Pharmaniaga Co-Amoxiclav

Amoxicillin trihydrate, potassium clavulanate.

Each film-coated tablet contains amoxicillin trihydrate equivalent to amoxicillin 500 mg and potassium clavulanate equivalent to clavulanic acid 125 mg.
Each 5 mL contains amoxicillin trihydrate equivalent to amoxicillin 200 mg and potassium clavulanate equivalent to clavulanic acid 28.50 mg.

Pharmacology: Amoxicillin/clavulanate is an antibiotic agent with a broad spectrum of activity against the commonly occurring bacterial pathogens. The amoxicillin is bactericidal in action which inhibits bacterial cell wall synthesis. It inactivates and binds to penicillin-binding proteins located on the inner membrane of the bacterial cell wall, resulting in the weakening of the cell wall and lysis. The β-lactamase inhibitory action of clavulanate extends the spectrum of amoxicillin to embrace a wider range of organisms eg, many resistant to other β-lactam antibiotics.
Resistance to many antibiotics is caused by bacterial enzymes which destroy the antibiotic before it can act on the pathogen. The clavulanate anticipates this defense mechanism by blocking the β-lactamase enzymes; thus, rendering the organisms sensitive to amoxicillin's rapid bactericidal effect at concentrations readily attainable in the body. Clavulanate by itself has little antibacterial activity, however, in association with amoxicillin it produces an antibiotic agent of broad spectrum.
Microbiology: Amoxicillin/clavulanate is bactericidal to a wide range of organisms.
Gram-Positive: Aerobes: Staphylococcus aureus, coagulase-negative staphylococci (including Staphylococcus epidermidis), Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Enterococcus faecalis, Bacillus anthracis, Listeria monocytogenes; Corynebacterium sp.
Anaerobes: Clostridium and Peptococcus spp, Peptostretococcus sp.
Gram-Negative: Aerobes: Escherichia coli*, Proteus mirabilis*, Proteus vulgaris*, Klebsiella*, Salmonella* and Shigella spp*, Bordetella pertussis, Brucella sp*, Neisseria meningitidis, Neisseria gonorrhoea*, Haemophilus influenzae*, Pasteurella multocida, Vibrio cholerae, Moraxella catarrhalis.
Anaerobes: Bacteriodes sp eg, Bacteroides fragilis*.
*β-lactamase-producing strains resistant to ampicillin and amoxicillin are included.
Pharmacokinetics: Amoxicillin and potassium clavulanate are well absorbed from the gastrointestinal tract after oral administration. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. The pharmacokinetics of the 2 components are closely matched. Peak serum levels both occur about 1 hr after oral administration. Absorption is optimized at the start of a meal. The half-life of amoxicillin after oral administration of the product is 1.3 hrs and that of clavulanic acid is 1 hr. Doubling the dosage of amoxicillin/clavulanate approximately doubles the serum levels achieved.
Approximately 50-70% of the amoxicillin and approximately 25-40% of the clavulanic acid are excreted unchanged in urine during the first 6 hrs after administration of a single amoxicillin/clavulanate 250 or 500 mg tablet.
Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component is highly protein bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain 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.

Treatment of upper and lower respiratory tract infections eg, sinusitis, otitis media, bronchitis; skin and soft tissue infections eg, boils, abcesses, cellulitis, wound infections; genitourinary tract infections eg, cystitis, urethritis, pyelonephritis; bone and joint infections eg, osteomyelitis.

Tab: Adults and Children >12 years: Mild to Moderate Infections: 1 tab (625 mg) 2 times daily. Severe Infections: 1 tab (1 g) 2 times daily.
Renal Impairment: Severe Impairment [Creatinine Clearance (CrCl) <10 mL/min]: 1 tab (625 mg) 24 hrly. Moderate Impairment (CrCl 10-30 mL/min): 1 tab (625 mg) 2 times daily. Mild Impairment (CrCl >30 mL/min): No change in dosage. Oral Susp: Usual Recommended Dose: Mild to Moderate Infections (Upper Respiratory Tract Infections eg, Recurrent Tonsilitis; Lower Respiratory Infections and Skin and Soft Tissue Infections): 25/3.6 mg/kg daily. Children 7-12 years (22-40 kg): 10 mL 2 times daily; 2-6 years (13-21 kg): 5 mL 2 times daily. Serious Infections (Upper Respiratory Tract Infections eg, Otitis Media and Sinusitis; Lower Respiratory Tract Infections eg, Bronchopneumonia and Urinary Tract Infections): 45/6.4 mg/kg daily. Children 2-6 years (13-21 kg): 10 mL 2 times daily.
Administration: Shake the bottle to loosen the powder. Add freshly boiled, and cooled water and shake well. Make up to the required volume as stated.

Most patients have been asymptomatic following overdosage or have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting and diarrhea. Rash, hyperactivity or drowsiness have also been observed in a small number of patients. In the case of overdosage, discontinue amoxicillin/clavulanate and 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. Interstitial nephritis resulting in oliguria and renal failure has been reported in a small number of patients after overdosage with amoxicillin. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis. 

