LEVMENTIN 1 g/200 mg Powder for solution for injection/infusion IV Vial

Powder for solution for injection/for infusion.

Vials containing a sterile white to off-white powder.

Each vial contains 1 g of amoxicillin (as amoxicillin sodium) and 200 mg of clavulanic acid (as potassium clavulanate).

The amount of sodium contained in each vial is 62,9 mg (2,7 mmol).

The amount of potassium contained in each vial is 39,3 mg (1,0 mmol).

For the full list of excipients, see section Composition.

Excipients:

LEVMENTIN is indicated for the treatment of the following infections in adults and children (see sections Dosage and administration, Warnings and precautions and Pharmacodynamics) :

• severe ENT infections (such as mastoiditis, peritonsillar infections, epiglottitis and sinusitis, when accompanied by severe systemic signs and symptoms),
• exacerbation of chronic bronchitis (appropriately diagnosed),
• acute 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,
• intra-abdominal infections,
• female genital infections.

Prophylaxis of postoperative infections in adults involving:

• the digestive tract,
• the pelvic cavity,
• the head and neck,
• the biliary system.

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 LEVMENTIN 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 age, weight and renal function of the patient (see below).

The use of other formulations of LEVMENTIN (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).

LEVMENTIN powder for solution for injection/for infusion provides a total daily dose of 3 g of amoxicillin and 600 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 intravenous formulation of LEVMENTIN in order to avoid the unnecessary administration of high daily doses of clavulanic acid.

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).

Local recommendations regarding the frequency of administration of amoxicillin/clavulanic acid should be taken into account.

Adults and children ≥ 40 kg

For the treatment of infections, as indicated in section Indications : 1 g/200 mg every 8 hours.

For surgical prophylaxis	For procedures lasting less than 1 hour, the recommended dose of LEVMENTIN is 1 g/200 mg to 2 g/200 mg administered at induction of anaesthesia (to obtain doses of 2 g/200 mg, use another IV formulation of LEVMENTIN).
	For procedures lasting longer than 1 hour, the recommended dose of LEVMENTIN is 1 g/200 mg to 2 g/200 mg administered at induction of anaesthesia, which may be continued up to 3 doses of 1 g/200 mg over 24 hours.
	Clinical signs of infection during the procedure will require postoperative administration of curative intravenous or oral treatment.

Children < 40 kg

Recommended doses:

• Children aged 3 months and older : 25 mg/5 mg per kg every 8 hours
• Children aged under 3 months or weighing less than 4 kg : 25 mg/5 mg per kg every 12 hours.

Elderly patients

No dose adjustment is considered necessary.

Patients with renal impairment

Dose adjustments are based on the recommended maximum concentration of amoxicillin.

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

Adults and children ≥ 40 kg

CrCl: 10 to 30 ml/min	Initial dose of 1 g/200 mg, then 500 mg/100 mg twice daily
CrCl < 10 ml/min	Initial dose of 1 g/200 mg, then 500 mg/100 mg every 24 hours
Haemodialysis	Initial dose of 1 g/200 mg, then 500 mg/100 mg every 24 hours, plus a dose of 500 mg/100 mg at the end of dialysis (as serum concentrations of amoxicillin and clavulanic acid are decreased)

Children < 40 kg

CrCl: 10 to 30 ml/min	25 mg/5 mg per kg every 12 hours
CrCl < 10 ml/min	25 mg/5 mg per kg every 24 hours
Haemodialysis	25 mg/5 mg per kg every 24 hours, plus a dose of 12,5 mg/2,5 mg per kg at the end of dialysis (because serum concentrations of amoxicillin and clavulanic acid are reduced)

Patients with hepatic impairment

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

Method of administration

LEVMENTIN is intended for intravenous administration.

LEVMENTIN may be administered either by slow intravenous injection over a period of 3 to 4 minutes directly into a vein or as an infusion over 30 to 40 minutes. LEVMENTIN is not suitable for intramuscular administration.

In children under 3 months of age, LEVMENTIN must be administered by infusion only.

Treatment with LEVMENTIN may be started with an intravenous formulation and completed with an appropriate oral formulation, depending on the patient.

For instructions on reconstitution and dilution of the medicinal product before administration, see section Disposal and handling.

