Amoxicillin-clavulanate: Dosage guidelines and indications for amoxicillin trihydrate-potassium clavulanate combinations

Active Name: Amoxicillin-Clavulanate Oral
Version Number: 24
Version Date: 12 December 2017
GLOBAL DATASHEET
Amoxicillin-clavulanate (Oral)
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GLOBAL PRESCRIBER INFORMATION
TITLE
Amoxicillin trihydrate-potassium clavulanate
SCOPE
Trade Name(s)
AUGMENTIN
Formulation, Strength and Device* (*if appropriate)

The following strengths and ratios are currently available:
Strength1 Strength (co-amoxiclav) Ratio

(amoxicillin/clavulanate) (amoxicillin:clavulanate)
Film-coated tablets
125/62.5mg 187.5mg 2:1
250/125 mg 375 mg 2:1
500/125 mg 625 mg 4:1
875/125 mg 1g 7:1
500/62.5 mg 562.5 mg 8:1
Dispersible tablets
250/125 mg 375 mg 2:1
500/125 mg 625 mg 4:1
Chewable tablets
125/31.25 mg 156.25 mg 4:1
250/62.5 mg 312.5 mg 4:1
200/28.5 mg 228.5 mg 7:1
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400/57 mg 457 mg 7:1
Powder for oral suspension (in bottles)

50/12.5 mg/ml 2 62.5 mg/ml 4:1
125/31.25 mg/5 ml 156.25 mg/5 ml 4:1
250/62.5 mg/5 ml 312.5 mg/5 ml 4:1
200/28.5 mg/5 ml 228.5 mg/5 ml 7:1
400/57 mg/5 ml 457 mg/5 ml 7:1
100/12.5 mg/ml 2 112.5 mg/ml 8:1
Powder for oral suspension (in sachets)

125/31.25 mg 156.25 mg 4:1
250/62.5 mg 312.5 mg 4:1
500/125 mg 625 mg 4:1
400/57 mg 457 mg 7:1
875/125 mg 1g 7:1
250/31.25 mg 281.25 mg 8:1
500/62.5 mg 562.5 mg 8:1
1000/125 mg 1.125 g 8:1
Granules for oral suspension

10%/5% 15% 2:1
1 Amoxicillin is present as amoxicillin trihydrate. Clavulanate is present as potassium
clavulanate.
2 Also referred to as paediatric drops.
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Excipients
It is mandatory for country product information to include both the complete list of
excipients for all locally marketed presentations, and any locally imposed excipient
warning statements.
Suspensions, Sachets, Chewable tablets
Aspartame (Statement required)

CLINICAL INFORMATION
General description
Amoxicillin-clavulanate (beta-lactam antibacterial penicillin coformulated with a beta-

lactamase inhibitor) is an antibiotic agent with a notably broad spectrum of activity
against the commonly occurring bacterial pathogens in general practice and hospital. The
beta-lactamase inhibitory action of clavulanate extends the spectrum of amoxycillin to
embrace a wider range of organisms, including many resistant to other beta-lactam
antibiotics.
Indications
Amoxicillin-clavulanate should be used in accordance with local official antibiotic-
prescribing guidelines and local susceptibility data.
Adult formulations:
Amoxicillin-clavulanate is indicated for short term treatment of bacterial infections at the

following sites when caused by amoxicillin-clavulanate-susceptible organisms:
- Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis,

sinusitis, otitis media, typically caused by Streptococcus pneumoniae, Haemophilus
influenzae#, Moraxella catarrhalis# and Streptococcus pyogenes.
- Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis,

lobar and bronchopneumonia, typically caused by Streptococcus pneumoniae,
Haemophilus influenzae# and Moraxella catarrhalis#.
- Genito-urinary tract tnfections e.g. cystitis, urethritis, pyelonephritis, female genital

infections typically caused by Enterobacteriaceae* (mainly Escherichia coli #),
Staphylococcus saprophyticus and Enterococcus species and gonorrohoea caused
by Neisseria gonorrhoeae#.
- Skin and soft tissue infections typically caused by Staphylococcus aureus#,

Streptococcus pyogenes and Bacteroides species#.
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- Bone and joint infections e.g. osteomyelitis typically caused by Staphylococcus

aureus#, where more prolonged therapy may be appropriate.
- Other Infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.
Paediatric formulations:
Amoxicillin-clavulanate is indicated for short term treatment of bacterial infections at the

following sites when caused by amoxicillin-clavulanate sensitive organisms:
- Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis,

sinusitis, otitis media typically caused by Streptococcus pneumoniae, Haemophilus
influenzae#, Moraxella catarrhalis# and Streptococcus pyogenes.
- Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis,

lobar and bronchopneumonia typically caused by Streptococcus pneumoniae,
Haemophilus influenzae# and Moraxella catarrhalis#.
- Genito-urinary tract infections e.g. cystitis, urethritis, pyelonephritis, female genital

infections typically caused by Enterobacteriaceae# (mainly Escherichia coli#)
Staphylococcus saprophyticus and Enterococcus species, and gonorrhoea caused by
Neisseria gonorrhoeae#.
- Skin and soft tissue infections typically caused by Staphylococcus aureus#,

