Medoclav

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEDIKLAV (MEDOCLAV)

Composition:

Active substances: amoxicillin, clavulanic acid;

One vial contains sodium amoxicillin equivalent to amoxicillin 1 g and potassium clavulanate equivalent to clavulanic acid 0.2 g.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Amoxicillin is a semisynthetic penicillin (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 compound 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 as monotherapy.

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, reducing the affinity of the antibacterial agent for its target.

Bacterial impermeability or efflux pump mechanisms may also contribute to or cause resistance, particularly in Gram-negative bacteria.

Breakpoints. The minimum inhibitory concentration (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; therefore, 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.

Typically susceptible organisms

Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible), Coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae¹, Streptococcus pyogenes, and other beta-hemolytic streptococci, Streptococcus viridans group.

Gram-negative aerobes: Actinobacillus actinomycetemcomitans, Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae², Moraxella catarrhalis, Neisseria gonorrhoeae^§, Pasteurella multocida.

Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp.

Organisms for which acquired resistance may be a problem

Gram-positive aerobes: Enterococcus faecium^$.

Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris.

Naturally resistant microorganisms

Gram-negative aerobes: Acinetobacter spр., Citrobacter freundii, Enterobacter spр., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas spр., Serratia spр., Stenotrophomonas maltophilia.

Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.

$ Naturally moderate susceptibility in the absence of acquired resistance mechanisms.

£ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid.

§ All strains resistant to amoxicillin not mediated by beta-lactamases are resistant to amoxicillin/clavulanic acid.

¹ This dosage form of amoxicillin/clavulanic acid may be inappropriate for treatment of Streptococcus pneumoniae resistant to penicillin (see sections "Special precautions" and "Method of administration and dosage").

² Strains with reduced susceptibility have been reported in certain European Union countries with a frequency exceeding 10%.

Pharmacokinetics.

Absorption. Pharmacokinetic data obtained from studies in a group of healthy volunteers who received amoxicillin/clavulanic acid 1000/200 mg (1.2 g) as an intravenous bolus injection are presented below.

Clavulanic acid

Distribution. Approximately 25% of the total plasma volume of clavulanic acid and 18% of 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 not revealed any evidence of significant retention of substances derived from any component of the drug in body tissues. Amoxicillin, like most penicillins, may be found in breast milk. A small amount of clavulanic acid may also be detected in breast milk (see section "Use during pregnancy or breastfeeding"). It has been shown that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use during pregnancy or breastfeeding").

Biological transformation. 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 of amoxicillin is via the kidneys, whereas clavulanic acid is eliminated both by the kidneys and through 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/hour. Various studies have shown that urinary excretion amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. In the case of clavulanic acid, the greatest amount 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 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 the 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 reduced renal function. The reduction in 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. Patients with hepatic insufficiency should be treated cautiously with this medicinal product, and liver function should be monitored regularly.

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to Medoclav, such as:

• severe infections of the throat, nose, and ears (e.g., mastoiditis, peritonsillar infections, epiglottitis, and sinusitis with accompanying severe systemic signs and symptoms);
• exacerbations of chronic bronchitis (after diagnosis has been confirmed);
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including bacterial cellulitis, animal bites, severe dental-alveolar 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 other components of the medicinal product.

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

History of jaundice or hepatic dysfunction induced by amoxicillin/clavulanic acid (see section "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants. Oral anticoagulants and penicillin-class antibiotics are commonly used together in clinical practice, with no 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 discontinuing Medoclav. Additionally, dosage 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 of probenecid may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

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 concentration 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 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 Medoclav, it is essential to carefully assess the patient's history for hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections "Contraindications" and "Side effects").

Severe, and sometimes even fatal, cases of hypersensitivity (including anaphylactic reactions and serious skin reactions) have been observed in patients during penicillin therapy. Hypersensitivity reactions progressing to Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction—have been reported (see section "Side effects"). These reactions are most likely to occur in individuals with a history of similar reactions to penicillin. If allergic reactions occur, Medoclav therapy should be discontinued and appropriate alternative therapy initiated.

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

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin (see section "Side effects"). 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 have been reported, including progression to shock.

