SUMMARY OF MEDICINE CHARACTERISTICS

[Link] OF THE MEDICATION

Clavamox 500, 500 mg/125 mg, film-coated tablets

Clavamox 125, 125 mg/31.25 mg/5 ml, powder for oral suspension
Clavamox 250, 250 mg/62.5 mg/5 ml, powder for oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

CLAVAMOX contains amoxicillin (in the form of trihydrated amoxicillin) and acid
clavulanic (in the form of potassium clavulanate). It is available in
the following dosages and presentations:

Form Dosage Proportion Content Content

Pharmaceutical in in acid
amoxicillin clavulanic
(mg) (mg)

Powder for 125mg/31.25mg/5ml 4:1 125 31.25

oral suspension
Powder for 250mg/62.5mg/5ml 4:1 250 62.5
oral suspension
Tablets 500mg/125mg 4:1 500 125
coated with
movie

Excipients:

Each film-coated tablet of CLAVAMOX 500 contains a maximum of

0.882 mg (0.0384 mmol) of sodium (in the form of sodium carboxymethyl amide).

CLAVAMOX 125 contains 12.55 mg/5 ml of aspartame (E951) and a maximum of 2.56
mg/5ml (0.11 mmol/5 ml) of sodium (in the form of sodium citrate and benzoate of
sodium).

CLAVAMOX 250 contains 12.55 mg/5 ml of aspartame (E951) and a maximum of 2.56
sodium (in the form of sodium citrate and benzoate) mg/5ml (0.11 mmol/5 ml)
sodium).

Complete list of excipients, see section 6.1.

[Link] FORM
500 mg/125 mg film-coated tablets
Film-coated tablets.

125 mg/31.25 mg/5 ml and 250 mg/62.5 mg/5 ml powder for oral suspension
Powder for oral suspension

[Link] INFORMATION

4.1 Therapeutic indications

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

Acute bacterial sinusitis (adequately diagnosed)

Acute otitis media
Acute exacerbations of chronic bronchitis (properly diagnosed)
Community-acquired pneumonia
Cystitis
Pyelonephritis
Skin and soft tissue infections, particularly cellulitis; animal bites;
severe dental abscess with disseminated cellulitis
Bone and joint infections, particularly osteomyelitis.

The official guidelines for the appropriate use of agents must be considered.
antibacterials.

4.2 Dosage and method of administration

The doses are expressed in terms of the content of amoxicillin and clavulanic acid.
except when presented in terms of individual components.

The dose of Clavamox selected to treat a particular infection must have in

consideration:

The expected pathogens and their susceptibility to antibacterial agents (see

section 4.4)
The location and severity of the infection
The age, weight, and kidney function of the patient as indicated below.

The use of alternative formulations of Clavamox (for example those that contain
higher doses of amoxicillin and/or different ratios of amoxicillin to acid
clavulanic acid) should be considered if necessary (see section 4.4 and 5.1).

For adults and children 40 kg, this formulation of Clavamox provides a dose
total daily dose of 1500mg of amoxicillin and 375mg of clavulanic acid, when
administered as recommended below. For children < 40 kg, this formulation of
Clavamox provides a maximum daily dose of 2400mg of amoxicillin and 600mg of
clavulanic acid, when administered as recommended below. If it is considered
if a higher dose of amoxicillin is needed, the selection of
another formulation of Clavamox to avoid the administration of high doses
unnecessary clavulanic acid (see sections 4.4 and 5.1).

The duration of treatment should be determined by the patient's response. Some

infections (for example, osteomyelitis) require longer periods of treatment. The
treatment should not extend beyond a period of 14 days without evaluation (see
section 4.4 on prolonged treatment.

Adults and adolescents ≥ 40 kg

A dose of 500 mg/125 mg three times a day.

Children < 40 kg

20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day divided into 3 doses

Children can be treated with Clavamox in tablets or suspensions.

children aged 6 years or younger should be treated preferably with
Clavamox in suspensions.

There are no clinical data available on Clavamox 4:1 formulation doses.

greater than 40mg/10mg/kg/day of Clavamox in children under 2 years of age.

Elderly

No dose adjustment is necessary.

