KLAMENTIN 500 125

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KLAMENTIN 500/125

 

INFORMATION FOR MEDICAL STAFF

 

COMPOSITION:

Amoxicillin (as amoxicillin trihydrate) ......... 500 mg

Clavulanic acid (as potassium clavulanate & avicel) ..... 125 mg

Excipients.q.s ...................................... 1 caplet

(Colloidal silicon dioxide, polyplasdone XL, microcrystalline cellulose M112, magnesium stearate, sepifilm LP914, titanium dioxide, talc).

PHARMACEUTICAL FORM:

Film coated caplet.

PHARMACODYNAMIC PROPERTIES:

ATC code: J01CR02

Amoxicillin is a beta-lactam semi-synthetic antibiotic with a broad-spectrum of bactericidal activity against many Gram-positive and Gram-negative microorganisms due to inhibition of bacterial cell wall synthesis. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes.

Clavulanic acid has beta-lactam structure resembling that of penicillin and acts as an inhibitor on beta-lactamases produced by most Gram-negative bacteria and Staphylococcus. Particularly, clavulanic acid potently inhibits the plasmid medicated beta-lactamases, resulting in resistance to penicillins and cephalosporins.

The formulation of clavulanic acid and amoxicillin in Klamentin protects amoxicillin from degradation by beta-lactamases enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and microorganisms resistant to other penicillins and cephalosporins.

Spectrum:

Gram-positive bacteria:

Aerobic micro-organisms: Streptococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Staphylococcus aureus, Corynebacterium, Bacillus anthracis, Listeria monocytogenes.

Anaerobic micro-organisms: Species of Clostridium, Peptococcus, Peptostreptococcus.

Gram-negative bacteria:

Aerobic micro-organisms: Haemophilus influenzae, Escherichia coli, Proteus mirabilis, Proteus vulgaris, species of Klebsiella, Salmonella, Shigella, Bordetella, Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pasteurella multocida.

Anaerobic micro-organisms: Bacteroides spp. including B. fragilis.

PHARMACOKINETIC PROPERTIES:

Absorption: Amoxicillin and clavulanic acid are well absorbed by oral administration. Peak serum concentrations are generally attained within 1 - 2 hours following oral administration. Presence of food does not affect oral absorption of the drug. However the drug is optimally absorbed when administered orally at the beginning of a standardized meal.

Distribution: Orally administered doses of 500-mg amoxicillin and 125-mg clavulanic acid result in serum concentration 3.7 - 4.8 microgram/ml for amoxicillin and 2.1 - 3.9 microgram/ml for clavulanic acid. Both amoxicillin and clavulanic acid are distributed into the lung, pleural fluid and peritoneal fluid and have been shown to cross the placental barrier. Amoxicillin can be detected in breast milk and no data has shown that clavulanic acid is in the milk of lactating mothers. Oral bioavailability of amoxicillin is 90% and that of clavulanic acid is 75%. The serum half-life of amoxicillin is 1 - 2 hours and that of clavulanic acid is about 1 hour. Approximately 55 - 73% and 25 - 45% of the amoxicillin and clavulanic acid doses, respectively, are excreted unchanged in urine.

Metabolism: Amoxicillin is poorly excreted in the body as the penicilloic acid. Clavulanic acid is partly metabolised as the metabolite with low molecular weight.

Elimination: The major route of elimination for amoxicillin and clavulanic acid is via the kidney. Serum concentrations of amoxicillin and of clavulanic acid are higher and the serum half-lives prolonged in patients with renal impairment. In patients with creatinine clearances of 9 ml/minute, the serum half-lives of amoxicillin and clavulanic acid were 7.5 and 4.3 hours, respectively. Amoxicillin and clavulanic acid are both removed by hemodialysis. Clavulanic acid is also removed by peritoneal dialysis. Only minimal amounts of amoxicillin appear to be removed by peritoneal dialysis. Probenecid prolongs the excretion of amoxicillin but does not affect the excretion of clavulanic acid.

PRESENTATION:

Box of 1 pack x 3 blisters x 4 caplets

Box of 1 pack x 2 blisters x 7 caplets

THERAPEUTIC INDICATIONS:

Klamentin is indicated for the treatment of the following infections in adults and children:

Acute 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, dental abscess.

Bone and joint infections, in particular osteomyelitis.

DOSAGE & ADMINISTRATION:

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 Klamentin that is selected to treat an individual infection should take into account: the expected pathogens and their likely susceptibility to antibacterial agents; the severity and the site of the infection; the age, weight and renal function of the patient.

The use of alternative presentations of Klamentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary.

For adults and children ³ 40 kg, this formulation of Klamentin 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 Klamentin 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 Klamentin is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid.

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.

The caplet(s) should be swallowed whole and not be chewed. If needed, the caplet(s) can be broken in half, then swallowing.

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 Klamentin caplets or paediatric sachets.

Children aged 6 years and below or weighing less than 25 kg must not be treated with Klamentin caplets as the caplets cannot be divided.

No clinical data are available in children under 2 years.

Elderly: No dose adjustment is considered necessary, given as adult dose.

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: 500 mg/125 mg twice daily.

CrCl < 10 ml /min: 500 mg/125 mg once daily.

Haemodialysis: 500 mg/125 mg every 24 hours, plus 500 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:

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 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. Not enough data to provide the recommended dose.

Klamentin should be administered at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid.

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

Or as prescribed by a physician.

CONTRAINDICATIONS:

History of a hypersensitivity reaction to another beta-lactam agent (e.g. a penicillin, cephalosporin) or to any of the ingredients of the drug.

History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid.

PRECAUTIONS:

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

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. 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 Klamentin 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.

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 of a feverish generalised erythema requires Klamentin discontinuation and contra-indicates any subsequent administration of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment.

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. 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.

Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening. 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.

In patients with renal impairment, the dose should be adjusted according to the degree of impairment.

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained.

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 Klamentin 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.

Pregnancy and lactation:

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

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.

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. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

Effects of on ability to drive and use machines:

Undesirable effects may occur e.g. dizziness, headache, which may influence the ability to drive and use machines, work at height and other cases.

INTERACTIONS:

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.

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

Probenecid: Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin

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.

UNDESIRABLE EFFECTS:

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

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

Common: Mucocutaneous candidosis

Not known: Overgrowth of non-susceptible organisms

Blood and lymphatic system disorders

Rare: Reversible leucopenia (including neutropenia), thrombocytopenia

Not known: Reversible agranulocytosis, haemolytic anaemia, prolongation of bleeding time and prothrombin time

Immune system disorders

Not known: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis

Nervous system disorders

Uncommon: Dizziness, headache

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