Orapen-S

Co-amoxiclav: Amoxicillin and clavulanic acid.

312.5 mg/5 mL: A white to off white free flowing powder filled in 60 mL marked amber coloured glass bottle. On reconstitution with water, white to off white homogenous suspension, having characteristic flavor.
Each 5 mL of reconstituted suspension contains: Amoxicillin Trihydrate eq. to Amoxicillin USP 250 mg, Clavulanate potassium eq. to Clavulanic acid 62.5 mg.
457 mg/5 mL: A white to off white free flowing powder filled in 60 mL and 70 mL marked amber coloured glass bottle. On reconstitution with water, white to off white homogenous suspension, having characteristic flavor.
Each 5 mL of reconstituted suspension contains: Amoxicillin Trihydrate eq. to Amoxicillin USP 400 mg, Clavulanate Potassium eq. to Clavulanic acid 57 mg.

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.
Pharmacology: The efficacy of Amoxicillin with Clavulanic acid is the result of bactericidal activity of Amoxicillin combined with the inhibitory activity of Clavulanic acid on B-lactamase produced by different bacterial strains. Like other B-lactams, Clavulanic acid penetrates through the bacterial cell wall but it generally possesses poor intrinsic antimicrobial activity and is generally a more potent inhibitor of cell free B-lactamases. The binding of B-lactamases with Clavulanic acid is a complex physiochemical process which rapidly leads to lysis of the cell.
Pharmacodynamics: 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.
Pharmacokinetic/pharmacodynamic relationship: 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.
Pharmacokinetics: 312.5 mg/5 mL: Amoxicillin with Clavulanic acid are well absorbed from the gastrointestinal tract after oral administration of Amoxicillin with Clavulanic acid. The safety and efficacy of Amoxicillin with Clavulanic acid have been established in clinical trials where Amoxicillin with Clavulanic acid was taken without regard to meals. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the bread and spinal fluid. The results of experiments involving the administration of Clavulanic acid to animals suggest that this compound, like Amoxicillin, is well distributed in body tissues. Approximately 50% to 70% of the Amoxicillin and approximately 25% to 40% of the Clavulanic acid are excreted unchanged in urine during the first 6 hour after oral administration of 500 + 125 mg of Amoxicillin with Clavulanic acid Tablet. Concurrent administration of probenecid delays renal excretion of Amoxicillin but does not delay renal excretion of Clavulanic acid.
457 mg/5 mL: 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.
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.
Both amoxicillin and clavulanic acid have been shown to cross the placental barrier.
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 nonrenal 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 Augmentin 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.
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.
Hepatic impairment: Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

312.5 mg/5 mL: Amoxicillin with Clavulanic acid is indicated in the treatment of infections caused by susceptible strains listed: Lower Respiratory Tract Infections: Caused by B-lactamase producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.
Otitis media & Sinusitis: Caused by B-lactamase producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.
Skin and Skin Structure Infections: caused by B-lactamase producing strains of Staphylococcus aureus, Escherichia coli and Klebsiella spp. and Enterobacter spp.
Urinary Tract Infections: Caused by B-lactamase producing strains of Escherichia coli, Klebsiella spp. and Enterocobacter spp.
457 mg/5 mL: Indicated for the treatment of the following infections in adults and children: Acute bacterial 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, severe dental abscess with spreading cellulitis.

