Nature of contents and container updates and excipients

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SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Augmentin 1000 mg/100 mg powder for solution for injection/infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial or bottle contains sodium amoxicillin equivalent to 1000 mg amoxicillin and potassium clavulanate equivalent to 100 mg of clavulanic acid.

The sodium content of each vial or bottle is 62.9 mg (2.7 mmol).

The potassium content of each vial or bottle is 19.6 mg (0.5 mmol), which at less than 39 mg (1 mmol) is considered essentially ‘potassium-free’.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injection/infusion.Vials or bottles containing a white to off-white sterile powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Augmentin 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.

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4.2 Posology and method of administration

Posology

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

The dose of Augmentin 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 Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see section 5.1).

This Augmentin powder for solution for injection/infusion provides a total daily dose of up to 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 Augmentin 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:

Recommended doses for treatment of infections as indicated in section 4.1:

1000 mg/100 mg every 8-12 hours or 2000 mg/200 mg every 12 hours.

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

For surgical prophylaxis For procedures less than 1 hour in duration, the recommended dose is 1000 mg/100 mg to 2000 mg/200 mg given at induction of anaesthesia.

For procedures greater than 1 hour in duration, the recommended dose is 1000 mg/100 mg to 2000 mg/200 mg given at induction of anaesthesia, with up to 3 doses of 1000 mg/100 mg in 24 hours.

Clear clinical signs of infection at operation will require a normal course of intravenous or oral therapy post-operatively.

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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 necessary for patients with creatinine clearance (CrCl) greater than 30 ml/min.

In patients with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 10:1 is not recommended, as no dose adjustments are available. In such patients, Augmentin formulations with an amoxicillin to clavulanic acid ratio of 5:1 are recommended.

Hepatic impairment

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

Method of administration

Augmentin is for intravenous use.

Augmentin may be administered either by slow intravenous injection over a period of 3 to 4 mindirectly into a vein or via a drip tube or by infusion over 30 to 40 min. Augmentin is not suitable for intramuscular administration.

Children aged less than 3 months should be administered Augmentin by infusion only.

Treatment with Augmentin 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.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in section 6.1.

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

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

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4.4 Special warnings and precautions for use

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

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

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

This presentation of Augmentin 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. At recommended doses of up to 1000 mg/100 mg every 8 hours, this presentation may not be suitable for 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 Augmentin 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

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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 contraindicated in this situation.

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

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

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

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

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

The presence of clavulanic acid in Augmentin 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 AspergillusEIA 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 62.9 mg (2.7 mmol) of sodium per vial or bottle, equivalent to 3.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants

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

Methotrexate

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

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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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data onthe 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 beassociated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.

Breastfeeding

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, 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)

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Rare (1/10,000 to <1/1,000)Very rare (<1/10,000)Not known (cannot be estimated from the available data)

Infections and infestationsMucocutaneous candidosis CommonOvergrowth of non-susceptible organisms Not known

Blood and lymphatic system disordersReversible leucopenia (including neutropenia)

Rare

Thrombocytopenia RareReversible agranulocytosis Not knownHaemolytic anaemia Not knownProlongation of bleeding time andprothrombin time1

Not known

Immune system disorders10

Angioneurotic oedema Not knownAnaphylaxis Not knownSerum sickness-like syndrome Not knownHypersensitivity vasculitis Not known

Nervous system disordersDizziness UncommonHeadache UncommonConvulsions2 Not knownAseptic meningitis Not known

Vascular disordersThrombophlebitis3 Rare

Gastrointestinal disordersDiarrhoea CommonNausea UncommonVomiting UncommonIndigestion UncommonAntibiotic-associated colitis4 Not known

Hepatobiliary disordersRises in AST and/or ALT5 UncommonHepatitis6 Not knownCholestatic jaundice6 Not known

Skin and subcutaneous tissue disorders 7

Skin rash UncommonPruritus UncommonUrticaria UncommonErythema multiforme RareStevens-Johnson syndrome Not knownToxic epidermal necrolysis Not knownBullous exfoliative-dermatitis Not known

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Acute generalised exanthemous pustulosis (AGEP)9

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Not known

Renal and urinary disordersInterstitial nephritis Not knownCrystalluria8 Not known

1 See section 4.42 See section 4.43 At the site of injection4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4)5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam

class antibiotics, but the significance of these findings is unknown.6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see

section 4.4).8 See section 4.99 See section 4.410 See sections 4.3 and 4.4

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 listed in Appendix V.