Streptococcus pyogenes and Bacteroides species#.
Amoxicillin-clavulanate Paediatric three times daily.
The paediatric three times daily dosing regimen is also indicated for the following
infections:
- Bone and joint infections e.g. osteomyelitis typically caused by Staphylococcus

aureus#, where more prolonged therapy may be appropriate.
- Other infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.
All formulations:
# Some members of these species of bacteria produce beta-lactamase, rendering them
insensitive to amoxicillin alone (see Clinical Pharmacology, Pharmacodynamic effects
for further information).
Susceptibility to amoxicillin-clavulanate will vary with geography and time. Local

susceptibility data should be consulted where available, and microbiological sampling
and susceptibility testing performed where necessary.
Infections caused by amoxicillin-susceptible organisms are amenable to amoxicillin-

clavulanate treatment due to its amoxicillin content. Mixed infections caused by
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amoxicillin-susceptible organisms in conjunction with amoxicillin-clavulanate-

susceptible beta-lactamase-producing organisms may therefore be treated by amoxicillin-
clavulanate.
Dosage and Administration

Dosage depends on the age, weight and renal function of the patient and the severity of
the infection.
Dosages are expressed throughout in terms of amoxicillin-/clavulanate content except

when doses are stated in terms of an individual component.
To minimise potential gastrointestinal intolerance, administer at the start of a meal.
The absorption of amoxicillin-clavulanate is optimised when taken at the start of a meal.
Treatment should not be extended beyond 14 days without review.
Therapy can be started parenterally and continued with an oral preparation
Populations
• Adults
Formulation Mild to moderate infections Severe infections

Ratio Including chronic and recurrent
(amoxicillin: urinary tract infections and
clavulanate) infections of the lower respiratory
tract.
250/125 mg 2 times 250/125 mg
2:1
given 3 times daily given 3 times daily
500/125 mg 1 to 2 times 500/125 mg

4:1
given 2 or 3 times daily given 3 times daily
875/125 mg 875/125 mg
7:1
given twice daily given 2 or 3 times daily
1000/125 mg 1000/125 mg
8:1
given twice daily given 3 times daily
Two amoxicillin-clavulanate 250/125 mg tablets should not be substituted for one

amoxicillin-clavulanate 500/125 mg tablet since they are not equivalent.
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• Children
Dosage should be expressed in terms of the age of the child and either in mg/kg/day
(given in 2 or 3 divided doses) or ml of suspension per dose or equivalent for other
presentations.
Children weighing 40 kg and over should be dosed according to the adult

recommendations.
Children up to 12 years
Formulation Lower dose Higher dose

ratio Recommended for infections such Recommended for infections such
(amoxicillin: as skin and soft tissue and as otitis media, sinusitis, lower
clavulanate) recurrent tonsillitis. respiratory tract infections and
urinary tract infections.
20/5 to 40/10 mg/kg/day 40/10 to 60/15 mg/kg/day
4:1
given as 3 divided doses given as 3 divided doses (1)
25/3.6 to 45/6.4 mg/kg/day 45/6.4 to 70/10 mg/kg/day
7:1
given as 2 divided doses (2) given as 2 divided doses (1,2)
40/5 mg/kg/day 80/10 mg/kg/day
8:1
given as 3 divided doses (3) given as 3 divided doses (3)
(1) No clinical data are available on doses of these formulations higher than
40/10 mg/kg/day (4:1) or 45/6.4 mg/kg/day (7:1) in children under 2 years.
(2) There are no clinical data for the 7:1 formulation for patients under 2 months of age.
Dosing recommendations in this population therefore cannot be made.
(3) There are no clinical data for the 8:1 formulation for patients under 1 month of age.
Dosing recommendations in this population therefore cannot be made.
Premature
No dosage recommendation can be made for this category.
• Elderly
No adjustment needed; dose as for adults. If there is evidence of renal impairment, dose
should be adjusted as for renally impaired adults.
• Renal impairment
Dosage adjustments are based on the maximum recommended level of amoxicillin.
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Adults
Creatinine clearance greater than No adjustment necessary.

30 ml/min
Creatinine clearance 10 to 30 ml/min 1 times 500/125 mg given twice daily OR
1 to 2 times 250/125 mg, depending upon

severity of infection, given twice daily (+)
Creatinine clearance less than 1 times 500/125 mg given once daily OR

10 ml/min
1 to 2 times 250/125 mg; depending upon
severity of infection, given once daily (+)
(+) The 7:1 and 8:1 presentations should only be used in patients with a creatinine
clearance of more than 30 ml/min.
Children
Creatinine clearance greater than No adjustment necessary.

30 ml/min
Creatinine clearance 10 to 30 ml/min 15/3.75 mg/kg given twice daily (maximum

500/125 mg twice daily) (+)
Creatinine clearance less than 15/3.75 mg/kg given as a single daily dose
10 ml/min (maximum 500/125 mg) (+)
In the majority of cases, parenteral therapy, where available, may be preferred.
Haemodialysis
Adults
1 times 500/125 mg OR 2 times 250/125 mg every 24 h, PLUS 1 dose during dialysis, to

be repeated at the end of dialysis (as serum concentrations of both amoxicillin and
clavulanic acid are decreased). (+)
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Children
15/3.75 mg/kg/day given as a single daily dose.
Prior to haemodialysis one additional dose of 15/3.75 mg/kg should be administered. In

order to restore circulating drug levels, another dose of 15/3.75 mg/kg should be
administered after haemodialysis. (+)
• Hepatic impairment
Dose with caution; monitor hepatic function at regular intervals.
There are insufficient data on which to base a dosage recommendation.
Contraindications
Amoxicillin-clavulanate is contra-indicated
- in patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and

cephalosporins
- in patients with a previous history of amoxicillin-clavulanate-associated