Direction for Reconstitution: Tap the bottle until all the powders flows freely. Add water up to the vertical circular mark and shake vigorously until the powder is evenly suspended. Refrigerate the suspension after reconstitution and use within 7 days. Do not freeze.
Shake the bottle well before each dose.
312.5 mg/5 mL: Children : The usual recommended daily dosage is 25 mg/kg/day in divided doses every eight hours. Under 1 year: 25 mg/kg/day a 7.5 kg child would require 2 mL of Co-Amoxiclav 156.25 mg/5mL Suspension three times a day.
1-6 years (10-18 kg): 5 mL of Co-Amoxiclav 156.25mg/5mL Suspension three times a day.
Over 6 years (18-40 kg): 5 mL of Co-Amoxiclav 312.5mg/5mL Suspension three times a day.
Or as prescribed by the physician.
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.
Children <40 kg: CrCl: 10-30 ml/min-15 mg/3.75 mg/kg twice daily (maximum 500 mg/125 mg twice daily).
CrCl: 10-30 ml/min-15 mg/3.75 mg/kg as a single daily dose (maximum 500 mg/125 mg).
Hemodialysis: 15 mg/3.75 mg/kg per day once daily. Prior to haemodialysis 15 mg/3.75 mg/kg. In order to restore circulating drug levels, 15mg/3.75 mg per kg should be administered after haemodialysis.
Hepatic impairment: Dose with caution and monitor hepatic function at regular intervals.
457 mg/5 mL: For children <40 kg, this formulation of amoxicillin/clavulanic provides a maximum daily dose of 1000-2800 mg amoxicillin/143-400 mg clavulanic acid, when administered as recommended as follows. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of amoxicillin/clavulanic is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid.
Adults and children ≥40 kg should be treated with the adult formulations of amoxicillin/clavulanic.
Children <40 kg: Lower dose: 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses; Higher dose: 45 mg/6.4 mg/kg/day to 70 mg/10 mg/kg/day given as two divided doses may be considered for some infections (such as otitis media, sinusitis and lower respiratory tract infections). (See Table.)

Click on icon to see table/diagram/image

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.
There are no clinical data for amoxicillin/clavulanic 7:1 formulations for patients under 2 months of age. Dosing recommendations in this population therefore cannot be made.
Children aged 6 years and below should preferably be treated with amoxicillin/clavulanic suspension.
Elderly: No dose adjustment is considered necessary. Elderly patients should be treated with adult formulations.
Renal impairment: No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.
In patients with creatinine clearance less than 30 ml/min, the use of amoxicillin/clavulanic presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available.
Hepatic impairment: Dose with caution and monitor hepatic function at regular interval.
Method of administration: For oral use.
Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid.

Most patients have been asymptomatic following overdosage or have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting and diarrhoea. Rash, hyperactivity or drowsiness has also been observed in a small number of patients.
Amoxicillin crystalluria, in some cases leading to renal failure, has been observed.
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.
In the case of overdosage, discontinue Amoxicillin with Clavulanic acid, treat symptomatically and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed.
Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

Amoxicillin with Clavulanic acid is contraindicated in patients with allergic reactions to any penicillin.
History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
It is also contraindicated in patients with a previous history of Amoxicillin with Clavulanic acid associated cholestatic jaundice/ hepatic dysfunction.

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy.
Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of amorbilliform 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). This reaction requires discontinuation and contraindicates any subsequent administration of amoxicillin.
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.
Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening.
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.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted. While Amoxicillin with Clavulanic acid possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of long therapy. A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin class antibiotics should not be administered to patients with mononucleosis.

Pregnancy: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Use should be avoided during pregnancy, unless considered essential by the physician.
Lactation: Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhea and fungus infection of the mucous membranes are possible in the breast-fed infact, 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 breast-feeding after benefit/risk assessment by the physician in charge.

Amoxicillin with Clavulanic acid is generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature. The most frequently reported adverse effects were diarrhoea/loose stools, nausea, skin rashes, urticaria, vomiting and vaginitis (1%). The overall incidence of side effects and in particular diarrhoea, increased with the higher recommended dose. Other less frequently reported reactions include abdominal discomfort, flatulence and headache.
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 time: Not known.
Immune system disorders: 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.
Convulsions: Not known.
Aeseptic meningitis: Not known.
Gastrointestinal disorders: Diarrhoea: Common.
Nausea: Common.
Vomiting: Common.
Indigestion: Uncommon.
Antibiotic-associated colitis: Not known.
Black hairy tongue: Not known.
Tooth discolouration: Not known.
Hepatobiliary disorders: Rises in AST and/or ALT: Uncommon.
Hepatitis: Not known.
Cholestatic jaundice: Not known.
Skin and subcutaneous tissue disorders: 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): Not known.
Drug reaction with eosinophilia and systemic symptoms (DRESS): Not known.
Renal and urinary disorders: Interstitial nephritis: Not known.
Crystalluria: Not known.

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of Amoxicillin with Clavulanic acid may result in increased and prolonged blood levels of Amoxicillin.
Amoxicillin with clavulanic acid may reduce the efficacy of oral contraceptives.
The possibilities of prolonged bleeding time in individuals receiving anticoagulants concurrently should be borne in mind.
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Store at temperatures not exceeding 30°C.

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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