Medoclav®

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

Composition:

Active ingredients: amoxicillin, clavulanic acid;

5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 400 mg and clavulanic acid (as potassium clavulanate) 57 mg;

Excipients: xanthan gum (E 415), hypromellose 2910 (E 5), sodium saccharin (E 954), colloidal anhydrous silicon dioxide, silicon dioxide (E 551), strawberry flavor, peach flavor, lemon flavor, succinic acid (E 363).

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or almost white free-flowing powder.

Pharmacotherapeutic group. Antibacterials for systemic use.

Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (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 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 as monotherapy.

PK/PD relationship

The time above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining efficacy for amoxicillin.

Resistance mechanisms

There are two 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;
• Alteration of PBPs, reducing the affinity of the antibacterial agent for its target.

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

Breakpoints

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, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid 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 intake. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

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

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 approximately 0.2 L/kg for clavulanic acid.

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

Animal studies have not revealed any evidence of significant retention of substances derived from either component of the drug 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").

It has been demonstrated 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 humans and is excreted in urine and feces, as well as in the form of carbon dioxide in expired air.

Elimination. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both via the kidneys and through 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 approximately 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 identical 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 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 in adults and children 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 dent alveolar abscess 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 drug, 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 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-type antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant use of these drugs is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions 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 of probenecid may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil. In patients treated with 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 level may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of 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 amoxicillin/clavulanic acid, a thorough history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Adverse reactions").

Serious and, in rare cases, fatal hypersensitivity reactions (including anaphylactic reactions and severe skin 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"). 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 alone, switching from amoxicillin/clavulanic acid to amoxicillin should be considered 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 primarily by persistent vomiting (1–4 hours after drug intake) 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 when there is a high risk that the likely pathogens are resistant to beta-lactam agents via mechanisms not susceptible to inhibition by clavulanic acid. This formulation should not be used for the treatment of penicillin-resistant S. pneumoniae.

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

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

Concomitant use of allopurinol during treatment with amoxicillin increases the likelihood of developing skin allergic reactions.

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

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

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

Hepatic complications have been reported, predominantly in males and elderly patients, which may be associated with prolonged treatment. Reports in children are very rare. In all patient groups, symptoms usually occur during or shortly after treatment, but in some cases may only become apparent several weeks after treatment has ended. These effects are usually reversible. Hepatic complications may be severe and, in extremely rare cases, fatal. Such events have always been observed in patients with severe underlying disease or those concurrently receiving drugs with known potential hepatotoxic effects (see section "Adverse reactions").

Antibiotic-associated colitis, varying in severity from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Adverse reactions"). Therefore, this diagnosis should be considered in patients presenting with diarrhea during or following antibiotic therapy. If antibiotic-associated colitis develops, Medoclav® should be discontinued immediately, medical advice sought, and appropriate treatment initiated. The use of antiperistaltic agents is contraindicated in such cases.

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

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

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

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

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used for testing 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 erythrocyte membranes, resulting in false-positive Coombs test results.

Positive results in the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported with the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories). Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Pregnancy. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/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 of women with premature rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in neonates. The use of this medicinal product during pregnancy should be avoided unless considered necessary by the physician.

Breast-feeding. Both components are excreted in breast milk (there are no data on the effect of clavulanic acid on the breastfed infant). Therefore, diarrhea and fungal infections of mucous membranes 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.

Studies on the ability of the drug to affect reaction speed while driving or operating machinery have not been conducted. However, undesirable effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery (see section "Adverse reactions").

Dosage and Administration

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of individual components.

When selecting the dosage of Medoclav® for treatment of a specific infection, the following should be considered:

• the likely pathogens and their probable 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, as described below.

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

For children weighing <40 kg, this dosage form of Medoclav® provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when administered as recommended below. If a higher dose of amoxicillin is considered necessary, an alternative dosage form of Medoclav® is recommended to avoid excessive daily doses of clavulanic acid (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

The duration of treatment should be determined individually for each patient. For certain infections (e.g., osteomyelitis), prolonged treatment may be required. Treatment should not exceed 14 days without re-evaluation (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Children with body weight ≥ 40 kg: other formulations of the drug should be used.