History of allergic reactions to any penicillin or β-lactamase inhibitors. Patients with previous history of amoxicillin with clavulanate or penicillin-associated jaundice/hepatic dysfunction. Attention should be paid to possible cross-sensitivity with other β-lactam antibiotics.

Amoxicillin/clavulanate should be used with 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 up to 6 weeks after treatment has ceased. In patients with moderate or severe renal impairment, dosage should be adjusted. 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 history of penicillin hypersensitivity.
Erythematous rashes have been associated with glandular fever in patients receiving amoxicillin. Prolonged use may also occasionally result in overgrowth of nonsusceptible organisms.
During the administration of high-dose amoxicillin/clavulanate, adequate fluid intake and urinary output should be maintained to minimize the possibility of crystalluria. When present at high concentrations in urine at room temperature, amoxicillin may precipitate in bladder catheters. A regular check on patency should be maintained.
Risk-benefit should be considered when medical problems eg, gastrointestinal disease, especially pseudomembranous colitis and infectious mononucleosis exist. A mobiliform skin rash may occur in a high percentage of patients taking ampicillin.
In patients with moderate or severe renal impairment, tablet dosage should be adjusted (see Dosage & Administration), but not recommended for oral suspension 228 mg/5 mL. The oral suspension contain aspartame and caution should be taken in phenylketonuria conditions.
Use in pregnancy & lactation: Reproduction studies in animals (mice and rats) with orally and parenterally administered amoxicillin/clavulanate have shown no teratogenic effects. There is limited experience in human pregnancy. As with all medicines, use should be avoided in pregnancy, especially during the 1st trimester, unless considered essential by the physician.
Although significant problems in human have not been documented, caution should be exercised when amoxicillin/clavulanate is administered to nursing mothers, because, it may lead to sensitization, diarrhea, candidiasis and skin rash in the infant.

Reproduction studies in animals (mice and rats) with orally and parenterally administered amoxicillin/clavulanate have shown no teratogenic effects. There is limited experience in human pregnancy. As with all medicines, use should be avoided in pregnancy, especially during the 1st trimester, unless considered essential by the physician.
Although significant problems in human have not been documented, caution should be exercised when amoxicillin/clavulanate is administered to nursing mothers, because, it may lead to sensitization, diarrhea, candidiasis and skin rash in the infant.

Adverse effects are uncommon, and mainly of a mild and transitory nature. Diarrhea, pseudomembranous colitis, indigestion, nausea, vomiting and candidiasis have been reported. Nausea, although uncommon, is more often associated with higher oral dosages. If gastrointestinal adverse effects occur with oral therapy, these may be reduced by taking the drug at the start of meals.
Hepatitis and cholestatic jaundice have been reported rarely with amoxicillin/clavulanate. However, may be severe and continue for several months. These are reported as occurring predominantly in adult or elderly patients and slightly more frequent in males.
Signs and symptoms may occur during treatment but are more frequently reported after cessation of therapy with a delay of up to 6 weeks. The hepatic events are usually reversible. However, in extremely rare circumstances deaths have been reported. Urticarial and erythematous rashes sometimes occur.
Rarely, erythema multiform, Stevens-Johnson syndrome, toxic epidermal necrolysis and exfoliative dermatitis have been reported. Treatment should be discontinued if one of these types of rash appears. In common with other β-lactam antibiotics, angioedema and anaphylaxis have been reported.
Interstitial nephritis and hematuria can occur rarely. As with other antibiotics the incidence of gastrointestinal side effects may be raised in children <2 years. In clinical trials, however, only 4% of children <2 years were withdrawn from treatment. As with other β-lactams, transient leukopenia, thrombocytopenia and hemolytic anemia have been reported rarely.
The following adverse reactions have been reported for ampicillin class antibiotics: Haemic and Lymphatic Systems: Anemia eg, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in <1% of the patients treated with amoxicillin/clavulanate. There have been reports of increased prothrombin time in patients receiving amoxicillin/clavulanate and anticoagulant therapy concomitantly.
Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia and reversible hyperactivity have been reported rarely.
Superficial tooth discoloration has been reported which can be removed by brushing. 

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin/clavulanate may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenacid cannot be recommended. The concurrent administration of allopurinol and ampicillin substantially increases the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with amoxicillin/clavulanate and allopurinol administered concurrently. In common with other broad-spectrum antibiotics, amoxicillin/clavulanate may reduce the efficacy of oral contraceptives.
Prolongation of bleeding time and prothrombin time have been reported in some patients receiving amoxicillin/clavulanate and should be used with care in patients on anticoagulation therapy.

Store below 25°C. Protect from light and moisture.
Reconstituted suspension should be stored in a refrigerator (2°-8°C) and used within 7 days.

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.

B