Abiklav®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABYCLAV®

Composition:

Active substances: One film-coated tablet contains amoxicillin trihydrate in an amount equivalent to 500 mg of amoxicillin and potassium clavulanate in an amount equivalent to 125 mg of clavulanic acid, or amoxicillin trihydrate in an amount equivalent to 875 mg of amoxicillin and potassium clavulanate in an amount equivalent to 125 mg of clavulanic acid;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, Opadry White (06B58855).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 500/125 mg: white, oval, film-coated tablets, embossed with "A" on one side and "64" on the other;

Tablets 875/125 mg: white, capsule-shaped, film-coated tablets, embossed with "A" on one side and "6" and "5" on the other, with a score line between them.

Pharmacotherapeutic group.

Antibacterials for systemic use. ATC code J01CR02.

Pharmacological properties.

Pharmacodynamics.

Amoxicillin is a semi-synthetic antibiotic with a broad spectrum of antibacterial activity against many Gram-positive and Gram-negative microorganisms. Amoxicillin is sensitive to β-lactamase and is degraded under its influence; therefore, the spectrum of activity of amoxicillin does not include microorganisms producing this enzyme. Clavulanic acid has a β-lactam structure similar to penicillins and inactivates β-lactamase enzymes produced by penicillin- and cephalosporin-resistant microorganisms. In particular, clavulanic acid exhibits pronounced activity against clinically important plasmid-mediated β-lactamases, which are often responsible for the development of cross-resistance to antibiotics. The presence of clavulanic acid in the formulation protects amoxicillin from degradation by β-lactamases and extends the antibacterial spectrum of amoxicillin to include many microorganisms resistant to amoxicillin, other penicillins, and cephalosporins.

The microorganisms listed below are classified according to their in vitro susceptibility to amoxicillin/clavulanate.

Susceptible microorganisms

Gram-positive aerobes: Bacillus anthracis, Enterococcus faecalis, Listeria monocytogenes, Nocardia asteroids, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, other β-hemolytic Streptococcus species, Staphylococcus aureus (methicillin-susceptible strains), Staphylococcus saprophyticus (methicillin-susceptible strains), coagulase-negative staphylococci (methicillin-susceptible strains).

Gram-negative aerobes: Bordetella pertussis, Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Moraxella catarrhalis, Neisseria gonorrhoeae, Pasteurella multocida, Vibrio cholerae.

Others: Borrelia burgdorferi, Leptospira icterohaemorrhagiae, Treponema pallidum.

Gram-positive anaerobes: Clostridium species, Peptococcus niger, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus species.

Gram-negative anaerobes: Bacteroides species (including Bacteroides fragilis), Capnocytophaga species, Eikenella corrodens, Fusobacterium species, Porphyromonas species, Prevotella species.

Strains with possible acquired resistance

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

Gram-positive aerobes: Corynebacterium species, Enterococcus faecium.

Resistant microorganisms

Gram-negative aerobes: Acinetobacter species, Citrobacter freundii, Enterobacter species, Hafnia alvei, Legionella pneumophila, Morganella morganii, Providencia species, Pseudomonas species, Serratia species, Stenotrophomonas maltophilia, Yersinia enterocolitica.

Others: Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia species, Coxiella burnetii, Mycoplasma species.

Pharmacokinetics.

The pharmacokinetic parameters of the two components of the drug are closely related. Peak serum concentrations of both components are reached approximately 1 hour after oral administration of the drug. Optimal absorption is achieved when the drug is taken at the beginning of a meal.

Doubling the dose of Augmentin approximately doubles the serum concentration of the drug.

Both components of the drug, clavulanate and amoxicillin, have low protein binding in serum, with approximately 70% remaining unbound in serum.

Clinical characteristics.

Indications.

Film-coated tablets 500 mg/125 mg

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

• acute bacterial sinusitis;
• acute otitis media;
• acute exacerbation of chronic bronchitis;
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including cellulitis, animal bites, severe dentatoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

Film-coated tablets 875 mg/125 mg

Treatment of bacterial infections in adults and children caused by microorganisms sensitive to the drug, such as:

• acute bacterial sinusitis;
• acute otitis media;
• acute exacerbation of chronic bronchitis;
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including cellulitis, animal bites, severe dentatoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

Contraindications.

• Hypersensitivity to the active substances, to any penicillin antibiotic, or to any excipient.
• Severe immediate-type hypersensitivity reaction (e.g., anaphylaxis) in medical history to another β-lactam agent (e.g., cephalosporin, carbapenem, or monobactam).
• Cholestatic jaundice or hepatic dysfunction associated with previous use of amoxicillin and clavulanic acid.

Interaction with other medicinal products and other forms of interaction.

Probenecid. Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent administration with Augmentin may result in prolonged elevated blood levels of amoxicillin, but does not affect clavulanic acid levels.

Allopurinol. Concurrent use of allopurinol during amoxicillin therapy may increase the likelihood of skin allergic reactions. There are no data on concomitant use of this medicinal product and allopurinol.

