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 powder for 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 powder for suspension: After reconstitution, each 5 mL (1 teaspoonful) suspension contains: Amoxicillin (as trihydrate) 400 mg; Clavulanic acid (as potassium clavulanate) 57 mg.
Co-amoxiclav (Amoclav) 642.9 mg/5 mL powder for oral suspension: Co-amoxiclav (AmoClav) 642.9 mg per 5 mL is a cream-while, raspberry-odored homogenous powder for suspension.
After reconstitution, each 5 mL (1 teaspoonful) suspension contains: Amoxicillin (as trihydrate) 600 mg; Clavulanic acid (as potassium clavulanate) 42.9 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 powder for suspension and 642.9 mg/5 mL powder for oral 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 Tables 3, 4 and 5.

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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 6.)

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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 Interactions).
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 powder for suspension and 642.9 mg/5 mL powder for oral suspension: 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 C_max of amoxicillin were 9.4, 9.7, and 6.5 mcg/mL and of clavulanic acid were 2.1, 4.4, and 2.5 mcg/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 mcg/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 mcg/mL, T_max 1.164 hours, AUC_0-t 12.21 mcg/mL·hr and AUC_0-∞12.855 mcg/mL·hr for amoxicillin, and C_max 1.379 mcg/mL, T_max 1.039 hours, AUC_0-t 2.492 mcg/mL·hr and AUC_0-∞ 2.727 mcg/mL·hr 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 t_1/2 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 t_1/2 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.

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 powder for suspension: For the short-term 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.
642.9 mg/5 mL powder for oral suspension: For the short-term treatment of bacterial infections in pediatric patients at the following sites when caused by Co-Amoxiclav-susceptible microorganisms: Upper respiratory tract infections (including ENT infections) e.g., recurrent or persistent acute otitis media due to Streptococcus pneumoniae (penicillin minimum inhibitory concentration (MIC) ≤4 μg/mL), Haemophilus influenzae and Moraxella catarrhalis.
Such patients are often characterized by antibiotic exposure for acute otitis media within the preceding 3 months, and are either aged ≤2 years or attend daycare; tonsillopharyngitis and sinusitis typically caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes.
Lower respiratory tract infections e.g., lobar and bronchopneumonia typically caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.
Skin and soft tissue infections typically caused by Staphylococcus pyogenes.

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 7.

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Children <40 kg: See Table 8.

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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 powder for 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: Use the measuring spoon included in the box.
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 9 and 10.)

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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 11.

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642.9 mg/5 mL powder for oral 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.
For pediatric patients 3 months and older: Use the measuring spoon included in the box.
The recommended dose is 90/6.4 mg/kg/day in 2 divided doses at 12-hourly intervals for 10 days (refer to the table as follows). There is no experience in pediatric patients weighing >40 kg or in adults. (See Table 12.)

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Co-amoxiclav 642.9 mg per 5 mL powder for suspension does not contain the same amount of clavulanate (as the potassium salt) as any of the other Co-amoxiclav (AmoClav) suspensions. This medicine contains 42.9 mg of clavulanic acid per 5 mL and is not interchangeable with other Co-Amoxiclav (AmoClav) suspensions.
Directions for Reconstitution: Tap the bottle several times to loosen the powder before reconstitution. Fill the bottle with water to just below the mark on bottle label. Then add with water exactly to the mark and shake vigorously until all contents are evenly suspended. Pre-boiled and cooled water may be used to prepare the suspension.
Shake well before taking each dose. Once reconstituted, the suspension must be stored in a refrigerator (2°C to 8°C) and should be used within 14 days. Do not freeze. Discard any unused portion after 14 days.

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 powder for suspension and 642.9 mg/5 mL powder for oral 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. Convulsions may occur in patients with impaired renal function or those receiving high doses.
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.
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 powder for suspension and 642.9 mg/5 mL powder for oral suspension: Hypersensitivity to penicillin or any component of the product.
History of severe immediate hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to another β-lactam antibiotic (e.g. a cephalosporin, carbapenem or monobactam).
Patients with a previous history of cholestatic jaundice/hepatic impairnent 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.

