Bactoclav

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BACTOCLAV (BACTOCLAV)

Composition:

Active substances: amoxicillin; clavulanic acid;

One tablet contains amoxicillin trihydrate equivalent to amoxicillin 500 mg, potassium clavulanate equivalent to clavulanic acid 125 mg;

Excipients: microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), talc, propylene glycol, dimethicone, Tabcoat TC-1709 MB white (hydroxypropylmethylcellulose, propylene glycol, ethylcellulose, talc, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, oval-shaped, film-coated tablets with a score line on one side.

Pharmacotherapeutic group. Antibacterial agents for systemic use.

ATC code J01CR02.

Pharmacological properties.

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

Thus, Augmentin exhibits properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor, exerting a bactericidal effect against a wide range of the following microorganisms:

Gram-positive aerobes: Bacillus anthracis*, Corynebacterium species, Enterococcus faecalis*, Enterococcus faecium*, Listeria monocytogenes, Nocardia asteroides, Staphylococcus aureus*, coagulase-negative staphylococci (including Staphylococcus epidermidis), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans.

Gram-positive anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus species.

Gram-negative aerobes: Bordetella pertussis, Brucella species, Escherichia coli*, Gardnerella vaginalis, Haemophilus influenzae*, Helicobacter pylori, Klebsiella species*, Legionella species, Moraxella catarrhalis* (Branhamella catarrhalis), Neisseria gonorrhoeae*, Neisseria meningitidis*, Pasteurella multocida, Proteus mirabilis*, Proteus vulgaris*, Salmonella species*, Shigella species**, Vibrio cholerae, Yersinia enterocolitica*.

Gram-negative anaerobes: Bacteroides species (including Bacteroides fragilis), Fusobacterium species.

Other microorganisms: Borrelia burgdorferi, Chlamydia species, Leptospira icterohaemorrhagiae, Treponema pallidum.

*Some representatives of these bacterial species produce beta-lactamase, rendering them insensitive to amoxicillin monotherapy.

Pharmacokinetics. Both components of Augmentin are well absorbed after oral administration. Food does not affect the extent of absorption. Amoxicillin is characterized by a high volume of distribution into body fluids and tissues, except for the brain and cerebrospinal fluid. Clavulanic acid, similar to amoxicillin, is well distributed into body tissues.

Approximately 60–70% of amoxicillin and approximately 40–65% of clavulanic acid are excreted unchanged in urine within the first 6 hours after oral administration. Concurrent administration with probenecid delays renal excretion of amoxicillin but does not interfere with the excretion of clavulanic acid.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with reduced renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosage adjustment should 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, along with regular monitoring of liver function.

Clinical characteristics.

Indications. For the treatment of bacterial infections caused by microorganisms sensitive to Augmentin, such as:

• acute bacterial sinusitis (confirmed);
• acute otitis media;
• confirmed acute 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 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 cholestatic jaundice or hepatic dysfunction related to the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class 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 administration 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 decreases renal tubular secretion of amoxicillin. Concurrent administration with Augmentin may lead to prolonged elevated blood levels of amoxicillin, but does not affect clavulanic acid levels.

Azathioprine

In patients receiving azathioprine, co-administration of amoxicillin/clavulanic acid may lead to increased risk of myelosuppression, as both drugs may be metabolized by xanthine oxidase. Therefore, concomitant use should be approached with caution and patients should be monitored closely for signs of bone marrow suppression.

Mycophenolate mofetil

In patients treated with mycophenolate mofetil, initiation of oral amoxicillin/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 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.

Concomitant use of allopurinol during amoxicillin therapy increases the likelihood of allergic skin reactions. There are no data on concomitant use of Augmentin and allopurinol.

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

During clinical trials in patients with hematologic malignancies receiving idelalisib, and in the post-marketing period, rare cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported when idelalisib was administered concomitantly with other medicinal products associated with these events (bendamustine, rituximab, allopurinol, amoxicillin, and sulfamethoxazole/trimethoprim). Stevens-Johnson syndrome or toxic epidermal necrolysis occurred within one month of concomitant administration of the above-mentioned medicinal products and resulted in fatal outcomes.

