Amoxil-k 625

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMOXIL-K 625 (AMOXIL-K 625)

Composition:

Active substances: 1 tablet contains amoxicillin trihydrate, calculated as amoxicillin – 500 mg, and a mixture of potassium clavulanate and microcrystalline cellulose in a ratio (1:1), calculated as clavulanic acid – 125 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, coating mixture "Opadry II White" 33G28707 (contains: hypromellose (hydroxypropylmethylcellulose); titanium dioxide (E 171); lactose monohydrate; polyethylene glycol (macrogol) 3000; triacetin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color, oval-shaped, biconvex surface, with a score line on one side of the tablet.

Pharmacotherapeutic group. Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (a beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential 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 degradation by beta-lactamases produced by resistant bacteria; therefore, the antimicrobial spectrum of amoxicillin as monotherapy does not include organisms producing these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid has no clinically useful antibacterial activity when used alone.

PK/PD relationship

Time above the minimum inhibitory concentration (T>MIC) is considered the primary 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 themselves inhibited by clavulanic acid, including Class B, C, and D enzymes;
• Alteration of PBPs, leading to reduced affinity of the antibacterial agent for its target.

Impermeability of bacterial cells or efflux pump mechanisms may contribute to or cause bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

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 information on susceptibility is desirable, especially when treating severe infections. An expert opinion should be sought if local resistance prevalence is such that the benefit of the drug, at least for certain 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 following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

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

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

Following intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, abdominal tissue, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile, and pus. Amoxicillin does not distribute adequately into cerebrospinal fluid.

Animal studies have not shown evidence of significant retention of substances derived from either component in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be detected in breast milk (see section "Use in pregnancy or lactation").

It has been demonstrated that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use in pregnancy or lactation").

Metabolism. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and excreted in urine and feces, as well as in the form of carbon dioxide in exhaled air.

Elimination. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both by the kidneys and via 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 amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. For clavulanic acid, the majority of the substance is excreted within the first 2 hours after administration.

Concomitant administration of probenecid slows the elimination of amoxicillin but does not affect the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. For infants during the first week of life (including premature infants), the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. Since elderly patients are more likely to have decreased renal function, dosage should be selected with caution; monitoring of renal function is also recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreased renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a greater fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosing should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Method of administration and dosage").

Hepatic impairment. Caution is recommended when administering the drug to patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to the drug, such as: acute bacterial sinusitis; acute otitis media; confirmed exacerbation of chronic bronchitis; community-acquired pneumonia; cystitis; pyelonephritis; skin and soft tissue infections, including cellulitis, animal bites, severe dentofacial abscesses with spreading cellulitis; bone and joint infections, including osteomyelitis.

Contraindications.

Hypersensitivity to any component of the drug or to any antibacterial agent of the penicillin group.

History of severe hypersensitivity reactions (including anaphylaxis) associated with the use of other beta-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 forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant administration of these drugs is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions" and "Adverse reactions").

Methotrexate

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent administration may lead to elevated and prolonged blood levels of amoxicillin (but not clavulanic acid).

Mycofenolate mofetil

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

Special precautions for use

Before initiating therapy with Amoxil-K 625, a thorough history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Adverse reactions").

Serious and, in some cases, fatal hypersensitivity reactions (including anaphylactoid reactions and severe cutaneous adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). Such reactions are more likely in patients with a history of penicillin hypersensitivity or those with atopic disorders. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued immediately and appropriate alternative therapy initiated.

If the infection is confirmed to be caused by microorganism(s) susceptible to amoxicillin alone, switching from amoxicillin/clavulanic acid to amoxicillin should be considered in accordance with established guidelines.

Amoxil-K 625 is not appropriate for use when there is a high risk that likely pathogens have reduced susceptibility or resistance to beta-lactam agents not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. This dosage form should not be used for the treatment of penicillin-resistant S. pneumoniae.

Seizures may occur in patients with impaired renal function or in those receiving high doses of the drug (see section "Adverse reactions").

Amoxicillin/clavulanic acid should be avoided in suspected cases of infectious mononucleosis, as amoxicillin use has been associated with the development of maculopapular rash in such patients.

Concomitant administration of allopurinol during amoxicillin therapy increases the likelihood of developing skin allergic reactions.

Prolonged use may, in some cases, lead to overgrowth of microorganisms not susceptible to the drug.

The onset of fever-associated generalized erythema with pustule formation at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Adverse reactions"). This reaction requires discontinuation of the drug and constitutes a contraindication to further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients showing signs of hepatic dysfunction (see sections "Dosage and administration", "Contraindications", and "Adverse reactions").

