Amoclav Suspension

Co-amoxiclav (Amoclav) 156.25 mg/5 mL powder for oral suspension: Each 5 mL (1 teaspoonful) contains: Amoxicillin (as trihydrate) 125 mg, Clavulanic acid (potassium salt) 31.25 mg.
Co-amoxiclav (Amoclav) 228.5 mg/5 mL suspension: After reconstitution, each 5 mL (1 teaspoonful) suspension contains: Amoxicillin (as trihydrate) 200 mg; Clavulanic acid (as potassium clavulanate) 28.5 mg.
Co-amoxiclav (Amoclav) 312.5 mg/5 mL powder for oral suspension: Each 5 mL (1 teaspoonful) contains: Amoxicillin (as trihydrate) 250 mg, Clavulanic acid (potassium salt) 62.5 mg.
Co-amoxiclav (Amoclav) 457 mg/5 mL suspension: After reconstitution, each 5 mL (1 teaspoonful) suspension contains: Amoxicillin (as trihydrate) 400 mg; Clavulanic acid (as potassium clavulanate) 57 mg.

Pharmacotherapeutic group: 156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Antibacterials for systemic use; beta-lactam antibacterials, penicillins; combinations of penicillins, incl. beta-lactamase inhibitors. ATC code: J01CR02.
Pharmacology: Pharmacodynamics: 156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: 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.
Breakpoints: MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (See Table 1.)

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The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. (See Table 2.)

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228.5 mg/5 mL & 457 mg/5 mL suspension: Amoxicillin (an aminopenicillin antibiotic) and potassium clavulanate (a β-lactamase inhibitor) [Co-amoxiclav] is usually bactericidal in action. Concurrent administration of clavulanic acid does not alter the mechanism of action of amoxicillin. However, because clavulanic acid has a high affinity for and binds to certain β-lactamases that generally inactivate amoxicillin by hydrolyzing its β-lactam ring, concurrent administration of the drug with amoxicillin results in synergistic bactericidal effect which expands amoxicillin's spectrum of activity against many strains of β-lactamase-producing bacteria resistant to amoxicillin alone.
Antimicrobial Spectrum of Activity: In vitro and clinical studies have demonstrated the susceptibility of the following microorganisms to Co-amoxiclav: See Table 3.

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Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with Co-amoxiclav in urinary tract infections caused by these organisms.
Co-amoxiclav has demonstrated in vitro activity against most strains of the following microorganisms; however, clinical significance is unknown: See Table 4.

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Pharmacokinetics: 156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: 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. 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 (T_max) in each case is approximately one hour.
The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (875 mg/125 mg tablets given twice daily) was administered in the fasting state to groups of healthy volunteers are presented as follows. (See Table 5.)