jaundice/hepatic dysfunction.
Warnings and Precautions

Before initiating therapy with amoxicillin-clavulanate, careful enquiry should be made
concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other
allergens.
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. If an allergic reaction occurs, amoxicillin-clavulanate therapy should be
discontinued and appropriate alternative therapy instituted. Serious anaphylactic
reactions require immediate emergency treatment with adrenaline. Oxygen, i.v. steroids
and airway management, including intubation may also be required.
Amoxicillin-clavulanate 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.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
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Pseudomembranous colitis has been reported with the use of antibiotics and may range in
severity from mild to life-threatening. Therefore, it is important to consider its diagnosis
in patients who develop diarrhoea during or after antibiotic use. If prolonged or
significant diarrhoea occurs or the patient experiences abdominal cramps, treatment
should be discontinued immediately and the patient investigated further.
In general amoxicillin-clavulanate is well tolerated and possesses the characteristic low

toxicity of the penicillin group of antibiotics. Periodic assessment of organ system
functions, including renal, hepatic and haematopoietic function is advisable during
prolonged therapy.
Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in
patients receiving amoxicillin-clavulanate and oral anticoagulants. Appropriate
monitoring should be undertaken when anticoagulants are prescribed concurrently.
Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired
level of anticoagulation.
Amoxicillin-clavulanate should be used with caution in patients with evidence of hepatic

dysfunction.
In patients with renal impairment, dosage should be adjusted according to the degree of
impairment (see Dosage and Administration − Renal impairment).
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 (see Overdosage).
Amoxicillin-clavulanate Suspensions/Sachets/Chewable Tablets (where applicable),

contain aspartame, which is a source of phenylalanine and so should be used with caution
in patients with phenylketonuria.
Interactions
Concomitant use of probenecid is not recommended. Probenecid decreases the renal
tubular secretion of amoxicillin. Concomitant use with amoxicillin-clavulanate may result
in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.
Concomitant use of allopurinol during treatment with amoxicillin can increase the
likelihood of allergic skin reactions. There are no data on the concomitant use of
amoxicillin-clavulanate and allopurinol.
In common with other antibiotics, amoxicillin-clavulanate may affect the gut flora,
leading to lower oestrogen reabsorption and reduced efficacy of combined oral
contraceptives.
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In the literature there are rare 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.
In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the

active metabolite mycophenolic acid 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.
Pregnancy and Lactation
Fertility
No Text.
Pregnancy
Reproduction studies in animals (mice and rats at doses up to 10 times the human dose)
with orally and parenterally administered amoxicillin-clavulanate have shown no
teratogenic effects. In a single study in women with pre-term, premature rupture of the
foetal membrane (pPROM), it was reported that prophylactic treatment with amoxicillin-
clavulanate may be associated with an increased risk of necrotising enterocolitis in
neonates. As with all medicines, use should be avoided in pregnancy, unless considered
essential by the physician.
Lactation
Amoxicillin-clavulanate may be administered during the period of lactation. With the

exception of the risk of sensitization, associated with the excretion of trace quantities in
breast milk, there are no known detrimental effects for the breast-fed infant.
Ability to perform tasks that require judgement, motor or cognitive

skills
Adverse effects on the ability to drive or operate machinery have not been observed.
Adverse Reactions
Data from large clinical trials was used to determine the frequency of very common to
rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e.,
those occurring at <1/10,000) were mainly determined using post-marketing data and
refer to a reporting rate rather than a true frequency.
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The following convention has been used for the classification of frequency:
very common ≥1/10
common ≥1/100 and <1/10
uncommon ≥1/1000 and <1/100
rare ≥1/10,000 and <1/1000
very rare <1/10,000.
Infections and infestations
Common Mucocutaneous candidiasis
Blood and lymphatic system disorders
Rare Reversible leucopenia (including neutropenia) and

thrombocytopenia
Very rare Reversible agranulocytosis and haemolytic anaemia.

Prolongation of bleeding time and prothrombin time
Immune system disorders
Very rare Angioneurotic oedema, anaphylaxis, serum sickness-like

syndrome, hypersensitivity vasculitis
Nervous system disorders
Uncommon Dizziness, headache
Very rare Reversible hyperactivity and convulsions. Convulsions may

occur in patients with impaired renal function or in those
receiving high doses.
Gastrointestinal disorders
Adults:
Very common Diarrhoea
Common Nausea, vomiting
Children:
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Common Diarrhoea, nausea, vomiting
All populations:
Nausea is more often associated with higher oral dosages. If gastrointestinal reactions
are evident, they may be reduced by taking amoxicillin-clavulanate at the start of a
meal.
Uncommon Indigestion
Very rare Antibiotic-associated colitis (including pseudomembranous

colitis and haemorrhagic colitis). (See Warnings and
Precautions)
Black hairy tongue
Superficial tooth discolouration has been reported very rarely in

children. Good oral hygiene may help to prevent tooth
discolouration as it can usually be removed by brushing+.
+Thisstatement is core safety for the syrup, suspension and chewable tablet
formulations.
Hepatobiliary disorders
Uncommon 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.
Very rare Hepatitis and cholestatic jaundice. These events have been noted
with other penicillins and cephalosporins.
Hepatic events have been reported predominantly in males and elderly patients and
may be associated with prolonged treatment.
Children (additional statement):
These events have been very rarely reported in children.
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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.
Skin and subcutaneous tissue disorders
Uncommon Skin rash, pruritus, urticaria
Rare Erythema multiforme
Very rare Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous

