Clavucicin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLAUXICIN (KLAVUXICIN)

Composition:

Active substances: amoxicillin, clavulanic acid;

1 vial contains sodium amoxicillin equivalent to amoxicillin 500 mg or 1000 mg; potassium clavulanate equivalent to clavulanic acid 100 mg or 200 mg.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical characteristics: white to light yellowish-white powder.

Pharmacotherapeutic group. Antibacterial agents 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 beta-lactamase and undergoes degradation under its influence; therefore, the spectrum of activity of amoxicillin does not include microorganisms that produce this enzyme. Clavulanic acid has a beta-lactam structure similar to that of penicillins and is capable of inactivating beta-lactamase enzymes produced by microorganisms resistant to penicillins and cephalosporins. In particular, clavulanic acid is active against clinically important plasmid-mediated beta-lactamases, which are often responsible for the development of cross-resistance to antibiotics. In the composition of Clavuksicin, clavulanic acid protects amoxicillin from degradation by beta-lactamase enzymes and extends the antibacterial spectrum of amoxicillin to include many microorganisms generally resistant to amoxicillin and other penicillins and cephalosporins.

Thus, Clavuksicin possesses properties of both a broad-spectrum antibiotic and a beta-lactamase inhibitor.

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

Susceptible microorganisms

Gram-positive aerobes: Bacillus anthracis, Enterococcus faecalis, Gardnerella vaginalis, Listeria monocytogenes, Nocardia asteroides, 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, other 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, other Klebsiella species, Proteus mirabilis, Proteus vulgaris, other 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, other Chlamydia species, Coxiella burnetii, Mycoplasma species.

Pharmacokinetics.

Pharmacokinetic studies of intravenous Clavuksicin were conducted in a group of healthy volunteers who received doses of 500/100 (600) mg or 1000/200 mg (1.2 g). The obtained data are presented in the tables below.

Mean pharmacokinetic parameters for components of Clavuksicin - 600 mg and 1.2 g.

Table 1

Table 2

Distribution. After administration, therapeutic concentrations of amoxicillin and clavulanic acid are observed in tissues and interstitial fluid. Therapeutic concentrations of both substances have been detected in the gallbladder, abdominal tissues, skin, adipose and muscle tissues, as well as in synovial and peritoneal fluids, bile, and pus. Amoxicillin and clavulanic acid are weakly bound to plasma proteins; studies have shown that protein binding rates are 25% for clavulanic acid and 18% for amoxicillin of their total plasma concentrations. Animal studies have not demonstrated accumulation of either component in any organ.

Amoxicillin, like other penicillins, may be excreted in breast milk. Trace amounts of clavulanic acid may also be detected in breast milk. Reproductive function studies in animals have shown that both amoxicillin and clavulanic acid can cross the placental barrier. However, no data indicating adverse effects on fertility or harm to the fetus have been observed.

Excretion. As with other penicillins, the primary route of amoxicillin elimination is renal excretion, whereas clavulanate is eliminated both renally and via extrarenal mechanisms. Approximately 60–70% of amoxicillin and 40–65% of clavulanic acid are excreted unchanged in urine within the first 6 hours. Amoxic游戏副本

Clinical characteristics.

Indications.

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

• severe infections of the throat, nose, and ears (e.g., mastoiditis, peritonsillar infections, epiglottitis, and sinusitis with associated severe systemic signs and symptoms);
• exacerbations of chronic bronchitis (after diagnosis confirmation);
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including bacterial cellulitis, animal bites, severe dentoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis;
• intra-abdominal infections;
• genital infections in women.

Prophylaxis of bacterial infections during major surgical procedures in the following areas:

• gastrointestinal tract;
• pelvic organs;
• head and neck;
• biliary tract.

Contraindications.

Hypersensitivity to the active substances, penicillin, or to other components of the drug.

History of severe immediate-type allergic reaction (e.g., anaphylaxis) to another beta-lactam antibiotic (e.g., cephalosporin, carbapenem, or monobactam).

History of jaundice or hepatic dysfunction induced by amoxicillin/clavulanic acid (see section "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of allopurinol during amoxicillin treatment may increase the likelihood of allergic skin reactions. There are no data on the concomitant use of Clavuksicin and allopurinol.