Kidney failure

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

No dose adjustment is necessary in patients with creatinine clearance (ClCr)
above 30ml/min.

Adults and adolescents ≥ 40 kg

ClCr 10-30 ml/min A dose of 500mg/125mg twice
per day
ClCr < 10 ml/min A dose of 500mg/125mg once a day
day
Hemodialysis A dose of 500mg/125mg every 24 hours
another dose of 500mg/125mg during the
dialysis, to be repeated at the end of the dialysis
(given the decrease in serum concentration)
 of amoxicillin and clavulanic acid

Children < 40 kg
ClCr 10-30 ml/min 15mg/3.75mg/kg divided into two doses
per day (maximum 500 mg/125 mg twice
times a day)
CrCl < 10 ml/min 15mg/3.75mg/kg in a single daily dose
(maximum 500 mg/125mg)
Hemodialysis 15mg/3.75mg/kg in a single daily dose.
Before hemodialysis an additional dose
15mg/3.75mg/kg should be administered.
To restore the circulating concentration
adequate dosing of the drugs, another dose of
15mg/3.75mg/kg should be administered
after dialysis.

liver failure

Dosing with caution and monitoring liver function at regular intervals (see
section 4.3 and 4.4.

Route of administration:

Clavamox should be taken orally.

Administer at the beginning of meals to minimize potential intolerance.

gastrointestinal and optimize the absorption of amoxicillin and clavulanic acid.

The therapy can be initiated parenterally according to the RCM of the formulation.
intravenous and continuous with an oral formulation.

125 mg/31.25 mg/5 ml and 250 mg/62.5 mg/5 ml, powder for oral suspension
Shake to release the powder, add water as indicated, flip and shake.
Shake the bottle before each dose (see section 6.6).

4.3 Contraindications

Hypersensitivity to active substances, any penicillin or to any of the

excipients.

History of severe and sudden hypersensitivity reaction (e.g., anaphylaxis) to

another beta-lactam agent (for example, cephalosporin, carbapenem, or monobactam).

History of jaundice/liver failure due to amoxicillin/clavulanic acid (see

section 4.8)
4.4 Warnings and special precautions for use

Before starting therapy with amoxicillin/clavulanic acid, one must investigate

carefully the possibility of a previous history of reactions of
hypersensitivity to penicillins, cephalosporins, or another beta-lactam agent (see
section 4.3 and 4.8.

Serious and occasionally fatal hypersensitivity reactions have been reported.

(including serious cutaneous adverse reactions and anaphylactoid reactions) in patients undergoing therapy
with penicillin. These reactions are more likely to occur in individuals
with a history of hypersensitivity to penicillin and atopic individuals. In the case of
in the event of an allergic reaction, treatment with Clavamox should be discontinued and
appropriate alternative therapy instituted.

If it is proven that the infection is due to organisms susceptible to amoxicillin,

the possibility of switching from amoxicillin/clavulanic acid should be considered to
amoxicillin according to the official guidelines.
This Clavamox presentation may not be suitable for use when there is
a high risk that the presumed pathogens have resistance to beta agents
lactams not mediated by susceptible beta-lactamases that can be inhibited by acid
clavulanic. This presentation should not be used for the treatment of S.
penicillin-resistant pneumoniae.

Seizures can occur in patients with renal failure or in patients receiving

high doses (see section 4.8).

Clavamox should be avoided in cases of suspected infectious mononucleosis, as it

the occurrence of morbilliform rash has been associated in these cases with the use
of amoxicillin.

The concomitant administration of allopurinol during treatment with amoxicillin

can increase the likelihood of skin allergic reactions.

The prolonged administration of Clavamox may occasionally cause a

sharp growth of non-susceptible microorganisms.

The occurrence at the beginning of treatment of generalized and febrile erythema associated with
Pustules can be a symptom of acute generalized exanthematous pustulosis (AGEP)
(see section 4.8). This reaction requires the discontinuation of Clavamox and constitutes a contraindication.
indication for any subsequent administration of amoxicillin.
Amoxicillin/clavulanic acid should be used with caution in patients with
evidence of liver failure (see section 4.2).

