Augmentin BD film-coated tablets 875 mg + 125 mg blister No. 14

Instructions Augmentin BD film-coated tablets 875 mg + 125 mg blister No. 14

Composition

active ingredients: amoxicillin and clavulanic acid;

1 tablet contains amoxicillin (in the form of amoxicillin trihydrate) 875 mg, clavulanic acid (in the form of potassium clavulanate) 125 mg;

excipients: magnesium stearate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, microcrystalline cellulose, dimethicone;

tablet shell: titanium dioxide (E 171), hypromellose (5 cps), hypromellose (15 cps), macrogol 4000, macrogol 6000.

Dosage form

Film-coated tablets.

Main physicochemical properties: white or off-white capsule-shaped tablets, film-coated, with a breakline on one side and monograms A and C on both sides.

Pharmacotherapeutic group

Antibacterial agents for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors.

ATX code J01C R02.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often called penicillin-binding proteins, PBPs) in the biosynthetic metabolism of bacterial peptidoglycan, an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.

Amoxicillin is susceptible to cleavage by beta-lactamases produced by resistant bacteria, therefore, the spectrum of activity of amoxicillin as monotherapy does not include microorganisms that produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to the penicillins. It inactivates some beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid as monotherapy does not exhibit clinically useful antibacterial effects.

FC/FD ratio

The time at which the drug concentration is maintained above the minimum inhibitory concentration (MIC) is considered the main factor determining the efficacy of amoxicillin.

Resistance mechanisms

There are two main mechanisms of resistance to amoxicillin/clavulanic acid:

- inactivation by bacterial beta-lactamases that are not inhibited by clavulanic acid themselves, including classes B, C and D;

- conversion of PZB, which reduces the affinity of the antibacterial drug to the target.

Bacterial impermeability or efflux pump mechanism can cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Checkpoints

MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

The prevalence of resistance may vary geographically and over time for individual species, so local susceptibility information is desirable, particularly when treating severe infections. Expert opinion should be sought when the local prevalence of resistance is such that the utility of the agent, at least in some types of infections, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH. Both components are rapidly and well absorbed after oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% after oral administration. The plasma profiles of both components are identical and the time to maximum plasma concentration (Tmax) for each component is approximately one hour.

Serum concentrations of amoxicillin and clavulanic acid achieved with the amoxicillin/clavulanic acid combination are identical to those achieved with oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution: Approximately 25% of the total plasma clavulanic acid and 18% of the total plasma amoxicillin are protein bound. The apparent volume of distribution is approximately 0.3–0.4 l/kg for amoxicillin and approximately 0.2 l/kg for clavulanic acid.

After intravenous administration, amoxicillin and clavulanic acid have been found in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile and pus. Amoxicillin does not distribute sufficiently in the cerebrospinal fluid.

Animal studies have not revealed any evidence of significant retention of substances derived from any component of the drug in body tissues. Amoxicillin, like most penicillins, can be found in breast milk. Small amounts of clavulanic acid can also be found in breast milk (see section "Use during pregnancy or lactation").

Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section “Use during pregnancy or lactation”).

Biotransformation: Amoxicillin is partially excreted in the urine as inactive penicilloic acid in amounts equivalent to 10-25% of the initial dose. Clavulanic acid is extensively metabolized in humans and is excreted in the urine and feces and as carbon dioxide in exhaled air.

Excretion: The primary route of excretion of amoxicillin is the kidney, while clavulanic acid is excreted both renally and by extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour and the mean total clearance is approximately 25 l/h. Various studies have shown that urinary excretion is 50-85% for amoxicillin and 27-60% for clavulanic acid over a 24-hour period. The greatest amount of clavulanic acid is excreted within the first 2 hours after administration.

Concomitant use of probenecid slows down the elimination of amoxicillin, but does not delay the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other types of interactions").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children and adults. Since elderly patients are more prone to decreased renal function, dosage should be selected with caution, and monitoring of renal function is also recommended.

Renal impairment. The total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The decrease in drug clearance is more pronounced for amoxicillin than for clavulanic acid, since a greater proportion of amoxicillin is excreted by the kidneys. In renal insufficiency, the dosage should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).