exfoliative-dermatitis, acute generalised exanthemous pustulosis
(AGEP), and drug reaction with eosinophilia and systemic
symptoms (DRESS)
If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued.
Renal and urinary disorders
Very rare Interstitial nephritis, crystalluria (see Overdosage)
Overdosage
Symptoms and Signs
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
Warnings and Precautions).
Treatment
GI symptons may be treated symptomatically, with attention to the water/electrolyte

balance.
Amoxicillin-clavulanate can be removed from the circulation by haemodialysis
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Children (additional statement):
A prospective study of 51 paediatric patients at a poison control centre suggested that

overdosages of less than 250 mg/kg of amoxicillin are not associated with significant
clinical symptoms and do not require gastric emptying.
Drug abuse and dependence
Drug dependency, addiction and recreational abuse have not been reported as a problem
with this compound.
Clinical Pharmacology
Pharmacodynamics
ATC Code
J01CR02
Mechanism of Action
Amoxicillin is a semisynthetic antibiotic with a broad spectrum of antibacterial activity

against many gram-positive and gram-negative micro-organisms. Amoxicillin is,
however, susceptible to degradation by beta-lactamases 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 the penicillins, which possesses

the ability to inactivate a wide range of beta-lactamase enzymes commonly found in
micro-organisms resistant to penicillins and cephalosporins. In particular, it has good
activity against the clinically important plasmid mediated beta-lactamases frequently
responsible for transferred drug resistance. It is generally less effective against
chromosomally-mediated type 1 beta-lactamases.
The presence of clavulanic acid in amoxicillin-clavulanate formulations protects

amoxicillin from degradation by beta-lactamase enzymes and effectively extends the
antibacterial spectrum of amoxicillin to include many bacteria normally resistant to
amoxicillin and other penicillins and cephalosporins. Thus amoxicillin-clavulanate
possesses the distinctive properties of a broad spectrum antibiotic and a beta-lactamase
inhibitor.
Pharmacodynamic Effects
In the list below, organisms are categorised according to their in vitro susceptibility to
amoxicillin-clavulanate.
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In vitro susceptibility of micro-organisms to amoxicillin-clavulanate
Where clinical efficacy of amoxicillin-clavualanate has been demonstrated in clinical

trials this is indicated with an asterisk (*).
Organisms that do not produce beta-lactamase are identified (with †). If an isolate is
susceptible to amoxicillin, it can be considered susceptible to amoxicillin-clavulanate.
Commonly susceptible species

Gram-positive aerobes:
Bacillius anthracis
Enterococcus faecalis
Listeria monocytogenes
Nocardia asteroides
Streptococcus pyogenes*†
Streptococcus agalactiae*†
Streptococcus spp. (other β-hemolytic) *†
Staphylococcus aureus (methicillin susceptible)*
Staphylococcus saprophyticus (methicillin susceptible)
Coagulase negative staphylococcus (methicillin susceptible)
Gram-negative aerobes:
Bordetella pertussis
Haemophilus influenzae*
Haemophilus parainfluenzae
Helicobacter pylori
Moraxella catarrhalis*
Neisseria gonorrhoeae
Pasteurella multocida
Vibrio cholerae
Other:
Borrelia burgdorferi
Leptospira ictterohaemorrhagiae
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Treponema pallidum
Gram positive anaerobes:
Clostridium spp.
Peptococcus niger
Peptostreptococcus magnus
Peptostreptococcus micros
Peptostreptococcus spp.
Gram-negative anaerobes:
Bacteroides fragilis
Bacteroides spp.
Capnocytophaga spp.
Eikenella corrodens
Fusobacterium nucleatum
Fusobacterium spp.
Porphyromonas spp.
Prevotella spp.
Species for which acquired resistance may be a problem

Escherichia coli*
Klebsiella oxytoca
Klebsiella pneumoniae*
Klebsiella spp.
Proteus mirabilis
Proteus vulgaris
Proteus spp.
Salmonella spp.
Shigella spp.
Gram-positive aerobes:
Corynebacterium spp.
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Enterococcus faecium
Streptococcus pneumoniae*†
Viridans group streptococcus
Inherently resistant organisms

Acinetobacter spp.
Citrobacter freundii
Enterobacter spp.
Hafnia alvei
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas spp.
Serratia spp.
Stenotrophomas maltophilia
Yersinia enterolitica
Others:
Chlamydia pneumoniae
Chlamydia psittaci
Chlamydia spp.
Coxiella burnetti
Mycoplasma spp.
Pharmacokinetics
Absorption
The two components, of amoxicillin-clavulanate, amoxicillin and clavulanic acid are

fully dissociated in aqueous solution at physiological pH. Both components are rapidly
and well absorbed by the oral route of administration. Absorption of amoxicillin-
clavulanate is optimised when taken at the start of a meal.
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The pharmacokinetic results for two separate studies, in which amoxicillin-clavulanate