• 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 related to 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. The occurrence of any allergic manifestation requires discontinuation of treatment with amoxicillin/clavulanic acid and institution of another appropriate treatment.

Antibiotic-associated enterocolitis syndrome (drug-induced enterocolitis syndrome, DIES) has been reported mainly in children receiving amoxicillin/clavulanic acid (see section Adverse effects). DIES 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.

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, in accordance with official recommendations.

This formulation of LEVMENTIN may not be suitable when there is a significant risk that the expected pathogens are resistant to beta-lactams, not mediated by beta-lactamases sensitive to inhibition by clavulanic acid. As no specific data on T > MIC (Time above the minimum inhibitory concentration) is available and as data from comparable oral formulations are insufficient, this formulation (without additional amoxicillin) may not be suitable for the treatment of penicillin-resistant S. pneumoniae.

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 LEVMENTIN 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 LEVMENTIN 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, they may only occur several weeks after treatment has stopped. They are generally reversible. Hepatic effects may be severe and deaths have been reported in extremely rare circumstances. They have almost always concerned patients with 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; 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, LEVMENTIN must be discontinued immediately; a physician should be consulted and appropriate treatment initiated. Medicinal products that inhibit peristalsis are contraindicated in this situation.

During prolonged treatment, it is recommended to regularly monitor organ functions, in particular renal, hepatic and haematopoietic functions.

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 LEVMENTIN may cause non-specific binding of IgG and albumin to red blood cell membranes, leading to a falsely positive Coombs test.

Positive results 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.

This medicine contains 62,9 mg (2,7 mmol) of sodium per vial, which is equivalent to 3,2 % of the maximum recommended daily dietary intake of sodium by the WHO of 2 g of sodium per adult. To be taken into account in patients on a strict low-sodium diet.

This medicine contains 39,3 mg (1,0 mmol) of potassium per vial. To be taken into account in patients with renal impairment or patients on a low-potassium diet.

Oral anticoagulants

Oral anticoagulants are often administered simultaneously with antibiotics from 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 administration of amoxicillin.

If co-administration is necessary, Quick time or INR should be closely monitored when amoxicillin is added or withdrawn. Furthermore, 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 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 be 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 the amoxicillin/clavulanic acid combination in pregnant women do not indicate an increased risk of congenital malformations. A single study conducted in women with premature rupture of fetal membranes before term indicated that prophylactic treatment with amoxicillin/clavulanic acid could be associated with an increased risk of necrotising enterocolitis in newborns. The possibility of sensitisation must be taken into account. 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 amoxicillin/clavulanic acid combination should 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 LEVMENTIN are listed below by MedDRA system organ class.

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 disorders10
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
Convulsions2	Frequency not known
Aseptic meningitis	Frequency not known
Cardiac disorders
Kounis syndrome	Frequency not known
Vascular disorders
Thrombophlebitis3	Rare
Gastrointestinal disorders
Diarrhoea	Common
Nausea	Uncommon
Vomiting	Uncommon
Indigestion	Uncommon
Antibiotic-associated colitis4	Frequency not known
Drug-induced enterocolitis syndrome	Frequency not known
Acute pancreatitis	Frequency not known
Hepatobiliary disorders
Elevations of AST and/or ALT levels5	Uncommon
Hepatitis6	Frequency not known
Cholestatic jaundice6	Frequency not known
Skin and subcutaneous tissue disorders7
Skin rash	Uncommon
Pruritus	Uncommon
Urticaria	Uncommon
Erythema multiforme	Rare
Stevens-Johnson syndrome	Frequency not known
Acute necrotising epidermolysis	Frequency not known
Bullous or exfoliative dermatitis	Frequency not known
Acute generalised exanthematous pustulosis (AGEP)9	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
Crystalluria8 (including acute kidney injuries)	Frequency not known
1 See section Warnings and precautions 2 See section Warnings and precautions 3 At the injection site 4 Including pseudomembranous colitis and haemorrhagic colitis (see section Warnings and precautions) 5 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. 6 These effects have been observed with other penicillins and cephalosporins (see section Warnings and precautions). 7 If hypersensitivity dermatitis occurs, treatment must be discontinued (see section Warnings and precautions). 8 See section Overdose 9 See section Warnings and precautions 10 See sections Contraindications and Warnings and precautions

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 national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - 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: Combinations 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-lactamases and thereby 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 amoxicillin efficacy.