4.9 Overdose

Symptoms and signs of overdose

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

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

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

Treatment of intoxication

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

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

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 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)

Organism Susceptibility Breakpoints (g/ml)Susceptible Intermediate Resistant

Haemophilus influenzae1 ≤ 1 - > 1Moraxella catarrhalis1 ≤ 1 - > 1Staphylococcus aureus 2 ≤ 2 - > 2Coagulase-negative staphylococci 2

≤ 0.25 > 0.25

Enterococcus1 ≤ 4 8 > 8

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Streptococcus A, B, C, G5 ≤ 0.25 - > 0.25Streptococcus pneumoniae3 ≤ 0.5 1-2 > 2Enterobacteriaceae1,4 - - > 8

Gram-negative Anaerobes1 ≤ 4 8 > 8Gram-positive Anaerobes1 ≤ 4 8 > 8Non-species related breakpoints1

≤ 2 4-8 > 8

1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of clavulanic acid is fixed at 2 mg/l.

2 The reported values are oxacillin concentrations.3 Breakpoint values in the table are based on ampicillin breakpoints.4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are

reported resistant. 5 Breakpoint values in the table are based on benzylpenicillin breakpoints.

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

Commonly susceptible speciesAerobic Gram-positive micro-organisms Enterococcus faecalisGardnerella vaginalisStaphylococcus aureus (methicillin-susceptible)£Coagulase-negative staphylococci (methicillin-susceptible)Streptococcus agalactiaeStreptococcus pneumoniae1

Streptococcus pyogenes and other beta-haemolytic streptococciStreptococcus viridans group

Aerobic Gram-negative micro-organismsActinobacillus actinomycetemcomitansCapnocytophaga spp.Eikenella corrodensHaemophilus influenzae2

Moraxella catarrhalisNeisseria gonorrhoeae§Pasteurella multocida

Anaerobic micro-organismsBacteroides fragilisFusobacterium nucleatumPrevotella spp.

Species for which acquired resistance may be a problemAerobic Gram-positive micro-organismsEnterococcus faecium $

Aerobic Gram-negative micro-organismsEscherichia coliKlebsiella oxytoca

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Klebsiella pneumoniaeProteus mirabilisProteus vulgaris

Inherently resistant organismsAerobic Gram-negative micro-organismsAcinetobacter sp.Citrobacter freundiiEnterobacter sp.Legionella pneumophila Morganella morganiiProvidencia spp.Pseudomonas sp.Serratia sp.Stenotrophomonas maltophilia

Other micro-organismsChlamydia trachomatisChlamydophila pneumoniaeChlamydophila psittaciCoxiella burnetti Mycoplasma pneumoniae

$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance.£ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid.§ All strains with resistance to amoxicillin that is not mediated by beta-lactamases are

resistant to amoxicillin/clavulanic acid.1 This presentation of Augmentin may not be suitable for treatment of Streptococcus

pneumoniae that are resistant to penicillin (see sections 4.2 and 4.4).2 Strains with decreased susceptibility have been reported in some countries in the EU with a

frequency higher than 10%.

5.2 Pharmacokinetic properties

Absorption

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.

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Mean (SD) pharmacokinetic parameters

Intravenous infusion over 30 minDose administered

Dose Mean peak serum conc

(g/ml)

T 1/2 (h)

AUC (h.mg/l)

Urinary recovery (%, 0 to 6 h)

AmoxicillinAMX/CA2000 mg/200 mg

2000 mg 108 21

- 119 10.6

74.7

Clavulanic acidAMX/CA2000 mg/200 mg

200 mg 13.9 2.8

- 18.2 3.0

51.4

AMX – amoxicillin, CA – clavulanic acid

Distribution

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

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

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

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

Biotransformation

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

Elimination

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

Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of 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).