Liver events were predominantly reported in patients of the sex

male and elderly and may be associated with prolonged therapy. These events
they have been reported very rarely in children. In all populations, the signs and
symptoms usually occur during or shortly after treatment but in some
cases may not become apparent until several weeks after it is finished
treatment. They are usually reversible. The hepatic events can be
serious and, in extremely rare circumstances, fatal cases have been reported. Such
it almost always occurred in patients in serious condition or taking concomitant medication
known for having potential hepatic effects (see section 4.8).

Pseudomembranous colitis associated with the use of broad-spectrum antibiotics was reported.
spectrum including amoxicillin/clavulanic acid, and its severity may vary from
slight possible risk of life (see section 4.8). Therefore, it is important to consider your
diagnosis in patients who develop diarrhea during or after administration of
antibacterial agents. If antibiotic-associated colitis occurs, Clavamox should be
immediately discontinued, a doctor should be consulted and appropriate therapy provided
should be initiated. Antiperistaltic medications are contraindicated in this situation.

It is advisable to check the proper functional condition of the various organ systems,
including renal, hepatic, and hematopoietic, during prolonged therapy.

It was mentioned, rarely, an extension of prothrombin time in patients with a

we will take amoxicillin/clavulanic acid. For this reason, a must be done
appropriate monitoring when there is concomitant prescription of anticoagulants. Adjustments
the dosage of oral anticoagulants may be necessary to maintain the level
intended anticoagulation (see section 4.5 and 4.8).

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

In patients with low urinary output, crystalluria occurred very rarely,

predominantly with parenteral therapy. During the administration of doses
High doses of amoxicillin should maintain an adequate fluid intake and urinary output.
adequate, in order to reduce the risk of crystalluria due to amoxicillin. In patients
Allied, the condition of the catheter should be checked regularly (see section 4.9).

É recomendado que ao testar a presença da glucose na urina durante terapêutica com

Products containing amoxicillin should use oxidative enzymatic methods.
False positive results can occur with the use of non-methods.
enzymatic.

The presence of clavulanic acid in Clavamox may provoke an IgG binding and
albumin in red blood cells leading to a falsely positive result in the test
of Coombs.

Positive results were reported when using EIA tests for Platelia Aspergillus.
Bio-Rad Laboratories in patients receiving amoxicillin/clavulanic acid who are
subsequently discovered not to be infected by this microorganism. They were
notified cross-reactions with polysaccharides and non-Aspergillus polifuranoses to
use the EIA tests for Platelia Aspergillus from Bio-Rad Laboratories.
Consequently, positive test results in patients receiving
amoxicillin/clavulanic acid should be interpreted with caution and confirmed
through other diagnostic methods.

Clavamox 125 mg/31.25 mg/5 ml powder for oral suspension contains 2.51 mg of aspartame.
(E951) per ml which is a source of phenylalanine. These medications must be
used with caution in patients with phenylketonuria.

Clavamox 250 mg/62.5 mg/5 ml powder for oral suspension contains 2.51 mg of aspartame
(E951) per ml which is a source of phenylalanine. These medications should be
used with caution in patients with phenylketonuria.

4.5 Drug interactions and other forms of interaction

Oral anticoagulants
Oral anticoagulants and penicillin family antibiotics have been widely
used in clinical practice without reports of interaction. However, in the literature
there are cases of increased international normalized ratio in patients taking
acenocoumarol or warfarin to which amoxicillin therapy was prescribed. If the
concurrent administration is necessary, the prothrombin time or the ratio
normalized international must be carefully monitored with the addition or
withdrawal of amoxicillin. Additionally, adjustments in the dosage of oral anticoagulants.
may be necessary (see sections 4.4 and 4.8).

Methotrexate
Penicillins can decrease the excretion of methotrexate, causing a potential
increase in toxicity.

Probenecid
The concomitant administration of probenecid is not recommended. Probenecid decreases
the renal tubular secretion of amoxicillin. Its concurrent use with amoxicillin/acid
clavulanic can increase and prolong blood levels of amoxicillin, but not them
of clavulanic acid.