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 those of classes B, C and D;
• Modification of PBPs, 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 concentrations for amoxicillin/clavulanic acid are derived from EUCAST (European Committee on Antimicrobial Susceptibility Testing).

Organism	Clinical breakpoints for susceptibility (μg/ml)
	Susceptible	Intermediate susceptibility	Resistant
Haemophilus influenzae1	≤ 1	-	> 1
Moraxella catarrhalis1	≤ 1	-	> 1
Staphylococcus aureus2	≤ 2	-	> 2
Coagulase-negative staphylococci2	≤ 0,25		> 0,25
Enterococcus1	≤ 4	8	> 8
Streptococcus groups A, B, C, G5	≤ 0,25	-	> 0,25
Streptococcus pneumoniae3	≤ 0,5	1-2	> 2
Enterobacterales1,4	-	-	> 8
Gram-negative anaerobes1	≤ 4	8	> 8
Gram-positive anaerobes1	≤ 4	8	> 8
Species-independent critical concentrations1	≤ 2	4-8	> 8
1 The values indicated correspond to amoxicillin concentrations. For susceptibility testing, the clavulanic acid concentration is fixed at 2 mg/L. 2 The values indicated correspond to oxacillin concentrations. 3 The critical concentrations provided in the table are based on the critical concentrations of ampicillin. 4 The critical resistance concentration R > 8 mg/L ensures that all isolates with resistance mechanisms are reported as resistant. 5 The critical concentrations provided in the table are based on the critical concentrations of benzylpenicillin.

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 (methicillin-susceptible)£ Coagulase-negative staphylococci (methicillin-susceptible) Streptococcus agalactiae Streptococcus pneumoniae1 Streptococcus pyogenes and other beta-hemolytic streptococci Viridans group streptococci

Gram-negative aerobes Actinobacillus actinomycetemcomitans Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis Neisseria gonorrhoeae§ Pasteurella multocida

Anaerobes Bacteroides fragilis Fusobacterium nucleatum Prevotella spp.

Species with variable susceptibility (acquired resistance > 10 %)

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 Chlamydia trachomatis 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. § All strains resistant to amoxicillin, without beta-lactamase mediation, are resistant to the amoxicillin/clavulanic acid combination. 1 This presentation 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 reduced sensitivity has been reported in certain countries of the European Union with a frequency greater than 10 %.

Absorption

The pharmacokinetic results of studies in which the amoxicillin/clavulanic acid combination was administered to groups of healthy volunteers either as an intravenous bolus injection of 500 mg/100 mg or 1 g/200 mg are presented below.

Mean pharmacokinetic parameters (± SD) Intravenous bolus injection
Dose administered
	Dose	Mean serum concentration at peak (μg/ml)	T½ (h)	AUC (h.mg/L)	Urinary recovery (%, 0 to 6 h)
	Amoxicillin
AMX/AC 500 mg/100 mg	500 mg	32,2	1,07	25,5	66,5
AMX/AC 1 g/200 mg	1 000 mg	105,4	0,9	76,3	77,4
	Clavulanic acid
AMX/AC 500 mg/100 mg	100 mg	10,5	1,12	9,2	46,0
AMX/AC 1 g/200 mg	200 mg	28,5	0,9	27,9	63,8
AMX - amoxicillin, AC - clavulanic acid

Distribution

Approximately 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 the urine as the inactive penicilloic acid, in a proportion that can reach 10 to 25 % of the initial dose. Clavulanic acid is extensively metabolised in humans and eliminated in the urine and faeces, and as carbon dioxide in exhaled 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 an average elimination half-life of about one hour and an average total clearance of about 25 l/h in healthy subjects. About 60 to 70 % of the amoxicillin and about 40 to 65 % of the clavulanic acid are excreted unchanged in the urine within 6 hours following administration of a single dose of 500/100 mg or a single intravenous bolus injection of 1 g/200 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 after 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. Due to an increased likelihood of impaired renal function in elderly patients, the dose should be selected carefully and it may be useful to monitor renal function.

