Co-amoxiclav 2000 mg/200 mg powder for solution for infusion

Each vial contains 2000 mg amoxicillin (as amoxicillin sodium) and 200 mg clavulanic acid (as potassium clavulanate)

Each vial contains 5.5 mmol (125.9 mg) of sodium

Each vial contains 1 mmol (39.3 mg) of potassium

Powder for solution for infusion

White powder

Co-amoxiclav is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1):

• severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections, epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms)

• acute exacerbations of chronic bronchitis (adequately diagnosed)

• community acquired pneumonia

• cystitis

• pyelonephritis

• skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis

• bone and joint infections, in particular osteomyelitis

• intra-abdominal infections

• female genital infections

Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the:

• gastrointestinal tract

• pelvic cavity

• head and neck

• biliary tract surgery

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.

The dose of amoxicillin/clavulanic acid that is selected to treat an individual infection should take into account:

• the expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)

• the severity and the site of the infection

• the age, weight and renal function of the patient as shown below

The use of alternative presentations of amoxicillin/clavulanic acid (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1).

This powder for solution for infusion provides a total daily dose of 6000 mg amoxicillin and 600 mg clavulanic acid when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, this must not be achieved by increasing the Co-amoxiclav dose. This is in order to avoid administration of unnecessarily high daily doses of clavulanic acid.

The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy).

Consideration should be given to local guidelines on appropriate dosing frequencies for amoxicillin/clavulanic acid.

Adults and children ≥ 40 kg

For treatment of infections as indicated in section 4.1:

• amoxicillin/clavulanic acid 1000 mg/100 mg every 8 hours

• amoxicillin/clavulanic acid 2000 mg/ 200 mg every 12 hours

For very severe infections the dose can be increased to a maximum of 2000 mg/200 mg every 8 hour.

Children < 40 kg

Recommended doses:

• Children aged 3 months and over: 50 mg/5 mg per kg every 8 hours

• Children aged less than 3 months or weighing less than 4 kg: 50 mg/5 mg per kg every 12 hours

Elderly

No dose adjustment is considered necessary.

Renal impairment

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

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

Co-amoxiclav 2000 mg/200 mg should only be used in patients with a creatinine clearance (CrCl) of less than 30 ml / min for surgical prophylaxis when used in one infusion.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).

Method of administration

Co-amoxiclav is for intravenous use.

Co-amoxiclav 2000 mg/200 mg should be administered by intravenous infusion over 30 to 40 min. Co-amoxiclav 2000 mg/200 mg is not suitable for intramuscular administration.

Children aged less than 3 months should be administered Co-amoxiclav by infusion only.

Treatment with amoxicillin/clavulanic acid may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

• Hypersensitivity to the active substances or to penicillins

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

• History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/ clavulanic acid therapy must be discontinued, and appropriate alternative therapy instituted.

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.

This presentation of Co-amoxiclav may not be suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. As no specific data for T>MIC are available and the data for comparable oral presentations are borderline, this presentation (without additional amoxicillin) may not be suitable for the treatment of penicillin-resistant S. pneumoniae. For coverage of this pathogen, a dose of at least 2000 mg/200 mg every 12 hours is required.

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).

Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

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

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see section 4.8). This reaction requires amoxicillin/clavulanic acid discontinuation and contraindicates any subsequent administration of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8).

Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases, may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8).

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/ clavulanic acid should immediately be discontinued, a physician be consulted, and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/ clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

In patients with reduced urine output crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.

The presence of clavulanic acid in Co-amoxiclav may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

This medicinal product contains 125.9 mg sodium per vial, equivalent to 6.29% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 39.3 mg (1 mmol) of potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).

Methotrexate

Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50% has been reported following commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.

Breast-feeding

Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin /clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.

The ADRs derived from clinical studies and post-marketing surveillance with amoxicillin/clavulanic acid, sorted by MedDRA System Organ Class are listed below.

