Limoclav

White to off-white, biconvex, oval-shaped, plain film-coated tablet.
Each film-coated tablet contains: Amoxicillin (as Trihydrate) USP 500 mg and Potassium Clavulanate USP (equivalent to Clavulanic Acid) 125 mg.

Antibacterial (Penicillin-Beta-Lactamase Inhibitor Combination).
Pharmacology: Pharmacodynamics: Mechanism of Action: Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases and, therefore, the spectrum of activity does not include organisms that produce these enzymes.
Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance.
Thus, Co-amoxiclav possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
In the list, as follows, organisms are categorized according to their in vitro susceptibility to Co-amoxiclav (see table).

Click on icon to see table/diagram/image

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.
Pharmacokinetics: Absorption: The two components of co-amoxiclav, amoxicillin, and clavulanic acid is fully dissociated in an aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of Co-amoxiclav is optimized when taken at the start of a meal.
Distribution: Following IV 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 the 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% of clavulanic acid and 18% of 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 sensitization associated with this excretion, there are no known detrimental effects for the breastfeed 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 feces 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 hours 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, are typically caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Genitourinary tract infections e.g. cystitis, urethritis, pyelonephritis, and female genital infections typically caused by Enterobacteriaceae (mainly Escherichia coli), Staphylococcus saprophyticus and Enterococcus species and gonorrhea caused by Neisseria gonnorhoeae. Skin and soft tissue infections are 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. Other infections e.g. septic abortion, puerperal sepsis, intra-abdominal sepsis.
Pediatric 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. Genitourinary tract infections e.g. cystitis, urethritis, pyelonephritis, female genital infections typically caused by Enterobacteriacea (mainly Escherichia coli), Staphylococcus saprophyticus and Enterococcus species and gonorrhea caused by Neisseria gonorrhoeae. Skin and soft tissue infections are typically caused by Staphylococcus aureus, Streptococcus pyogenes, and Bacteroides species.
Amoxicillin-Clavulanate Pediatric Three Times Daily: The pediatric 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: A comprehensive list of sensitive organisms is provided in Pharmacology: Pharmacodynamics: Mechanism of Action under Actions. Some members of these species of bacteria produce beta-lactamase, rendering them insensitive to amoxicillin alone (see Pharmacology: Pharmacodynamics under Actions).
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 their amoxicillin content. Mixed infections caused by amoxicillin-susceptible organisms in conjunction with amoxicillin-clavulanate-susceptible beta-lactamase-producing organisms may therefore be treated with Co-amoxiclav.

The usual adult dose is 1 tablet three times a day or as prescribed by the physician.

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: Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Co-amoxiclav can be removed from circulation by hemodialysis.
Children (Additional Statement): A prospective study of 51 pediatric patients at a poison control center 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 inquiry 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, IV 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 the 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 diarrhea during or after antibiotic use. If prolonged or significant diarrhea 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 hematopoietic 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. 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. 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). Changes in liver function tests have been observed in some patients receiving Co-amoxiclav. The clinical significance of these changes is uncertain but Co-amoxiclav 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 six weeks after treatment has ceased.

Use in 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 fetal membrane (pPROM), it was reported that prophylactic treatment with Co-amoxiclav may be associated with an increased risk of necrotizing enterocolitis in neonates. As with all medicines, use should be avoided during pregnancy, unless considered essential by the physician.
Use in 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.

Gastrointestinal: Diarrhea, pseudomembrane colitis, emesis, indigestion, nausea, and stomatitis have been reported. Candidiasis and antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis) have been reported rarely. The overall incidence of side effects, and in particular nausea, increased with the higher recommended dose. If gastrointestinal reactions are evident, they may be reduced by taking Co-Amoxiclav at the start of the meal. As with other antibiotics, the incidence of gastrointestinal side effects may be raised in children under two years. In clinical trials, however, only 4% of children under two years were withdrawn from treatment.
Liver: Moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients with ampicillin class antibiotics but the significance of these findings is unknown. Hepatic dysfunction, including increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphate, has been infrequently reported with amoxicillin; potassium clavulanate. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction which may be severe is usually reversible. On rare occasions, death has been reported.
Hypersensitivity Reactions: Skin rashes (urticarial and erythematous rashes) sometimes occur. Rarely erythema multiform, Steven-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, acute generalized exanthematous pustulosis, and angioedema have been reported rarely. Treatment should be discontinued if one of these disorders occurs. In common with other β-lactamase antibiotics, angioedema, anaphylaxis serum sickness-like syndrome and hypersensitivity vasculitis have been reported.
Blood: As antibiotic other β-lactam, reversible leucopenia (including hypersensitivity and granulocytopenia), reversible thrombocytopenia and hemolytic anemia, thrombocytopenic purpura, eosinophilia, leucosis, agranulocytosis have been reported.
Central Nervous System: Side effects, such as reversible hypersensitivity, dizziness, headache, and convulsions have been reported rarely. Convulsions may occur in patients with impaired renal functions or those receiving a high dose.
Renal: Interstitial nephritis and hematuria have been reported rarely.
Other: Sometimes, dental discoloration has been reported rarely in children.

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 normalized 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.

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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