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

There have been 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 carefully monitored when initiating or discontinuing Clavuksicin therapy. Dose adjustment of oral anticoagulants may also be required (see sections "Special precautions for use" and "Adverse reactions").

Metotrexate

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

Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concomitant administration may result in increased and prolonged blood levels of amoxicillin.

Mycofenolate 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 concentration may not accurately reflect changes in total exposure to mycophenolic acid.

Special precautions for use

Before initiating therapy with Clavuksitsin, 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 "Side effects").

Severe, and sometimes even fatal, cases of hypersensitivity (including anaphylactoid reactions and severe skin reactions) have been observed in patients during penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome – a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). Such reactions are most likely in individuals with a history of similar reactions to penicillins. If allergic reactions occur, Clavuksitsin therapy should be discontinued and appropriate alternative treatment initiated.

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

If infection is proven to be 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.

Seizures may occur in patients with impaired renal function or when high doses are administered.

Clavuksitsin should be discontinued if infectious mononucleosis is suspected, as the development of a measles-like rash associated with this condition may be linked to amoxicillin use.

Concomitant use of allopurinol during amoxicillin treatment may increase the risk of skin allergic reactions.

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

Development of pustular polymorphic erythema at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (see section "Side effects"). In such cases, treatment should be discontinued, and subsequent use of amoxicillin is contraindicated.

Clavuksitsin should be used with caution in patients with impaired liver function.

Hepatitis occurs predominantly in males and elderly patients, and its development may be associated with prolonged treatment. Very rarely, such adverse reactions may occur in children. Signs and symptoms appear during or immediately after treatment, but in some cases may develop several weeks after completion of therapy. These effects are usually reversible. Fatal outcomes have been reported extremely rarely, particularly in patients with severe underlying disease or those receiving concomitant medications with hepatotoxic potential (see section "Side effects").

Antibiotic-associated colitis, ranging from mild to life-threatening, has been reported with almost all antibacterial agents (see section "Side effects"). Therefore, it is important to consider this possibility if patients develop diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Clavuksitsin therapy should be immediately discontinued, medical advice sought, and appropriate treatment initiated.

During prolonged therapy, monitoring of organ and system functions, including kidneys, liver, and hematopoietic system, is recommended.

Occasionally, patients receiving Clavuksitsin and oral anticoagulants may experience excessive prolongation of prothrombin time (elevated international normalized ratio (INR)). Appropriate monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the required level of anticoagulation (see sections "Side effects" and "Interaction with other medicinal products and other forms of interaction").

Dosage should be adjusted according to the degree of renal impairment in patients with renal insufficiency.

Crystalluria (including acute kidney injury) may occur very rarely in patients with reduced urine output, primarily with parenteral administration of the drug. Therefore, adequate fluid intake and monitoring of urine output are recommended when high doses of amoxicillin are used, to reduce the possibility of amoxicillin crystalluria (see section "Overdose"). In patients with urinary catheters, catheter patency should be checked regularly (see section "Side effects" 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.

There have been reports of false-positive results in tests for Aspergillus in patients receiving amoxicillin/clavulanic acid (using the Bio-Rad Laboratories Platelis Aspergillus EIA test). Therefore, such positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

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

When high-dose parenteral administration is required in patients on a sodium-restricted diet, attention should be paid to the sodium content in the solutions.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies do not provide sufficient evidence of direct or indirect adverse effects on pregnancy, embryonal/fetal development, labor, or postnatal development. Limited data on the use of amoxicillin/clavulanic acid for treatment in pregnant women do not indicate an increased risk of congenital malformations. In one study involving pregnant women with premature rupture of membranes, prophylactic use of amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. Use of the drug during pregnancy should be avoided unless considered necessary by the physician.

Breastfeeding

Both components of the drug are excreted in breast milk (no data available on the effects of clavulanic acid on the infant). Diarrhea and fungal mucosal infections in the infant may occur during breastfeeding, necessitating discontinuation of breastfeeding. Amoxicillin/clavulanic acid should be prescribed during breastfeeding only after the physician has evaluated the benefit-risk ratio.