4.6 Pregnancy and breastfeeding

Pregnancy
Animal studies do not indicate any direct or indirect harmful effects on
regarding pregnancy, embryonic/fetal development, childbirth or
postnatal development (see section 5.3). Limited data related to the use of
amoxicillin/clavulanic acid during pregnancy in humans does not indicate risk
increased congenital malformations. In a single study conducted in women with
premature rupture of the fetal membranes before the end of pregnancy, cases were reported.
in what the prophylactic treatment with Clavamox may be associated with the increase of
risk of necrotizing enterocolitis in newborns. Just like with all the
medications, the use of Clavamox during pregnancy should be avoided unless the
the doctor considers his prescription fundamental.

Lactation
Amoxicillin/clavulanic acid can be administered during the breastfeeding period.
after risk/benefit assessment by the doctor. Both substances are
excreted in breast milk, which may cause possible adverse events. However, the
vestigial amounts of these substances pose a minimal risk to the child
breastfed. The possibility of sensitization should be taken into consideration.

4.7 Effects on the ability to drive and operate machinery

The effects on the ability to drive and use machines have not been studied.
meanwhile, adverse events may occur (for example, allergic reactions, dizziness,
seizures), which may influence the ability to drive and operate machines (see
section 4.8).

4.8 Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are

diarrhea, nausea, and vomiting.

As RAMs collected from clinical trials and post-marketing surveillance

with Clavamox, organized according to the MedDRA organ classification system
are listed below.

The following convention was used for frequency classification: Very frequent
>1/10, frequentes >1/100 e <1/10, pouco frequentes >1/1 000 e <1/100, raros >1/10 000
less than 1 in 1,000, very rare less than 1 in 10,000, unknown (cannot be estimated from the
available data

Infections and infestations:

Mucocutaneous candidiasis Frequent
Proliferation of non-susceptible organisms Unknown
Blood and lymphatic system diseases
Reversible leukopenia (including neutropenia) or Strange
thrombocytopenia
Thrombocytopenia Rare
Reversible agranulocytosis Unknown
Hemolytic anemia Unknown
Prolongation of bleeding time and time of Unknown
prothrombin1
Diseases of the immune system 10:
Angioedema Unknown
Anaphylaxis Unknown
Syndrome similar to serum sickness Unknown
Hypersensitivity vasculitis Unknown
Diseases of the nervous system:
Dizziness Rarely
Headaches Rarely
Reversible hyperactivity Unknown
Convulsions2 Unknown
Gastrointestinal diseases:
500 mg/125 mg, film-coated tablets
Diarrhea Very frequent
Nausea3 Frequent
vomit Frequent
Indigestion Rarely
Antibiotic-associated colitis Unknown
Hairy black tongue Unknown
125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml, powder for oral suspension
Diarrhea Frequent
Nausea3 Frequent
Vomiting Frequent
Indigestion Rarely
Antibiotic-associated colitis Unknown
Hairy black tongue Unknown
Tooth discoloration11 Unknown
Hepatobiliary disorders
Increase in AST and/or ALT values Rarely
Hepatitis6 Unknown
Cholestatic jaundice Unknown
Skin and subcutaneous tissue disorders:7
Skin rash Rarely occurring
Itching Rarely
Urticaria Rarely
Erythema multiforme Rare
Stevens-Johnson Syndrome Unknown
Toxic epidermal necrolysis Unknown
Exfoliative and bullous dermatitis Unknown
Acute generalized pustular exanthem 9 Unknown
Drug reaction with eosinophilia and systemic symptoms Unknown
(DRESS)
Renal and urinary diseases:
Interstitial nephritis Unknown
Crystaluria8 Unknown
1 See section 4.4
Convulsions can occur in patients with renal insufficiency or in patients with
receive high doses
Nausea is most often associated with high oral doses. If it occurs
gastrointestinal events, these can be reduced by administering amoxicillin/clavulanic acid
clavulanic at the beginning of a meal.
4 Including pseudomembranous colitis and hemorrhagic colitis (see section 4.4)
A moderate increase in AST and/or ALT was reported in patients to be
treaties with antibiotics of the beta-lactam class, but the meaning of this
discovery is unknown.
6 These events have been reported with other penicillins and cephalosporins.
Liver events were predominantly reported in men and the elderly.
and may be associated with prolonged treatments. These events have rarely been
notified in children. In all populations, the signs and symptoms occur
usually during or shortly after the treatment, but in some cases it may not occur
can manifest up to several weeks after the end of treatment. They are usually
reversible. Liver events can be serious and, under circumstances
extremely rare, deaths have been reported. These have almost always occurred in
patients in critical condition or taking concomitant medication known to have
liver effects.
If there is any skin hypersensitivity reaction, the treatment should be
discontinued.
See section 4.9
See section 4.4
See section 4.3 and 4.4
125 mg/31.25 mg/5 ml, 250 mg/62.5 mg/5 ml, powder for oral suspension
Superficial tooth discoloration has been reported very rarely in
children. Good oral hygiene can help prevent tooth discoloration.
since this can usually be removed by brushing.

