Amoxycillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and gram-negative bacteria. Amoxycillin is, however, susceptible to degradation by beta-lactamases and, therefore, the spectrum of activity does not include organisms that produce these enzymes. Clavulanic acid is a beta-lactam structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms 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.

The formulation of amoxicyllin and clavulanic acid in Dhaviclav protects amoxicyllin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxycillin to include many bacteria normally resistant to amoxycillin.

Amoxycillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:

Gram-positive Bacteria
Staphylococcus aureus

Gram-negative Bacteria

• Enterobacter species
• Escherichia coli
• Haemophilus influenzae
• Klebsiella species
• Moraxella catarrhalis

Gram-positive Bacteria

• Enterococcus faecalis
• Staphylococcus epidermidis
• Staphylococcus saprophyticus
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Viridans group Streptococcus

Gram-negative Bacteria

• Eikenella corrodens
• Proteus mirabilis

Anaerobic Bacteria

• Bacteroides species, including Bacteroides fragilis
• Fusobacterium species
• Peptostreptococcus species

Amoxycillin and clavulanic acid, are fully dissociated in an aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxycillin/clavulanic acid is optimized when taken at the start of a meal. Following oral administration, amoxycillin 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 1 hour.

About 25% of total plasma clavulanic acid and 18% of total plasma amoxycillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxycillin and around 0.2 l/kg for clavulanic acid.

Both amoxycillin and clavulanic acid have been shown to cross the placental barrier.

Amoxycillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10-25% of the initial dose. Clavulanic acid is extensively metabolized in humans and eliminated in the urine and faeces, and as carbon dioxide in expired air.

The major route of elimination for amoxycillin is via the kidneys, whereas for clavulanic acid, it is by both renal and non-renal mechanisms.

Amoxycillin/clavulanic acid has a mean elimination half-life of approximately 1hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60-70% of the amoxycillin and approximately 40-65% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of single amoxycillin/clavulanic acid 250mg/125mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxycillin and between 27 and 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 amoxycillin excretion but does not delay renal excretion of clavulanic acid.

Renal Impairment
The total serum clearance of amoxycillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxycillin than for clavulanic acid, as a higher proportion of amoxycillin is excreted via the renal route. Doses in renal impairment must, therefore, prevent undue accumulation of amoxycillin while maintaining adequate levels of clavulanic acid.

Hepatic Impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

To reduce the development of drug resistant bacteria and maintain the effectiveness of amoxycillin/clavulanate potassium and other antibacterial drugs, amoxycillin/clavulanic acid should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

Dhaviclav is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below:

• Lower Respiratory Tract Infections caused by betalactamase-producing isolates of Haemophilus influenzae and Moraxella catarrhalis.
• Acute Bacterial Otitis Media caused by betalactamase-producing isolates of H. influenzae and M. catarrhalis.
• Sinusitis caused by betalactamase-producing isolates of H. influenzae and M. catarrhalis.
• Skin and Skin Structure Infections caused by betalactamase-producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species.
• Urinary Tract Infections caused by betalactamase-producing isolates of E. coli, Klebsiella species, and Enterobacter species.
• Bone and joint infections
• Other infections e.g.intra-abdominal sepsis and dental infections.

Dhaviclav Tablets

Adults and Children Aged Over 12 Years
Usual Dosages for the Treatment of Infection

Mild to Moderate Infections – One 625 mg tablet twice a day

Severe Infections – One 625 mg tablet thrice a day

Dentoalveolar abscess one tablet of Dhaviclav 625 mg twice a day for 5 days.

Renal Impairment

Adults
Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of <30 mL/min. should not receive the 1g tablet.

Mild impairment (creatinine clearance>30 mL/min) – No change in dosage

Moderate impairment (creatinine clearance 10-30 mL/min) – One 625 mg tablet twice a day

Severe impairment (creatinine clearance <10 mL/min) – Not more than one 625 mg tablet every 24 hours

Hepatic Impairment
Dose with caution; monitor hepatic function at regular intervals.

Tablets should be swallowed whole without chewing. If required, tablets may be broken in half and swallowed without chewing.

Dhaviclav Dry Syrup

Children Aged Over 2 Years
Usual Dosages for the Treatment of Infection

25/3.6 mg/kg/day

2 to 6 years (13-21 kg) – 5.0 mL Dhaviclav 228.5 mg Syrup b.i.d

7 to12 years (22-40 kg) – 10.0 mL Dhaviclav 228.5 mg Syrup b.i.d

45/6.4 mg/kg/day

2 to 6 years (13-21 kg) – 10.0 mL Dhaviclav 228.5 mg Syrup b.i.d

7 to12 years (22-40 kg) – 20.0 mL Dhaviclav 228.5 mg Syrup b.i.d

Children aged below 2 years should be dosed according to body weight.

Renal Impairment
For children with a GFR of >30 mL/min no adjustment in dosage is required. For children with a GFR of <30 mL/min, Dhaviclav 228.5 mg Suspension is not recommended.

Hepatic Impairment
Dose with caution; monitor hepatic function at regular intervals. There is, as yet, insufficient evidence on which to base a dosage administration.

Dispersible tablets should be dissolved in 30-60 mL of water before administration.

Dhaviclav is contraindicated in patients with a history of serious hypersensitivity reactions (e.g. anaphylaxis or Stevens-Johnson syndrome) to amoxycillin, clavulanate or to other betalactam antibacterial drugs (e.g.penicillins and cephalosporins).

Dhaviclav is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Dhaviclav.

Hypersensitivity Reactions
Serious, and occasionally fatal, hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including co-amoxyclav.

Hepatic Dysfunction
Hepatic dysfunction, including hepatitis and cholestatic jaundice, has been associated with the use of co-amoxyclav. Hepatic toxicity is usually reversible.

Clostridium difficile Associated Diarrhoea (CDAD)
Clostridium difficile-associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including co-amoxyclav.

Skin Rash in Patients with Mononucleosis
A high percentage of patients with mononucleosis who receive amoxycillin develop an erythematous skin rash.

Probenecid
Probenecid decreases the renal tubular secretion of amoxycillin but does not delay renal excretion of clavulanic acid. Concurrent use with co-amoxyclav may result in increased and prolonged blood concentrations of amoxycillin. Co-administration of probenecid is not recommended.

Oral Anticoagulants
Abnormal prolongation of prothrombin time (increased international normalized ratio) has been reported in patients receiving amoxycillin and oral anticoagulants

Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation
Amoxycillin has been shown to be excreted in human milk.

Amoxycillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxycillin/clavulanate potassium is administered to a nursing mother.

Paediatric Use
The safety and effectiveness of co-amoxyclav powder for oral suspension has been established in paediatric patients.

Dosing in Renal Impairment
Amoxycillin is primarily eliminated by the kidneys and dosage adjustment is usually required in patients with severe renal impairment (GFR renal impairment.

Store below 25ºC. Protect from moisture

Dhaviclav 625: Strip of 10 tablets

Dhaviclav 228.5 suspension: Bottle of 30 ml syrup