Ability to affect reaction speed when driving or operating machinery.

Studies on the ability to affect reaction speed when driving or operating machinery have not been conducted. However, adverse reactions such as allergic reactions, dizziness, and seizures may impair the ability to drive or operate machinery.

Dosage and Administration.

The doses are given as amoxicillin/clavulanic acid content, unless the dose of an individual component is specified.

When selecting the dose of Clavucicin for the treatment of a specific infection, the following should be considered:

• the likely pathogens and their expected susceptibility to antibacterial agents (see section "Special Instructions");
• the severity and site of infection;
• the patient's age, body weight, and renal function, as described below.

If necessary, alternative forms of Clavucicin (e.g., with higher doses of amoxicillin and/or different ratio of amoxicillin to clavulanic acid) may be used.

These Clavucicin dosage forms can be administered at a maximum daily dose of 3000 mg of amoxicillin and 600 mg of clavulanic acid. If higher doses of amoxicillin are required, another Clavucicin formulation should be prescribed to avoid excessively high daily doses of clavulanic acid.

The duration of treatment should be determined individually. Some infections (e.g., osteomyelitis) require prolonged treatment. The duration of treatment should not exceed 14 days without re-evaluation of treatment efficacy and clinical status (see section "Special Instructions").

Dosing for adults and children with body weight ≥ 40 kg.

Standard dose: 1000/200 mg every 8 hours.

Prophylaxis of complications during surgical procedures.

For surgical procedures lasting less than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at induction of anesthesia (the 2000/200 mg dose may be achieved by using another intravenous form of Clavucicin).

For surgical procedures lasting more than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at induction of anesthesia, and an additional dose of 1000/200 mg may be given 3 times within 24 hours.

If clear clinical signs of infection occur in the postoperative period, a full course of treatment with intravenous or oral administration of the drug should be initiated.

Dosing for children with body weight < 40 kg

Children aged 3 months and older: 25/5 mg/kg body weight every 8 hours.

Infants younger than 3 months or with body weight less than 4 kg: 25/5 mg/kg body weight every 12 hours.

Geriatric patients

Dose adjustment is not required.

Renal impairment

Dosage adjustment is based on the maximum recommended doses of amoxicillin.

Creatinine clearance > 30 mL/min – no dosage adjustment required.

Adults and children with body weight ≥ 40 kg

Adults and children with body weight < 40 kg

Impaired liver function

Exercise caution in dosing, with continuous monitoring of liver function at regular intervals.

Clavucicin must be administered by intravenous injection (bolus) or by intermittent infusion (intravenous drip). Clavucicin must not be administered intramuscularly.

In children under 3 months of age, Clavucicin should be administered only as an intravenous infusion.

Treatment with Clavucicin may be initiated by intravenous administration and continued with oral dosage forms.

Preparation of solution for intravenous injection

500/100 mg: dissolve the contents of the vial in 10 mL of water for injections (final volume 10.5 mL);

1000/200 mg: dissolve the contents of the vial in 20 mL of water for injections (final volume 20.9 mL).

During dissolution, a temporary pinkish discoloration may or may not appear, which disappears. Clavucicin solutions are usually colorless or have a yellow color.

Clavucicin should be administered within 20 minutes after reconstitution.

Preparation of solution for intravenous infusion

The reconstituted solution (as described above) of 500/100 mg should be further immediately added to 50 mL of infusion fluid, or 1000/200 mg solution to 100 mL of infusion fluid (it is preferable to use a mini-container or burette). The infusion should be administered over 30–40 minutes. After reconstitution, Clavucicin is chemically and physically stable for 2–3 hours at 25 °C or for 8 hours at 5 °C. From a microbiological standpoint, the prepared solution should be administered immediately.

Intravenous infusions of Clavucicin may be administered using various intravenous solutions. Adequate antibiotic concentration is maintained at 5 °C and at room temperature (25 °C) in the recommended volumes of the infusion solutions listed below. When the drug is reconstituted and stored at room temperature, infusions should be administered within the time specified below.