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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.

5.3 Preclinical safety data

Non-clinical 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Augmentin 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 of loss of activity of the aminoglycoside under these conditions.

Augmentin solutions should not be mixed with infusions containing glucose, dextran or bicarbonate.

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6.3 Shelf life

Powder in vials or bottles

2 years

Reconstituted vials or bottles (for intravenous injection or before dilution for infusion)

The reconstituted solution (1 vial or bottle with 20 ml of Water for Injections Ph. Eur.) should be used or diluted immediately, within 20 minutes.

Diluted for intravenous infusion

Chemical and physical in-use stability has been demonstrated for 1-2 hours at 25°C. From a microbiological point of view, the reconstituted and diluted solution (1 reconstituted vial or bottle in a minimum volume of 50 ml of infusion fluid) should be used immediately.

Intravenous infusions of amoxicillin/clavulanic acid may be given in a range of different intravenous fluids. Satisfactory antibiotic concentrations are retained at room temperature (25°C) in the recommended volumes of the following infusion fluids. If reconstituted and maintained at room temperature (25°C), infusions should be completed within the times stated in the following table:

Intravenous infusion Stability period at 25°C

Water for Injection Ph.Eur. 2 hours

0.9% w/v Sodium Chloride Intravenous Infusion (9 mg/ml) 2 hoursCompound Sodium Chloride Injection 1959 (Ringer's) 1 hourCompound Sodium Lactate Intravenous Infusion (Ringer-Lactate:Hartmann's)

2 hours

The stability of Augmentin IV solutions is concentration dependent. In the event that the use of more concentrated solutions is required, the stability period should be adjusted accordingly.

Augmentin IV is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solutions of amoxicillin/clavulanic acid may be injected into the drip tubing over a period of 3 to 4 min.

Any residual antibiotic solution should be discarded.

6.4 Special precautions for storage

Do not store above 25°C.Store in the original package to protect from moisture.

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

6.5 Nature and contents of container

Clear 25 ml glass vials (Type I or Type III) or clear 50 ml glass bottles (Type III) with chlorobutyl rubber stopper (Type I) and tamper evident sealing ring.Packs of 10 vials.Packs of 1 or 5 bottles.Not all pack sizes may be marketed.

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6.6 Special precautions for disposal and other handling

For single use only. Discard any unused solution.

The reconstitution/dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Any unused medicinal 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. Augmentin 1000 mg/100 mg should be dissolved in 20 ml of solvent. This yields approximately 20.9 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.

Augmentin IV for bolus injection should be administered within 20 min of reconstitution.

Preparation of solutions for intravenous infusion

Augmentin IV must be reconstituted as described above for injection. Without delay the reconstituted solution should be added to 50 ml of infusion fluid using a minibag or in-line burette.

Augmentin IV vials or bottles are not suitable for multi-dose use.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

{Name and address}<{Tel}><{Fax}><{e-mail}>

8. MARKETING AUTHORISATION NUMBER(S)


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}Date of latest renewal: {DD month YYYY}


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10. DATE OF REVISION OF THE TEXT

{MM/YYYY}{DD/MM/YYYY}{DD month YYYY}


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LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Augmentin 1000 mg/100 mg powder for solution for injection/infusion amoxicillin/clavulanic acid

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains sodium amoxicillin equivalent to 1000 mg amoxicillin and potassium clavulanate equivalent to 100 mg of clavulanic acid.

Each bottle contains sodium amoxicillin equivalent to 1000 mg amoxicillin and potassium clavulanate equivalent to 100 mg of clavulanic acid.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for solution for injection/infusion10 vials 1 bottle5 bottles

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use after reconstitution/dilution.Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHTAND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

For single use only. Discard any unused solution.Contains penicillin.