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 and convulsions), which may influence the ability to drive and use machines.
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.
228.5 mg/5 mL & 457 mg/5 mL powder for suspension and 642.9 mg/5 mL powder for oral suspension: Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse 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 anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be instituted.
Clostridium difficile-associated disease (CDAD): This has been reported with the use of nearly all antibacterial agents, including Co-amoxiclav, and may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agents. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Hepatic Dysfunction: Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of Co-amoxiclav. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.
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.
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.
As with other antibacterial drugs, long term or repeated use may result in overgrowth of non-susceptible organisms, including fungi.
642.9 mg/5 mL powder for oral suspension: Phenylketonurics: This product contains phenylalanine as one of the metabolites of aspartame.
228.5 mg/5 mL & 457 mg/5 mL powder for suspension and 642.9 mg/5 mL powder for oral suspension: Renal Impairment: Dosage adjustments are based on the maximum recommended level of amoxicillin. No adjustment in dose is required in patients with creatinine clearance greater than 30 mL/min.
Hepatic impairment: Dose with caution; monitor hepatic function at regular intervals for both adults and children.
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 powder for suspension and 642.9 mg/5 mL powder for oral suspension: (Pregnancy Category B). There are no adequate or controlled studies in pregnant women. The 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.
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. Co-amoxiclav use should be avoided in pregnancy unless considered essential by the physician.
Breast-feeding: 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.
Lactation: 228.5 mg/5 mL & 457 mg/5 mL powder for suspension and 642.9 mg/5 mL powder for oral suspension: Co-amoxiclav is distributed in human milk and may cause diarrhea, fungal infection of the mucous membrane and sensitization in the breastfed infant. Caution should be exercised if Co-amoxiclav is to be administered to a nursing mother.

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 13.)

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228.5 mg/5 mL & 457 mg/5 mL powder for suspension and 642.9 mg/5 mL powder for oral suspension: The most frequently reported adverse effects with co-amoxiclav include diarrhea, nausea and vomiting.
Infections and infestations: Mucocutaneous candidiasis, overgrowth of non-susceptible organisms.
Blood and lymphatic system disorders: Agranulocytosis, anemia, bleeding time prolonged, hemolytic anemia, eosinophilia, leukopenia, neutropenia, prothrombin time prolonged, thrombocytopenia, thrombocytopenia purpura.
Immune system disorders: Anaphylactic reaction, anaphylaxis, angioneurotic edema, serum sickness-like syndrome.
Metabolism and nutrition disorders: Anorexia.
Psychiatric disorders: Abnormal behavior, anxiety, reversible hyperactivity.
Nervous system disorders: Agitation, aseptic meningitis, confusion, convulsions, dizziness, headache, insomnia, reversible hyperactivity.
Vascular disorders: Hypersensitivity vasculitis.
Gastrointestinal disorders: Abdominal discomfort, black hairy tongue, Clostridium difficile-associated diarrhea and colitis, hemorrhagic colitis, dyspepsia, enterocolitis, flatulence, gastritis, glossitis, indigestion, pseudomembranous colitis stomatitis, tooth discoloration (brown, yellow or gray staining which is very rare in children).
Hepatobiliary disorders: Cholestatic jaundice, hepatic dysfunction, hepatitis, hepatitis cholestatic, hepatic coma, hepatic failure, increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin, hepatocellular damage, jaundice, liver injury.
Skin and subcutaneous tissue disorders: Acute generalized exanthemous pustulosis (AGEP), bullous exfoliative-dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, hypersensitivity vasculitis, maculopapular rash, pruritus, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Renal and urinary disorders: Crystalluria, hematuria, interstitial nephritis.
Reproductive system and breast disorders: Vaginitis.
General disorders and administration site conditions: Fever.

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 powder for suspension and 642.9 mg/5 mL powder for oral suspension: See Table 14.

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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.
Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estradiol-glucuronide, conjugated estrone, and estradiol has been noted.

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 15.)

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Shake the bottle well before each 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 powder for suspension: Store at temperatures not exceeding 25°C.
642.9 mg/5 mL powder for oral suspension: Store in a dry place 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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