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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 (see Use in Pregnancy & Lactation).
Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see Use in Pregnancy & Lactation).
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 non-renal 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 a single dose of amoxicillin/clavulanic acid 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 (see Interaction with other medicinal products and other forms of interaction).
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 (see Dosage & Administration).
Hepatic impairment: Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
228.5 mg/5 mL & 457 mg/5 mL suspension: Co-amoxiclav is stable in the presence of acidic gastric secretions and is well absorbed following oral administration. Peak serum concentrations of amoxicillin and of clavulanic acid are generally attained within 1 to 2.5 hours after oral administration.
In a study in children 2 to 5 years old with urinary tract infections who received a single oral dose of 125 mg of amoxicillin and 31.75 mg of clavulanic acid suspension, the mean serum concentrations (C_max) of amoxicillin were 9.4, 9.7, and 6.5 µg/mL and of clavulanic acid were 2.1, 4.4, and 2.5 µg/mL at 30, 60, and 90 minutes, respectively, after the dose.
In a study in fasting children who received a single amoxicillin dose of 35 mg/kg given as Co-amoxiclav oral suspension, concentrations of amoxicillin and of clavulanic acid in middle ear effusions averaged 3 and 0.5 µg/mL, respectively, 2 hours after the dose.
When a single 5 mL oral dose of Co-amoxiclav 457 mg/5 mL suspension was administered in healthy male and female subjects (fasted state), pharmacokinetic parameters reached were: C_max 5.789 µg/mL, T_max 1.164 hours, AUC_0-t 12.21 µg/mL·hr and AUC_0-∞12.855 µg/mL·hr for amoxicillin, and 1.379 µg/mL, 1.039 hours, 2.492 µg/mL·hr and 2.727 µg/mL·hr, respectively, for clavulanic acid.
Therapeutic concentrations of both amoxicillin and clavulanic acid have been found in the gall bladder, abdominal tissue, skin, fat, and muscle tissues; the synovial and peritoneal fluids, bile and pus. Animal studies show no evidence that either component may accumulate in any organ.
Neither amoxicillin nor clavulanic acid is highly protein-bound; studies show that about 13% to 25% of total plasma drug concentration of each compound is protein-bound.
Both Co-amoxiclav components readily cross the placenta. Only small amounts of amoxicillin and clavulanic acid are distributed in human milk.
Serum concentrations of amoxicillin and clavulanic acid both decline in a biphasic manner and their half-lives are similar. Approximately 50 to 73% of amoxicillin and 25 to 45% of clavulanic acid are excreted unchanged in urine within 6 to 8 hours following oral administration of a single dose of Co-amoxiclav in adults with normal renal function.
In a study in children 2 to 15 years old, the elimination half-lives of amoxicillin and clavulanic acid averaged 1.2 and 0.8 hours, respectively.
Toxicology: 156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Preclinical safety data: Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction.
Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.
Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.
228.5 mg/5 mL & 457 mg/5 mL suspension: Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of Co-amoxiclav has not been evaluated in long-term animal studies.
The mutagenic potential of the drug has been investigated in vitro using the Ames test, a human lymphocyte cytogenic assay, a yeast test and a mouse lymphoma forward mutation assay, and in vivo using mouse micronucleus tests and a dominant lethal test. Results were negative for all tests except for the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations.
Oral doses of Co-amoxiclav up to 1,200 mg/kg/day (5.7 times the maximum human dose) were found to have no effect on fertility and reproductive performance in rats dosed with a 2:1 ratio formulation of amoxicillin:clavulanic acid.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Co-amoxiclav is indicated for the treatment of the following infections in adults and children (see Dosage & Administration, Precautions and Pharmacology: Pharmacodynamics under Actions): 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; Bone and joint infections, in particular osteomyelitis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
228.5 mg/5 mL & 457 mg/5 mL suspension: For the treatment of the following infections caused by susceptible microorganisms: Upper respiratory tract infections (including ENT infections): Tonsillitis, sinusitis, otitis media.
Lower respiratory tract infections: Acute and chronic bronchitis, pneumonia, lung abscess.
Genito-urinary tract and abdominal infections: Cystitis, urethritis, pyelonephritis, female genital infections, septic abortion, pelvic or puerperal sepsis, intra-abdominal sepsis.
Skin and skin structure infections: Furuncle and abscess, cellulitis, wound infections.
Bone and joint infections: Osteomyelitis.
Dental infection: Dentoalveolar abscess.
Other infections: Septicemia, peritonitis, post-surgical infections.
Step down treatment for infections due to susceptible organisms, initially given antimicrobial therapy, particularly parenteral Co-amoxiclav.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.
The dose of amoxicillin/clavulanic acid that is selected to treat an individual infection should take into account: The expected pathogens and their likely susceptibility to antibacterial agents (see Precautions); The severity and the site of the infection; The age, weight and renal function of the patient as shown as follows.
The use of alternative presentations of amoxicillin/clavulanic acid (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see Precautions and Pharmacology: Pharmacodynamics under Actions).
For adults and children ≥40 kg, this formulation of co-amoxiclav provides a total daily dose of 1500 mg amoxicillin/375 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 co-amoxiclav is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see Precautions and Pharmacology: Pharmacodynamics under Actions).
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 (see Precautions regarding prolonged therapy).
Adults and children ≥ 40 kg: One 500 mg/125 mg dose taken three times a day.
Children <40 kg: 20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses.
Children may be treated with co-amoxiclav tablets, suspensions or pediatric sachets. Children aged 6 years and below should preferably be treated with co-amoxiclav suspension or pediatric sachets.
No clinical data are available on doses of co-amoxiclav 4:1 formulations higher than 40 mg/10 mg/kg per day in children under 2 years.
Elderly: No dose adjustment is considered necessary.
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.
Adults and children ≥40 kg: See Table 6.

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Children <40 kg: See Table 7.