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8. EXPIRY DATE

For storage conditions and in use shelf life of the reconstituted/diluted product see package leaflet.EXP {MM YYYY}

9. SPECIAL STORAGE CONDITIONS

Do not store above 25CStore in the original package to protect from moisture

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER


12. MARKETING AUTHORISATION NUMBER(S)


13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY


15. INSTRUCTIONS ON USE


16. INFORMATION IN BRAILLE


17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

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18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:SN:NN:

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL OR BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Augmentin 1000 mg/100 mg powder for solution for injection/infusion amoxicillin/clavulanic acidIV

2. METHOD OF ADMINISTRATION

Read the package leaflet before use

3. EXPIRY DATE

EXP {MM YYYY}

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

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PACKAGE LEAFLET

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Package leaflet: Information for the user

Augmentin 1000 mg/100 mg powder for solution for injection/infusion

amoxicillin/clavulanic acid

Read all of this leaflet carefully before you start using this medicine because it containsimportant information for you.- Keep this leaflet. You may need to read it again.- If you have any further questions, ask your doctor, pharmacist or nurse.- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet1. What Augmentin is and what it is used for2. What you need to know before you have Augmentin3. How Augmentin is given4. Possible side effects5. How to store Augmentin6. Contents of the pack and other information

1. What Augmentin is and what it is used for

Augmentin is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening.

Augmentin is used in adults and children to treat the following infections:

• severe ear, nose and throat infections• respiratory tract infections• urinary tract infections• skin and soft tissue infections including dental infections• bone and joint infections• intra-abdominal infections• genital organ infections in women.

Augmentin is used in adults and children to prevent infections associated with major surgical procedures.

2. What you need to know before you have Augmentin

You should not have Augmentin:• if you are allergic to amoxicillin, clavulanic acid, penicillin or any of the other ingredients of

this medicine (listed in section 6).• if you have ever had a severe allergic reaction to any other antibiotic. This can include a skin

rash or swelling of the face or throat.• if you have ever had liver problems or jaundice (yellowing of the skin) when taking an

antibiotic.

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Do not take Augmentin if any of the above apply to you. If you are not sure, talk to your doctor, pharmacist or nurse before having Augmentin.

Warnings and PrecautionsTalk to your doctor, pharmacist or nurse before having Augmentin if you:• have glandular fever• are being treated for liver or kidney problems• are not passing water regularly.If you are not sure if any of the above apply to you, talk to your doctor, pharmacist or nurse before taking Augmentin.

In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of Augmentin or a different medicine.

Conditions you need to look out for Augmentin can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking Augmentin, to reduce the risk of any problems. See ‘Conditions you need to look out for’ in Section 4.

Blood and urine testsIf you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking Augmentin. This is because Augmentin can affect the results of these types of tests.

Other medicines and AugmentinTell your doctor, pharmacist or nurse if you are using, have recently used or might use any other medicines.

If you are taking allopurinol (used for gout) with Augmentin, it may be more likely that you will have an allergic skin reaction.

If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of Augmentin.

If medicines to help stop blood clots (such as warfarin) are taken with Augmentin then extra blood tests may be needed.

Augmentin can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works.

Augmentin can affect how mycophenolate mofetil (a medicine used to prevent the rejection of transplanted organs) works.

Pregnancy, breast-feeding and fertilityIf you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.

Driving and using machinesAugmentin can have side effects and the symptoms may make you unfit to drive.Do not drive or operate machinery unless you are feeling well.

Augmentin contains sodium and potassium• Augmentin contains approximately 62.9 mg (2.7 mmol) of sodium (the main component of

cooking/table salt) per vial or bottle, which is equivalent to 3.2% of the recommended

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maximum daily dietary intake of sodium for an adult. This should be considered if you are on a controlled sodium diet.

• Augmentin contains approximately 19.6 mg (0.5 mmol) of potassium per vial or bottle, which at less than 39 mg (1 mmol) is considered essentially ‘potassium-free’.

3. How Augmentin is given

You will never give yourself this medicine. A qualified person, like a doctor or a nurse, will give you this medicine.

The recommended doses are:

Adults and children weighing 40 kg and over

Standard dose 1000 mg/100 mg every 8 to 12 hours.