The following terminologies have been used in order to classify the occurrence of undesirable effects.

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search fro MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms and signs of overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4).

Treatment of intoxication

Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.

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

Pharmacotherapeutic group: Antibacterials for systemic use; Combinations of penicillins, incl. beta-lactamase inhibitors

ATC code: J01CR02.

Mechanism of action

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

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

Pharmacokinetic/pharmacodynamic relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.

Mechanisms of resistance

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

• inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D

• alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

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

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Absorption

The pharmacokinetic results for studies in which amoxicillin/clavulanic acid was administered to groups of healthy volunteers as 2000 mg/200 mg given as an intravenous infusion over 30 min are presented below.

Distribution

About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.

Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.

From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6).

Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).

Biotransformation

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man, and eliminated in urine and faeces and as carbon dioxide in expired air.

Elimination

The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.

Amoxicillin and clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of a single 500/100 mg or a single 1000/200 mg bolus intravenous injection. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.

Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).

Age

The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal impairment

The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).

Hepatic impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction.

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.

Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.

None

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Co-amoxiclav should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions. If prescribed concomitantly with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions. Co-amoxiclav solutions should not be mixed with infusion solutions containing glucose, dextran or bicarbonate.

2 years

Shelf-life after dilution or reconstitution

Reconstituted vials (before dilution for infusion)

The reconstituted solution (1 vial in 20 mL of water for injection) should be further diluted immediately.

Reconstituted and diluted solution (for intravenous infusion)

Chemical and physical in-use stability has been demonstrated after reconstitution and further dilution to 100 mL as shown in the following table:

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used, immediately, in-use storage times and conditions are the responsibility of the user and would not be longer than the times stated above for the chemical and physical in-use stability.

Do not store above 25°C.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Clear glass vial (Ph.Eur. Type III) fitted with a chlorobutyl rubber stopper and an aluminium ring.

Pack sizes: 1 or 10 vials in a cardboard box.

Not all pack sizes may be marketed.

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

Reconstitution/dilution must be performed under aseptic conditions. The solution must be visually inspected for particulates and discolouration prior to administration. The solution should only be used if it is clear and free of particles.

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

Preparation of solutions for intravenous injection

Water for Injection Ph. Eur. is the normal solvent.

Co-amoxiclav 2000/200 mg should be dissolved in 20 ml of solvent. This yields approximately 21.4 ml of solution for single-dose use.

A transient pink colouration may or may not develop during reconstitution.

Reconstituted solutions are normally colourless or a pale straw colour.

Preparation of solutions for intravenous infusion

Co-amoxiclav vials are not suitable for multi-dose use.

Co-amoxiclav 2000/200 mg should be reconstituted as described above. Without delay the reconstituted solution should be diluted to at least 100 ml of infusion fluid using a minibag or in-line burette.

Intravenous infusions of Co-amoxiclav may be administered with the following infusion fluids.

Compatible diluents

Water for injections Ph.Eur.

Sodium chloride 9 mg/ml (0.9%) solution for infusion

Ringer Solution

Hartmann's Solution; Ringer-Lactate Solution

Sufficient antibiotic concentrations are obtained at room temperature (25 ° C) in the recommended volume of the above infusion fluids for the times stated in section 6.3. After reconstitution, dilution and storage at room temperature (25 ° C), infusions should be completed within the time indicated in the table in section 6.3.

The stability of amoxicillin/clavulanic acid solutions for intravenous use is concentration-dependent. If more concentrated solutions are required, the stability periods should be adjusted accordingly.

Amoxicillin/clavulanic acid for intravenous use is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solutions of amoxicillin/clavulanic acid should therefore not be premixed with such infusions but can be injected into the infusion tube over a period of 3 to 4 minutes.

IBIGEN Srl

Via Fossignano, 2

04011 Aprilia (LT)

Italy

PL 31745/0038

16/11/2021

16/11/2021