Special precautions for use.

Before initiating therapy with Bactoclav, it is necessary to carefully assess the patient's history for hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections "Contraindications" and "Adverse reactions").

Severe, and in some cases even fatal, hypersensitivity reactions (anaphylactoid reactions and severe cutaneous adverse reactions) have been reported in patients receiving penicillin therapy. Such reactions occur more frequently in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanate therapy should be discontinued and appropriate treatment initiated. Hypersensitivity reactions may also progress to Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions").

If infection is confirmed to be caused by microorganisms susceptible to amoxicillin, consideration should be given to switching from the combination of amoxicillin/clavulanic acid to amoxicillin alone, in accordance with accepted guidelines.

The Bactoclav dosage form is not suitable for use when there is a high risk that the likely causative pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases sensitive to inhibition by clavulanic acid. This dosage form should not be used for the treatment of penicillin-resistant S. pneumoniae.

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

Bactoclav should not be prescribed if infectious mononucleosis is suspected, as administration of amoxicillin in this condition has been associated with the occurrence of maculopapular rash.

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

Prolonged use of Bactoclav may occasionally lead to overgrowth of non-susceptible microorganisms.

The onset of fever-associated generalized erythema with pustule formation at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Adverse reactions"). This reaction requires discontinuation of Bactoclav 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 "Dosage and administration", "Contraindications", and "Adverse reactions"). Changes in liver function tests have been reported in some patients treated with Bactoclav, although the clinical significance of these changes is not fully established. Isolated reports of cholestatic jaundice, which may be severe but is usually reversible, have been documented. Symptoms may not appear until up to 6 weeks after completion of therapy. Hepatic complications have been reported primarily in men and elderly patients, often associated with prolonged treatment. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, but in some cases may only emerge several weeks after therapy has ended. These effects are usually reversible. However, hepatic complications may be severe and, in extremely rare cases, fatal. Such events have almost exclusively occurred in patients with severe underlying diseases or those receiving concomitant medications that may cause hepatic complications (see section "Adverse reactions").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with the use of nearly all antibacterial agents, including amoxicillin (see section "Adverse reactions"). Therefore, it is important to consider this diagnosis in patients presenting with diarrhea during or after antibiotic therapy. If antibiotic-associated colitis is suspected, Bactoclav should be discontinued immediately, 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 hematopoietic function, is recommended.

Occasionally, patients receiving Bactoclav and oral anticoagulants may exhibit an abnormally prolonged prothrombin time. Appropriate monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

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

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

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

Positive results in the enzyme immunoassay using Platelia Aspergillus (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have also been reported when using the Platelia Aspergillus immunoassay (Bio-Rad Laboratories).

Therefore, positive test results in patients receiving amoxicillin/clavulanic acid therapy should be interpreted with caution and confirmed by other diagnostic methods.

Cases of drug-induced enterocolitis syndrome have been reported, primarily in children receiving amoxicillin/clavulanic acid (see section "Adverse reactions"). 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, including progression to shock, have been documented.

This medicinal product contains propylene glycol, which may cause symptoms similar to those associated with alcohol consumption.

Use during pregnancy or breastfeeding.

The use of this medicinal product during pregnancy, especially during the first trimester, should be avoided unless the potential benefit outweighs the potential risk.

Both active components of the medicinal product 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.

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

Ability to affect reaction speed when driving or operating machinery.

No negative effects on the ability to drive or operate machinery have been observed. However, the potential for adverse effects such as dizziness, allergic reactions, and seizures, which may impair such abilities, should be considered (see section "Adverse reactions").

Method of Administration and Dosage

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

The recommended dosage range depends on the suspected pathogens, their susceptibility to antibacterial agents, severity of the disease, site of infection, age, body weight, and renal function of the patient.

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

If higher doses of amoxicillin are required for treatment, other amoxicillin/clavulanic acid combinations available on the market should be used to avoid administering 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.