Hepatic complications have been reported primarily in men and elderly patients, possibly related to prolonged treatment. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may appear only several weeks after therapy has ended. These events are usually reversible. Hepatic complications may be severe and, in exceptionally rare cases, fatal. Such events have almost always occurred in patients with severe underlying disease or those receiving concomitant medications known to have potential hepatotoxic effects (see section "Adverse reactions").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Adverse reactions"). Therefore, this diagnosis should be considered in patients presenting with diarrhea during or following antibiotic use. If antibiotic-associated colitis occurs, Amoxil-K 625 should be discontinued immediately, medical advice sought, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin/clavulanic acid (see section "Adverse reactions"). Drug-induced enterocolitis syndrome is an allergic reaction characterized primarily by persistent vomiting (1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases, including progression to shock, have been documented.

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

In rare cases, prolonged prothrombin time has been reported in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring is required when anticoagulants are co-administered. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Dosage adjustment is required in patients with impaired renal function depending on the degree of impairment (see section "Dosage and administration").

Crystalluria (including acute kidney injury) has been very rarely observed in patients with reduced urine output, predominantly during parenteral therapy. Adequate fluid intake and diuresis should be maintained during high-dose amoxicillin therapy to reduce the risk of amoxicillin-related crystalluria. In patients with urinary catheters, catheter patency should be checked regularly (see sections "Adverse reactions" and "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used for urine glucose testing, as non-enzymatic methods may yield false-positive results.

The presence of clavulanic acid in Amoxil-K 625 may lead to nonspecific binding of IgG and albumin to erythrocyte membranes, resulting in false-positive Coombs test results.

Positive results in the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been reported during immunoassay testing using Platelia Aspergillus (Bio-Rad Laboratories).

Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

The product contains lactose as an excipient and should not be used in patients with galactose intolerance, lactase deficiency, or glucose/galactose malabsorption.

This medicinal product contains less than 23 mg of sodium per dose (from 0.8624 mg/tablet to 1.2936 mg/tablet), i.e., it is practically sodium-free.

This medicinal product contains less than 39 mg of potassium per dose (24.52 mg/tablet), i.e., it is practically potassium-free.

Use during pregnancy or breastfeeding

Pregnancy. Reproductive studies in animals with oral and parenteral forms of amoxicillin/clavulanate (500 mg/125 mg) revealed no teratogenic effects. In one study involving women with premature rupture of membranes, prophylactic use of amoxicillin/clavulanate (500 mg/125 mg) was associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, Amoxil-K 625 should be avoided during pregnancy, especially in the first trimester, unless in the physician’s opinion the benefits outweigh the risks.

Breastfeeding period. Both active components of the drug are excreted in breast milk (there is no information regarding the effect of clavulanic acid on a breastfed infant). Diarrhea and fungal mucosal infections may therefore occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. Amoxil-K 625 may be used during breastfeeding only if, in the physician’s opinion, the benefit justifies the potential risk.

Ability to affect reaction speed when driving or operating machinery

No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, undesirable effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery (see section "Adverse reactions").

Method of administration and dosage.

The drug should be used in accordance with official recommendations for antibiotic therapy and local antibiotic susceptibility data. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. When necessary, local susceptibility data should be consulted, and if needed, microbiological identification and susceptibility testing should be performed.

When necessary, consideration should be given to using alternative formulations of amoxicillin/clavulanic acid (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special instructions" and "Pharmacodynamics").

The recommended dosage range depends on the expected pathogens and their susceptibility to antimicrobial agents, severity of the disease, site of infection, patient's age, body weight, and renal function.

For adults and children with body weight ≥ 40 kg, the total daily dose is 1500 mg of amoxicillin/375 mg of clavulanic acid (3 tablets) administered as described below.

For children aged 6 years and older with body weight between 25 and 40 kg, the maximum daily dose is 2400 mg of amoxicillin/600 mg of clavulanic acid (4 tablets) administered as described below.

If higher doses of amoxicillin are required for treatment, other formulations of amoxicillin/clavulanic acid should be used to avoid administering unnecessarily high doses of clavulanic acid.

The duration of treatment is determined by the patient's clinical response. Certain infections (e.g., osteomyelitis) may require prolonged treatment. Treatment should not exceed 14 days without re-evaluation (see section "Special instructions" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

1 tablet of Amoxilu-K 625 three times daily.