Higher dose 1000 mg/100 mg every 8 hours or 2000 mg/200 mg every 12 hours

For very severe infections, the dose may be increased up to 2000 mg/200 mg every 8 hours.

To stop infections during and after surgery 1000 mg/100 mg to 2000 mg/200 mg before the surgery when you are given your anaesthetic.

The dose can differ depending on the type of operation you are having. Your doctor may repeat the dose if your surgery takes longer than 1 hour.

Children weighing less than 40 kg• All doses are worked out depending on the child’s bodyweight in kilograms.

Children aged 3 months and over: 50 mg/5 mg for each kilogram of bodyweight every 8 hours.

Children aged less than 3 months or weighing less than 4 kg

50 mg/5 mg for each kilogram of bodyweight every 12 hours.

Patients with kidney and liver problems• If you have kidney problems you may be given a different dose. A different strength or a

different medicine may be chosen by your doctor.• If you have liver problems your doctor will keep a close check on you and you may have more

regular liver function tests.

How Augmentin will be given to you• Augmentin will be given as an injection into a vein or by intravenous infusion.• Make sure you drink plenty of fluids while having Augmentin.• You will not normally be given Augmentin for longer than 2 weeks without the doctor

reviewing your treatment.

If more Augmentin is given to you than recommendedIt is unlikely you will be given too much, but if you think you have been given too much Augmentin, tell your doctor, pharmacist or nurse immediately. Signs may be an upset stomach (feeling sick, being sick or diarrhoea) or convulsions.

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If you have any further questions about how this medicine is given, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects below may happen with this medicine.

Conditions you need to look out for

Allergic reactions: skin rash inflammation of blood vessels (vasculitis) which may be visible as red or purple raised spots on

the skin, but can affect other parts of the body fever, joint pain, swollen glands in the neck, armpit or groin swelling, sometimes of the face or throat (angioedema), causing difficulty in breathing collapse.

Contact a doctor immediately if you get any of these symptoms. Stop taking Augmentin.

Inflammation of large intestineInflammation of the large intestine, causing watery diarrhoea usually with blood and mucus, stomach pain and/or fever.

Contact your doctor as soon as possible for advice if you get these symptoms.

Common side effectsThese may affect up to 1 in 10 people thrush (candida - a yeast infection of the vagina, mouth or skin folds) diarrhoea

Uncommon side effectsThese may affect up to 1 in 100 people skin rash, itching raised itchy rash (hives) feeling sick (nausea), especially when taking high doses

→ if affected take Augmentin before food vomiting indigestion dizziness headache.

Uncommon side effects that may show up in your blood tests: increase in some substances (enzymes) produced by the liver.

Rare side effectsThese may affect up to 1 in 1000 people skin rash, which may blister, and looks like small targets (central dark spots surrounded by a

paler area, with a dark ring around the edge – erythema multiforme) if you notice any of these symptoms contact a doctor urgently.

swelling and redness along a vein which is extremely tender when touched

Rare side effects that may show up in your blood tests: low number of cells involved in blood clotting

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low number of white blood cells.

Frequency not knownFrequency cannot be estimated from the available data. Allergic reactions (see above) Inflammation of the large intestine (see above) Inflammation of the protective membrane surrounding the brain (aseptic meningitis) Serious skin reactions:

- a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome), and a more severe form, causing extensive peeling of the skin (more than 30% of the body surface – toxic epidermal necrolysis)

- widespread red skin rash with small pus-containing blisters (bullous exfoliative dermatitis)- a red, scaly rash with bumps under the skin and blisters (exanthemous pustulosis)- flu-like symptoms with a rash, fever, swollen glands, and abnormal blood test results (including

increased white blood cells (eosinophilia) and liver enzymes) (Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)).

Contact a doctor immediately if you get any of these symptoms.

inflammation of the liver (hepatitis) jaundice, caused by increases in the blood of bilirubin (a substance produced in the liver) which

may make your skin and whites of the eyes appear yellow inflammation of tubes in the kidney blood takes longer to clot convulsions (in people taking high doses of Augmentin or who have kidney problems).