Adults and children with body weight > 40 kg:

1 tablet of Bactoclav 500 mg / 125 mg three times daily.

Since the tablet cannot be divided, children with body weight < 40 kg should be administered amoxicillin/clavulanic acid in another pharmaceutical form and appropriate dosage.

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

Dosing in Renal Impairment

Dosing is based on the maximum amoxicillin concentration. There is no need to adjust the dose in patients with creatinine clearance > 30 mL/min.

Adults and children with body weight > 40 kg

Dosage in hepatic impairment.

Use with caution; regular monitoring of liver function is required.

The tablet should be swallowed whole, without chewing.

For optimal absorption and to reduce the potential gastrointestinal side effects, the medicinal product should be taken at the beginning of a meal.

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

Treatment with the combination amoxicillin/clavulanic acid may be initiated parenterally and then continued orally.

Children. Bactoclav can be administered to children aged 12 years and older with body weight of at least 40 kg.

Overdose.

Symptoms

Gastrointestinal disturbances and disturbances of fluid and electrolyte balance may occur. 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 and in patients receiving high doses of the medicinal product.

Precipitation of amoxicillin in urinary catheters has been reported, primarily after high-dose intravenous administration. The patency of catheters should be checked regularly.

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid and electrolyte balance.

Bactoclav 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.

Listed below are the adverse reactions known from clinical trials and post-marketing surveillance of Augmentin (Amoxicillin/Clavulanate), classified by organ systems according to MedDRA.

The following frequency classification of adverse effects 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 available data).

Infections and infestations

Common: Candidiasis of skin and mucous membranes.
Not known: Overgrowth of microorganisms not sensitive to the drug.

Blood and lymphatic system disorders

Rare: Reversible leukopenia (including neutropenia) and thrombocytopenia.
Not known: Reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin time.

Immune system disorders

Not known: Angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis, Coombs-positive hemolytic anemia (see section "Special precautions for use").

Nervous system disorders

Uncommon: Dizziness, headache.
Not known: Reversible hyperactivity and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses of the drug.
Not known: Aseptic meningitis.

Gastrointestinal disorders

Common: Diarrhea, nausea¹, vomiting.
Uncommon: Dyspepsia.
Not known: Antibiotic-associated colitis², "black hairy tongue", discoloration of tooth enamel⁵, drug-induced enterocolitis syndrome, acute pancreatitis.

Hepatobiliary disorders

Uncommon: Mild elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels.

Not known: Hepatitis³ and cholestatic jaundice³.

Mild elevations in AST and/or ALT levels have been observed in patients treated with beta-lactam antibiotics, although the clinical significance of this is not established.

Hepatitis has been reported primarily in men and elderly patients, and its occurrence may be associated with prolonged treatment. Such events are very rare in children. Symptoms usually appear during or immediately after treatment, but in some cases may occur several weeks after treatment has ended. These effects are usually reversible. Fatal outcomes have been reported extremely rarely, and only in patients with severe underlying diseases or in those receiving concomitant medications with hepatotoxic potential.

Skin and subcutaneous tissue disorders⁴

Uncommon: Skin rashes, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA bullous dermatosis.

Renal and urinary disorders

Very rare: Interstitial nephritis, crystalluria.
Not known: Crystalluria (including acute kidney injury).

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¹ Nausea is more frequently associated with higher oral doses of the medicinal product. The severity of gastrointestinal reactions may be reduced by taking Augmentin with food.

² Including pseudomembranous colitis and hemorrhagic colitis.

³ These events have been observed with other penicillin and cephalosporin antibiotics.

⁴ If hypersensitivity reactions (dermatitis) occur, the drug should be discontinued.

⁵ Tooth enamel discoloration has been very rarely observed in children. Careful oral hygiene may prevent this discoloration, as the effect can be removed by tooth brushing.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister strip; 1 strip per cardboard box.

Prescription category. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and site of operations.
Plot Nos. 16 & 24, Virasandra Industrial Area, Anekal Taluk, Bangalore (Bengaluru), Karnataka 560100, India