4.9 Overdose

Symptoms and signs of overdose

Gastrointestinal symptoms and disturbances of fluids and balance may occur.
electrolytic. Crystalluria associated with amoxicillin was observed in some cases.
causing kidney failure (see section 4.4)

Seizures can occur in patients with renal failure or those receiving high doses.

Amoxicillin can precipitate in urinary catheters, predominantly after the

administration of high doses. The obstruction of catheters should be checked
regularly

Intoxication treatment
Gastrointestinal events should be treated symptomatically, taking into account the
water-electrolyte balance.

Amoxicillin/clavulanic acid can be removed from circulation by hemodialysis.

[Link] PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 1.1.5 - Anti-infective medications. Antibacterials.

Penicillin associations with beta-lactamase inhibitors. ATC code: J01CR02

Mechanism of action
Amoxicillin is a semisynthetic antibiotic from the penicillin family (beta-
lactamic) that inhibits one or more enzymes (referred to in the literature as proteins of
binding to penicillin, PBPs) in the metabolic synthesis pathway of bacterial peptidoglycan.
This biopolymer is a structural component of the bacterial cell wall whose function
is related to the maintenance of cell shape and integrity. The inhibition of synthesis
the peptidoglycan leads to a weakening of the structure, usually followed by lysis
cell and death of the bacteria.

Amoxicillin is susceptible to degradation by beta-lactamases, so the

the activity spectrum of isolated amoxicillin does not include organisms that produce these
enzymes.

Clavulanic acid is a beta-lactam antibiotic, structurally related to

like penicillins.
It inactivates some beta-lactamases, thereby preventing the inactivation of amoxicillin.
Clavulanic acid alone does not exert any clinically useful antibacterial effect.

Pharmacokinetic/Pharmacodynamic Relationship
The time interval during which the drug concentration remains above the MIC.
(T>CIM) is considered one of the main determinants of antibiotic efficacy
beta-lactams.

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

Inactivation by bacterial beta-lactamases that are not inhibited by acid

clavulanic, including classes B, C, and D.
- Alteration of PBPs, which reduce the affinity of the antibacterial agent to its target.

Bacterial impermeability or efflux mechanisms that may cause or

contribute to bacterial resistance, particularly in Gram-negative bacteria.

Critical Concentrations (breakpoints)

The critical minimum inhibitory concentrations (MIC) for amoxicillin/clavulanic acid
clavulanic are those designated by the European Commission in the Susceptibility Test
antimicrobial (EUCAST).

Organism Critical concentration ( g/ml)

 Susceptible Intermediate Resistant

Haemophilus influenzae <= 1 - 1

Moraxella catarrhalis ≤1 - 1
Staphylococcus aureus 2 less than or equal to 2 - 2
Coagulase-negative ≤ 0.25 0.25
staphylococci 2
Enterococcus1 ≤4 8 8
Streptococcus A, B, C, G5 ≤ 0.25 - 0.25
Streptococcus <= 0.5 1-2 2
pneumoniae3
Enterobacteriaceae1,4 - - 8
Gram-negative less than or equal to 4 8 8
Anaerobes
Gram-positive Anaerobes1 ≤ 4 8 8
Non-species related <= 2 4-8 8
breakpoints1
The values included are concentrations of amoxicillin. For the purpose of testing
The susceptibility, the concentration of clavulanic acid was set at 2 mg/l
The reported values are for oxacillin.
The values of the critical concentrations in the table are based on the concentrations
criticisms of ampicillin.
The values of the critical resistance concentrations of R>8 mg/l ensure that all
isolated strains with resistance mechanisms are reported as resistant.
The values of the critical concentrations in the table are based on the concentrations
criticisms of benzylpenicillin.
The prevalence of resistances may vary geographically and over time for
specific species and local information is desirable, particularly for treatment
of severe infections. As needed, counseling with experts should be
obtained when the local prevalence of resistance is such that the usefulness of the agent in hair
except for some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive microorganisms
Enterococcus faecalis
Gardnerella vaginalis
Methicillin-susceptible Staphylococcus aureus
Coagulase-negative staphylococci (methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes and other beta-hemolytic streptococci
Streptococcus viridans group

