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CO-AMOXICLAV 1000MG/200MG POWDER FOR SOLUTION FOR INJECTION/INFUSION

Active substance(s): AMOXICILLIN SODIUM / POTASSIUM CLAVULANATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Co-Amoxiclav 1000mg/200mg powder for solution for injection/infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1000 mg of amoxicillin as amoxicillin sodium and 200 mg
clavulanic acid as potassium clavulanate

3

PHARMACEUTICAL FORM
1000 mg/200 mg powder for solution for injection/infusion
Powder for solution for injection/infusion
Vials containing a white to off-white powder.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Co-Amoxiclav 1000mg/200mg 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 and method of administration
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 Co-Amoxiclav 1000mg/200mg 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 Co-Amoxiclav 1000mg/200mg (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).
Co-Amoxiclav 1000mg/200mg powder for solution for injection/infusion provides a
total daily dose of 3000 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 it is recommended that an alternative intravenous formulation
of Co-Amoxiclav 1000mg/200mg is selected 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



4.2

For treatment of infections as indicated in section 4.1:


1000 mg/ 200 mg every 8 hours

For surgical
prophylaxis

For procedures less than 1 hour in duration, the recommended dose
of Co-Amoxiclav 1000mg/200mg is 1000 mg/200 mg to 2000
mg/200 mg given at induction of anaesthesia (Doses of 2000
mg/200 mg can be achieved by using an alternative intravenous
formulation of Co-Amoxiclav 1000mg/200mg).
For procedures greater than 1 hour in duration, the recommended
dose of Co-Amoxiclav 1000mg/200mg is 1000 mg/200 mg to 2000
mg/200 mg given at induction of anaesthesia, with up to 3 doses of
1000 mg/200 mg in 24 hours.
Clear clinical signs of infection at operation will require a normal
course of intravenous or oral therapy post-operatively

Children < 40 kg
Recommended doses:
Co-Amoxiclav 1000mg/200mg 1000 mg/200 mg powder for solution for
injection/infusion


Children aged 3 months and over: 25 mg/5 mg per kg every 8 hours;



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

Older people
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.
1000 mg/200 mg, powder for solution for injection/infusion



Adults and children

40 kg

CrCl: 10-30
ml/min

Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given
twice daily

CrCl < 10 ml
/min

Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given
every 24 hours

Haemodialysis Initial dose of 1000 mg/200 mg and then followed by 500 mg/100
mg every 24 hours, plus a dose of 500 mg/100 mg at the end of

dialysis (as serum concentrations of both amoxicillin and clavulanic
acid are decreased)

Children < 40 kg

CrCl: 10 to 30 25 mg/5 mg per kg given every 12 hours
ml/min
CrCl < 10 ml
/min

25 mg/5 mg per kg given every 24 hours

Haemodialysis 25 mg/5 mg per kg given every 24 hours, plus a dose of 12.5 mg/2.5
mg per kg at the end of dialysis (as serum concentrations of both
amoxicillin and clavulanic acid are decreased).

Hepatic impairment
Dose with caution and monitor hepatic function at regular intervals (see sections 4.3
and 4.4).
Method of administration
Co-Amoxiclav 1000mg/200mg is for intravenous use.
Co-Amoxiclav 1000mg/200mg 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.
Children aged less than 3 months should be administered Co-Amoxiclav
1000mg/200mg by infusion only.
Co-Amoxiclav 1000mg/200mg is not suitable for intramuscular administration.
Treatment with Co-Amoxiclav 1000mg/200mg may be initiated by the use of an
intravenous preparation and completed with an appropriate oral presentation as
considered appropriate for the individual patient.

4.3

Contraindications
Hypersensitivity to the active substances or to any of the 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).

