Medoclav®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MЕDОCLAV® (MEDOCLAV)

Composition:

Active substances: 1 film-coated tablet contains amoxicillin trihydrate 1004 mg equivalent to amoxicillin 875 mg, potassium clavulanate 148.9 mg equivalent to clavulanic acid 125 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate; the film coating contains: polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), talc, macrogol 4000, lecithin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, biconvex capsule-shaped tablets, film-coated, with core dimensions of 21.5 mm × 10.0 mm.

Pharmacotherapeutic group.

Antibacterials for systemic use. 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 microorganisms 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, when used as monotherapy, does not exhibit clinically useful antibacterial activity.

Pharmacokinetic/pharmacodynamic relationship. The time during which drug concentration remains 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 classes B, C, and D; and modification of PBPs, which reduces the affinity of the antibacterial agent for its target.

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

Breakpoints.

The amoxicillin/clavulanic acid MIC breakpoints 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 needed if local resistance prevalence renders the benefit of the drug, at least for certain types of infections, questionable.

Usually susceptible species

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

Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae², Moraxella catarrhalis, Pasteurella multocida.

Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp.

Species with potential for acquired resistance

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 sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas sp., Serratia sp., 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.

¹ This formulation of amoxicillin/clavulanic acid should not be used to treat patients whose infection is caused by Streptococcus pneumoniae strains resistant to penicillin (see sections “Dosage and method of administration” and “Special precautions for use”).

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

Pharmacokinetics

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions 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 (T_max) for each component is approximately one hour.

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of the combination of amoxicillin/clavulanic acid are identical to those achieved after 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, peritoneum, 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 any component-derived substances 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 during pregnancy or breastfeeding”). Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section “Use during pregnancy or breastfeeding”).

Biotransformation. 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 non-renal 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 that urinary excretion of amoxicillin ranges from 50–85% and of clavulanic acid from 27–60% over a 24-hour period. The majority of clavulanic acid 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. 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 clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosage must be adjusted to prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section “Dosage and method of administration”).

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.

For the treatment in adults and children of bacterial infections caused by microorganisms sensitive to Medoclav®, such as: confirmed 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 dentoalveolar abscesses with spreading cellulitis; bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, the principles of their appropriate use should be followed.

Contraindications.

Hypersensitivity to any component of the medicinal product, to any antibacterial agents 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 types of interactions.

Oral anticoagulants. Oral anticoagulants and penicillin-class antibiotics are widely used in clinical practice without reports of interaction. However, isolated data indicate an increased international normalized ratio (INR) in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant use is necessary, prothrombin time or INR should be carefully monitored when starting or stopping amoxicillin. Additionally, dosage adjustment of oral anticoagulants may be required (see sections "Special precautions for use" and "Adverse reactions").

Methotrexate. Penicillins may reduce methotrexate excretion, leading to increased toxicity.

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

Mycophenolate mofetil. In patients receiving mycophenolate mofetil, administration 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 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, careful monitoring is necessary during concomitant use and for some time after completion of antibiotic therapy.

Special precautions for use.

Prior to initiating therapy with amoxicillin/clavulanic acid, a careful history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Side effects").

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

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

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 product should not be used if there is a high likelihood of reduced susceptibility or resistance of the causative pathogens to beta-lactam agents not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. This medicinal product should not be used for the treatment of penicillin-resistant Streptococcus pneumoniae.

Seizures may occur in patients with impaired renal function and in those receiving high doses of the drug (see "Side effects").

Amoxicillin/clavulanic acid should be avoided in suspected cases of infectious mononucleosis, as administration of amoxicillin has been associated with the development of a morbilliform rash.

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

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms resistant to Mедоклав®.

The early onset of fever-associated generalized erythema with pustules may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Side effects"). This reaction requires discontinuation of Медоклав® 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 "Side effects").

Hepatic side effects have occurred primarily in males and elderly patients and have been associated with prolonged treatment. In children, such events have been reported very rarely. In all patient groups, symptoms and signs usually appeared during or immediately after treatment, although in some cases they emerged several months after treatment cessation. These effects are generally reversible. Hepatic complications may be severe and very rarely fatal. They have always occurred in patients with severe underlying diseases or concomitant use of medicinal products known to have potential hepatotoxic effects (see section "Side effects").

Antibiotic-associated colitis, ranging from mild to life-threatening, has been reported with 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, the drug should be discontinued immediately, a physician should be consulted, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

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

Rarely, patients receiving amoxicillin/clavulanic acid concomitantly with oral anticoagulants may experience prolonged prothrombin time. Appropriate laboratory monitoring is necessary when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be required to maintain the desired level of anticoagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Dosage adjustment should be made 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, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained when high doses of amoxicillin are administered to reduce the risk of amoxicillin-related crystalluria. In patients with urinary catheters, catheter patency should be checked regularly (see sections "Side effects" and "Overdose").

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

The presence of clavulanic acid in Медоклав® may lead to non-specific 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 who were later confirmed not to have Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported during testing with the Platelia Aspergillus assay (Bio-Rad Laboratories). 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 any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not suggest an increased risk of congenital malformations. In a single study involving women with premature rupture of fetal membranes, prophylactic use of amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. The drug should be avoided during pregnancy unless the physician considers it necessary.

