative aerobes

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Proteus vulgaris

Naturally resistant species

Gram-negative aerobes

Acinetobacter sp.

Citrobacter freundii

Enterobacter sp. Legionella pneumophila Morganella morganii

Providencia spp.

Pseudomonas sp.

Serratia sp.

Stenotrophomonas maltophilia

Other microorganisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetti

Mycoplasma pneumoniae

$ Moderate natural sensitivity in the absence of an acquired resistance mechanism. £ All methicillin-resistant staphylococci are resistant to the amoxicillin/clavulanic acid combination. 1 This formulation of the amoxicillin/clavulanic acid combination may not be suitable for the treatment of Streptococcus pneumoniae penicillin-resistant (see sections Dosage and administration and Warnings and precautions). 2 The existence of certain strains with decreased susceptibility has been reported in certain countries of the European Union with a frequency greater than 10%.

Absorption

Amoxicillin and clavulanic acid are completely dissociated in aqueous solution at physiological pH. These two components are rapidly absorbed after oral administration.

After oral administration, amoxicillin and clavulanic acid have a bioavailability of approximately 70 %. The plasma profiles of these two components are similar, and the time to reach maximum plasma concentration (Tmax) is approximately one hour in each case.

The pharmacokinetic results of a study in which the amoxicillin/clavulanic acid combination (powder for oral suspension in sachet 1000 mg/125 mg, three times daily) was administered fasting to groups of healthy volunteers are presented below.

Mean pharmacokinetic parameters (± SD)
Active substances administered	Dose	Cmax	Tmax*	AUC(0-∞)	T1/2
	(mg)	(μg/ml)	(h)	(μg.h/ml)	(h)
Amoxicillin
AMX/AC	1000	14,4	1,5	38,2	1,1
1000 mg/125 mg		±3,1	(0,75-2,0)	± 8,0	±0,2
Clavulanic acid
AMX/AC	125	3,2	1,0	6,3	0,91
1000 mg/125 mg		±0,85	(0,75-1,0)	±1,8	±0,09
AMX – amoxicillin, AC – clavulanic acid * Median (range)

The serum concentrations of amoxicillin and clavulanic acid obtained with the amoxicillin/clavulanic acid combination are similar to those obtained after 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 are protein-bound.

The apparent volume of distribution is approximately 0,3 to 0,4 L/kg for amoxicillin and approximately 0,2 L/kg for clavulanic acid.

After intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into cerebrospinal fluid.

Animal studies have not shown significant tissue accumulation of drug-derived substance for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Traces of clavulanic acid are also found in breast milk (see section Fertility, pregnancy and breastfeeding).

Amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section Fertility, pregnancy and breastfeeding).

Biotransformation

Amoxicillin is partially excreted in urine as inactive penicilloic acid, in a proportion of up to 10 to 25 % of the initial dose. Clavulanic acid is extensively metabolised in humans and eliminated in urine and faeces, and as carbon dioxide in expired air.

Elimination

The main route of elimination of amoxicillin is renal, whereas clavulanic acid is eliminated by both renal and non-renal mechanisms.

The amoxicillin/clavulanic acid combination 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 amoxicillin and approximately 40 to 65 % of clavulanic acid are excreted unchanged in the urine within 6 hours following administration of single tablets of amoxicillin/clavulanic acid 250 mg/125 mg or 500 mg/125 mg. Various studies have shown that urinary excretion is 50 to 85 % for amoxicillin and 27 to 60 % for clavulanic acid over a period of 24 hours. In the case of clavulanic acid, most of the medicinal product is excreted within the first 2 hours following administration.

Concomitant use of probenecid delays the excretion of amoxicillin, but does not delay the renal excretion of clavulanic acid (see section Interactions).

Age

The elimination half-life of amoxicillin in young children aged about 3 months to 2 years is similar to that of older children and adults. In very young children (including premature newborns), during the first week of life, administration should be limited to twice daily due to the immaturity of the renal elimination pathway. Because of an increased probability of impaired renal function in elderly patients, the dose should be selected carefully and it may be useful to monitor renal function.

Sex

After oral administration of amoxicillin/clavulanic acid to healthy men and women, sex has no significant effect on the pharmacokinetic characteristics of amoxicillin or clavulanic acid.

Patients with renal impairment

The total serum clearance of the amoxicillin/clavulanic acid combination decreases in proportion to the decline in renal function. A more pronounced reduction in clearance of the medicinal product is observed for amoxicillin compared with clavulanic acid, because a greater proportion of amoxicillin is excreted via the kidneys.

In case of renal impairment, the dose should therefore be selected so as to avoid unnecessary accumulation of amoxicillin while maintaining an adequate concentration of clavulanic acid (see section Dosage and administration).

Patients with hepatic impairment

The amoxicillin/clavulanic acid combination should be used with caution in patients with hepatic impairment, and hepatic function should be monitored regularly.

Non-clinical data from conventional safety pharmacology, genotoxicity and reproductive function studies revealed no particular risk for humans.

Repeated-dose toxicology studies conducted in dogs with the amoxicillin/clavulanic acid combination show a potential for gastric irritation, vomiting and discolouration of the tongue.

No carcinogenesis studies have been conducted with the amoxicillin/clavulanic acid combination or its components.

Before reconstitution : 2 years.

After reconstitution : the suspension is stored for 7 days at a temperature between 2°C and 8°C (in a refrigerator).

Before reconstitution : Store at a temperature not exceeding 25°C and protect from moisture.

After reconstitution : the suspension is stored at a temperature between 2°C and 8°C (in a refrigerator).

Bottles with a graduation mark on the label:

Before use, check that the sealing cap is intact. Shake the bottle to loosen the powder, then add water just below the mark indicated on the bottle label by an arrow. Replace the cap, turn the bottle over and shake well to obtain a homogeneous liquid. Allow the foam to disperse, then make up to the volume with water precisely to the level marked by the line indicated by an arrow. Replace the cap, turn the bottle over and shake well again.

Shake the bottle well before each use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400937595308 (Fl/14g).

Price:

4,41 euros (Fl/14g).

Social Security reimbursement at 65%.
Collection.