This medicinal form of Medoclav is not suitable for use when there is a high risk that the likely pathogens are resistant to beta-lactam agents via mechanisms not mediated by beta-lactamases that are susceptible to inhibition by clavulanic acid. Since specific data on T>MIC are lacking and data on oral formulations are limited, this medicinal form (without additional amoxicillin) may be inappropriate for the treatment of penicillin-resistant S. pneumoniae. Seizures may occur in patients with impaired renal function or when high doses of the drug are administered.

Medoclav should be discontinued if infectious mononucleosis is suspected, as the development of a measles-like rash associated with this disease may be linked to amoxicillin use.

Concomitant use of allopurinol during amoxicillin therapy 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 lesions resembling erythema multiforme at the beginning of treatment may be a sign of acute generalized exanthematous pustulosis (see section "Side effects"). In such cases, treatment must be discontinued, and subsequent administration of amoxicillin is contraindicated.

Medoclav should be used with caution in patients with impaired liver function.

Hepatitis occurs predominantly in men and elderly patients and may be associated with prolonged treatment. Very rarely, such adverse reactions may occur in children. Signs and symptoms may appear during or immediately after treatment, but in some cases may manifest several weeks after treatment has ended. These effects are usually reversible. Fatal outcomes have been reported extremely rarely and have always occurred in patients with severe underlying diseases or those receiving concomitant medications with hepatotoxic potential (see section "Side effects").

Antibiotic-associated colitis, ranging from mild to life-threatening severity, has been reported with the use of nearly all antibacterial agents (see section "Side effects"). Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Medoclav therapy should be immediately discontinued, medical advice should be sought, and appropriate treatment initiated.

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

Rarely, patients receiving Medoclav and oral anticoagulants may exhibit 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 "Interaction with other medicinal products and other types of interactions" and "Side effects").

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

Crystalluria (including acute kidney injury) has been reported very rarely in patients with reduced urine output, primarily following parenteral administration of the drug. Therefore, adequate fluid intake and monitoring of urine output are recommended when high doses of amoxicillin are used, to reduce the risk of amoxicillin crystalluria (see sections "Side effects" 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.

False-positive results in Aspergillus antigen tests have been reported 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 Medoclav may cause nonspecific binding of IgG and albumin to erythrocyte membranes, potentially leading to a false-positive Coombs test.

This medicinal product contains 62.9 mg (2.7 mmol) of sodium per vial. Caution is advised when administering to patients on a sodium-restricted diet.

This medicinal product contains 39.3 mg (1.0 mmol) of potassium per vial. Caution is advised when administering to patients with impaired renal function or those on a potassium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not provide sufficient data to conclude on direct or indirect adverse effects on pregnancy, embryonic/fetal development, labor, or postnatal development. Limited data on the use of amoxicillin/clavulanic acid in pregnant women do not indicate an increased risk of congenital malformations. In one study involving pregnant women with premature rupture of membranes, prophylactic use of amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. The use of this drug during pregnancy should be avoided except when, in the opinion of the physician, its use is considered necessary.

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

Ability to influence the speed of reactions when driving vehicles or operating machinery. No studies on the effect on the ability to drive vehicles or operate machinery have been conducted. However, side effects such as allergic reactions, dizziness, and seizures may affect the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage.

Dosages are expressed as the content of amoxicillin/clavulanic acid, unless the dose of an individual component is specified.

When selecting the dose of Medoclav for treating specific infections, the following factors should be considered:

• the expected pathogens and their anticipated susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use");
• the severity and site of infection;
• the patient's age, body weight, and renal function status, as described below.

If necessary, alternative formulations of Medoclav may be used (e.g., those with higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid). These medicinal forms of Medoclav can be administered at a total daily dose of up to 3000 mg of amoxicillin and 600 mg of clavulanic acid. If a higher dose of amoxicillin is required, another formulation of Medoclav should be prescribed to avoid excessively high daily doses of clavulanic acid.

The duration of treatment should be determined individually. Certain infections (e.g., osteomyelitis) require prolonged treatment. Treatment duration 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 complications during surgical procedures.

For surgeries 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 by using another intravenous formulation of amoxicillin/clavulanic acid).

For surgeries lasting more than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at induction of anesthesia, and the 1000/200 mg dose may be repeated every 8 hours for up to 24 hours.

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

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.

Geriatric patients. Dose adjustment is not required.