250/125 (375) or 2 x 250/125 and 500/125 (625) mg tablets (in comparison with the two
components given separately) were administered in the fasting state to groups of healthy
volunteers, are presented below.
Mean pharmacokinetic parameters
Drug Dose C max T max AUC T 1/2
administered (mg) (mg/l) (h) (mg.h/l) (h)
Amoxicillin
Amoxicillin- 250 3.7 1.1 10.9 1.0

clavulanate
250/125 mg
Amoxicillin- 500 5.8 1.5 20.9 1.3

clavulanate
250/125 mg x 2
Amoxicillin- 500 6.5 1.5 23.2 1.3

clavulanate
500/125 mg
Amoxicillin 500 6.5 1.3 19.5 1.1

500 mg
Clavulanate
Amoxicillin- 125 2.2 1.2 6.2 1.2

clavulanate
250/125 mg
Amoxicillin- 125 2.8 1.3 7.3 0.8

clavulanate
500/125 mg
Clavulanic acid 125 3.4 0.9 7.8 0.7

125 mg
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Amoxicillin- 250 4.1 1.3 11.8 1.0

clavulanate
250/125 mg x 2
Amoxicillin serum concentrations achieved with amoxicillin-clavulanate are similar to

those produced by the oral administration of equivalent doses of amoxicillin alone.
Distribution
Following i.v. administration, therapeutic concentrations of both amoxicillin and

clavulanic acid may be detected in the tissues and interstitial fluid. Therapeutic
concentrations of both drugs have been found in gall bladder, abdominal tissue, skin, fat,
and muscle tissues; fluids found to have therapeutic levels include synovial and
peritoneal fluids, bile and pus.
Neither amoxicillin nor clavulanic acid is highly protein bound, studies show that about
25% for clavulanic acid and 18% for amoxicillin of total plasma drug content is bound to
protein.
From animal studies there is no evidence to suggest that either component accumulates in
any organ.
Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of
clavulanate can also be detected in breast milk. With the exception of the risk of
sensitisation associated with this excretion, there are no known detrimental effects for the
breast-fed infant.
Reproduction studies in animals have shown that both amoxicillin and clavulanic acid
penetrate the placental barrier. However, no evidence of impaired fertility or harm to the
foetus was detected.
Metabolism
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities
equivalent to 10 to 25% of the initial dose.Clavulanic acid is extensively metabolized in
man to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-
amino-4-hydroxy-butan-2-one and eliminated in urine and faeces as carbon dioxide in
expired air.
Elimination
As with other penicillins, the major route of elimination for amoxicillin is via the kidney,
whereas for clavulanate it is by both renal and non-renal mechanisms.
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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 250/125 mg or a single 500/125 mg tablet.
Concomitant use of probenecid delays amoxicillin excretion but does not delay renal
excretion of clavulanic acid (see Interactions).
Special Patient Populations
No Text.
Clinical Studies
No Text.
NON-CLINICAL INFORMATION
No further information of relevance.
PHARMACEUTICAL INFORMATION
Chemical Structure
No Text.
Shelf-Life
Formulation and pack specific.
Tablets:
Swallow film-coated: 3 to 4 years temperate and 3 years tropical in a desiccated pack.
2 years both temperate and tropical in an undesiccated pack.
12 weeks temperate or 4 weeks tropical in a broached pack (e.g. PVC/PVDC blister).
Dispersible: 2 years in an undesiccated pack.
Chewable: 2 years in an undesiccated pack.
Dry Powder Suspensions:
400/57 mg/5 ml and 200/28.5 mg/5 ml (7:1) suspensions: 18 months in a well sealed
container.
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All other dry powder suspensions: 2 years in a well sealed container.
Once reconstituted, 7 to 10 (maximum) days when kept in a refrigerator 5o(C) but not
frozen (dependent on overage and local registration requirements).
Sachets:
Sugar based: 18 to 36 months temperate and 18 months tropical.
Sugar free: 2 years all markets.
Granules: 2 years.
Storage
All amoxicillin-clavulanate preparations should be stored in unopened well sealed
original packs in a dry place at less than 25oC. Bottles of tablets should be kept tightly
closed and moisture-proof containers used for dispensing. Keep out of reach of children.
Nature and Contents of Container
Only moisture-proof containers should be used.
Market and formulation specific.
Incompatibilities
None known.
Use and Handling

Dispersible tablets and sachet contents should be stirred into water before taking.
Children:
For administration of suspensions to children below 3 months, a syringe graduated to

permit accurate and reproducible volumes to be dispensed, should be used.
For administration to children up to 2 years old, amoxicillin-clavulanate suspensions may

be diluted to half-strength using water.
Page 22 of 36
Version Number: 24
GLOBAL PATIENT LEAFLET

<Tradename> 125 mg/62.5 mg tablets
<Tradename> 250 mg/125 mg tablets
<Tradename> 500 mg/62.5 mg tablets
<Tradename> 125 mg/31.25 mg powder for oral suspension (sachets)
<Tradename> 500 mg/125 mg powder for oral suspension (sachets)
<Tradename> 50 mg/12.5 mg/mL powder for oral suspension (bottles)
<Tradename> 125 mg/31.25 mg/5 mL powder for oral suspension (bottles)
<Tradename> 400 mg/57 mg/5 mL powder for oral suspension (bottles)
<Tradename> 100 mg/12.5 mg/mL powder for oral suspension (bottles)
Amoxicillin/clavulanic acid
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again. If you have any questions, ask your
doctor or pharmacist.
This medicine has been prescribed for you personally. Don’t pass it on to other people - it
may harm them even if their symptoms seem to be the same as yours.
In this leaflet
1. What <Tradename> is and what it is used for

2. Before you take <Tradename>
3. How to take <Tradename>
4. Possible side effects
5. How to store <Tradename>
6. Further information
Page 23 of 36
Version Number: 24
1. What <Tradename> is and what it is used for