Gram-negative aerobic microorganisms

Capnocytophaga spp.
Eikenella corrodens
Haemophilus influenzae2
Moraxella catarrhalis
Pasteurella multocida

Anaerobic microorganisms
Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.

Species in which acquired resistance can be problematic

Aerobic Gram-positive microorganisms
Enterococcus faecium

Gram-negative aerobic microorganisms

Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris

Inherently resistant organisms

Gram-negative aerobic microorganisms
Acinetobacter sp.
Citrobacter freundii
Enterobacter sp.
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas sp.
Serratia sp.
Stenotrophomonas maltophilia

Other microorganisms
Chlamydophila pneumoniae
Chlamydophila psittaci
Coxiella burnetti
Mycoplasma pneumoniae
Natural intermediate susceptibility in the absence of resistance mechanisms
acquired.
All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid.
clavulanic
1 Penicillin-resistant Streptococcus pneumoniae should not be treated with it.
presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4)
2 lineages with decreased susceptibility have been reported in some countries.
Europeans with a frequency higher than 10%.
5.2 Pharmacokinetic properties

Absorption
Amoxicillin and clavulanic acid are completely dissociated in aqueous solution of
Physiological pH. Both components are rapidly and easily absorbed orally.
The absorption of amoxicillin and clavulanic acid is optimized when taken with
start of meals. Following oral administration, the bioavailability of amoxicillin
the bioavailability of clavulanic acid is approximately 70%. The plasma profiles of both
components are similar and the time to maximum plasma concentration (Tmax) in
each case is approximately one hour.

The following table presents pharmacokinetic data obtained from a study in which
amoxicillin/clavulanic acid tablets were administered (500mg/125mg.
three times a day) to groups of healthy fasting volunteers:

AVERAGE PHARMACOKINETIC PARAMETERS

Administration of Dose Cmax Tmax * AUC T1/2
active substance(s) (mg) (µg/ml) (hours) (0-24h) (hours)
(µg.h/ml)
Amoxicillin
Amx/AC 500/125mg 500 7.19 1.5 53.5 1.15
+/- 2.26 (1.0-2.5) +/- 8.87 +/- 0.20
Clavulanic Acid
Amx/AC 500/125mg 125 2.40 1.5 15.72 0.98
+/- 0.83 (1.0-2-0) +/- 3.86 +/- 0.12
Amx–amoxicillin, AC–clavulanic acid, * - Average

The serum concentrations of amoxicillin achieved with Clavamox are similar to the
obtained with the administration of equivalent doses of isolated amoxicillin by oral route

Distribution
Studies have shown that about 25% clavulanic acid and 18% amoxicillin of the
The total serum amount of each of the compounds circulates bound to proteins. The volume
the apparent distribution is about 0.3-0.4 l/kg for amoxicillin and about 0.2
l/kg for clavulanic acid.

After intravenous administration, therapeutic concentrations can be detected of

amoxicillin and clavulanic acid in the gallbladder, abdominal tissue, skin, adipose tissue
muscular; therapeutic levels of fluids include peritoneal and synovial fluids,
bile and pus. Amoxicillin does not distribute adequately in the cerebrospinal fluid.

In the studies conducted on the animal, there was no suggestive evidence of accumulation.
organic of any of the compounds. Amoxicillin, like most penicillins,
can be detected in breast milk. They can also be detected in breast milk
vestigial amounts of clavunalate (see section 4.6).
Reproductive studies in animals have shown that both amoxicillin and
clavulanic acid crosses the placental barrier (see section 4.6).

