Moxiclav BIS

Amoxicillin trihydrate, potassium clavulanate.

Moxiclav Bis contains 400 mg amoxicillin and 57 mg clavulanic acid per 5ml (co-amoxiclav 400/57).
The amoxicillin is present as amoxicillin trihydrate and the clavulanic acid is present as potassium clavulanate.
Excipient with known effect: sucrose.
Excipients/Inactive Ingredients: Xanthan gum (E415), hypromellose E5 2910, saccharin sodium (E954), colloidal anhydrous silica, silicon dioxide (E551), strawberry flavor (maltodextrin, sucrose, propylene glycol (E1520), acetic acid (E260), modified maize starch (E1450)), peach flavor (maltodextrin, propylene glycol (E1520), Arabic gum (E414)), lemon flavor (maltodextrin, acacia (E414), ascorbic acid (E300)), succinic acid (E363).

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors. ATC code: J01CR02.
Pharmacodynamics: Mode 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.
PK/PD relationship: The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
Pharmacokinetics: Absorption: Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (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 1.)

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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 single 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.
Toxicology: 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 Moxiclav Bis or its components.
Microbiology: 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.
In the list as follows, organisms are categorised according to their in vitro susceptibility to amoxicillin/clavulanic acid. (See Table 2.)

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Infections caused by amoxicillin-susceptible organisms are amenable to Moxiclav Bis treatment due to its amoxicillin content. Mixed infections caused by amoxicillin-susceptible organisms in conjunction with Moxiclav Bis-susceptible beta-lactamase producing organisms may therefore be treated with Moxiclav Bis.

Moxiclav Bis should be used in accordance with local official antibiotic prescribing guidelines and local susceptibility data.
Moxiclav Bis suspension for twice daily oral dosing, is indicated for short term treatment of bacterial infections at the following sites when amoxicillin resistant beta-lactamase producing strains are suspected as the cause. In other situations, amoxicillin alone should be considered.
Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media.
Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis, lobar and bronchopneumonia.
Urinary tract infections e.g. cystitis, urethritis, pyelonephritis.
Skin and soft tissue infections e.g. cellulitis, animal bites.
Susceptibility to Moxiclav Bis will vary with geography and time.
Local susceptibility data should be consulted where available, and microbiological sampling and susceptibility testing performed where necessary.
Mixed infections caused by amoxicillin-susceptible organisms in conjunction with Moxiclav Bis susceptible beta-lactamase producing organisms may be treated with Moxiclav Bis suspension 457 mg/5 ml. These infections should not require the addition of another antibiotic resistant to beta-lactamases.

Posology: 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 Moxiclav Bis 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 Moxiclav (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).
The usual recommended daily dosage is: 25/3.6 mg/kg/day in mild to moderate infections (upper respiratory tract infections e.g. recurrent tonsillitis, lower respiratory infections and skin and soft tissue infections).
45/6.4 mg/kg/day for the treatment of more serious infections (upper respiratory tract infections e.g. otitis media and sinusitis, lower respiratory tract infections e.g. bronchopneumonia and urinary tract infections).
No clinical data are available on doses above 45/6.4 mg/kg/day in children under 2 years.
There are no clinical data for Moxiclav Bis suspension 457 mg/5 mL to make dosage recommendations for children under 2 months old.
The tables as follows give dosage guidance for children. (See Table 3.)

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Children aged 2 months to under 2 years: Children under 2 years should be dosed according to body weight. (See Table 4.)

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Elderly: No dose adjustment is considered necessary.
Renal impairment: No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.
In patients with creatinine clearance less than 30 ml/min, the use of Moxiclav Bis presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available.
Hepatic impairment: Dose with caution and monitor hepatic function at regular intervals (see Contraindications and Precautions). There is, as yet, insufficient evidence on which to base a dosage recommendation.
Method of administration: Moxiclav Bis is for oral use.
Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid.
Treatment should not exceed 14 days without review.
Therapy can be started parenterally according to the SmPC 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 Special precautions for disposal and other handling under Cautions for Usage).
For instructions on reconstitution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.

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.

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in Description.
History of hypersensitivity to beta-lactams, e.g. cephalosporins.
History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see Adverse Reactions).

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 (including anaphylactoid and severe cutaneous adverse reactions) 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. Serious anaphylactic reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous (i.v.) steroids and airway management (including intubation) may also be required.
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 Moxiclav Bis is not suitable for use when there is a high risk that the presumptive pathogens have 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.
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 Moxiclav Bis discontinuation and contra-indicates 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).
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.
Pseudomembranous 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. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, Moxiclav Bis should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated 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, Moxiclav Bis is not recommended.
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 Moxiclav Bis 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.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Effects on ability to drive and use machines: Adverse effects on the ability to drive or operate machinery have not been observed.

Pregnancy: Reproduction studies in animals (mice and rats) with orally and parenterally administered amoxicillin/clavulanic acid have shown no teratogenic effects. 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.
Breast-feeding: Moxiclav Bis may be administered during the period of lactation. With the exception of the risk of sensitisation, associated with the excretion of trace quantities in breast milk, there are no detrimental effects for the infant.

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 5.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Oral anticoagulants: 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.
Allopurinol: 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 Moxiclav Bis and allopurinol.
Oral contraceptives: In common with other antibiotics, Moxiclav Bis may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.
Mycophenolate Mofetil: 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.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of drinking water (as indicated as follows) invert and shake well. Alternatively fill the bottle with drinking water to just below the mark on bottle label, invert and shake well, then top up with drinking water exactly to the mark, invert and again shake well. (See Table 6.)

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Shake the bottle well before each dose.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Shelf life: 24 months.
Reconstituted suspensions: 7 days when stored in a refrigerator (2-8°C).
Store below 25°C in the original package in order to protect from light and moisture.
For storage conditions after reconstitution, see Shelf life as previously mentioned.

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.

POM