Amoxyl-k

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

Composition:

Active substances: amoxicillin, clavulanic acid;

1 vial contains a sterile mixture (5:1) of sodium amoxicillin and potassium clavulanate, equivalent to 1.0 g of amoxicillin and 0.2 g of clavulanic acid.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white hygroscopic powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Combinations of penicillins, including beta-lactamase inhibitors.

ATC code J01CR02.

Pharmacological properties.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often termed 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 pharmacokinetic/pharmacodynamic parameter determining the efficacy of amoxicillin.

Mechanisms of resistance

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.

Reduced bacterial permeability or efflux pump mechanisms may contribute to or cause bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

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

The prevalence of resistance of individual species may vary geographically and over time, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice may be necessary if local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Pharmacokinetics.

Absorption.

Pharmacokinetic data obtained in studies involving a group of healthy volunteers who received Amoxil-K at a dose of 1000/200 mg (1.2 g) as a bolus intravenous injection are presented below.

Distribution. Approximately 25% of the total plasma volume of 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 about 0.2 L/kg for clavulanic acid.

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

Animal studies have shown no evidence of significant retention of substances derived from any component of the drug in body tissues. Like most penicillins, amoxicillin may be found in breast milk. A small amount of clavulanic acid may also be present 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 is eliminated in urine and feces, as well as in the form of carbon dioxide in expired air.

Excretion. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both renally 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 about 25 L/h. Various studies have shown urinary excretion of 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 administration of probenecid slows the elimination of amoxicillin but does not delay 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 similar in children aged 3 months to 2 years, older children, and adults. For neonates (including premature infants) during the first week of life, 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 selection should be cautious, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger 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 Amoxilu-K, such as:

• severe infections of the throat, nose, and ears (e.g., mastoiditis, peritonsillar infections, epiglottitis, and sinusitis with associated severe systemic signs and symptoms);
• acute exacerbations of chronic bronchitis (after diagnosis confirmation);
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including bacterial cellulitis, animal bites, severe dentoalveolar abscesses with extensive cellulitis;
• bone and joint infections, including osteomyelitis;
• intra-abdominal infections;
• genital tract infections in women.

Prophylaxis of bacterial infections during major surgical procedures in the following areas:

• gastrointestinal tract;
• pelvic organs;
• head and neck;
• biliary tract.

When prescribing antibacterial agents, appropriate use guidelines should be followed.

Contraindications.

Hypersensitivity to the active substances, penicillin, or to other components of the drug.

Severe immediate-type allergic reaction (e.g., anaphylaxis) to another beta-lactam antibiotic (cephalosporin, carbapenem, or monobactam) in medical history.

History of jaundice/liver function disorders induced by amoxicillin/clavulanic acid.

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. If concomitant use 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 for use" 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 increased and prolonged blood levels of amoxicillin (but not clavulanic acid).

Mycofenolate mofetil

In patients treated with 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 concentration may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is generally not required unless there is clinical evidence of transplant dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

Before initiating therapy with Amoxyl-K, it is necessary to carefully assess the patient's history for hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections "Contraindications" and "Adverse reactions").

Severe, and sometimes even fatal, cases of hypersensitivity (including anaphylactic reactions and severe skin adverse reactions) have been observed in patients during penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome—a serious allergic reaction that can lead to myocardial infarction (see section "Adverse reactions"). These reactions are most likely to occur in individuals with a history of similar reactions to penicillin. In case of allergic reactions, Amoxyl-K therapy should be discontinued and appropriate alternative treatment initiated.

If the infection is proven to be caused by microorganisms sensitive to amoxicillin, consideration should be given to switching from the combination amoxicillin/clavulanic acid to amoxicillin alone, in accordance with official recommendations.

Amoxyl-K in this pharmaceutical form is not suitable for use when there is a high risk that the likely pathogens exhibit resistance to beta-lactam agents not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. Since specific data on T > MIC are lacking, and data on oral dosage forms are limited, this formulation (without additional amoxicillin) may be unsuitable for treating penicillin-resistant S. pneumoniae.

Seizures may occur in patients with impaired renal function or when high doses are administered.

Amoxyl-K should be discontinued if infectious mononucleosis is suspected, as the development of a measles-like rash associated with this condition may be linked to amoxicillin intake.

Concomitant use of allopurinol during amoxicillin treatment may increase the risk of skin allergic reactions.

Prolonged use of the drug may occasionally lead to overgrowth of non-susceptible microorganisms.

Development of pustular polymorphic erythema at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (see section "Adverse reactions"). In such cases, treatment must be discontinued, and further administration of amoxicillin is contraindicated.

Amoxyl-K should be used with caution in patients with impaired liver function.

