Rhea Co-amoxiclav

Co-amoxiclav: Amoxicillin and clavulanic acid.

Tablets: Co-amoxiclav 625 mg Tablet: Each tablet contains 500 mg amoxicillin and 125 mg clavulanic acid.
Co-amoxiclav (beta-lactam antibacterial penicillin coformulated with a beta-lactamase inhibitor) is an antibiotic agent with a notably broad spectrum of activity against the commonly occurring bacterial pathogens in general practice and hospital. The beta-lactamase inhibitory action of clavulanate extends the spectrum of amoxicillin to embrace a wider range of organisms, including many resistant to other beta-lactam antibiotics.
Powder for Suspension (in bottles): Co-amoxiclav 312.5 mg/5mL Powder for Suspension: Bottles of powder for the preparation of fruit flavoured suspension. When reconstituted, each 5mL contains 250 mg amoxicillin and 62.5 mg clavulanic acid.
Co-amoxiclav 457 mg/5mL Powder for Suspension: Bottles of powder for the preparation of strawberry flavoured suspension. When reconstituted, each 5mL contains 400mg amoxicillin and 57 mg clavulanic acid.

Pharmacology: Pharmacodynamics: Mechanism of Action: Amoxicillin is a semisynthetic antibiotic with a broad spectrum of antibacterial activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by beta-lactamases 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 the penicillins, which possesses the ability to inactivate a wide range of beta-lactamase enzymes commonly found in micro-organisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance. It is generally less effective against chromosomally-mediated type 1 beta-lactamases.
The presence of clavulanic acid in co-amoxiclav formulations protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other penicillins and cephalosporins. Thus amoxicillin-clavulanate possesses the distinctive properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.
Pharmacodynamic Effects: In the list as follows, organisms are categorised according to their in vitro susceptibility to amoxicillin-clavulanate. (See Table 1.)

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Pharmacokinetics: Absorption: The two components of co-amoxiclav, 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 co-amoxiclav is optimised when taken at the start of a meal.
The pharmacokinetic results for two separate studies, in which co-amoxiclav 250/125 (375) or 2 x 250/125 and 500/125 (625) mg tablets (in comparison with the two components given separately) were administered in the fasting state to groups of healthy volunteers, are presented as follows. (See Table 2.)

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Amoxicillin serum concentrations achieved with co-amoxiclav are similar to those produced by the oral administration of equivalent doses of amoxicillin alone.
Distribution: Following i.v. administration, therapeutic concentrations of both amoxicillin and clavulanic acid may be detected in the tissues and interstitial fluid. Therapeutic concentrations of both drugs have been found in gall bladder, abdominal tissue, skin, fat, and muscle tissues; fluids found to have therapeutic levels include synovial and peritoneal fluids, bile and pus.
Neither amoxicillin nor clavulanic acid is highly protein bound, studies show that about 25% for clavulanic acid and 18% for amoxicillin of total plasma drug content is bound to protein.
From animal studies there is no evidence to suggest that either component accumulates in any organ.
Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanate can also be detected in breast milk. With the exception of the risk of sensitisation associated with this excretion, there are no known detrimental effects for the breast-fed infant.
Reproduction studies in animals have shown that both amoxicillin and clavulanic acid penetrate the placental barrier.
However, no evidence of impaired fertility or harm to the foetus was detected.
Metabolism: Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to 10 to 25% of the initial dose.
Clavulanic acid is extensively metabolized in man to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one and eliminated in urine and faeces as carbon dioxide in expired air.
Elimination: As with other penicillins, the major route of elimination for amoxicillin is via the kidney, whereas for clavulanate it is by both renal and non-renal mechanisms.
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 a single 250/125 mg or a single 500/125 mg tablet. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see Interactions).