Biotransformation
Amoxicillin is partially excreted in the urine as penicilloic acid.
inactive, in amounts equivalent to 10–25% of the initially administered dose.
In humans, clavulanic acid is extensively metabolized and is eliminated in urine.
in feces, and in the expired air in the form of carbon dioxide

Elimination
Just like with other penicillins, the main route of excretion for amoxicillin is the
renal, while the elimination of clavulanate occurs through renal and non-renal mechanisms.

Amoxicillin/clavulanic acid has an average elimination half-life of

approximately one hour and an average total purification of approximately 25 l/h
in healthy individuals. About 60-70% of amoxicillin and about 40-65% of acid
clavulanic is excreted unchanged in the urine during the first 6 hours after
administration of a single Clavamox tablet 250 mg/125 mg or 500 mg/125
mg. Several studies have shown a urinary excretion of 50-85% for amoxicillin.
and between 27-60% for clavulanic acid over a 24-hour period. In the case of acid
clavulanic, the largest amount of the drug is excreted during the 2 hours that it
they follow the administration.

The concomitant use of probenecid delays the excretion of amoxicillin, but not the
renal excretion of clavulanic acid (see section 4.5).

Age
The elimination half-life of amoxicillin is not different in children from 3 months to
2 years when compared to older children and adults and presents values
consistent in daily or bi-daily intake without showing notable accumulation. The experience
the clinic did not identify differences in responses between younger patients and older patients
old, but a greater sensitivity of some elderly individuals cannot be excluded.
Given the higher prevalence of renal insufficiencies in the elderly, some care must be taken.
taken in dose selection and it may be useful to monitor kidney function.

Genre
The monitoring of the oral administration of Clavamox to male volunteers and
feminines did not reveal any significant impact on the pharmacokinetics of either
amoxicillin wants clavulanic acid.

Renal Insufficiency
The total serum clearance of amoxicillin/clavulanic acid decreases proportionally.
with the decrease in renal function. The reduction in the clearance of these drugs is more
more pronounced for amoxicillin than for clavulanic acid, since one
a greater proportion of amoxicillin is excreted via the kidneys. The doses in renal insufficiency
renal must consequently prevent the undesirable accumulation of amoxicillin but
simultaneously maintaining adequate levels of clavulanic acid.

Liver Failure
In patients with liver failure, the dosage should be chosen with caution and
the liver function monitored at regular intervals.

5.3 Pre-clinical safety data

Non-clinical data do not reveal special risks to humans, according to studies.

pharmacological safety, genotoxicity, and reproductive toxicity.
Toxicity studies with repeated doses of amoxicillin/clavulanic acid conducted
dogs showed gastric irritation and vomiting and discoloration of the tongue.
No carcinogenicity studies have been conducted with Clavamox or any of the
your components.

6. PHARMACEUTICAL INFORMATION

6.1 List of excipients

Each film-coated tablet 500 mg/125 mg contains:

Nucleus:
Sodium carboxymethyl amide,
anhydrous colloidal silica,
magnesium stearate,
microcrystalline cellulose,

Coating:
Titanium dioxide (E171),
hypromellose
macrogol 4000
macrogol 6000
dimethicone.

Oral suspension powder 125 mg/31.25 mg/5 ml or 250 mg/62.5 mg/5 ml contains:

Anhydrous citric acid,

sodium citrate
sodium benzoate
microcrystalline cellulose,
xanthan gum
anhydrous colloidal silica,
hydrated colloidal silica,
aspartame (E951)
strawberry aromas
banana aroma.

6.2 Incompatibilities

Not applicable.

6.3 Expiration date

Coated tablets 500 mg/125 mg/5 ml: 2 years.

Oral suspension powder 125mg/31.25mg/5ml and 250mg/62.5mg/5ml: 2 years.

After reconstitution, all oral suspensions must be stored in the refrigerator.

(2°C to 8°C). Oral suspensions of Clavamox should be used within 7 days.
days, except for the presentation of 150 ml which must be used within 10 days
days.

Do not freeze.

6.4 Special conservation precautions

Do not store above 25ºC.

Keep in the original packaging to protect from humidity.
Conditions for the conservation of the reconstituted medication, see section 6.3.

6.5 Nature and content of the container

Clavamox 500 film-coated tablets are packaged in blisters.

Alu/Alu are inserted in a cardboard box. The following presentations are available: 12
and 16 tablets.
Not all presentations may be sold.

Oral suspension of Clavamox 125 and Clavamox 250: type III glass bottle, amber color,
containing powder for oral suspension, packaged in a cardboard box.

The following presentations are available: powder for 60 ml, 75 ml, 100 ml, and 150 ml of
oral suspension.
Not all presentations may be marketed.

6.6 Special precautions for disposal and handling

There are no special requirements.

125 mg/31.25 mg/5 ml powder for oral suspension:

Check if the seal of the cap is intact before use. Shake the bottle to loosen the powder.
Add water volume (according to the table below), invert and shake well.
Alternatively, fill the jar with water just below the mark on the label.
from the bottle, invert and shake well. Then, fill with water to the mark, invert the
bottle and shake well.

Concentration Volume of water to be Final volume of suspension

added when reconstituted oral (ml)
reconstitution (ml)
125 mg/31.25 mg/5 ml Until the marking 60
74 80
92 100

Shake the bottle before each dose.

250 mg/62.5 mg/5 ml powder for oral suspension:

Check if the seal on the cap is intact before use. Shake the bottle to loosen the powder.
Add water volume (according to the table below), invert and shake well.
Alternatively, fill the jar with water up to just below the mark on the label.
from the bottle, invert and shake well. Then, fill with water to the marking, invert the
shake well.

Concentration Volume of water to be Final volume of suspension

added when of the reconstituted oral (ml)
reconstitution (ml)
250 mg/62.5 mg/5 ml Until the marking 60
72 80
90 100
Shake the bottle before each dose.

7. HOLDER OF THE AUTHORIZATION FOR MARKET INTRODUCTION

BIAL–Portela & Co., S.A.

At Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal

8. AUTHORIZATION NUMBER(S) FOR MARKET INTRODUCTION

CLAVAMOX 500 500 mg + 125 mg film-coated tablets

Nº de registo: 4717591 - 12 comprimidos, 500 mg + 125 mg, blister Alu/Alu
Nº de registo: 9588822 - 16 comprimidos, 500 mg + 125 mg, blister Alu/Alu
CLAVAMOX 125 125 mg/31.25 mg/5 ml powder for oral suspension
Nº de registo: 9596239 - pó para 60 ml de suspensão oral, 125 mg/31,25 mg/5 ml,
amber glass vial
Nº de registo: 4727897 - pó para 75 ml de suspensão oral, 125 mg/31,25 mg/5 ml,
amber glass bottle
Nº de registo: 9596213 - pó para 100 ml de suspensão oral, 125 mg/31,25 mg/5 ml,
amber glass vial
Registration number: 4823191 - powder for 150 ml of oral suspension, 125 mg/31.25 mg/5 ml,
amber glass bottle

CLAVAMOX 250 250 mg/ 62.5 mg/5 ml powder for oral suspension
Nº de registo: 9596247 - pó para 60 ml de suspensão oral, 250 mg/ 62,5 mg/5 ml, frasco
of amber glass
Nº de registo: 4727699 - pó para 75 ml de suspensão oral, 250 mg/ 62,5 mg/5 ml, frasco
amber glass
Nº de registo: 9596254 - pó para 100 ml de suspensão oral, 250 mg/ 62,5 mg/5 ml,
amber glass bottle
Registration number: 4727798 - powder for 150 ml oral suspension, 250 mg/62.5 mg/5 ml,
amber glass bottle

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION OF

INTRODUCTION TO THE MARKET

CLAVAMOX 500 mg/125 mg film-coated tablets

Date of the first authorization: May 23, 1984
Review date: September 15, 1994
Date of last renewal: September 15, 2004

CLAVAMOX 125 mg/31.25 mg/5 ml powder for oral suspension

Date of the first authorization: October 10, 1984
Data de revisão: 15 de Setembro de 1994
Date of last renewal: September 15, 2004

CLAVAMOX 250 mg/62.5 mg/5 ml powder for oral suspension

Date of the first authorization: October 10, 1984
Review date: September 15, 1994
Date of last renewal: September 15, 2004

10. DATE OF TEXT REVIEW