Hepatic impairment. Patients with hepatic insufficiency are recommended to use the drug with caution and regularly monitor liver function.

Indication

Treatment of bacterial infections in adults and children caused by microorganisms sensitive to Augmentin, such as:

acute bacterial sinusitis (confirmed);

acute otitis media;

confirmed exacerbation of chronic bronchitis;

community-acquired pneumonia;

cystitis;

pyelonephritis;

skin and soft tissue infections, including cellulitis, animal bites, severe odontogenic abscesses with widespread cellulitis;

Bone and joint infections, including osteomyelitis.

When prescribing antibacterial drugs, one should follow the rules for their proper use.

Contraindication

Hypersensitivity to any components of the drug, to any antibacterial agents of the penicillin group.

History of severe hypersensitivity reactions (including anaphylaxis) associated with the use of other β-lactam agents (including cephalosporins, carbapenems or monobactams).

History of jaundice or liver dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other types of interactions

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics are widely used in practice without reports of interaction. However, cases of increased international normalization ratio have been described in patients taking acenocoumarol or warfarin and who were prescribed a course of amoxicillin. If concomitant use of such drugs is necessary, the prothrombin index or international normalization ratio should be carefully monitored when amoxicillin is added or discontinued. In addition, dose adjustment of oral anticoagulants may be required (see sections "Special instructions for use" 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 reduces the renal tubular secretion of amoxicillin. Concomitant use of probenecid may lead to increased levels and duration of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients treated with mycophenolate mofetil, the overdosage concentration of the active metabolite, mycophenolic acid, may decrease by approximately 50% after initiation of oral amoxicillin/clavulanic acid. This change in overdosage level may not fully reflect the change in total mycophenolic acid exposure. Therefore, a change in mycophenolate mofetil dosage is not usually necessary unless there is clinical evidence of graft dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Application features

Before initiating therapy with amoxicillin/clavulanic acid, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam drugs (see sections 4.3 and 4.8).

Serious and in some cases fatal hypersensitivity reactions (including anaphylactic reactions and severe cutaneous adverse reactions) have been reported in patients treated with penicillin. Such reactions are more likely to occur in patients with a history of hypersensitivity to penicillin and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued and appropriate alternative therapy should be initiated.

If the infection is proven to be caused by an organism(s) susceptible to amoxicillin, a switch from amoxicillin/clavulanic acid to amoxicillin should be considered in accordance with generally accepted guidelines.

This formulation of Augmentin should not be used when there is a high risk that the likely causative agents of the disease have reduced susceptibility or resistance to beta-lactam drugs that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This formulation should not be used to treat patients with disease caused by penicillin-resistant Streptococcus pneumoniae.

In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur (see section "Adverse reactions").

Amoxicillin/clavulanic acid should be avoided in suspected infectious mononucleosis, as a crust-like rash has been associated with the use of amoxicillin in this case.

Concomitant use of allopurinol during treatment with amoxicillin increases the likelihood of allergic skin reactions.

Prolonged use in some cases may lead to excessive reproduction of microorganisms insensitive to the drug.

The occurrence of febrile generalized erythema associated with pustular eruption at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section 4.8). Such a reaction requires discontinuation of Augmentin and is a contraindication to further use of amoxicillin.

Hepatic complications have been reported predominantly in men and elderly patients and may be associated with long-term treatment. Such complications have been reported very rarely in children. In all patient groups, symptoms usually occur during or shortly after treatment, but in some cases may not appear until several weeks after the end of treatment. Such events are usually reversible. Hepatic complications can be severe and in rare cases fatal. Such events have almost always been observed in patients with severe underlying disease or in those taking concomitant medications known to cause hepatic complications (see section 4.8).

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 diarrhea during or after taking any antibiotic. If antibiotic-associated colitis occurs, Augmentin should be discontinued immediately, medical attention should be sought, and appropriate treatment should be initiated. The use of antiperistaltic agents is contraindicated in such cases.

With prolonged therapy, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is recommended.