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Hepatic impairment: Dose with caution and monitor hepatic function at regular intervals (see Contraindications and Precautions).
Method of administration: Co-amoxiclav is for oral use.
Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid.
Therapy can be started parenterally according to the SPC of the IV formulation and continued with an oral preparation.
Shake to loosen powder, add water as directed, invert and shake.
Shake the bottle before each dose (see Instructions for Use and Handling under Cautions for Usage).
228.5 mg/5 mL & 457 mg/5 mL suspension: Administer Co-amoxiclav at the start of a meal to minimize potential gastrointestinal intolerance and to optimize absorption.
Drink plenty of water to ensure proper state of hydration and adequate urinary output.
Treatment should not exceed 14 days without first re-evaluating the patient.
Usual Oral Dosage in Children up to 12 years old: Co-amoxiclav is dosed based on the amoxicillin component and is given in divided doses every 12 hours.
Children below 1 year old: 30 mg/kg body weight/day.
For Mild to Moderate Infections: 25 mg/kg body weight/day.
For Severe Infections: 45 mg/kg body weight/day. (See Tables 8 and 9.)

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Dosage in Children up to 12 years old on Hemodialysis: 15 mg/kg body weight once daily. Patients should receive an additional dose of 15 mg/kg body weight both during and at the end of dialysis.
Dosage in Children up to 12 years old with Hepatic Impairment: Dose with caution and monitor hepatic function regularly.
Directions for Reconstitution: See Table 10.

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156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Symptoms and signs of overdose: 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).
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 (see Precautions).
Treatment of intoxication: Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.
228.5 mg/5 mL & 457 mg/5 mL suspension: Clinical features of overdosage with Co-amoxiclav may include gastrointestinal symptoms, fluid and electrolyte imbalance. Amoxicillin crystalluria, leading to renal failure, has also been observed in some cases.
Symptomatic treatment is recommended. Co-amoxiclav can be removed by hemodialysis.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.
History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see Adverse Reactions).
228.5 mg/5 mL & 457 mg/5 mL suspension: Known hypersensitivity to penicillin or any ingredient in this product.
Cross-sensitivity with other β-lactam antibiotics, e.g., cephalosporins.
Patients with a previous history of jaundice/liver impairment associated with Co-amoxiclav or penicillin.
Patients with glandular fever or lymphatic lymphoma should not be given Co-amoxiclav as the amoxicillin component is likely to cause a maculopapular rash.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see Contraindications and Adverse Reactions).
Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.
In the case that an infection is proven to be due to an amoxicillin-susceptible organism(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.
This presentation of Amoxicillin/ Clavulanic acid is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae.
Convulsions may occur in patients with impaired renal function or in those receiving high doses (see Adverse Reactions).
Amoxicillin/clavulanic acid 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.
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) (see Adverse Reactions). This reaction requires Amoxicillin/clavulanic acid discontinuation and contraindicates any subsequent administration of amoxicillin.
Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see Dosage & Administration, Contraindications and Adverse Reactions).
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. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see Adverse Reactions).
Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin and may range in severity from mild to life threatening (see Adverse Reactions). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation.
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 (see Interactions and Adverse Reactions).
In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see Dosage & Administration).
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. In patients with bladder catheters, a regular check of patency should be maintained (see Overdosage).
During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.
The presence of clavulanic acid in amoxicillin/clavulanic acid may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see Adverse Reactions).
228.5 mg/5 mL & 457 mg/5 mL suspension: Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. Careful inquiry should be made concerning previous hypersensitivity to penicillins, cephalosporins, or other drugs before initiating therapy with Co-amoxiclav. Serious anaphylactoid reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be instituted.
Clostridium difficile-associated diarrhea and colitis have been reported with nearly all antibacterial agents, and may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhea following administration of antibacterial agents.
Since hepatic toxicity has been associated with Co-amoxiclav therapy, the drug should be used with caution in patients with evidence of hepatic dysfunction.
In patients with renal impairment, the dose of Co-amoxiclav should be adjusted based on the degree of impairment (see Dosage & Administration).
During administration of high doses of amoxicillin, it is recommended to maintain adequate fluid intake and urinary output in order to reduce the possibility of crystalluria associated with amoxicillin therapy.
Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly with Co-amoxiclav since prolongation of prothrombin time has been reported rarely in patients receiving Co-amoxiclav.
Although Co-amoxiclav has a low toxicity profile, the renal, hepatic, and hematopoietic status of patients undergoing prolonged treatment with the drug should be evaluated periodically.
As with other antibacterial drugs, long term or repeated use may result in overgrowth of non-susceptible organisms, including fungi.
Use in Children: Children weighing over 40 kg should be dosed based on recommended dosing in adult patients. The safety and efficacy of Co-amoxiclav tablets in children weighing less than 40 kg have not been established.
Use in the Elderly: Since elderly patients have increased risk of renal impairment, dose adjustment and renal function monitoring may be necessary.