Amoxicillin-clavulanate should be used in accordance with local official antibiotic-prescribing guidelines and local susceptibility data.
Adult formulations: Co-amoxiclav is indicated for short term treatment of bacterial infections at the following sites when caused by amoxicillin-clavulanate-susceptible organisms: Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media, typically caused by Streptococcus pneumoniae, Haemophilus influenzae^#, Moraxella catarrhalis^# and Streptococcus pyogenes.
Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis, lobar and bronchopneumonia, typically caused by Streptococcus pneumoniae, Haemophilus influenzae^# and Moraxella catarrhalis^#.
Genito-urinary tract infections e.g. cystitis, urethritis, pyelonephritis, female genital infections typically caused by Enterobacteriaceae* (mainly Escherichia coli^#), Staphylococcus saprophyticus and Enterococcus species and gonorrohoea caused by Neisseria gonorrhoeae^#.
Skin and soft tissue infections typically caused by Staphylococcus aureus^#, Streptococcus pyogenes and Bacteroides species^#.
Bone and joint infections e.g. osteomyelitis typically caused by Staphylococcus aureus^#, where more prolonged therapy may be appropriate.
Dental infections e.g. dentoalveolar abscess.
Other Infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.
Paediatric formulations: Co-amoxiclav is indicated for short term treatment of bacterial infections at the following sites when caused by amoxicillin-clavulanate sensitive organisms: Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media typically caused by Streptococcus pneumoniae, Haemophilus influenzae^#, Moraxella catarrhalis^# and Streptococcus pyogenes.
Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis, lobar and bronchopneumonia typically caused by Streptococcus pneumoniae, Haemophilus influenzae^# and Moraxella catarrhalis^#.
Genito-urinary tract infections e.g. cystitis, urethritis, pyelonephritis, female genital infections typically caused by Enterobacteriaceae^# (mainly Escherichia coli^#) Staphylococcus saprophyticus and Enterococcus species, and gonorrhoea caused by Neisseria gonorrhoeae^#.
Skin and soft tissue infections typically caused by Staphylococcus aureus^#, Streptococcus pyogenes and Bacteroides species^#.
Amoxicillin-clavulanate Paediatric three times daily: The paediatric three times daily dosing regimen is also indicated for the following infections: Bone and joint infections e.g. osteomyelitis typically caused by Staphylococcus aureus^#, where more prolonged therapy may be appropriate.
Other infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.
All formulations: ^#Some members of these species of bacteria produce beta-lactamase, rendering them insensitive to amoxicillin alone. (see Pharmacology: Pharmacodynamics: Pharmacodynamic effects under Actions for further information).
Susceptibility to amoxicillin-clavulanate will vary with geography and time. Local susceptibility data should be consulted where available, and microbiological sampling and susceptibility testing performed where necessary.
Infections caused by amoxicillin-susceptible organisms are amenable to co-amoxiclav treatment due to its amoxicillin content. Mixed infections caused by amoxicillin-susceptible organisms in conjunction with amoxicillin-clavulanate-susceptible beta-lactamase-producing organisms may therefore be treated by co-amoxiclav.

Dosage depends on the age, weight and renal function of the patient and the severity of the infection.
Dosages are expressed throughout in terms of co-amoxiclav content except when doses are stated in terms of an individual component.
To minimise potential gastrointestinal intolerance, administer at the start of a meal.
The absorption of co-amoxiclav is optimised when taken at the start of a meal.
Treatment should not be extended beyond 14 days without review.
Therapy can be started parenterally and continued with an oral preparation.
Populations: Adults: See Table 3.

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Two co-amoxiclav 250/125 mg tablets should not be substituted for one co-amoxiclav 500/125 mg tablet since they are not equivalent.
Children: Dosage should be expressed in terms of the age of the child and either in mg/kg/day (given in 2 or 3 divided doses) or ml of suspension per dose or equivalent for other presentations.
Children weighing 40 kg and over should be dosed according to the adult recommendations.
Children up to 12 years: See Table 4.

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The lower dose is recommended for infections such as skin and soft tissue and recurrent tonsillitis.
The higher dose is recommended for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections.
No clinical data are available on doses of these formulations higher than 40/10 mg/kg/day (4:1) or 45/6.4 mg/kg/day (7:1) in children under 2 years.
There are no clinical data for the 7:1 formulation for patients under 2 months of age. Dosing recommendations in this population therefore cannot be made.
The 8:1 ratio formulation is recommended for dosing at 40/5 to 80/10 mg/kg/day (in three divided doses) in children aged 1 to 30 months, depending upon severity of infection.
Premature: No dosage recommendation can be made for this category.
Elderly: No adjustment needed; dose as for adults. If there is evidence of renal impairment, dose should be adjusted as for renally impaired adults.
Renal impairment: Dosage adjustments are based on the maximum recommended level of amoxicillin.
Adults: See Table 5.

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Children: See Table 6.

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In the majority of cases, parenteral therapy, where available, may be preferred.
Haemodialysis: Adults: 1 times 500/125 mg OR 2 times 250/125 mg every 24 hours, PLUS 1 dose during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased) (⁺)
(+) The 875/125 mg and 1000/125 mg presentations should only be used in patients with a creatinine clearance of more than 30 ml/min.
Children: 15/3.75 mg/kg/day given as a single daily dose.
Prior to haemodialysis one additional dose of 15/3.75 mg/kg should be administered. In order to restore circulating drug levels, another dose of 15/3.75 mg/kg should be administered after haemodialysis.
Hepatic impairment: Dose with caution; monitor hepatic function at regular intervals.
There are insufficient data on which to base a dosage recommendation.