Side effects that may show up in your blood or urine tests: severe reduction in the number of white blood cells low number of red blood cells (haemolytic anaemia) crystals in urine.

Reporting of side effectsIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine

5. How to store Augmentin

The expiry date and storage instructions stated on the label are for the doctor, nurse or pharmacist’s information. The doctor, pharmacist or nurse will make up your medicine. It should be used within 20 minutes of reconstitution.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date (EXP) shown on the carton. The expiry date refers to the last day of that month.

Do not store above 25°C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

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6. Contents of the pack and other information

What Augmentin contains

• The active substance are amoxicillin and clavulanic acid. Each vial or bottle contains sodium amoxicillin equivalent to 1000 mg amoxicillin and potassium clavulanate equivalent to 100 mg of clavulanic acid.

There are no other ingredients. However, see section 2 for further important information about sodium and potassium in Augmentin.

The doctor, nurse or pharmacist will make up the injection before use using an appropriate fluid (such as Water for Injections or an injection/infusion fluid).

What Augmentin looks like and contents of the pack

Augmentin IV 1000 mg/100 mg powder for solution for injection/infusion is supplied as clear glass vials or bottles of sterile powder for making up as an injection or infusion. The vials are supplied in packs of 10. The bottles are supplied in packs of 1 or 5.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer


This medicinal product is authorised in the Member States of the EEA under the following names:

1000 mg/100 mg powder for solution for injection/infusionAustria – Augmentin intravenös, Clavamox intravenösBelgium – AugmentinGermany – Augmentan IVLuxembourg – Augmentin

This leaflet was last revised in {MM/YYYY} {month YYYY}.


---------------------------------------------------------------------------------------------------------------------------The following information is intended for healthcare professionals only:

Please refer to the Summary of Product Characteristics for further information

Administration

Augmentin may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Augmentin is not suitable for intramuscular administration.

Reconstitution

For single use only. Discard any unused solution.

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The reconstitution/dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Augmentin IV vials or bottles are not suitable for multi-dose use.

Any unused medicinal 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. Augmentin IV 1000 mg/100 mg should be dissolved in 20 ml of solvent. This yields approximately 20.9 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.

Augmentin IV for bolus injection should be administered within 20 min of reconstitution.

Preparation of solutions for intravenous infusion

Augmentin IV must be reconstituted as described above for injection. Without delay the reconstituted solution should be added to 50 ml of infusion fluid using a minibag or in-line burette.

Stability of prepared solutions

Reconstituted vials or bottles (for intravenous injection or before dilution for infusion)

The reconstituted solution (1 vial or bottle with 20 ml of Water for Injections Ph.Eur.) should be used or diluted immediately, within 20 minutes.

Diluted for intravenous infusion

Chemical and physical in-use stability has been demonstrated for 1-2 hours at 25°C. From a microbiological point of view, the reconstituted and diluted solution (1 reconstituted vial or bottle in a minimum volume of 50 ml of infusion fluid) should be used immediately.

Intravenous infusions of amoxicillin/clavulanate may be given in a range of different intravenous fluids. Satisfactory antibiotic concentrations are retained at room temperature (25°C) in the recommended volumes of the following infusion fluids. If reconstituted and maintained at room temperature (25°C), infusions should be completed within the times stated in the following table:

Intravenous infusion Stability period at 25°C

Water for Injection Ph.Eur. 2 hours

0.9% w/v Sodium Chloride Intravenous Infusion (9 mg/ml) 2 hoursCompound Sodium Chloride Injection 1959 (Ringer's) 1 hourCompound Sodium Lactate Intravenous Infusion (Ringer-Lactate:Hartmann's)

2 hours

The stability of Augmentin IV solutions is concentration dependent. In the event that the use of more concentrated solutions is required, the stability period should be adjusted accordingly.

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Augmentin IV is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solutions of Augmentin may be injected into the drip tubing over a period of 3 to 4 min.

Any residual antibiotic solution should be discarded.

Nature of contents and container updates and excipients

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