Medoclav®

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

Composition:

Active substances: 1 film-coated tablet contains amoxicillin trihydrate 574 mg, equivalent to 500 mg of amoxicillin; potassium clavulanate 148.9 mg, equivalent to 125 mg of clavulanic acid.

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate; the film coating contains: hydroxypropylmethylcellulose, propylene glycol, polyethylene glycol 6000, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, biconvex capsule-shaped tablets, film-coated, with core dimensions of 19 mm × 10 mm.

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 (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 spectrum of activity of amoxicillin as monotherapy does not include microorganisms that produce 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.

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 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.

Critical breakpoints.

The 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 required if local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is 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.

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

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

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

² Strains with reduced susceptibility have been reported in some 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. 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 amoxicillin/clavulanic acid combination 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.

After 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 adequately distribute 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 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”).

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 renally 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 should be selected with caution; monitoring of renal function is also 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, dosing should be adjusted to prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section “Dosage and 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 of bacterial infections caused by microorganisms sensitive to Medoclav®, such as: acute bacterial sinusitis (confirmed); acute otitis media; confirmed exacerbation of chronic bronchitis; community-acquired pneumonia; cystitis; pyelonephritis; skin and soft tissue infections, including cellulitis, animal bites, severe dental alveolar abscesses with spreading cellulitis; bone and joint infections, including osteomyelitis.

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

Contraindications.

Hypersensitivity to any component of the medicinal product or 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 hepatic dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other types of interactions.

Oral anticoagulants. Oral anticoagulants and penicillin-type 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 closely monitored when initiating or discontinuing amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions" and "Adverse reactions").

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

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

Mycophenolate 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 levels may not correlate with 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.

Before 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 "Adverse reactions").

Severe 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 "Adverse reactions"). These reactions are more likely to occur in patients with a history of penicillin hypersensitivity or those 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 a microorganism(s) susceptible to amoxicillin alone, consideration should be given to switching from the combination of amoxicillin/clavulanic acid to amoxicillin monotherapy in accordance with established guidelines.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin (see section "Adverse reactions"). Drug-induced enterocolitis syndrome is an allergic reaction characterized mainly 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 formulation 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 "Adverse reactions").

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

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

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms not susceptible to Medoclav®.

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

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

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

Antibiotic-associated colitis, ranging from mild to life-threatening, has been reported with nearly all antibacterial agents (see section "Adverse reactions"). 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, medical advice sought, and appropriate treatment initiated. The use of antiperistaltic agents is contraindicated in such cases.

With prolonged therapy, periodic monitoring 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 coagulation (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 very rarely been observed in patients with reduced urine output, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained during administration of high doses of amoxicillin 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 treatment with amoxicillin, 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 Medoclav® may lead to non-specific binding of IgG and albumin to red blood cell membranes, potentially resulting in false-positive direct 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 to be free of Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have also been reported with the Platelia Aspergillus assay. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Medoclav® contains propylene glycol, which may cause symptoms similar to those of alcohol consumption.

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 preterm rupture of membranes, prophylactic use of amoxicillin/clavulanic acid was reported to increase the risk of necrotizing enterocolitis in neonates. The drug should be avoided during pregnancy unless considered necessary by the physician.

Breastfeeding. 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 therefore occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered. Medoclav® may be used during breastfeeding only if, in the physician’s opinion, the benefits outweigh the risks.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

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 regimen 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 1500 mg amoxicillin/375 mg clavulanic acid, as specified below.

For children aged 6 years and older with body weight between 25 and 40 kg, the maximum daily dose is 2400 mg amoxicillin/600 mg clavulanic acid, as specified below.

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

The duration of treatment should be determined based on the clinical response. Some infections (e.g., osteomyelitis) may require prolonged treatment. Treatment should not exceed 14 days without review (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg: 1 tablet of Medoclav® 500 mg/125 mg three times daily.

Children aged 6 years and older with body weight from 25 to 40 kg: Dose 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 dosage form is not recommended for children weighing less than 25 kg.

Elderly patients. Dose adjustment is not required for elderly patients. If necessary, dosage should be adjusted according to renal function.

Dosage in renal impairment. Dosage is based on the maximum amoxicillin level. 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 from 25 to 40 kg. Since the tablet cannot be divided, this medicinal product is not recommended for children with body weight from 25 to 40 kg, with creatinine clearance less than 30 mL/min, or for children undergoing hemodialysis.

Dosage in hepatic impairment. Use with caution; liver function should be monitored regularly.

Method of administration. 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 medicinal product should be taken with food to minimize potential gastrointestinal intolerance. The duration of treatment should be 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.

This formulation of Medoclav® can be used in children aged 6 years and older with body weight of at least 25 kg.

Overdose.

Symptoms. Symptoms may include gastrointestinal disturbances and disturbances in fluid and electrolyte balance. Crystalluria associated with amoxicillin intake has been observed, which in some cases led to renal failure (see section "Special precautions for use").

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. The patency of catheters should be checked regularly (see section "Special precautions for use").

Treatment. Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Side effects

The most commonly reported side effects were diarrhea, nausea and vomiting.

The adverse reactions to the medicinal product observed during clinical trials of amoxicillin/clavulanic acid and in post-marketing surveillance are listed below, classified by organ systems according to MedDRA. The following frequency classification of adverse reactions is applied: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000; very rare < 1/10,000; not known (frequency cannot be estimated from the available data).

Infections and infestations: common – candidiasis of 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 time1.

Immune system disorders8: not known – angioneurotic edema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders: uncommon – dizziness, headache; not known – reversible hyperactivity and convulsions1, aseptic meningitis.

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

Gastrointestinal disorders: common – diarrhea, nausea2, vomiting; uncommon – gastrointestinal discomfort; not known – antibiotic-associated colitis3, "black hairy tongue", discoloration of tooth enamel9, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders: uncommon – increased levels of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)4; not known – hepatitis5 and cholestatic jaundice5.

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 pustulosis1, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders: very rare – interstitial nephritis, crystalluria7 (including acute kidney injury).

1See section "Special precautions for use".

2Nausea is more frequently associated with higher oral doses of the drug. Gastrointestinal reactions may be minimized by taking Medoclav® with food.

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

4Mild 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.

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

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

7See section "Overdose".

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

9Discoloration of tooth enamel has been very rarely observed in children. Careful oral hygiene may prevent this discoloration, as this effect is reversible with tooth brushing.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical 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. 8 tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited.

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