Children aged 6 years and older with body weight from 25 to 40 kg

Dosage from 20 mg/5 mg/kg body weight/day to 60 mg/15 mg/kg body weight/day, divided into three doses.

Since the tablet cannot be divided, this formulation Amoxilu-K 625 should not be prescribed to children with body weight less than 25 kg.

Elderly patients

Dosage adjustment in elderly patients is not required. If necessary, dosage should be adjusted according to renal function.

Dosing in renal impairment

Dosing is based on the calculation of the maximum level of amoxicillin. There is no need to adjust the dose in patients with creatinine clearance > 30 mL/min.

Adults and children with body weight ≥ 40 kg

Children aged 6 years and older with body weight between 25 and 40 kg

Since the tablet cannot be divided, this formulation of Amoxil-C 625 should not be prescribed to children with body weight between 25 and 40 kg and creatinine clearance below 30 mL/min, or to children undergoing hemodialysis.

Dosing in hepatic impairment

Use with caution; liver function should be monitored regularly.

The tablet should be swallowed whole, without chewing. If necessary, to facilitate swallowing, the tablet may be split in half and the halves swallowed without chewing.

The medication should be taken with food to minimize potential gastrointestinal intolerance.

The duration of treatment is determined individually. Treatment should not be continued for more than 14 days without reassessment of the patient's condition.

Treatment may be initiated parenterally and then continued orally.

Children

Amoxil-C 625 is indicated for children aged 6 years and older with body weight of at least 25 kg.

Overdose

Symptoms

Gastrointestinal disturbances and disturbances in fluid and electrolyte balance may occur. Crystalluria associated with amoxicillin administration has been observed, which in some cases led to renal failure (see section "Special precautions").

Seizures may occur in patients with impaired renal function or in patients receiving high doses of the drug.

Precipitation of amoxicillin in urinary catheters has been reported, primarily after high-dose intravenous administration. Catheter patency should be checked regularly (see section "Special precautions").

Treatment

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

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

Side effects.

The most commonly reported adverse reactions to the medicinal product (ARs) are diarrhea, nausea, and vomiting.

The list of known adverse drug reactions from clinical trials of amoxicillin/clavulanate and post-marketing surveillance, classified by MedDRA System Organ Class, is provided below.

The following classification of adverse reaction frequencies is used:

very common ≥ 1/10;

common ≥ 1/100 and < 1/10;

uncommon ≥ 1/1000 and < 1/100;

rare ≥ 1/10,000 and < 1/1000;

very rare < 1/10,000;

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

Infections and infestations.

Common: candidiasis of the skin and mucous membranes.

Not known: overgrowth of microorganisms not sensitive to the medicinal product.

Disorders of the blood and lymphatic system.

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.

Not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index1.

Disorders of the immune system 10.

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

Disorders of the nervous system.

Uncommon: dizziness, headache.

Not known: reversible hyperactivity and convulsions2.

Not known: aseptic meningitis.

Cardiac disorders.

Not known: Kounis syndrome.

Gastrointestinal disorders.

Common: diarrhea, nausea3, vomiting.

Uncommon: gastric disorders.

Not known: antibiotic-associated colitis4, "black hairy tongue", discoloration of tooth enamel11, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders.

Uncommon: increased levels of AST and/or ALT5.

Not known: hepatitis6 and cholestatic jaundice6.

Disorders of the skin and subcutaneous tissue 7.

Uncommon: skin rashes, pruritus, 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), linear immunoglobulin A (IgA) disease.

Disorders of the renal and urinary system.

Very rare: interstitial nephritis, crystalluria8 (including acute kidney injury).

1 See section "Special precautions".

2 See section "Special precautions".

3 Nausea is more frequently associated with higher oral doses of the medicinal product. Gastrointestinal reactions may be reduced in severity by taking Amoksyl-K 625 during meals.

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

5 Mild elevations in AST and/or ALT levels have been more frequently observed in patients receiving beta-lactam antibiotics, but the clinical significance of these findings is unknown.

6 These events have been observed with other penicillin and cephalosporin antibiotics (see section "Special precautions").

7 If hypersensitivity reactions (dermatitis) occur, the medicinal product should be discontinued (see section "Special precautions").

8 See section "Overdose".

9 See section "Special precautions".

10 See section "Contraindications" and "Special precautions".

11 Discoloration of tooth enamel has been very rarely reported in children. Careful oral hygiene may prevent such discoloration, as this phenomenon can be removed by tooth brushing.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children.

Packaging. 7 tablets per blister pack, 2 or 3 blister packs per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kievmedpreparat".

Address of manufacturer and location of business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.