Amoksiklav

Amoksiklav 2x tablets 1000 mg film-coated tablets: 1 tablet contains 875 mg of amoxicillin in the form of trihydrate and 125 mg of clavulanic acid in the form of potassium salt.
Excipients/Inactive Ingredients: Anhydrous colloidal silica, magnesium stearate, talc, povidone K25, microcrystalline cellulose, crospovidone, triethyl citrate, hypromellose, talc, titanium dioxide, aqueous dispersion ethylcellulose.

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors. ATC code: J01CR02.
Pharmacology: Pharmacodynamics: Mode of action: Amoxicillin is a semi-synthetic 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.
Mechanisms of resistance: The two mains 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 or 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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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 (250 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented as follows. (See Table 3.)

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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 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 male 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 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.

Treatment of bacterial infections induced by Gram-negative and Gram-positive amoxicillin-resistant microorganisms whose resistance is caused by β-lactamases which however are sensitive to the combination of amoxicillin and clavulanic acid.
Amoksiklav 2x tablets 1000 mg are suitable for treatment of the following indications when known or likely to be due to susceptible organisms (see Pharmacology: Pharmacodynamics under Actions).
Infections of the upper respiratory tract (including ear-nose-throat) e.g. sinusitis, otitis media, peritonsillar abscess, tonsillitis.
Infections of the lower respiratory tract e.g. acute exacerbations of chronic bronchitis, bronchopneumonia, pneumonia.
Genito-urinary tract infections e.g. cystitis, urethritis, pyelonephritis, chancroid, gonorrhea, septic abortion.
Infections of the skin and soft tissues e.g. boils, abscesses, cellulitis, wound infections, bites of animals and man.
Infections of bone and joint e.g. osteomyelitis.
Dental infections e.g. dentoalveolar abscess.
Other infections: cholecystitis.
Treatment of mixed infections due to gram-negative and gram-positive microorganisms and anaerobes: chronic sinusitis, and otitis, peritonsillar abscess, mammary abscess, aspiration pneumonia, peritonitis, cholangitis, postoperative intra-abdominal complications, abdominal infections.

Dosage in adults and children over 12 years of age and weight over 40 kg: Severe infections: One Amoksiklav 2x tablet 1000 mg two times a day or every 12 hours.
Amoksiklav 2x tablets 1000 mg is not recommended in children under 12 years of age and weight less than 40 kg.
Dosage in renal insufficiency: With renal impairment the dose should be reduced in accordance with the severity of the dysfunction and the patient's weight.
No change in dosage for patients with mild renal insufficiency (creatinine clearance more than 30 ml/min)
In anuria the dosing interval should be prolonged to 48 hours or more.
Maximum daily dosage for clavulanic acid (in the form of potassium salt) is 600 mg for adults and 10 mg/kg body weight for children.
Maximum daily dosage for amoxicillin is 6 grams for adults and 45 mg/kg body weight for children.
Dosage in hepatic functional impairment: Administer with caution. The liver function should be monitored at regular intervals. The experience in the use of the product in hepatic insufficiency is not adequate in order to give dose recommendations.
Method of administration: Amoxicillin/clavulanic acid is recommended to be taken at the start of meals to reduce any possible gastrointestinal discomfort.
Duration of administration: 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 by the physician.

Symptoms and signs of overdose: Gastrointestinal symptoms and disturbance of the fluid 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.
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).

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 contraindicated in this situation.
Periodic assessment of organ system functions, including renal, hepatic and haematopoeitic 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).

Pregnancy: 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 human 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.
Breast-feeding: 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.

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 occurence 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).
Infections and infestations: Common: Mucocutaneous candidosis.
Not known; Overgrowth of non-susceptible organisms.
Blood and lymphatic system disorders: Rare: Reversible leucopenia (including neutropenia), thrombocytopenia.
Not known: Reversible agranulocytosis, haemolytic anaemia, prolongation of bleeding time and prothrombin time¹.
Immune system disorders¹⁰: Not known: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis.
Nervous system disorders: Uncommon: Dizziness, headache.
Not known: Reversible hyperactivity, convulsions², aseptic meningitis.
Gastrointestinal disorders: Very common: Diarrhoea.
Common: Nausea³, vomiting.
Uncommon: Ingestion.
Not known: Antibiotic-associated colitis⁴, back hairy tongue, tooth discolouration¹¹.
Hepatobiliary disorders: Uncommon: Rises in AST and/or ALT⁵.
Not known: Hepatitis⁶, cholestatic jaundice⁶.
Skin and subcutaneous tissue disorders⁷: Uncommon: Skin rash, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalized exanthemous pustulosis (AGEP)⁹ and drug reaction with eosinophilia and systemic symptoms (DRESS).
Renal and urinary disorders: Not known: Interstitial nephritis, crystalluria⁸.
¹See Precautions.
²See Precautions.
³Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid at the start of a meal.
⁴Including pseudomembranous colitis and haemorrhagic colitis (see Precautions).
⁵A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown.
⁶These events have been noted with other penicillins and cephalosporins (see Precautions)
⁷If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see Precautions).
⁸See Overdosage.
⁹See Precautions.
¹⁰See Contraindications and Precautions.
¹¹Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.

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.

Special precautions for disposal: No special precautions.
Incompatibilities: Not applicable.

Do not store above 30°C.
Keep in the original container. Protect from light and moisture.

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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