Symptoms and Signs: Symptoms and Signs 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 Precautions).
Treatment: GI symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Co-amoxiclav can be removed from the circulation by haemodialysis.
Children (additional statement): A prospective study of 51 paediatric patients at a poison control centre suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.
Drug abuse and dependence: Drug dependency, addiction and recreational abuse have not been reported as a problem with this compound.

Co-amoxiclav is contraindicated: in patients with a history of hypersensitivity to beta-lactams, e.g. penicillins and cephalosporins; in patients with a previous history of amoxicillin-clavulanate-associated jaundice/hepatic dysfunction.

Before initiating therapy with co-amoxiclav, 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, co-amoxiclav therapy should be discontinued and appropriate alternative therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, i.v. steroids and airway management, including intubation may also be required.
Co-amoxiclav 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.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further.
In general co-amoxiclav is well tolerated and possesses the characteristic low toxicity of the penicillin group of antibiotics. 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-clavulanate 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.
Co-amoxiclav should be used with caution in patients with evidence of hepatic dysfunction.
In patients with renal impairment, dosage should be adjusted according to the degree of impairment (see Renal Impairment under Dosage & Administration).
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 (see Overdosage).
Co-amoxiclav Suspensions/Sachets/Chewable Tablets (where applicable), contain aspartame, which is a source of phenylalanine and so should be used with caution in patients with phenylketonuria.
Ability to Perform Tasks that Require Judgement, Motor, or Cognitive Skills: Adverse effects on the ability to drive or operate machinery have not been observed.

Pregnancy: Reproduction studies in animals (mice and rats at doses up to 10 times the human dose) with orally and parenterally administered co-amoxiclav have shown no teratogenic effects. In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with co-amoxiclav may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, unless considered essential by the physician.
Lactation: Co-amoxiclav may be administered during the period of lactation. With the exception of the risk of sensitization, associated with the excretion of trace quantities in breast milk, there are no known detrimental effects for the breast-fed infant.

Data from large clinical trials was used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e., those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency.
The following convention has been used for the classification of frequency: very common >1/10; common >1/100 and <1/10; uncommon >1/1000 and <1/100; rare >1/10,000 and <1/1000; very rare <1/10,000.
Infections and infestations: Common: Mucocutaneous candidiasis.
Blood and lymphatic system disorders: Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia.
Very rare: Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time.
Immune system disorders: Very rare: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis.
Nervous system disorders: Uncommon: Dizziness, headache.
Very rare: Reversible hyperactivity and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Gastrointestinal disorders: Adults: Very common: Diarrhoea.
Common: Nausea, vomiting.
Children: Common: Diarrhoea, nausea, vomiting.
All populations: Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking co-amoxiclav at the start of a meal. Uncommon: Indigestion.
Very rare: Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis) (See Precautions); Black hairy tongue; Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing⁺.
+This statement is core safety for the syrup, suspension and chewable tablet formulations.
Hepatobiliary disorders: Uncommon: 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.
Very rare: Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins. Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment.
Children (additional statement): These events have been very rarely reported in children.
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.
Skin and subcutaneous tissue disorders: Uncommon: Skin rash, pruritus, urticaria.
Rare: Erythema multiforme.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthematous pustulosis (AGEP).
If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued.
Renal and urinary disorders: Very rare: Interstitial nephritis, crystalluria (see Overdosage).

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use with amoxicillin-clavulanate may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.
Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of co-amoxiclav and allopurinol.
In common with other antibiotics, co-amoxiclav may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.
In the literature there are rare 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.
In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid 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.

Instructions for Use and Handling: For administration of suspensions to children below 3 months, a syringe graduated to permit accurate and reproducible volumes to be dispensed, should be used.
For administration to children up to 2 years old, co-amoxiclav suspensions may be diluted to half-strength using water.

Co-amoxiclav 625mg tablet should be stored at temperatures not exceeding 30ºC. Protect from moisture.
Co-amoxiclav powder for suspension should be stored at temperatures not exceeding 25ºC.
The reconstituted suspension should be stored and kept in a refrigerator (2-8ºC) and used within 7 to 10 (maximum days). Do not freeze.

Penicillins

J01CR02 - amoxicillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

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