AUGMENTIN 500 mg/62,5 mg Film-coated tablet adult Box of 16

Film-coated tablet.
Box of 16 or of 24, in blister packs.

For a film-coated tablet:

Amoxicillin: 500 mg (as amoxicillin trihydrate)
Clavulanic acid: 62,5 mg (as potassium clavulanate)

Amoxicillin/clavulanic acid ratio: 8/1.

AUGMENTIN 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,
• 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.

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 AUGMENTIN chosen to treat a particular infection should 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 AUGMENTIN (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 adults and children ≥ 40 kg, this formulation of AUGMENTIN provides a total daily dose of 2 000 mg of amoxicillin/250 mg of clavulanic acid, in two daily doses, and 3 000 mg of amoxicillin/375 mg of clavulanic acid, in three daily doses, when administered in accordance with the recommendations below.

For children < 40 kg, this formulation of AUGMENTIN provides a maximum daily dose of 1 600-3 000 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 AUGMENTIN in order to avoid the 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

Recommended doses:

• standard dose (for all indications): 1 000 mg/125 mg three times a day;
• lower dose (in particular for skin and soft tissue infections, and non-severe sinusitis): 1 000 mg/125 mg twice a day.

Children < 40 kg

In children, use AUGMENTIN in tablet, suspension or pediatric sachet form.

Recommended dose:

• of 40 mg/5 mg/kg/day to 80 mg/10 mg/kg/day (not exceeding 3 000 mg/375 mg per day) in three doses, depending on the severity of the infection.

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 AUGMENTIN formulations with an amoxicillin to clavulanic acid ratio of 8/1 is not recommended, as no dose adjustment recommendation is available.

Patients with hepatic impairment

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

Method of administration

AUGMENTIN is intended for oral administration.

Take the medicine at the start of a meal, in order to minimise the risk of gastrointestinal intolerance and to improve absorption of amoxicillin/clavulanic acid.

Treatment may be initiated parenterally according to the SmPC of the IV formulation and continued with a formulation for oral 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 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. 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. The occurrence of any allergic manifestation requires discontinuation of treatment with amoxicillin/clavulanic acid and initiation of another appropriate treatment.

Haemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving amoxicillin/clavulanic acid (see section Adverse effects). HLH is a life-threatening syndrome characterised by fever, rash, neurological symptoms, hepatomegaly and/or splenomegaly, lymphadenopathy, cytopenias, a high serum ferritin level and hypertriglyceridaemia.

Patients should be monitored to detect clinical signs and symptoms of HLH. If HLH is suspected, amoxicillin/clavulanic acid must be discontinued to allow a diagnostic work-up, and treatment of HLH should be initiated. If HLH is confirmed, administration of amoxicillin/clavulanic acid must be stopped.

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 AUGMENTIN may not be suitable when there is a significant risk that the expected pathogens 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 AUGMENTIN 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 AUGMENTIN 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, amoxicillin/clavulanic acid combination must be stopped immediately; a physician should be consulted and appropriate treatment should be 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. When high doses of amoxicillin are administered, it is advisable to maintain adequate fluid intake and urine output to reduce the risk of crystalluria. In patients with urinary catheters, catheter patency 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 AUGMENTIN 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.

Oral anticoagulants

Oral anticoagulants are often administered concomitantly with penicillin-family antibiotics 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 (Quick time) or INR should be closely monitored when amoxicillin is added or discontinued. In addition, 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 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 amoxicillin-clavulanic acid combination may be used during breastfeeding only after assessment of the benefit/risk ratio by the treating physician.

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.

Adverse effects identified in clinical studies and since the marketing of AUGMENTIN 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).
• Frequent (≥ 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).
• Frequency not determinable (cannot be estimated from the available data).

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 semi-synthetic 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 bacterial peptidoglycan biosynthesis pathway, 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 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 concentrations

The critical concentrations or breakpoints of minimum inhibitory concentrations (MIC) by which the susceptibility of the bacterial strain is interpreted are established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for amoxicillin/clavulanic acid and are as follows:

https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

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.

Absorption

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

Absorption of amoxicillin/clavulanic acid is improved when the medicine is taken at the start of a meal. 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 (oral suspension powder in sachet 1 000 mg/125 mg, three times a day) was administered fasting to groups of healthy volunteers, are presented below.

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

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 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 the urine over the 6 hours following administration of single tablets of AUGMENTIN 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, the majority 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. 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.

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 did not reveal any 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 AUGMENTIN or its constituents.

2 years.

Store at a temperature not exceeding 25 °C.

No special requirements.

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