<Tradename> is an antibiotic used in adults and children to treat infections in different
parts of the body caused by certain types of bacteria.
<Tradename> contains two different medicines called amoxicillin and clavulanic acid.
Amoxicillin is a penicillin antibiotic. Amoxicillin can sometimes be stopped from
working (made inactive). The other active medicine, clavulanic acid, stops this from
happening.
<
2. Before you take <Tradename>
Don’t take <Tradename>
 if you’re allergic (hypersensitive) to amoxicillin, clavulanic acid, other

penicillin based antibiotics, or similar antibiotics called cephalosporins.
 if you have ever had liver problems or jaundice (yellowing of the skin and/or
whites of the eyes) when taking an antibiotic.
 if you think any of these apply to you, check with your doctor before you take
<Tradename>.
Take special care with <Tradename>

Before you take <Tradename> your doctor needs to know:
 if you have ever had an allergic reaction to any other antibiotics or medicines.
This might include a skin rash or swelling of the face or neck.
 if you have glandular fever (mononucleosis)
 if you’re taking medicines, such as warfarin, that are used to prevent blood
clots
 If you have liver problems
 if you have kidney disease
 if you’re not urinating regularly or not able to drink very much.
Note for GSK operating companies
Page 24 of 36
Version Number: 24
Include the following information if you have a formulation containing aspartame

registered in your country:
------------------------------------------------------------------------------------------------------------
 if you have a genetic condition called phenylketonuria (see also ‘<Tradename>
contains aspartame” later in Section 2)
------------------------------------------------------------------------------------------------------------
 Check with your doctor if you think any of these may apply to you. Your
doctor will decide whether <Tradename> is suitable for you and may need to
adjust your dose or give you a different medicine.
Look out for important symptoms

<Tradename> can make some existing conditions worse, or cause serious side effects,
such as severe allergic reactions, serious skin reactions, serious liver problems or
severe diarrhoea or inflammation of the large intestines (pseudomembranous
colitis). You must look out for certain symptoms while you’re taking <Tradename> to
help reduce the risk of any problems. See ‘Look out for important symptoms’ in
Section 4.
While you’re taking <Tradename>
Other medicines and <Tradename>

Tell your doctor or pharmacist if you're taking any other medicines, if you’ve taken
any recently, or if you start taking new ones. This includes medicines bought without a
prescription.
Some medicines may affect how <Tradename> works, or make it more likely that you’ll
have side effects. These include:
 probenecid and allopurinol (used to treat gout).

 anticoagulants (used to prevent blood clots) such as warfarin and
acenocoumarol
 mycophenolate mofetil (a medicine used to prevent the rejection of
transplanted organs).
 Tell your doctor or pharmacist if you’re taking any of these.
Page 25 of 36
Version Number: 24
<Tradename> may reduce how well the contraceptive pill works. If you’re taking the
contraceptive pill while you’re being treated with <Tradename>, you should also use a
barrier method of contraception (such as condoms). Ask your doctor for advice.
Pregnancy and breast-feeding

If you’re pregnant, or think you could be, or if you’re planning to become pregnant,
don’t take <Tradename> without checking with your doctor. Your doctor will consider
the benefit to you and the risk to your baby of taking <Tradename> while you’re
pregnant.
You can usually breast-feed while you’re taking <Tradename>. If you’re breast-feeding
or considering breast-feeding, check with your doctor before you take <Tradename>.
Include the following information if you have a formulation containing aspartame

------------------------------------------------------------------------------------------------------------
<Tradename> contains aspartame

<Tradename> contains aspartame, which is a source of phenylalanine. If you have an
intolerance to aspartame or have a condition called phenylketonuria (PKU):
 Check with your doctor that <Tradename> suspension is right for you.
------------------------------------------------------------------------------------------------------------
3. How to take <Tradename>

Always take <Tradename> exactly as your doctor or pharmacist has told you to.
Check with your doctor or pharmacist if you're not sure.
How much to take

Your doctor will decide on the correct dosage for you
Patients with kidney or liver problems
 If you have kidney problems, your doctor may give you a different strength or a
different medicine.
 If you have liver problems, you may have more frequent blood tests to check
how your liver is working.
Page 26 of 36
Version Number: 24
How to take
 Take <Tradename> at the start of a meal or slightly before.
Select the appropriate section below (depending on the formulation) for your local
patient information leaflet.
------------------------------------------------------------------------------------------------------------
Tablets
 Swallow the tablets whole with a glass of water.
------------------------------------------------------------------------------------------------------------
Oral Suspension Sachets
 Open the sachet and mix the contents with a glass of water. Swallow the mixture
immediately.
------------------------------------------------------------------------------------------------------------
Oral Suspension Bottles
 Shake the bottle well before taking each dose.

 A dosing syringe, spoon or cup may be supplied with the pack, which you can
use to measure the dose accurately.
 A dosing syringe should be used to give the correct dose to children below 3
months.
------------------------------------------------------------------------------------------------------------
Do not take <Tradename> for more than 14 days. If you still feel unwell you should go
back to see your doctor.
If you forget to take <Tradename>

Don't take a double dose to make up for a missed dose. Just take it as soon as you
remember.
If you’re not sure what to do, ask your doctor or pharmacist.
Page 27 of 36
Version Number: 24
If you take too much <Tradename>

If you accidently take too much <Tradename>, it is unlikely to cause any serious
problems. The most common side effects of taking too much <Tradename> are nausea,
vomiting and diarrhoea. If you’re worried, or you feel unwell:
 Ask your doctor or pharmacist for advice.
Don’t stop taking <Tradename> without advice