Breastfeeding period. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Therefore, diarrhea and fungal mucosal infections may occur in the breastfed infant, and breastfeeding should be discontinued during treatment. The possibility of allergic reactions should also be considered. Use of amoxicillin/clavulanic acid during breastfeeding is possible only after a physician has evaluated the risk-benefit ratio.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted to assess the effect of the medicinal product on the ability to drive or operate machinery. However, side effects (e.g., allergic reactions, dizziness, seizures) may occur that could impair the ability to drive or operate machinery (see section "Side effects").

Dosage and Administration.

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of a single component.

When selecting the dosage for treatment of a specific infection, the following should be considered: the likely pathogens involved and their probable susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use"); the severity and site of infection; and the patient's age, body weight, and renal function, as indicated below.

If necessary, consideration should be given to using alternative dosage forms (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

For adults and children with body weight ≥ 40 kg, the total daily dose is 1750 mg amoxicillin/250 mg clavulanic acid (2 tablets), administered in two divided doses. For children with body weight < 40 kg, the maximum daily dose is 1000–2800 mg amoxicillin / 143–400 mg clavulanic acid, as prescribed below.

If higher doses of amoxicillin are required for treatment, other formulations of amoxicillin/clavulanic acid combination should be used to avoid unnecessarily high doses of clavulanic acid. The duration of treatment should be determined based on 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 Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg: the recommended standard dose (for all indications) is 875 mg/125 mg twice daily.

Children with body weight from 25 to 40 kg: the medicinal product can be administered in tablet or suspension form.

Recommended doses:

• from 25 mg/3.6 mg/kg body weight/day to 45 mg/6.4 mg/kg body weight/day, divided into two doses;
• for treatment of certain infections (such as otitis media, sinusitis, and lower respiratory tract infections), up to 70 mg/10 mg/kg body weight/day, divided into two doses, may be used.

Since the tablet cannot be divided, this dosage form is not recommended for children with body weight below 25 kg.

The table below indicates the dose in mg/kg body weight received by a child with body weight from 25 kg to 40 kg when administered one tablet of Medoclav® 875/125 mg.

For children with body weight below 25 kg, it is preferable to prescribe Medoclav® in the form of suspension. There are no clinical data on the use of dosage forms of amoxicillin/clavulanic acid 7:1 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 amoxicillin/clavulanic acid 7:1 dosage forms in children under 2 months of age. Therefore, dosing recommendations for this patient group are not available.

Dosing in elderly patients. Dose adjustment in elderly patients is not required.

Dosing in renal impairment. In patients with creatinine clearance greater than 30 ml/min, dose adjustment is not required. In patients with creatinine clearance less than 30 ml/min, the use of dosage forms containing amoxicillin/clavulanic acid in a 7:1 ratio is not recommended, as there are no recommendations for dose adjustment.

Dosing in hepatic impairment. Use with caution; liver function should be monitored regularly (see sections "Contraindications" and "Special precautions").

Method of administration. The tablet should be swallowed whole, without chewing. The medication should be taken with food to minimize potential gastrointestinal intolerance.

Treatment may be initiated with parenteral administration according to the instructions for medical use of the injectable form of Medoclav®, and continued with oral formulations.

Children.

This medicinal product in this dosage strength and pharmaceutical form is not recommended for the treatment of children with body weight below 25 kg.

Overdose.

Symptoms. Symptoms typical of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin intake has been observed, which in some cases led to the development of 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. Catheter patency 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 were diarrhea, nausea, and vomiting.

Below is a list of adverse drug reactions observed during clinical trials of amoxicillin/clavulanic acid and in post-marketing surveillance, classified by organ systems according to MedDRA. The following frequency classification is applied: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1,000; 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 non-susceptible to the drug.

Blood and lymphatic system disorders: rare – reversible leukopenia (including neutropenia) and thrombocytopenia; not known – reversible agranulocytosis, hemolytic anemia, prolonged bleeding time and prothrombin index\1.

Immune system disorders\8: not known – angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders: uncommon – dizziness, headache; not known – reversible hyperactivity and convulsions\1, aseptic meningitis.

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

Gastrointestinal disorders: common – diarrhea, nausea\2, vomiting; uncommon – gastrointestinal discomfort; not known – antibiotic-associated colitis\3, "black hairy tongue", discoloration of tooth enamel\9, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders: uncommon – increased levels of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)\4; not known – hepatitis\5\ and cholestatic jaundice\5.

Skin and subcutaneous tissue disorders\6: uncommon – skin rashes, pruritus, urticaria; rare – erythema multiforme; not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis\1, drug reaction with eosinophilia and systemic symptoms (DRESS), linear immunoglobulin A (IgA) disease.

Renal and urinary disorders: very rare – interstitial nephritis, crystalluria\7\ (including acute kidney injury).

\1\ See section "Special precautions for use".

\2\ Nausea is more frequently associated with higher oral doses of the drug. The severity of gastrointestinal reactions may be reduced by taking Medoclav® with food.

\3\ Including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions for use").

\4\ 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.

\5\ These events have been reported with other penicillin and cephalosporin antibiotics (see section "Special precautions for use").

\6\ If hypersensitivity reactions (dermatitis) occur, the drug should be discontinued (see section "Special precautions for use").

\7\ See section "Overdose".

\8\ See sections "Contraindications" and "Special precautions for use".

\9\ Tooth enamel discoloration has very rarely been observed in children. Careful oral hygiene may prevent this effect, as discoloration can be removed by tooth brushing.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to 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 at temperatures not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Packaging. 7 tablets in a blister; 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited.

Manufacturer's address.
Agios Athanassios Industrial Area, Iapetou 48, Limassol, 4101, Cyprus.