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)
• Cystitis
• Pyelonephritis
• Cellulitis
• Animal bites
• Severe dental abscess with spreading cellulitis.
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 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 adults and children ≥ 40 kg, this formulation of Klavox provides a total daily
dose of 750 mg amoxicillin/375 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).
Treatment should not be extended beyond 14 days without review.
Adults and children ≥ 40 kg
One tablet taken three times a day.
Children < 40 kg
Klavox 250 mg/125 mg film-coated tablets are not recommended in children < 40 kg.
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

CrCl: 10-30 ml/min	250 mg/125 mg twice daily
CrCl < 10 ml /min	250 mg/125 mg once daily
Haemodialysis	Two doses of 250 mg/125 mg every 24 hours, plus two doses of 250 mg/125 mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg
In children < 40 kg with creatinine clearance less than 30 ml/min, the use of Klavox
presentations with an amoxicillin to clavulanic acid ratio of 2:1 is not recommended,
as no dose adjustments are available. In such patients, Klavox formulations with an
amoxicillin to clavulanic acid ratio of 4:1 are recommended.
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.

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.
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 (e.g. penicillin-insusceptible 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 sections 4.2, 4.3 and 4.8).
Hepatic events have been reported predominantly in males and elderly patients and
may be associated with prolonged treatment. These events have been very rarely
reported in children. In all populations, signs and symptoms usually occur during or
shortly after treatment but in some cases may not become apparent until several
weeks after treatment has ceased. These are usually reversible. Hepatic events may
be severe and, in extremely rare circumstances, deaths have been reported. These
have almost always occurred in patients with serious underlying disease or taking
concomitant medications known to have the potential for hepatic effects (see section
4.8).

Antibiotic-associated colitis has been reported with nearly all antibacterial agents 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 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.

 

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 section 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
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.
Breastfeeding
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 breastfeeding
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)

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
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 amoxicillin/clavulanic acid at the start of 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  10 See sections 4.3 and 4.4

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via:

To report any side effect(s):   The National Pharmacovigilance and Drug Safety Centre (NPC)  o Fax: +966-11-205-7662  o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.  o Reporting hotline: 19999.  o E-mail: npc.drug@sfda.gov.sa  o Website: www.sfda.gov.sa/npc

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. 

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. 

Pharmacodynamic effects 

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). 

Organism	Susceptibility Breakpoints (μg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae1	≤ 1	-	> 1
Moraxella catarrhalis1	≤ 1	-	> 1
Staphylococcus aureus 2	≤ 2	-	> 2
Coagulase-negative staphylococci 2	≤ 0.25		> 0.25
Enterococcus1	≤ 4	8	> 8
Streptococcus A, B, C, G5	≤ 0.25	-	> 0.25
Streptococcus pneumoniae3	≤ 0.5	1-2	> 2
Enterobacteriaceae1,4	-	-	> 8
Gram-negative Anaerobes1	≤ 4	8	> 8
Gram-positive Anaerobes1	≤ 4	8	> 8
Non-species related breakpoints1	≤ 2	4-8	> 8
1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l.  2 The reported values are Oxacillin concentrations.  3 Breakpoint values in the table are based on Ampicillin breakpoints.  4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant.  5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

 

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. 

Commonly susceptible species

Aerobic Gram-positive micro-organisms  Enterococcus faecalis  Staphylococcus aureus (methicillin-susceptible) £  Streptococcus agalactiae  Streptococcus pneumoniae1  Streptococcus pyogenes and other beta-hemolytic streptococci  Streptococcus viridans group  Aerobic Gram-negative micro-organisms  Capnocytophaga spp.  Eikenella corrodens  Haemophilus influenzae2  Moraxella catarrhalis  Pasteurella multocida  Anaerobic micro-organisms  Bacteroides fragilis  Fusobacterium nucleatum  Prevotella spp.

Species for which acquired resistance may be a problem

Aerobic Gram-positive micro-organisms  Enterococcus faecium $  Aerobic Gram-negative micro-organisms  Escherichia coli  Klebsiella oxytoca  Klebsiella pneumoniae  Proteus mirabilis  Proteus vulgaris

Inherently resistant organisms

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

$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance.  £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid  1Streptococcus pneumoniae that is fully susceptible to penicillin may be treated with this presentation of amoxicillin/clavulanic acid. Organisms that show any degree of reduced susceptibility to penicillin should not be treated with this presentation (see sections 4.2 and 4.4).  2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.

 

 

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 (250 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below. 

Mean (± SD) pharmacokinetic parameters
Active substance(s) administered	Dose	Cmax	Tmax *	AUC (0-24h)	T 1/2
	(mg)	(μg/ml)	(h)	((μg.h/ml)	(h)
Amoxicillin
AMX/CA  250 mg/125 mg	250	3.3  ± 1.12	1.5  (1.0-2.0)	26.7±4.56	1.36  ± 0.56
Clavulanic acid
AMX/CA  250 mg/125 mg	125	1.5  ± 0.70	1.2  (1.0-2.0)	12.6  ± 3.25	1.01  ± 0.11
AMX – amoxicillin, CA – clavulanic acid  * Median (range)

 

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 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.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction. 

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue. 

Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components. 

Excipients

Magnesium Stearate

Colloidal Silicon Dioxide

Sodium Starch Glycolate

Avicel PH 112

Coating Material

Opadry OY-S-7300

Silicon Oil

Not applicable

3 Years

Store in a dry place below 25°C. 

20/pack Transparent PVC/PVDC blister strip with aluminium foil packed in pouch. 

No Special Disposal