Like other antibiotics, this medicinal product may affect gut flora, leading to reduced reabsorption of estrogens and reduced efficacy of combined oral contraceptives.

MTX (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. Concomitant use may lead to increased and prolonged blood levels of amoxicillin.

There are isolated reports of increased international normalized ratio (INR) in patients receiving acenocoumarol or warfarin and taking amoxicillin. If concomitant use is necessary, prothrombin time or INR should be closely monitored when initiating or discontinuing Augmentin therapy.

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 accurately reflect changes in total exposure to mycophenolic acid.

Penicillins may reduce the elimination of methotrexate, potentially increasing its toxicity.

Special precautions for use

Before initiating treatment with the medicinal product, a careful assessment of the history of hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be performed.

Severe, and sometimes even fatal, cases of hypersensitivity (including anaphylactoid reactions and severe skin adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome – a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). Such reactions are more likely in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. In the event of allergic reactions, treatment with Augmentin should be discontinued and alternative therapy initiated.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin/clavulanic acid (see section "Adverse reactions"). Drug-induced enterocolitis syndrome is an allergic reaction characterized by persistent vomiting (1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhoea, hypotension, or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock.

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

The medicinal product should not be used when there is a high risk that pathogens are resistant to β-lactams and is not indicated for the treatment of pneumonia caused by penicillin-resistant S. pneumoniae strains.

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

Augmentin**®** should not be prescribed in suspected cases of infectious mononucleosis, as rash resembling measles has been observed when amoxicillin is administered in this condition.

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

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

The development of erythema multiforme with pustules at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis. In such cases, treatment must be discontinued and subsequent use of amoxicillin is contraindicated.

The medicinal product should be administered with caution in patients showing signs of impaired liver function. Hepatic adverse reactions have occurred mainly in males and elderly patients and have been associated with prolonged treatment. Such events have been very rarely reported in children. In all patient groups, symptoms and signs usually occurred during or immediately after treatment, although in some cases they appeared several months after discontinuation of therapy. Overall, these events were reversible. Hepatic adverse reactions may be severe and very rarely may be fatal. They have always occurred in patients with serious underlying diseases or when concomitant medications known to have potential hepatotoxic effects were administered.

Colitis associated with antibiotic use, ranging from mild to life-threatening, has been reported with nearly all antibacterial agents. Therefore, it is important to consider this possibility when patients develop diarrhoea during or after antibiotic use. If antibiotic-associated colitis occurs, Augmentin therapy should be immediately discontinued, medical advice should be sought, and appropriate treatment initiated. The use of antiperistaltic agents is contraindicated in such cases.

During prolonged therapy, periodic monitoring of organ system functions, including renal, hepatic, and haematopoietic functions, is recommended.

Rarely, patients receiving Augmentin**®** and oral anticoagulants may experience prolonged prothrombin time (increased INR). Appropriate laboratory monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of coagulation.

Dosage adjustment is required in patients with impaired renal function according to the degree of renal impairment.

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

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

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

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). Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported when using the Platelia Aspergillus immunoassay (Bio-Rad Laboratories). Therefore, positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by alternative diagnostic methods.

Use during pregnancy or breastfeeding

In one study involving women with preterm premature rupture of membranes, prophylactic use of amoxicillin combined with clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, use during pregnancy, especially in the first trimester, should be avoided unless, in the opinion of the physician, the benefits outweigh the potential risks.

Both active components of the medicinal product are excreted in breast milk (there is no information on the effect of clavulanic acid on breastfed infants). Therefore, diarrhoea and fungal mucosal infections may occur in breastfed infants, and breastfeeding should be discontinued.

The medicinal product may be used during breastfeeding only if, in the physician’s opinion, the benefit of treatment outweighs the potential risk.

Ability to influence the speed of reactions when driving or operating machinery

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

Dosage and Administration

The product should be used in accordance with official recommendations for antibiotic therapy and local antibiotic susceptibility data. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. Local susceptibility data should be consulted when available, and microbiological identification and susceptibility testing should be performed as necessary.

The recommended dosage range depends on the expected pathogens and their susceptibility to antibacterial agents, the severity and site of infection, as well as the patient's age, body weight, and renal function.

For adults and children with body weight ≥ 40 kg, the daily dose is 1750 mg of amoxicillin/250 mg of clavulanic acid, divided into 2 doses.

For children with body weight < 40 kg, the maximum daily dose is 1000–2800 mg of amoxicillin/143–400 mg of clavulanic acid, administered as specified below.

If higher doses of amoxicillin are required for treatment, alternative formulations of the product 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. Some infections (e.g., osteomyelitis) may require prolonged treatment.

For optimal absorption and to minimize gastrointestinal adverse effects, the product should be taken at the beginning of a meal.

The duration of treatment should be individualized. Treatment should not be continued for more than 14 days without reassessment of the patient's condition.