Renal impairment. Dosage adjustment is based on the maximum recommended doses of amoxicillin. For creatinine clearance > 30 mL/min – no dosage adjustment is required.

Adults and children with body weight ≥ 40 kg

Adults and children with body weight < 40 kg

Hepatic impairment. Caution is required in dosing, with regular monitoring of liver function at regular intervals. Medoclav should be administered by intravenous injection (bolus) or by intermittent infusion (drip). Medoclav must not be administered intramuscularly.

Medoclav should be administered to infants under 3 months of age only as intravenous infusion.

Treatment with Medoclav may be initiated with intravenous administration and continued with oral formulations.

Preparation of solution for intravenous injection. 1000/200 mg: dissolve the contents of the vial in 20 mL of water for injection (final volume 20.9 mL). Medoclav should be administered by slow intravenous injection over 3–5 minutes, but no later than 20 minutes after reconstitution. It may be administered directly into the vein or via an infusion line.

Preparation of solution for intravenous infusion. The reconstituted solution (1000/200 mg) as described above should be immediately added without delay to 100 mL of infusion fluid (preferably using a mini-container or burette). The infusion should be administered over 30–40 minutes. Medoclav must be administered within 4 hours after reconstitution if water for injection is used, or within 3 hours if 0.9% sodium chloride for injection or Ringer’s lactate solution is used.

From a microbiological standpoint, the prepared solution should be administered immediately.

Medoclav 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 discarded according to current regulations.

Children. Medoclav is indicated for use in children from the first days of life.

Overdose.

Symptoms. Gastrointestinal disturbances and fluid and electrolyte imbalances may occur. Crystalluria associated with amoxicillin 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.

Amoxicillin precipitation 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 and electrolyte balance. Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Side effects.

The most commonly reported adverse reactions to the drug were diarrhea, nausea, and vomiting. The list of adverse reactions known from clinical trials of amoxicillin/clavulanic acid and post-marketing surveillance, classified by MedDRA system organ class, is provided below. The following classification of frequency of adverse reactions 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); frequency not known (cannot be estimated from available data).

Infections and infestations: common – candidiasis of skin and mucous membranes; frequency not known – overgrowth of microorganisms resistant to the drug.

Blood and lymphatic system disorders: rare – reversible leukopenia (including neutropenia) and thrombocytopenia; frequency not known – reversible agranulocytosis and hemolytic anemia. Prolongation of bleeding time and prothrombin index¹.

Immune system disorders¹⁰: frequency not known – angioneurotic edema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders: uncommon – dizziness, headache; frequency not known – convulsions², aseptic meningitis.

Cardiac disorders: frequency not known – Quincke's syndrome.

Vascular disorders: rare – thrombophlebitis³.

Gastrointestinal disorders: common – diarrhea; uncommon – nausea, vomiting, dyspepsia; frequency not known – antibiotic-associated colitis⁴, including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions"), drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders: uncommon – increased levels of AST and/or ALT; frequency not known – hepatitis⁶ and cholestatic jaundice⁶.

Skin and subcutaneous tissue disorders⁷: uncommon – skin rashes, pruritus, urticaria; rare – erythema multiforme; frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis⁹, drug reaction with eosinophilia and systemic symptoms (DRESS), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders: very rare – interstitial nephritis, crystalluria⁸ (including acute kidney injury).

1 See section "Special precautions".

2 See section "Special precautions".

3 At the injection site.

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 drug should be discontinued (see section "Special precautions").

8 See section "Overdose".

9 See section "Special precautions".

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

Reporting suspected adverse reactions. Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store below 25 °C in the original packaging, out of reach of children.

Incompatibilities. Medoclav must not be mixed with blood products, other protein-containing solutions, including protein hydrolysates, or fat emulsions for intravenous administration.

If Medoclav is used concomitantly with an aminoglycoside, the antibiotics must not be mixed in the same syringe, intravenous container, or other vessels, as the aminoglycoside may lose its activity. Medoclav must not be mixed with infusions containing glucose, dextran, or bicarbonate.

Packaging. Vials of 1 g/0.2 g powder in vial; 10 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited.

Manufacturer's address and location of operations.

Agios Athanassios Industrial Area, Iapetou 48, Limassol, 4101, Cyprus.