Pregnancy: 156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.
228.5 mg/5 mL & 457 mg/5 mL suspension: (Pregnancy Category B). There are no adequate or controlled studies in pregnant women and safe use in pregnancy has not been definitely established. However, oral Co-amoxiclav has been administered to pregnant women, particularly in the treatment of urinary tract infections, without evidence of adverse effects to the fetus.
Lactation: 156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant).
Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, 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.
228.5 mg/5 mL & 457 mg/5 mL suspension: Since Co-amoxiclav is distributed in human milk, use with caution when breastfeeding.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.
The ADRs derived from clinical studies and post-marketing surveillance with amoxicillin/clavulanic acid, sorted by MedDRA System Organ Class are listed as follows.
The following terminologies have been used in order to classify the occurrence of undesirable effects: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). (See Table 11.)

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228.5 mg/5 mL & 457 mg/5 mL suspension: Dermatologic and Hypersensitivity Reactions: Angioneurotic edema, anaphylaxis, serum sickness-like syndrome, fever, hypersensitivity vasculitis, skin rash, pruritus, urticaria, angioedema, erythema multiforme (rarely Stevens-Johnson syndrome), toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP).
Gastrointestinal Effects: Abdominal discomfort, anorexia, and flatulence, dyspepsia, diarrhea/loose stools, nausea, vomiting, indigestion, Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis), gastritis, stomatitis, glossitis, black "hairy" tongue, mucocutaneous candidiasis, enterocolitis.
Hematologic Effects: Reversible leukopenia (including neutropenia) and thrombocytopenia, thrombocytopenic purpura, reversible agranulocytosis, anemia (including hemolytic anemia), slight thrombocytosis, eosinophilia, abnormal platelet aggregation, prolonged bleeding time and prothrombin time.
Nervous System Effects: Dizziness, headache, reversible hyperactivity and convulsions particularly in patients with impaired renal functions or those receiving high doses, agitation, anxiety, behavioral changes, confusion, insomnia.
Hepatic Effects: A moderate rise in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), serum bilirubin and/or alkaline phosphatase, hepatitis, cholestatic jaundice, acute hepatic dysfunction.
Renal and Genitourinary Effects: Acute interstitial nephritis, crystalluria, vaginal itching, soreness and discharge.
Other Effects: Superficial tooth discoloration (brown, yellow, or gray staining).

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Oral anticoagulants: Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are 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 normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see Precautions and Adverse Reactions).
Methotrexate: Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
Probenecid: Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.
Mycophenolate mofetil: In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) 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. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
228.5 mg/5 mL & 457 mg/5 mL suspension: See Table 12.

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Interference with Laboratory Tests: High urine concentrations of ampicillin may result in false-positive reactions when testing for urinary glucose using cupric sulfate (e.g., Clinitest, Benedict's Solution). Since this effect may also occur with amoxicillin, glucose oxidase methods (e.g., Clinistix) should be used when urinary glucose determinations are indicated in patients receiving Co-amoxiclav.
Although not reported to date with Co-amoxiclav, positive direct antiglobulin (Coombs') test results have been reported in patients who received ticarcillin and clavulanic acid and appear to be caused by clavulanic acid. This reaction may interfere with hematologic studies or transfusion cross-matching procedures and therefore should be considered in patients receiving Co-amoxiclav.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Incompatibilities: Not applicable.
Instructions for Use and Handling: Check if cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated as follows) invert and shake well. Alternatively fill the bottle with water to just below the ring-mark on the bottle, invert and shake well, then top up with water exactly to the ring-mark, invert and again shake swell. (See Table 13.)

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Shake the bottle well before use.

156.25 mg/5 mL & 312.5 mg/5 mL powder for oral suspension: Powder for suspension: Store at temperatures not exceeding 25°C.
The reconstituted suspension should be stored in a refrigerator (2°-8°C) and used within 7 days.
228.5 mg/5 mL & 457 mg/5 mL suspension: Store in a dry place at temperatures not exceeding 25°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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