Klavox is indicated for the treatment of the following infections in adults and

children (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.

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

when doses are stated in terms of an individual component.

To make up to 70ml: first shake bottle to loosen powder. Then add 62ml of water and

shake well or add water to 2/3 of fill line level on label, shake well and fill up to the line.

Shake well before taking each dose.

The dose of Klavox 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 Klavox (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 children < 40 kg, this formulation of Klavox provides a maximum daily dose of

1000-2800 mg amoxicillin/143-400 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 Klavox 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).

Children ≥ 40 kg should be treated with the adult formulations of Klavox.

Children < 40 kg

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

Recommended doses:

• 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses;

• up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some

infections (such as otitis media, sinusitis and lower respiratory tract infections).

No clinical data are available for Klavox 7:1 formulations regarding doses higher than 45 mg/6.4 mg per kg per day in children under 2 years

There are no clinical data for Klavox 7:1 formulations for patients under 2 months of age.

Dosing recommendations in this population therefore cannot be made.

Elderly

No dose adjustment is considered necessary.

Renal impairment

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

In patients with creatinine clearance less than 30 ml/min, the use of Klavox presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no

recommendations for dose adjustments are available.

Hepatic impairment

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

Method of administration

Klavox is for oral use.

Administer at the start of a meal to minimise potential gastrointestinal intolerance and

optimise absorption of amoxicillin/clavulanic acid.

Therapy can be started parenterally according to the SmPC of the IV-formulation and continued with an oral preparation.

Shake to loosen powder, add water as directed, invert and shake. 

Shake the bottle before each dose (see section 6.6).

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 (anaphylactoid) reactions have been

reported in patients on penicillin therapy. These reactions are more likely to occur in

individuals with a history of penicillin hypersensitivity and in atopic individuals. If an

allergic reaction occurs, amoxicillin/clavulanic acid therapy 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 Klavox 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 Klavox 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 and 4.8).

Hepatic events have been reported predominantly in males and elderly patients and

may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or

shortly after treatment but in some cases may not become apparent until several

weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section4.8).

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.

Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin 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 (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 non-enzymatic methods.

The presence of Clavulanic acid in Klavox 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.

Klavox powder for oral suspension contains 2.5 mg of aspartame (NF) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria.

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the

prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).

Methotrexate

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

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50% has been reported following commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

Pregnancy

Pregnancy category: B.

Animal studies do not indicate direct or indirect harmful effects with respect to

pregnancy, embryonal/foetal development, parturition or postnatal development (see

section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy

in humans do not indicate an increased risk of congenital malformations. In a single

study in women with preterm, premature rupture of the foetal membrane it was

reported that prophylactic treatment with amoxicillin/clavulanic acid may be

associated with an increased risk of necrotising enterocolitis in neonates. Use should

be avoided during pregnancy, unless considered essential by the physician.

Lactation

Both substances are excreted into breast milk (nothing is known of the effects of

clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus

infection of the mucous membranes are possible in the breast-fed infant, so that

breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should

only be used during breast-feeding after benefit/risk assessment by the physician in

charge.

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).

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

and vomiting.

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

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)

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: Combinations of penicillins, incl. beta-lactamase

inhibitors; ATC code: J01CR02.

Mode 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. Absorptionof amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oraladministration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasmaprofiles 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 (875 mg/125 mg

tablets given twice daily) was administered in the fasting state to groups of healthy volunteersare 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 section4.6).

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 Klavox 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 Klavox or its components.

Klavox Powder for Oral Suspension excipients

● Xantham Gum

● Hydroxypropyl Methyl cellulose

● Aspartame NF

● Colloidal Silicon Dioxide

● Succinic Acid

● Silicon Dioxide NF 18 Silica Gel

● Raspberry Dry Flavour NN07943

● Orange Dry Flavour 61027 1 E

● Orange Dry Flavour 9/027108

● Orange Dry Flavour 653970

● Golden Syrup Dry Flavour 52.927

Not applicable

Store below 25°C

Klavox 457mg/5ml Powder for Oral Suspension: 100 ml/pack

Clear bottle with white child-resistant cap.

No special disposal