In patients receiving amoxicillin/clavulanic acid, prolongation of the prothrombin time has been reported in isolated cases. Appropriate monitoring should be carried out when anticoagulants are administered concomitantly. Adjustment of the oral anticoagulant dose may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted depending on the degree of impairment (see section "Method of administration and dosage").

Crystalluria has been observed very rarely in patients with reduced diuresis, mainly with parenteral therapy. Adequate fluid intake and diuresis should be maintained during high doses of amoxicillin to reduce the likelihood of crystalluria associated with amoxicillin. In patients with bladder catheterization, the patency of the catheters should be checked regularly (see section "Overdose").

During treatment with amoxicillin, enzymatic methods for determining glucose oxidase should be used when testing for the presence of glucose in the urine, since the use of non-enzymatic methods is likely to produce false-positive results.

The presence of clavulanic acid in Augmentin may lead to nonspecific binding of IgG and albumin on erythrocyte membranes, which may lead to false-positive Coombs test results.

Positive results have been reported in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection using the Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported in patients receiving Bio-Rad Laboratories Platelia Aspergillus enzyme immunoassay. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Use during pregnancy or breastfeeding

Pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not indicate an increased risk of congenital malformations. A single study in women with premature rupture of membranes reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotizing enterocolitis in the newborn. Use during pregnancy should be avoided unless considered essential by the physician.

Breastfeeding. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on a breastfed infant). Thus, diarrhea and fungal infection of the mucous membranes may occur in a breastfed infant, so breastfeeding should be discontinued during treatment with the drug. The possibility of allergic reactions should be taken into account. The use of amoxicillin/clavulanic acid during breastfeeding is possible only after a doctor has assessed the risk/benefit ratio.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the ability of the drug to affect the reaction rate when driving vehicles and operating other mechanisms have not been conducted. However, undesirable effects (such as allergic reactions, dizziness, convulsions) may occur, which may affect the ability to drive a car and operate other mechanisms (see the section "Adverse reactions").

Method of administration and doses

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except in cases where dosage is expressed in terms of a separate component.

When choosing the dosage of Augmentin for the treatment of a particular infection, the following should be considered:

probable pathogens and their likely sensitivity to antibacterial drugs (see section "Peculiarities of use");

severity and location of the infection;

the patient's age, body weight and renal function as indicated below.

If necessary, alternative formulations of Augmentin (i.e. those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered (see sections 4.4 and 5.1).

For adults and children weighing ≥ 40 kg, the total daily dose is 1750 mg amoxicillin/250 mg clavulanic acid (2 tablets), the daily dose is divided into 2 doses. For children weighing < 40 kg, the maximum daily dose is 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when administered as indicated below.

If higher doses of amoxicillin are required for treatment, other forms of Augmentin should be used to avoid the administration of excessively high doses of clavulanic acid (see sections "Special instructions for use" and "Pharmacodynamics").

The duration of treatment is determined by the patient's clinical response to treatment. Some infections (e.g. osteomyelitis) require longer treatment. Treatment should not exceed 14 days without review (see section 4.4 for long-term therapy).

Adults and children weighing ≥ 40 kg

Recommended standard dose (for all indications): 875 mg/125 mg 2 times a day.

Children weighing 25 to 40 kg

Treatment can be carried out with Augmentin in the form of tablets or suspension.

Recommended doses:

25 mg/3.6 mg/kg body weight/day to 45 mg/6.4 mg/kg body weight/day, divided into 2 doses;

For the treatment of some infections (such as otitis media, sinusitis, and lower respiratory tract infections), up to 70 mg/10 mg/kg body weight/day, divided into 2 doses, may be used.

Since the tablet cannot be divided, this form of Augmentin is not prescribed to children weighing less than 25 kg.

The table below shows the dose in mg/kg of body weight that a child weighing 25 kg to 40 kg receives when using one Augmentin 875/125 mg tablet.

For children weighing less than 25 kg, it is advisable to prescribe treatment with Augmentin in the form of a suspension.

There are no clinical data on the use of doses of Augmentin 7:1 dosage forms exceeding 45 mg/6.4 mg/kg body weight per day in children under 2 years of age.

There are no clinical data on the use of Augmentin 7:1 formulations in children under 2 months of age. Therefore, no dosage recommendations are available for this patient group.