Treatment may be initiated with parenteral administration, followed by oral therapy.

The tablet should be swallowed whole, without chewing.

Tablets 500 mg/125 mg

For adults and children with body weight ≥ 40 kg, the daily dose is 1500 mg of amoxicillin/375 mg of clavulanic acid (3 tablets), administered 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 of amoxicillin/600 mg of clavulanic acid (4 tablets), administered as specified below.

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

Adults and children with body weight ≥ 40 kg: 1 tablet of Abiklav 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 3 doses.

Since the tablet cannot be divided, this formulation should not be prescribed to children with body weight less than 25 kg.

Elderly patients

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

Dosing in Renal Impairment

Dosing is based on the maximum level of amoxicillin. Dose adjustment is not necessary in patients with creatinine clearance > 30 mL/min.

Adults and children with body weight ≥ 40 kg

Children aged 6 years with body weight from 25 to 40 kg

Since the tablet cannot be divided, this formulation of Augmentin should not be prescribed to children aged 6 years with body weight from 25 to 40 kg, with creatinine clearance less than 30 mL/min, or to children undergoing hemodialysis.

Dosing in hepatic impairment

Use with caution; liver function should be monitored regularly.

875 mg/125 mg tablets

Children with body weight < 40 kg

Dosage from 25 mg/3.6 mg/kg body weight/day to 45 mg/6.4 mg/kg body weight/day, divided into two doses.

Elderly patients

Dosage adjustment in elderly patients is not required. If necessary, the dose should be adjusted according to renal function.

Dosing in hepatic impairment

Use with caution; liver function should be monitored at regular intervals. Insufficient data are available to make dosing recommendations.

Dosing in renal impairment

Augmentin**®** 875/125 mg should only be prescribed for treatment of patients with creatinine clearance greater than 30 mL/min. Augmentin**®** 875/125 mg should not be used in patients with renal impairment and creatinine clearance less than 30 mL/min.

Children

Augmentin**®** 500 mg/125 mg can be used in children aged 6 years and older with body weight of at least 25 kg.

Augmentin**®** 875/125 mg is not recommended for treatment of children under 12 years of age.

Overdose

Overdose may be associated with gastrointestinal symptoms and disturbances of fluid and electrolyte balance. These effects should be treated symptomatically, with attention to correction of fluid and electrolyte balance. Cases of crystalluria have been reported, which in some instances may lead to renal failure. The drug can be removed from the bloodstream by hemodialysis.

Adverse Reactions.

Infections and infestations: Candidiasis of the skin and mucous membranes, overgrowth of non-susceptible microorganisms.

Blood and lymphatic system disorders: Reversible leukopenia (including neutropenia) and thrombocytopenia, reversible agranulocytosis and hemolytic anemia, prolonged bleeding time and prothrombin time.

Cardiac disorders: Kounis syndrome.

Immune system disorders: Angioedema, anaphylaxis, serum sickness-like reactions, allergic vasculitis.

Nervous system disorders: Dizziness, headache, reversible hyperactivity, aseptic meningitis, and convulsions. Seizures may occur in patients with impaired renal function or in those receiving high doses of the drug.

Gastrointestinal disorders: Diarrhea, nausea, vomiting, dyspepsia, antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis), black "hairy" tongue, drug-induced enterocolitis syndrome (DIES), acute pancreatitis. Nausea is more commonly associated with higher doses of the drug. The above gastrointestinal symptoms may be reduced if the drug is taken at the beginning of a meal.

Hepatobiliary disorders: Mild elevations in AST and/or ALT levels have been observed in patients treated with β-lactam antibiotics; however, the clinical significance of this is not established. Hepatitis and cholestatic jaundice have been reported. These events have occurred with other penicillins and cephalosporins.

Hepatitis has occurred primarily in males and elderly patients, and its occurrence may be related to prolonged treatment with the drug.

Such events are very rare in children.

Signs and symptoms of liver disease may appear during or immediately after treatment, but in some cases may occur several weeks after completion of therapy. These events are usually reversible. Fatal cases are extremely rare (less than 1 report per approximately 4 million prescriptions) and always occur in patients with severe underlying diseases or in patients receiving concomitant medications with hepatotoxic potential.

Skin and subcutaneous tissue disorders: Skin rashes, pruritus, urticaria, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis, linear IgA disease.

If any allergic dermatitis occurs, treatment should be discontinued.

Renal and urinary disorders: Interstitial nephritis, crystalluria (including acute kidney injury).

Shelf life. 2 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

Tablets 500/125 mg: 5 tablets in a blister, 4 blisters in a cardboard pack.

Tablets 875/125 mg: 5 tablets in a blister, 2 blisters in a cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Aurobindo Pharma Limited.

Manufacturer's address and place of business.

Unit XII, Survey No. 314, Bachupally, Bachupally Mandal Medchal Malkajgiri District, Hyderabad, 500090, India.