Patients with renal impairment

Total serum clearance of the amoxicillin/clavulanic acid combination decreases in proportion to the decline in renal function. A more pronounced reduction in drug clearance is observed for amoxicillin compared with clavulanic acid, because a greater proportion of amoxicillin is excreted renally. In cases 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 carcinogenicity studies have been conducted with the amoxicillin/clavulanic acid combination.

This medicine must not be mixed with other medicines, except those mentioned in the section Disposal and handling.

LEVMENTIN must not be mixed with blood products or with other protein-containing fluids such as protein hydrolysates or intravenous lipid emulsions. Should LEVMENTIN be prescribed with an aminoglycoside, these two antibiotics must not be mixed, either in the syringe, in the infusion bottle or in the infusion set, as this would result in a loss of aminoglycoside activity.

Solutions of LEVMENTIN must not be mixed with infusions containing glucose, dextran or bicarbonate.

Powder in vial : 3 years.

Reconstituted solution (for intravenous injection or before dilution for infusion) :

The reconstituted solution (with 20 ml of water for injection Ph.Eur.) must be used or diluted immediately, or at the latest within 20 minutes.

Diluted solution for intravenous infusion :

Physicochemical stability after dilution has been demonstrated for 2-3 hours at a temperature of 25 °C, or for 6 hours at a temperature of 5 °C.

From a microbiological point of view, the reconstituted and diluted solution (1 reconstituted vial, diluted in an infusion fluid of 100 ml) must be used immediately.

Intravenous infusions of amoxicillin/clavulanic acid may be prepared using different infusion fluids. Storage of reconstituted antibiotic solutions at a temperature of 5 °C or at room temperature (25 °C), in the recommended volume of the injectable solutions indicated below, maintains a satisfactory antibiotic concentration. If the reconstituted, diluted product is stored at a temperature of 25 °C, infusion durations should not exceed the durations indicated in the following table:

Solutions for intravenous infusion	Stability at 25 °C (hours)
Water for injections Ph.Eur.	3 hours
Solution for intravenous infusion of sodium chloride at 0,9 % (9 mg/ml)	3 hours
Injectable solution composed of sodium chloride (Ringer's solution)	2 hours
Sodium lactate solution (Ringer-Lactate: Hartmann's)	2 hours
Solution composed of potassium chloride at 0,3 % and sodium chloride solution at 0,9 % (3 mg/ml and 9 mg/ml)	2 hours

For storage at a temperature of 5 °C, reconstituted solutions of LEVMENTIN may be transferred into pre-refrigerated infusion bags containing either water for injections Ph. Eur. or sodium chloride solution (0,9 %), and may then be stored for up to 6 hours. Infusion solutions must subsequently be administered immediately after reaching room temperature.

The stability of LEVMENTIN solutions depends on their concentration. Where the use of more concentrated solutions proves necessary, the stability period must be adjusted accordingly.

LEVMENTIN is less stable when used in infusion with injectable solutions based on glucose, dextran or bicarbonate. Reconstituted amoxicillin/clavulanic acid solutions may be injected into the drip system for 3 to 4 minutes.

Any unused antibiotic solution must be discarded.

Before opening:

Do not store above 25 °C. Store in the original package, protected from moisture.

For storage conditions of the medicinal product after reconstitution, see section Shelf life.

For single use only. Any unused solution must be discarded.

Reconstitution/dilution must be carried out under aseptic conditions. Before administration, the solution must be visually inspected to ensure it contains no particles and shows no discolouration. The solution should only be used if it is clear and no particles are visible.

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

Preparation of solutions for intravenous injection

Water for injections Ph.Eur. is the solvent to be used. LEVMENTIN 1 g/200 mg must be dissolved in 20 ml of solvent, resulting in the preparation of approximately 20,9 ml of solution for single-dose administration. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or yellow.

LEVMENTIN when used for bolus injection must be administered within 20 minutes of reconstitution.

Preparation of solutions for intravenous infusion

LEVMENTIN must be reconstituted as described above for injection. The reconstituted solution must be immediately added to 100 ml of infusion fluid using a small bag or a burette infusion set.

LEVMENTIN vials are not suitable for multidose administration.

List I

Marketing authorisation (AMM)

CIP 3400933040253 (Vial). CIP 3400935077455 (10 Vials).

Price:

3,22 euros (Vial).

Reimbursed by Social Security at 65 % and approved for Collect (1 Vials).
Hospital packs (10 Vials): Collect.