Elderly patients

No dose adjustment is required.

Dosage in renal impairment

No dose adjustment is required for patients with a creatinine clearance (CrCl) greater than 30 mL/min. Augmentin formulations with a 7:1 amoxicillin to clavulanic acid ratio are not recommended for patients with a creatinine clearance less than 30 mL/min, as no dose adjustment recommendations are available.

Dosage in liver dysfunction.

Use with caution, liver function should be monitored at regular intervals (see sections "Contraindications" and "Special Instructions").

Method of application

The drug is intended for oral use.

The tablet should be swallowed whole without chewing. If necessary, the tablet can be broken in half and swallowed whole without chewing.

The drug should be taken with meals to minimize potential gastrointestinal intolerance.

Therapy can be initiated with parenteral administration, according to the instructions for medical use of the injectable form of Augmentin, and continued with oral forms.

Children

The drug in this dosage and dosage form is not recommended for the treatment of children weighing less than 25 kg.

Overdose

Symptoms

In patients with impaired renal function and in patients taking high doses of the drug, seizures may occur.

Amoxicillin has been reported to settle in bladder catheters, mainly after intravenous administration at high doses. Catheter patency should be checked regularly (see section 4.4).

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Adverse reactions

The most commonly reported adverse drug reactions were diarrhea, nausea, and vomiting.

The list of adverse drug reactions known from clinical studies of Augmentin and post-marketing surveillance and classified by MedDRA system organ class is listed below.

The following classification of the frequency of side effects is used:

very often ≥ 1/10;

often ≥ 1/100 and < 1/10;

uncommon ≥ 1/1000 and < 1/100;

rare ≥ 1/10,000 and < 1/1,000;

very rare < 1/10,000;

not known (frequency cannot be estimated from the available data).

Infections and invasions.

Common: candidiasis of the skin and mucous membranes.

Not known: overgrowth of microorganisms insensitive to the drug.

Disorders of the hematopoietic and lymphatic systems.

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.

Not known: reversible agranulocytosis and haemolytic anaemia; increased bleeding time and prothrombin time1.

Immune system disorders10.

Not known: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders.

Uncommon: dizziness, headache.

Not known: reversible hyperactivity and convulsions2.

Not known: aseptic meningitis.

Gastrointestinal disorders.

Very common: diarrhea.

Common: nausea3, vomiting.

Uncommon: stomach upset.

Unknown: antibiotic-associated colitis 4, black hairy tongue.

Hepatobiliary disorders.

Uncommon: increased AST and/or ALT5.

Not known: hepatitis6 and cholestatic jaundice6.

Skin and subcutaneous tissue disorders7.

Uncommon: skin rash, itching, urticaria.

Rare: erythema multiforme.

Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis9, drug reaction with eosinophilia and systemic symptoms (DRESS).

Kidney and urinary tract disorders.

Not known: interstitial nephritis, crystalluria8.

1 See section "Application features".

2 See section "Application features".

3 Nausea is more commonly associated with higher oral doses of the drug. If gastrointestinal reactions occur, their severity may be reduced by taking Augmentin with food.

4 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special warnings and precautions for use").

5 Moderate elevations in AST and/or ALT levels were more frequently observed in patients treated with beta-lactam antibiotics, but the significance of these findings is unknown.

6 These phenomena have been observed with other penicillin and cephalosporin antibiotics (see section "Special warnings and precautions for use").

7 If hypersensitivity reactions (dermatitis) occur, the use of the drug should be discontinued (see section "Special instructions").

8 See section “Overdose”.

9 See section "Application features".

10 See sections “Contraindications” and “Special instructions for use”.

Expiration date

3 years. After opening the package – 30 days.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging. Keep out of the reach of children.

Packaging

7 tablets in a blister; 1 blister placed in an aluminum foil bag, where a sachet with moisture-absorbing granules is additionally placed; 2 bags in a cardboard box.

Vacation category

According to the recipe.

Producer

SmithKline Beecham Pharmaceuticals, United Kingdom.

Location of the manufacturer and address of its place of business

SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom. SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.