It is important that you take the full course of <Tradename>. Don’t stop unless your
doctor advises you too – even if you’re feeling better. If you don’t complete the full
course of treatment, the infection may come back.
4. Possible side effects

Like all medicines, <Tradename> can cause side effects, but not everybody gets them.
Look out for important symptoms
Severe allergic reactions
These are very rare in people taking <Tradename>. Signs include:
 raised, itchy rash (hives)

 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 mouth (angioedema), which may cause
difficulty in swallowing or breathing
 collapse.
 Get medical help immediately if you get any of these symptoms. Stop taking
<Tradename>.
Serious skin reactions
These are rare in people taking <Tradename>. Signs include:
 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).
Page 28 of 36
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These are very rare in people taking <Tradename>. Signs include:
 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 blisters and peeling skin on much of the body surface (toxic epidermal
necrolysis)
 a widespread, red, skin rash with small blisters containing pus (exanthemous
pustulosis)
 a red, itchy, scaly rash with blisters and bumps under the skin (bullous
exfoliative dermatitis)
 flu-like symptoms with a rash, fever, swollen glands, and abnormal blood test
results (including white blood cells (eosinophilia) and liver enzymes) (Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS)).
 Get medical help immediately if you get any of these symptoms. Stop taking
<Tradename>.
Serious liver problems
On rare occasions, medicines like <Tradename> can cause liver problems, causing
yellowing of the skin and/or whites of the eyes.
 Tell your doctor as soon as possible if you get any of these symptoms.
Severe diarrhoea (Pseudomembranous colitis)
On rare occasions, medicines like <Tradename> can cause inflammation of the colon
(large intestine), causing diarrhoea, usually with blood and mucus, stomach pain and
fever.
 Tell your doctor as soon as possible if you get any of these symptoms.
Very common side effects

These may affect more than 1 in 10 people:
 diarrhoea (in adults).
Page 29 of 36
Version Number: 24
Common side effects

These may affect up to 1 in 10 people:
 thrush (fungal infection caused by Candida in the vagina, mouth or skin folds)
 feeling sick (nausea)
 vomiting
 diarrhoea (in children).
Uncommon side effects

These may affect up to 1 in 100 people:
 dizziness
 headache
 indigestion
 skin rash
 itching
 itchy, bumpy rash (hives)
Uncommon side effects that may show up in blood tests are:
 increase in some substances (enzymes) produced by the liver
Rare side effects

These may affect up to 1 in 1,000 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) (See ‘serious skin reactions’ earlier in Section 4)
Rare side effects that may show up in blood tests are:
 decrease in the number of white blood cells (leucopenia, including neutropenia

 decrease in the number of cells that help blood to clot (thrombocytopenia
Very rare side effects

These may affect up to 1 in 10,000 people:
 severe allergic reactions (See also ‘severe allergic reactions’ earlier in

Section 4)
Page 30 of 36
Version Number: 24
 serious skin reactions (See also ‘serious skin reactions’ earlier in Section 4)
 inflammation of the liver (hepatitis) (See also ‘serious liver problems’ earlier in
Section 4)
 yellowing of the whites of the eyes or skin (jaundice) (See also ‘serious liver
problems’ earlier in Section 4)
 inflammation of the large intestines (See also ‘severe diarrhoea’ earlier in
Section 4)
 inflammation of the kidney (nephritis)
 an increase in the time blood takes to clot
 being unusually active (hyperactivity)
 fits (seizures)
 black tongue which looks hairy
Include the following information the suspension (bottle or sachet) formulations

------------------------------------------------------------------------------------------------------------
 stained teeth that can usually be removed by brushing
------------------------------------------------------------------------------------------------------------
Very rare side effects that may show up in blood or urine tests are:
 severe decrease in the number of white blood cells (agranulocytosis)

 red blood cells destroyed too quickly (haemolytic anaemia)
 crystals in urine
 Tell your doctor or pharmacist if any of the side effects listed becomes
severe or troublesome, or if you notice any side effects not listed in this
leaflet.
5. How to Store <Tradename>

------------------------------------------------------------------------------------------------------------
All formulations: You must provide here storage conditions (for each formulation)
registered with your local authority.
Page 31 of 36
Version Number: 24
------------------------------------------------------------------------------------------------------------
Keep out of the sight and reach of children.
Do not take <Tradename> after the expiry date shown on the pack.
Store in original packaging.
Do not store <Tradename> above 25°C (77°F).
Don’t dispose of medicines in waste water or household waste. Ask your pharmacist
how to dispose of medicines no longer required. This will help to protect the
environment.
------------------------------------------------------------------------------------------------------------
Additional in-use storage text for the Powder for oral suspensions (bottles):
Include the following information if you have these formulations registered in your
country:
------------------------------------------------------------------------------------------------------------
Once made up, the suspension should be used within 7 to 10 days.
Store in a refrigerator (5°C).
Do not freeze.
------------------------------------------------------------------------------------------------------------
6. Further information
What <Tradename> contains

The active substances are amoxicillin and clavulanic acid.
<Tradename> tablets come in different strengths.
Each tablet contains either:

 amoxicillin trihydrate equivalent to 125 mg amoxicillin and potassium clavulanate
equivalent to 62.5 mg clavulanic acid
equivalent to 125 mg clavulanic acid
Page 32 of 36
Version Number: 24

Sachets of <Tradename> powder for oral suspension come in different strengths.
Each sachet contains either:

