The Cathay Drug Co., Inc.
Co-amoxiclav is an antibacterial combination of amoxicillin (as sodium) and the beta-lactamase inhibitor, clavulanic acid (as potassium clavulanate).
Amoxicillin is the 4-hydroxy analogue of ampicillin. Amoxicillin hinders the cell wall synthesis of sensitive bacteria and is bactericidal against many Gram-positive and Gram-negative bacteria. It is active against all penicillin-sensitive bacteria (eg. streptococci) and most strains of pneumococci, gonococci and meningococci. Bacteria that produce beta-lactamase (e.g. most of the staphylococci) are resistant. Amoxicillin is also active against strains of Haemophilus influenza that do not produce beta-lactamase.
Clavulanic acid has a beta-lactam structure resembling that of penicillin nucleus, except that the fused thiazolidine ring seen in penicillins is replaced by an oxazolidine ring. In general, clavulanic acid has only weak antibacterial activity. It is potent progressive inhibitor of plasmid-mediated and some chromosomal beta-lactamases produced by Gram-negative bacteria including Haemophilus ducreyi, H.influenzae, Neisseria gonorrhoeae, Moraxella catarrhalis (Branhamella catarrhalis), Bacteroides fragilis and some Enterobacteriacese. It is also an inhibitor of the beta-lactamases produced by Staphylococcus aureus. Clavulanic acid can permeate bacterial cell walls and can therefore inactivate both extracellular enzymes and those that are bound to the cell. Its mode of action depends on the particular enzyme inhibited, but it generally acts as a competitive, and often, irreversible, inhibitor. Clavulanic acid consequently enhances the activity of penicillin and cephalosporin antibacterials against many resistant strains of bacteria.
Amoxicillin and clavulanate appear to be well absorbed into systemic circulation after oral administration. The pharmacokinetic disposition characteristics of amoxicillin and clavulanate are unaffected when the two drugs are administered together at the same patient. Peak serum levels of both occur about one hour after the oral administration. Absorption of co-amoxiclav is optimized at the start of a meal. Both clavulanate and amoxicillin have low levels of serum binding; about 70% remains free in the serum.
Amoxicillin is metabolized to a limited extent to penicilloic acid and primarily eliminated from the body by the kidneys as an unchanged drug and undergoes active renal tubular secretion. Concurrent probenacid will competitively inhibit the clearance of the drug. Amoxicillin can be removed by hemodialysis. High concentrations have been reported in bile, some maybe excreted in feces. Clavulanic acid undergoes considerable metabolism although, the route is unknown. It is postulated that clavulanic acid is hydrolyzed with subsequent decarboxylation. The clavulanic acid that is excreted in the urine appears to undergo simple glomerular filtration with no active secretion. Clearance of clavulanic acid decreases with decreasing renal function, but to the same extent as amoxicillin. Clavulanic acid is removed by hemodialysis..
Coamoxiclav oral preparations are indicated for short term treatment of bacterial infections at the following sites when amoxicillin resistant beta-lactamase producing strains are suspected the cause. In other situations, amoxicillin alone should be considered.
- Upper Respiratory Tract Infection (sinusitis, otitis media, recurrent tonsillitis) caused by Streptococcus pneumonia, Haemophilus influenza, Moraxella catarrhalis and Streptococcus pyogenes.
- Lower Respiratory Tract Infection (acute exacerbations of chronic bronchitis, bronchopneumonia) caused by Streptococcus oneumoniae, Haemophilus influenza and Moraxella catarrhalis.
- Genito Urinary Tract and Abdominal Infections in particular cystitis, septic abortion, pelvic or puerperal sepsis or intra-abdominal sepsis. These infections are often caused by Enterobacterriaciae (mainly coli), Staphylococcus saprophyticus, Enterococcus sp.
- Skin and soft tissue infections in particular cellulitis, animal bites and severe dental abcess with spreading cellulitis. These infections are often caused by Staphylococcus aureus, Streptococcus pyogenes and Bacteroides sp.
Some members of these species of bacteria produce beta-lactamase, rendering then insensitive to amoxicillin alone. Mixed infections caused by amoxicillin susceptible organisms in conjunction with co-amoxiclav susceptible beta lactamase producing organisms may be treated with co-amoxiclav. These infections should not require another antibiotic resistant to beta-lactamases.