If stored at 5 °C, solutions of 1000/200 mg and 500/100 mg may be added to a previously cooled infusion solution (water for injections or 0.9 % sodium chloride solution); the resulting preparation may be stored at the specified temperature for up to 8 hours.

After the solution reaches room temperature, it should be used immediately.

The stability of Clavucicin solutions depends on concentration. If a solution of higher concentration is prepared, the stability period increases proportionally.

Clavucicin is less stable in glucose, dextran, and bicarbonate solutions; therefore, preparations based on these solutions must be used within 3-4 minutes after reconstitution.

Any unused solution should be disposed of according to current regulations.

Children.

Can be used in children from the first days of life.

Overdose.

Overdose may be accompanied by gastrointestinal symptoms and disturbances of water and electrolyte balance. These symptoms should be treated symptomatically, with special attention to correction of water and electrolyte balance.

Amoxicillin crystalluria may occur, which sometimes may lead to renal failure (see section «Special precautions»). There have been reports of amoxicillin precipitation in urinary catheters following high-dose intravenous administration of Clavucicin. The patency of the catheter should be monitored regularly (see section «Special precautions»).

Clavucicin can be removed from the bloodstream by hemodialysis.

Adverse Reactions

Adverse effects have been classified according to their frequency of occurrence, from very common to very rare. The frequency of other adverse effects (e.g., those occurring at a rate of <1 in 10,000) is primarily based on post-marketing data and reflects the frequency of reported adverse events rather than the actual incidence.

The following classification of adverse reaction frequency is used:

• 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;
• frequency not known – cannot be estimated from available data.

Infections and infestations

Common – cutaneous and mucocutaneous candidiasis.

Frequency not known – overgrowth of non-susceptible microorganisms.

Blood and lymphatic system disorders

Rare – reversible leukopenia (including neutropenia) and thrombocytopenia.

Frequency not known – reversible agranulocytosis and hemolytic anemia. Prolongation of bleeding time and prothrombin time (see section "Special precautions for use").

Immune system disorders

Frequency not known – angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders

Uncommon – dizziness, headache.

Frequency not known – seizures (see section "Special precautions for use"), aseptic meningitis.

Vascular disorders

Rare – thrombophlebitis at the injection site.

Cardiac disorders

Frequency not known – Kounis syndrome.

Gastrointestinal disorders

Common – diarrhea.

Uncommon – nausea, vomiting, dyspepsia.

Frequency not known – antibiotic-associated colitis, including pseudomembranous colitis and hemorrhagic colitis, acute pancreatitis, drug-induced enterocolitis syndrome (DIES) (see section "Special precautions for use").

Hepatobiliary disorders

Uncommon – mild elevations in AST and/or ALT levels have been observed in patients receiving beta-lactam antibiotics.

Frequency not known – hepatitis and cholestatic jaundice. These events have been reported with other penicillins and cephalosporins (see section "Special precautions for use").

Skin and subcutaneous tissue disorders

Uncommon – skin rash, pruritus, urticaria.

Rare – erythema multiforme.

Frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis (see section "Special precautions for use"), linear IgA dermatosis.

If any allergic dermatitis occurs, treatment should be discontinued (see section "Special precautions for use").

Renal and urinary system disorders

Frequency not known – interstitial nephritis, crystalluria (including acute renal impairment) (see section "Overdose").

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and 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 in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Incompatibilities.

Clavucicin should not be mixed with blood products, other protein-containing solutions (including protein hydrolysates), or fat emulsions intended for intravenous administration.

If Clavucicin is used concomitantly with an aminoglycoside, the antibiotics should not be mixed in the same syringe, intravenous container, or other container, as the aminoglycoside may lose its activity.

Packaging.

Powder in a glass vial stoppered with a rubber stopper and sealed with an aluminum crimp cap equipped with a flip-off cap providing tamper-evidence.

1 or 5 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

ASTRAL STERITECH PRIVATE LIMITED

Manufacturer's address.

911, G.I.D.C., Makarpura, Vadodara, Gujarat, 390 010, India
911, Gidc, Makarpura, Vadodara, Gujarat 390 010, India (IND)

Marketing Authorization Holder.

M.Biotech Ltd

Address of Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom