Curam® is indicated for the treatment of the following infections in adults andchildren (see sections 4.2, 4.4 and 5.1):

 Acute bacterial sinusitis (adequately diagnosed)

 Acute otitis media

 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.

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

Posology

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are

stated in terms of an individual component.

The dose of Curam® 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 Curam® (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).

For adults and children ³ 40 kg, this formulation of Curam® provides a total daily

dose of 1500 mg amoxicillin/375 mg clavulanic acid, when administered as recommended below. For

children < 40 kg, this formulation of Curam® provides a maximum daily dose of

2400 mg amoxicillin/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 another

preparation of Curam® is selected in order to avoid administration of

unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1).

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).

Adults and children ³ 40 kg

One 500 mg/125 mg dose taken three times a day.

Children < 40 kg

20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses.

Children may be treated with Curam® tablets, suspensions or paediatric sachets.

As the tablets cannot be divided children weighing less than 25 kg must not be treated with

Curam® tablets.

The table below presents the received dose (mg/kg body weight) in children weighing 25 kg to 40 kg

upon administering a single 500/125 mg tablet.

 

 

 

Body weight (kg)	40	35	30	25	Single dose recommended [mg/kg body weight] (see above)
Amoxicillin [mg/kg body weight] per single dose (1 film-coated tablet)	12.5	14.3	16.7	20.0	6.67 - 20
Clavulanic acid [mg/kg body weight] per single dose (1 film-coated tablet)	3.1	3.6	4.2	5.0	1.67 - 5

 

Children aged 6 years and below or weighing less than 25 kg should preferably be treated with

Curam® suspension or paediatric sachets.

No clinical data are available on doses of Curam® 4:1 formulations higher than

40 mg/10 mg/kg per day in children under 2 years.

Elderly

No dose adjustment is considered necessary.

Renal impairment

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

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

Adults and children ≥ 40 kg

Children < 40 kg

CrCl: 10-30 ml/min	15 mg/3.75 mg/kg twice daily (maximum 500 mg/125 mg twice daily).
CrCl < 10 ml /min	15 mg/3.75 mg/kg as a single daily dose (maximum 500 mg/125 mg).
Haemodialysis	15 mg/3.75 mg/kg per day once daily. Prior to haemodialysis 15 mg/3.75 mg/kg. In order to restore circulating drug levels, 15 mg/3.75 mg per kg should be administered after haemodialysis.

 

Hepatic impairment

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

Method of administration

Curam® is for oral use.

Curam® should be administered with a meal to minimise potential

gastrointestinal intolerance.

Therapy can be started parenterally according the SPC of the IV-formulation and continued with an

oral preparation.

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in section 6.1. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning

previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see

sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe

cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are

more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic

individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued

and appropriate alternative therapy instituted.

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then

consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in

accordance with official guidance.

This presentation of Curam® is not suitable for use when there is a high risk that

the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not

mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should

not be used to treat 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 exanthemous pustulosis (AGEP) (see Section 4.8). This

reaction requires Curam® 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 section 4.2, 4.3; 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 and may range in

severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this

diagnosis in patients who present with diarrhoea during or subsequent to the administration of any

antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately

be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic

medicinal products are contra-indicated in this situation.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function

is advisable during prolonged therapy.

Prolongation of prothrombin time has been reported rarely in patients receiving

amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are

prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to

maintain the desired level of anticoagulation (see 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 the administration of high doses of amoxicillin, it is advisable to maintain

adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria.

In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever

testing for the presence of glucose in urine because false positive results may occur with nonenzymatic

methods.

The presence of Clavulanic acid in Curam® 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.

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 coadministration 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.

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. The possibility

of sensitisation should be taken into account. Amoxicillin/clavulanic acid should only be used during

breast-feeding after benefit/risk assessment by the physician in charge.

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 Curam®, 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
Angioneurotic oedema	Not known
Anaphylaxis	Not known
Serum sickness-like syndrome	Not known
Hypersensitivity vasculitis	Not known
Nervous system disorders
Dizziness	Uncommon
Headache	Uncommon
Reversible hyperactivity	Not known
Convulsions2	Not known
Aseptic meningitis	Not known

Gastrointestinal disorders
Diarrhoea	Very common
Nausea3	Common
Vomiting	Common
Indigestion	Uncommon
Antibiotic-associated colitis4	Not known
Black hairy tongue	Not known
Hepatobiliary disorders
Rises in AST and/or ALT5	Uncommon
Hepatitis6	Not known
Cholestatic jaundice6	Not known
Skin and subcutaneous tissue disorders 7
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 exanthemous pustulosis (AGEP)9	Not known
Drug reaction with eosinophilia and systemic symptoms (DRESS)	Not known
Renal and urinary disorders
Interstitial nephritis	Not known
Crystalluria8	Not known

 

 

 

 

 

 

 

 

 

 

1 See section 4.4 2  See section 4.4 3  Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking [nationally completed name] with a meal. 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 beta-lactam class antibiotics, but the significance of these findings is unknown. 6   These events have been noted with other penicillins and cephalosporins (see section 4.4). 7  If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8  See section 4.9 9  See section 4.4 10See sections 4.3 and 4.4

 

 

Symptoms and signs of overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident.

Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

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

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous

administration of large doses. A regular check of patency should be maintained (see section 4.4).

Treatment of intoxication

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

balance.

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

Pharmacotherapeutic group: Antibacterials for systemic use; betalactam antibacterials, penicillins;

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)

The prevalence of resistance may vary geographically and with time for selected species, and local

information on resistance is desirable, particularly when treating severe infections. As necessary,

expert advice should be sought when the local prevalence of resistance is such that the utility of the

agent in at least some types of infections is questionable.

 

Absorption

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/clavulanic acid is optimised when taken at the start of a meal. Following oral

administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma

profiles of both components are similar and the time to peak plasma concentration (Tmax) in each

case is approximately one hour.

The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (500 mg/125 mg tablets

three times daily) was administered in the fasting state to groups of healthy volunteers are presented

below.

Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are

similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic

acid alone.

Distribution

About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein.

The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for

clavulanic acid.

Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall

bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus.

Amoxicillin does not adequately distribute into the cerebrospinal fluid.

From animal studies there is no evidence for significant tissue retention of drug-derived material for

either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities

of clavulanic acid can also be detected in breast milk (see section 4.6).

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

Biotransformation

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to

up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated

in urine and faeces and as carbon dioxide in expired air.

Elimination

The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by

both renal and non-renal mechanisms.

Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean

total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the

amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine

during the first 6 h after administration of single Curam® 250 mg/125 mg or 500

mg/125 mg tablets. 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.

Gender

Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects,

gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.

Renal impairment

The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing

renal function. The reduction in drug clearance is more pronounced for amoxicillin than for

clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal

impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate

levels of clavulanic acid (see section 4.2).

Hepatic impairment

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

intervals.

Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology,

genotoxicity and toxicity to reproduction.

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric

irritancy and vomiting, and discoloured tongue.

Carcinogenicity studies have not been conducted with Curam® or its components.

Magnesium stearate

Talc

Povidone K25

Microcrystalline cellulose

Croscarmellose sodium

Triethyl citrate

Hypromellose

Ethylcellulose

Sodium lauryl sulfate

Cetyl alcohol

Titanium dioxide (E 171)

Not applicable

36 months.

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

Protect from light.

Sealed strips of aluminium foil with polyethylene coating.

Single pack of 10, 12, 15, 16, 20, 24, 30, 36, 100x1 film-coated tablets

Hospital pack of 100 film-coated tablets

Not all pack sizes may be marketed.

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

requirements.