Bottles of <Tradename> powder for oral suspension comes in different strengths.
Each mL of reconstituted suspension contains either:

 amoxicillin trihydrate equivalent to 100 mg amoxicillin and potassium clavulan#’;ate
Each 5 mL of reconstituted suspension contains either:

Page 33 of 36
Version Number: 24

The other ingredients are:
------------------------------------------------------------------------------------------------------------
You must provide here a complete list of the excipients (including excipient components
of flavours and colours, where available) for all formulations registered with your local
regulatory authority.
------------------------------------------------------------------------------------------------------------
What <Tradename> looks like and contents of the pack

------------------------------------------------------------------------------------------------------------
You must provide here a description of each formulation registered with your local
regulatory authority using the template below.
------------------------------------------------------------------------------------------------------------
Tablets
The [X/X] mg [tablets] are [colour], [X-shaped], [Standard form tablets] marked with [X]
on one side [and [X] on the other].
Powder for Oral Suspension (sachets)
<TRADE NAME> powder for oral suspension is available in sachets; each sachet
contains [powder description]. The powder needs to be reconstituted with water before
oral administration. The powder in each sachet provides [X] mg of amoxicillin and
[X] mg of clavulanic acid when reconstituted as recommended.
Powder for Oral Suspension (bottles)
Page 34 of 36
Version Number: 24
<TRADE NAME> powder for oral suspension is available in bottles; each [Bottle type]
contains [powder description]. The powder needs to be reconstituted with water before
oral administration. The powder in each bottle provides [X] mg of amoxicillin and
[X] mg of clavulanic acid per [X] mL when reconstituted as recommended.
------------------------------------------------------------------------------------------------------------
Page 35 of 36
Version Number: 24
GLOBAL PACKAGING COMPONENTS
TITLE
No Text.
Trade marks are owned by or licensed to the GSK group of companies
Page 36 of 36

Amoxicillin-clavulanate: Dosage guidelines and indications for amoxicillin trihydrate-potassium clavulanate combinations

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Amoxicillin-clavulanate: Dosage guidelines and indications for amoxicillin trihydrate-potassium clavulanate combinations

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Active Name: Amoxicillin-Clavulanate Oral

GLOBAL PRESCRIBER INFORMATION

Formulation, Strength and Device* (*if appropriate)

Strength1 Strength (co-amoxiclav) Ratio

250/125 mg 375 mg 2:1

500/125 mg 625 mg 4:1

500/62.5 mg 562.5 mg 8:1

500/125 mg 625 mg 4:1

250/62.5 mg 312.5 mg 4:1

200/28.5 mg 228.5 mg 7:1

400/57 mg 457 mg 7:1

Powder for oral suspension (in bottles)

125/31.25 mg/5 ml 156.25 mg/5 ml 4:1

250/62.5 mg/5 ml 312.5 mg/5 ml 4:1

200/28.5 mg/5 ml 228.5 mg/5 ml 7:1

400/57 mg/5 ml 457 mg/5 ml 7:1

100/12.5 mg/ml 2 112.5 mg/ml 8:1

Powder for oral suspension (in sachets)

250/62.5 mg 312.5 mg 4:1

500/125 mg 625 mg 4:1

400/57 mg 457 mg 7:1

250/31.25 mg 281.25 mg 8:1

500/62.5 mg 562.5 mg 8:1

1000/125 mg 1.125 g 8:1

Granules for oral suspension

Aspartame (Statement required)

Amoxicillin-clavulanate (beta-lactam antibacterial penicillin coformulated with a beta-

Amoxicillin-clavulanate is indicated for short term treatment of bacterial infections at the

- Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis,

- Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis,

- Genito-urinary tract tnfections e.g. cystitis, urethritis, pyelonephritis, female genital

- Skin and soft tissue infections typically caused by Staphylococcus aureus#,

- Bone and joint infections e.g. osteomyelitis typically caused by Staphylococcus

- Other Infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.

Amoxicillin-clavulanate is indicated for short term treatment of bacterial infections at the

- Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis,

- Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis,

- Genito-urinary tract infections e.g. cystitis, urethritis, pyelonephritis, female genital

- Skin and soft tissue infections typically caused by Staphylococcus aureus#,

Amoxicillin-clavulanate Paediatric three times daily.

- Bone and joint infections e.g. osteomyelitis typically caused by Staphylococcus

- Other infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.

Susceptibility to amoxicillin-clavulanate will vary with geography and time. Local

Infections caused by amoxicillin-susceptible organisms are amenable to amoxicillin-

amoxicillin-susceptible organisms in conjunction with amoxicillin-clavulanate-

Dosage and Administration

Dosages are expressed throughout in terms of amoxicillin-/clavulanate content except

To minimise potential gastrointestinal intolerance, administer at the start of a meal.

The absorption of amoxicillin-clavulanate is optimised when taken at the start of a meal.

Treatment should not be extended beyond 14 days without review.

Therapy can be started parenterally and continued with an oral preparation

Formulation Mild to moderate infections Severe infections

500/125 mg 1 to 2 times 500/125 mg

Two amoxicillin-clavulanate 250/125 mg tablets should not be substituted for one

Children weighing 40 kg and over should be dosed according to the adult

Formulation Lower dose Higher dose

No dosage recommendation can be made for this category.

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

Creatinine clearance greater than No adjustment necessary.

Creatinine clearance 10 to 30 ml/min 1 times 500/125 mg given twice daily OR

1 to 2 times 250/125 mg, depending upon

Creatinine clearance less than 1 times 500/125 mg given once daily OR