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 section 4.3 and 4.8).
Serious and occasionally fatal hypersensitivity (anaphylactoid) 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 should be discontinued
and appropriate alternative therapy instituted.
In the case that an infection is proven to be due to an amoxicillin-susceptible
organism(s) then consideration should be given to switching from
amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.
This presentation of Amoxicillin/Clavulanic acid [MAH] may not be suitable for use
when there is a high risk that the presumptive pathogens have resistance to betalactam 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, the presentation 1000 mg/200 mg (without additional
amoxicillin) may not be suitable for the treatment of penicillin-resistant S.
pneumoniae
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 exanthematous
pustulosis (AGEP) (see Section 4.8). This reaction requires Amoxicillin/Clavulanic

acid [MAH] discontinuation and contra-indicates 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 [MAH] should
immediately be discontinued, a physician be consulted and an appropriate therapy
initiated. Anti-peristaltic drugs 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
section 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 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 Amoxicillin/Clavulanic acid [MAH] 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 62.9 mg (2.7 mmol) of sodium per vial. To be taken
into consideration by patients on a controlled sodium diet.
This medicinal product contains 39.3 mg (1.0 mmol) of potassium per vial. To be
taken into consideration by patients with reduced kidney function or patients on a
controlled potassium 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.

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 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.

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
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)
Infections and infestations
Mucocutaneous candidosis

Common

Overgrowth of non-susceptible
organisms

Not known

Blood and lymphatic system disorders
Reversible leucopenia (including
neutropenia)

Rare

Thrombocytopenia

Rare

Reversible agranulocytosis

Not known

Haemolytic anaemia

Not known

Prolongation of bleeding time and
prothrombin time1

Not known

Immune system disorders10
Angiooedema

Not known

Anaphylaxis

Not known

Serum sickness-like syndrome

Not known

Hypersensitivity vasculitis

Not known

Nervous system disorders
Dizziness

Uncommon

Headache

Uncommon

Convulsions2

Not known

Aseptic meningitis

Not known

Vascular disorders
Thrombophlebitis3

Rare

Gastrointestinal disorders
Diarrhoea

Common

Nausea

Uncommon

Vomiting

Uncommon

Indigestion

Uncommon
4

Antibiotic-associated colitis

Not known

Hepatobiliary disorders
Rises in AST and/or ALT5

Uncommon

Hepatitis6

Not known

Cholestatic jaundice

6

Not known

Skin and subcutaneous tissue disorders7
Skin rash

Uncommon

Pruritus

Uncommon

Urticaria

Uncommon

Erythema multiforme

Rare

Stevens-Johnson syndrome

Not known

Toxic epidermal necrolysis

Not known

Bullous exfoliative-dermatitis

Not known

Acute generalised exanthematous
pustulosis (AGEP)9

Not known

Renal and urinary disorders
Interstitial nephritis
Crystalluria

8

Not known
Not known

1

See section 4.4

2

See section 4.4

3

At the site of injection

4

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 betalactam 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 4.9

9

See section 4.4

10

See sections 4.3 and 4.4

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any
possible side effects not listed in this leaflet. You can also report side effects directly
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on the safety of this
medicine.

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/electrolyte balance.
Amoxicillin/Clavulanic acid can be removed from the circulation by haemodialysis.

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.
PK/PD 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)

Susceptibility Breakpoints ( g/ml)
Susceptible

Enterococcus1
Streptococcus A, B,
C, G5

>1

1

-

>1

2

-

>2

0.25

> 0.25

4

8

>8

-

> 0.25

1-2

>2

-

>8



Coagulase-negative
staphylococci 2

-



Staphylococcus
aureus 2

1



Moraxella
catarrhalis1

Resistant



Haemophilus
influenzae1

Intermediate



Organism



0.25

Streptococcus
pneumoniae3



0.5

Enterobacteriaceae1,4

-

>8

4

8

>8

2

4-8

>8



Non-species related
breakpoints1

8



Gram-positive
Anaerobes1

4



Gram-negative
Anaerobes1

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 species
Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Gardnerella vaginalis
Staphylococcus aureus (rnethicillin-susceptible)£
Streptococcus agalactiae
Streptococcus pneumoniae1
Streptococcus pyogenes and other beta-haemolytic streptococci
Streptococcus viridans group
Aerobic Gram-negative micro-organisms
Actinobacillus actinomycetemcomitans
Capnocytophaga spp.
Eikenella corrodens
Haemophilus influenzae2
Moraxella catarrhalis
Neisseria gonorrhoeae §
Pasteurella multocida
Anaerobic micro-organisms

Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.

Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
Enterococcus faecium $
Aerobic Gram-negative micro-organisms
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris

Inherently resistant organisms
Aerobic Gram-negative micro-organisms
Acinetobacter sp.
Citrobacter freundii
Enterobacter sp.
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas sp.
Serratia sp.
Stenotrophomonas maltophilia

Other micro-organisms
Chlamydia trachomatis Chlamydophila pneumoniae Chlamydophila psittaci
Coxiella 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 amoxicillin/clavulanic acid 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 either 500 mg/100 mg or 1000
mg/200 mg given as a bolus intravenous injection are presented below.

Mean (+SD) pharmacokinetic parameters
Bolus intravenous injection
Dose
Amoxicillin
administe
Dose
Mean peak
red
serum conc
( g/ml)

T 1/2 (h)

AUC (h.mg/l) Urinary
recovery
(%, 0 to 6 h )

AMX/CA
500
mg/100
mg

500 mg

32.2

1.07

25.5

66.5

1000 mg

105.4

0.9

76.3

77.4

AMX/CA
1000
mg/200
mg

Clavulanic acid
AMX/CA
500
mg/100
mg

100 mg

10.5

1.12

9.2

46.0

200 mg

28.5

0.9

27.9

63.8

AMX/CA
1000
mg/200
mg

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 drugderived 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).
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).
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
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
[MAH] or its components.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
None

6.2

Incompatibilities
Amoxicillin/Clavulanic acid [MAH] should not be mixed with blood products, other
proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.
If Amoxicillin/Clavulanic acid [MAH] is prescribed concurrently 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.
Amoxicillin/Clavulanic acid [MAH] is less stable in infusions containing glucose,
dextran or bicarbonate.
Reconstituted solutions should not therefore be added to such infusions.

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

6.3

Shelf life
Unopened: 2 years
Reconstituted solutions for injection should be administered within 15 min after
reconstitution.
The time interval between the beginning of reconstitution and the end of intravenous
infusion should not exceed one hour.

6.4

Special precautions for storage
Do not store above 25°C.
Keep the vial in the outer carton in order to protect from light
For storage conditions after reconstitution of the medicinal product, see section 6.3

6.5

Nature and contents of container
Clear glass vials of 20ml, nominal volume, fitted with chlorobutyl rubber
stoppers aluminium overseals and flip-top lids packed in cartons of 1, 5, 10 or
50 vials.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
The reconstitution/dilution is to be made under aseptic conditions. The solution is to
be inspected visually for particulate matter and discolouration prior to administration.
The solution should only be used if the solution is clear and free from particles.
Preparation of solutions for intravenous injection

Amoxicillin/Clavulanic acid [MAH] 1000 mg/200 mg powder for solution for
injection/infusion should be dissolved in 20 ml of water for injections. This yields
approximately 20.9 ml of solution for single-dose use (47.8 mg/9.6 mg/ml). A
transient pink colouration may or may not develop during reconstitution.
Reconstituted solutions are normally colourless or a pale straw colour.
Amoxicillin/Clavulanic acid [MAH] should be administered within 15 min of
reconstitution.
Amoxicillin/Clavulanic acid [MAH] 1000 mg/200 mg should be reconstituted as
described above for injection. Without delay the reconstituted solution should be
added to 100 ml of 9 mg/ml (0.9 %) NaCl solution using a minibag or in-line burette.
Amoxicillin/Clavulanic acid [MAH] vials are not suitable for multi-dose use. Discard
any unused solution.
No special requirements
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Fresenius Kabi Limited
Address: Cestrian Court, Eastgate Way, Manor Park
Runcorn, Cheshire WA7 1NT
United Kigdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 08828/0245

9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/02/2014

10

DATE OF REVISION OF THE TEXT
04/02/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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