Hepatitis occurs predominantly in males and elderly patients, and its occurrence may be associated with prolonged treatment. Very rarely, such adverse reactions may occur in children. Signs and symptoms typically appear during or immediately after treatment, but in some cases may manifest several weeks after completion of therapy. These events are usually reversible. Fatal cases have been reported extremely rarely, always occurring in patients with severe underlying diseases or those receiving concomitant medications with hepatotoxic potential (see section "Adverse reactions").

Cases of antibiotic-associated colitis, ranging from mild to life-threatening severity, have been reported with almost all antibacterial agents (see section "Adverse reactions"). Therefore, it is important to consider this possibility when patients develop diarrhea during or after antibiotic use. In case of antibiotic-associated colitis, Amoxyl-K therapy should be immediately discontinued, medical advice sought, and appropriate treatment initiated.

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 of the medicinal product) 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.

During prolonged therapy, monitoring of organ and system functions—including kidneys, liver, and hematopoietic system—is recommended.

Rarely, patients receiving Amoxyl-K and oral anticoagulants may experience excessive prolongation of prothrombin time (elevated international normalized ratio, INR). Appropriate monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections "Adverse reactions" and "Interaction with other medicinal products and other forms of interaction").

Dosage should be adjusted according to the degree of renal impairment in patients with renal insufficiency.

Crystalluria (including acute kidney injury) may very rarely occur in patients with reduced urine output, primarily with parenteral administration of the drug. Therefore, when high doses of amoxicillin are used, adequate fluid intake and monitoring of urine output are recommended to minimize the risk of amoxicillin crystalluria (see sections "Adverse reactions" and "Overdose").

When monitoring urinary glucose levels during amoxicillin therapy, enzymatic glucose oxidase methods should be used, as other methods may yield false-positive results.

There have been reports of false-positive results in Aspergillus antigen tests in patients receiving amoxicillin/clavulanic acid (using the Bio-Rad Laboratories Platelia Aspergillus EIA test). Therefore, positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by alternative diagnostic methods.

The presence of clavulanic acid in Amoxyl-K may cause non-specific binding of IgG and albumin to erythrocyte membranes, potentially leading to a false-positive Coombs test.

Each vial of this medicinal product contains 62.95 mg (or 2.7 mmol) of sodium. Caution is advised when administering to patients on a sodium-controlled diet.

Each vial of this medicinal product contains 39.24 mg (or 1.0 mmol) of potassium. Caution is advised when administering to patients with impaired renal function or those on a potassium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive studies in animals with oral and parenteral formulations of amoxicillin/clavulanic acid showed no teratogenic effects. However, in one study involving women with premature rupture of fetal membranes, prophylactic use of Amoxyl-K was associated with an increased risk of necrotizing enterocolitis in newborns. The drug should be avoided during pregnancy, especially in the first trimester, unless, in the physician’s opinion, its use is considered necessary.

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

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the ability of Amoxyl-K to affect reaction speed when driving or operating machinery. However, adverse reactions such as allergic reactions, dizziness, and seizures may impair the ability to drive or operate machinery.

Dosage and Administration

The doses are expressed as the content of amoxicillin/clavulanic acid, unless otherwise specified for individual components.

When selecting the dose of Amoxilu-K for treating a specific infection, the following should be considered:

• Expected pathogens and their presumed susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use");
• Severity and site of infection;
• Patient's age, body weight, and renal function, as described below.

This dosage form of Amoxilu-K can be used at a maximum daily dose of 3000 mg of amoxicillin and 600 mg of clavulanic acid. If higher doses of amoxicillin are required, another formulation of Amoxilu-K should be prescribed to avoid excessively high daily doses of clavulanic acid.

The duration of treatment is determined individually by the physician. Some infections (e.g., osteomyelitis) require prolonged treatment. The duration of treatment should not exceed 14 days without re-evaluation of treatment response and clinical status (see section "Special Warnings and Precautions for Use").

Dosing for adults and children with body weight ≥ 40 kg

Standard dose: 1000/200 mg every 8 hours.

Prophylaxis of postoperative complications in surgical procedures

For surgical procedures lasting less than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at induction of anesthesia (the 2000/200 mg dose may be achieved using another intravenous formulation of amoxicillin/clavulanic acid).

For surgical procedures lasting more than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at induction of anesthesia, followed by 1000/200 mg every 8 hours (three doses within 24 hours).

If clinical signs of infection occur in the postoperative period, a full course of treatment with intravenous or oral administration of the drug should be initiated.

Dosing for children with body weight < 40 kg

Children aged 3 months and older: 25/5 mg/kg body weight every 8 hours.

Children under 3 months of age or with body weight less than 4 kg: 25/5 mg/kg body weight every 12 hours.

Elderly patients

Dose adjustment is not required.

Renal impairment

Dose adjustment is based on maximum recommended doses of amoxicillin.