DOSAGE AND ADMINISTRATION
Co-amoxiclav may be taken without regard to meals; however, absorption of clavulanate is enhanced when administered at the start of a meal.
To minimize the potential for GI intolerance, co-amoxiclav should be taken at the start of a meal.
The usual adult dose is one 625mg tablet of co-amoxiclav every 12 hours or one 375mg tablet of co-amoxiclav every 8 hours. For more infections and infections of the respiratory tract, the dose should be one 1g co-amoxiclav every 12 hours or one 625mg co-amoxiclav every 8 hours.
Patients with impaired renal function do not generally a reduction in the dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of <30ml/min should not receive the 1g tablet. Patients with a glomerular filtration rate of 10 – 30ml/min, should receive 625mg or 375mg every 12 hours, depending on the severity of the infection. Patients with less than 10ml/min GFR should receive 625mg or 375mg every 24 hours, depending on the severity of the infection. Hemodialysis patients should receive 625mg or 375mg every 24 hours, depending on the severity of the infection.
Pediatric patients weighing 40kgs or more should be dose according to the adult recommendations.
Co-amoxiclav should not be given to patients with known hypersensitivity to penicillin. Attention should be given to possible cross sensitivity with other beta lactamase antibiotics (e.g. cephalosporins).
WARNINGS AND PRECAUTIONS
- A previous history of co-amoxiclav or penicillin associated jaundice/hepatic dysfunction. Changes in liver function have been observed in some patients receiving co-amoxiclav. The clinical significance of these changes is uncertain but co-amoxiclav should be used in caution in patients with evidence of hepatic dysfunction. Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for several weeks after treatment has ceased.
- In patients with renal impairment, dosage should be adjusted according to the degree of impairment.
- In patients with reduced urine output, crystalluria has been observed very rarely, predominately with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to have adequate oral fluid intake and urinary output in order to reduce the possibility of amoxicillin crystaluria.
- Serious and occasionally fatal hypersensitivity reactions have reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity. Erythematous rashes have been associated with grandular fever in patients receiving amoxicillin.
- Prolonged use may occasionally cause over growth of non-susceptible organisms.
- Prolongation of bleeding time and prothrombin time may occur in patients taking co-amoxiclav. These should be used with care in patients on anticoagulation therapy.
Adverse effects with co-amoxiclav are uncommon and mainly of the transitory nature.
- GI: diarrhea, indigestion, nausea, vomiting, mucocutaneous candidiasis can occur. Antibiotic associated colitis (including Pseudomembranous colitis and Hemorrhagic colitis) occur rarely.
- Renal: interstitial nephritis and hematuria occur rarely; crystaluria
- Genito-urinary: vaginal itching, soreness and discharge
- Hepatic: moderate and asymptomatic rises in AST and/or ALT occasionally. Hepatitis and cholestatic jaundice rarely. These hepatic reactions occur more commonly with coamoxiclav than with other penicillins. Hepatic events are more predominantly reported in males and elderly patients particularly those over 65 years old.
- Hypersensitivity reaction: urticarial and hypersensitivity reactions; rarely erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis, bulous exfoliative dermatitis, acute generalized exanthematous pustulosis, serum sickness like syndromes occur.
Probenecid decreases the renal tubular secretion of amoxicillin, but does not affect excretion of clavulanic acid. Concurrent use with Bactiv may result in increased and prolonged levels of amoxicillin.
Ingestion of alcohol while on β lactam antibiotic therapy has precipitated a disulfiram-like reaction in some patients.
Bactiv may reduce the efficacy of oral contraceptives.
PREGNANCY AND LACTATION
Women with preterm, premature rupture of fetal membrane. It was reported that prophylactic treatment with co-amoxiclav, may be associated with an increased risk of necvrotizing enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, especially during the first trimester unless considered essential by the physician. Co-amoxiclav may be administered during the period of lactation. With the risk of sensitization, associated with excretion of trace quantities in breast milk, there are no known detrimental effects for the breast fed infants.
Alu/Alu blister pack X 5 tablets (box of 15 tablets).
Store at temperatures not exceeding 30oC. Protect from moisture.