Children with body weight <40 kg

Recommended doses:

• from 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day, divided into two doses;
• for treatment of certain infections (such as otitis media, sinusitis, and lower respiratory tract infections), children aged 2 years and older may receive up to 70 mg/10 mg/kg/day, divided into two doses.

There are no clinical data available for Medoclav® 7:1 formulations at doses exceeding 45 mg/6.4 mg/kg/day in patients under 2 years of age.

There are no clinical data available for Medoclav® 7:1 formulations in patients under 2 months of age. Therefore, dosage recommendations for this patient group are not available.

Elderly patients

Dose adjustment is not required.

Renal impairment

No dosage adjustment is required for patients with creatinine clearance (CrCl) greater than 30 mL/min.

Medoclav® formulations with an amoxicillin to clavulanic acid ratio of 7:1 are not recommended for patients with CrCl less than 30 mL/min, as no dosage adjustment recommendations are available.

Hepatic impairment

Caution is recommended, with regular monitoring of liver function (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Administration method

Medoclav® is intended for oral administration.

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

Treatment may be initiated parenterally according to the instructions for the injectable form of Medoclav®, and continued with the oral formulation.

Instructions for preparation of suspension.

Before use, check the integrity of the seal on the cap. Shake the vial to loosen the powder. Add the required amount of water (as indicated below), invert and shake vigorously. Alternative method: fill the vial with water to slightly below the mark on the label, invert and shake thoroughly, then fill the vial with water up to the mark, invert, and shake again thoroughly.

Before each use, the vial should be shaken thoroughly.

Children. The drug is administered to children aged 2 months and older. Children with body weight above 40 kg should be prescribed the drug in another pharmaceutical form.

Overdose.

Symptoms

Gastrointestinal disorders and disturbances in fluid and electrolyte balance may occur. Crystalluria associated with amoxicillin has been observed, which in individual 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 bladder catheters has been reported, primarily after intravenous administration of high doses. The patency of catheters should be checked regularly (see section "Special precautions").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electrolyte 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. The list of undesirable effects known from clinical trials of Medoclav® and post-marketing surveillance, classified by MedDRA System Organ Class, is provided below.

The following classification of adverse reaction frequencies is applied: 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); frequency not known (frequency cannot be estimated from available data).

Infections and infestations. Common: candidiasis of skin and mucous membranes. Frequency not known: overgrowth of microorganisms not sensitive to the medicinal product.

Blood and lymphatic system disorders. Rare: reversible leukopenia (including neutropenia) and thrombocytopenia. Frequency not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin time1.

Immune system disorders10. Frequency not known: angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders. Uncommon: dizziness, headache. Frequency not known: reversible hyperactivity and convulsions2; aseptic meningitis.

Cardiac disorders. Frequency not known: Quincke’s edema (angioedema).

Gastrointestinal disorders. Common: diarrhea, nausea3, vomiting. Uncommon: stomach disorders. Frequency not known: antibiotic-associated colitis4, "black hairy tongue", discoloration of tooth enamel11, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders. Uncommon: increased levels of AST and/or ALT5. Frequency not known: hepatitis6 and cholestatic jaundice6.

Skin and subcutaneous tissue disorders7. Frequency not known: 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), linear 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 Nausea is more frequently associated with higher oral doses of the medicinal product. If gastrointestinal reactions occur, their severity may be reduced by taking Medoclav® with food.

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

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 for use").

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

8 See section "Overdose".

9 See section "Special precautions for use".

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

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. In case of adverse reactions or questions regarding the safety of the medicinal product, please contact via the feedback form on the website: www.ukraine.medochemie.com

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light and moisture, and keep out of reach of children. Prepared suspension should be stored in the refrigerator at 2–8 °C for up to 7 days.

Packaging. 1 bottle with powder for oral suspension (70 ml) with dosing syringe in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited.

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