Creatinine clearance > 30 mL/min – no dose adjustment required.

Adults and children with body weight ≥ 40 kg

Adults and children with body weight < 40 kg

Hepatic impairment

Caution is required in dosing; continuous monitoring of liver function at regular intervals is necessary.

Amoxil-K should be administered via intravenous injection (bolus) or via intermittent infusion (intravenous drip). Amoxil-K must not be administered intramuscularly.

For infants under 3 months of age, Amoxil-K should only be administered as an intravenous infusion.

Treatment with Amoxil-K may be initiated via intravenous administration and continued with oral dosage forms.

Preparation of solution for intravenous injection

1000/200 mg: dissolve the contents of the vial in 20 ml of water for injections (final volume – 20.9 ml).

A transient pinkish discoloration may appear during dissolution, which disappears. Amoxil-K solutions are usually colorless or pale yellow.

Amoxil-K must be administered within 20 minutes after reconstitution.

Preparation of solution for intravenous infusion

The reconstituted solution of 1000/200 mg, as described above, should be immediately added to 100 ml of infusion fluid (preferably using a mini-bag or burette). The infusion should be administered over 30–40 minutes. Amoxil-K is chemically and physically stable for 2–3 hours at 25 °C or for 8 hours at 5 °C after reconstitution. From a microbiological standpoint, the prepared solution should be used immediately.

Intravenous infusions of Amoxil-K can be carried out using various intravenous solutions. Adequate antibiotic concentration is maintained at 5 °C and at room temperature (25 °C) in the recommended volumes of the infusion fluids listed below. When the drug is reconstituted and stored at room temperature, infusions should be administered within the time periods specified below.

If stored at 5 °C, 1000/200 mg solutions may be added to a pre-cooled infusion solution (water for injections or 0.9 % sodium chloride solution); the resulting preparation may be stored at the specified temperature for up to 8 hours.

After the solution reaches room temperature, it should be used immediately.

The stability of Amoxyl-K solutions depends on concentration. If a solution of higher concentration is prepared, the solution's stability period increases proportionally.

Amoxyl-K is less stable in glucose, dextran, and bicarbonate solutions; therefore, solutions based on these must be used within 3-4 minutes after reconstitution.

Any unused solution should be disposed of according to current requirements.

Children.

Can be administered to children from the first days of life.

Overdose.

Symptoms

Symptoms of gastrointestinal disorders 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 and in patients receiving high doses of the drug.

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

Treatment

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

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

Adverse Reactions

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

Below is a list of adverse reactions observed during clinical trials and post-marketing use of amoxicillin/clavulanic acid. The reactions are presented according to the MedDRA system organ class.

The following classification of frequency of adverse reactions is used:

Very common ≥ 1/10;
Common ≥ 1/100 to < 1/10;
Uncommon ≥ 1/1000 to < 1/100;
Rare ≥ 1/10,000 to < 1/1000;
Very rare < 1/10,000;
Not known (frequency cannot be estimated from available data).

Infections and infestations

Common: Cutaneous and mucocutaneous candidiasis.
Not known: Overgrowth of non-susceptible microorganisms.

Blood and lymphatic system disorders

Rare: Reversible leukopenia (including neutropenia) and thrombocytopenia.
Not known: Reversible agranulocytosis and hemolytic anemia; prolonged 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: Seizures², aseptic meningitis.

Vascular disorders

Rare: Thrombophlebitis³.

Cardiac disorders

Not known: Quincke's edema (angioedema).

Gastrointestinal disorders

Common: Diarrhea.
Uncommon: Nausea, vomiting, gastric discomfort.
Not known: Antibiotic-associated colitis⁴, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders

Uncommon: Increased levels of AST and/or ALT⁵.
Not known: Hepatitis⁶ and cholestatic jaundice⁶.

Skin and subcutaneous tissue disorders⁷

Uncommon: Skin rashes, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis⁹, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders

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

1 See section "Special precautions for use".
2 See section "Special precautions for use".
3 At the injection site.
4 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions for use").
5 Moderate elevations in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 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 for use").
7 If hypersensitivity reactions (dermatitis) occur, the drug should be discontinued (see section "Special precautions for use").
8 See section "Overdose".
9 See section "Special precautions for use".
10 See section "Contraindications" and "Special precautions for use".

Shelf life. 2 years.

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

Incompatibilities

Amoxyl-K should not be mixed with blood products, other protein-containing fluids (including protein hydrolysates), or fat emulsions intended for intravenous administration.

If Amoxyl-K is administered concomitantly with an aminoglycoside, the antibiotics should not be mixed in the same syringe, intravenous container, or other receptacle, as the aminoglycoside may lose its activity.

Packaging. 1.2 g in vials. 1 or 10 vials per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.