Clavam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAVLAM (CLAVAM)

Composition:

Active substances: amoxicillin, clavulanic acid;

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

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.
Antibacterial agents for systemic use. Amoxicillin and enzyme inhibitor. 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 producing 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. The presence of clavulanic acid in the composition of Clavam protects amoxicillin from degradation by beta-lactamase enzymes and extends the antibacterial spectrum of amoxicillin to include many microorganisms generally resistant to amoxicillin, as well as to other penicillins and cephalosporins.

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

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

Sensitive 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-sensitive strains), Staphylococcus saprophyticus (methicillin-sensitive strains), coagulase-negative staphylococci (methicillin-sensitive 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.

Insensitive 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 main pharmacokinetic properties of amoxicillin and clavulanic acid are similar. Amoxicillin and clavulanic acid in combination do not affect each other's pharmacokinetics. Peak serum concentrations after a bolus injection of 1.2 g of the drug are 105.4 mg/L for amoxicillin and 28.5 mg/L for clavulanic acid. Both components are characterized by good distribution volume into body fluids and tissues (lungs, middle ear secretions, maxillary sinus secretions, nasal sinus secretions, pleural and peritoneal fluids, prostate gland, tonsils, sputum, bronchial secretions, liver, gallbladder, uterus, ovaries, synovial fluid, etc.). They cross the blood-brain barrier. Peak concentrations in tissues and body fluids are observed one hour after reaching peak serum concentrations.

Amoxicillin and clavulanic acid cross the placental barrier and are excreted in low concentrations into breast milk. Amoxicillin and clavulanic acid are protein-bound in plasma at 17–20% and 22–30%, respectively.

Amoxicillin is excreted in urine mainly in unchanged form, while clavulanic acid undergoes active hepatic metabolism and is primarily excreted via the kidneys into urine, and partially through the intestine in feces and via the lungs in exhaled air.

In patients with impaired renal function, drug elimination is slowed, requiring dosage adjustment—either dose reduction or increased dosing interval—according to the degree of impairment.

Clinical characteristics.

Indications.

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

• severe infections of the throat, nose, and ears (e.g., mastoiditis, peritonsillar infections, epiglottitis, and sinusitis with associated severe systemic 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 extensive 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.

Severe immediate-type allergic reaction (e.g., anaphylaxis) to another beta-lactam antibiotic (e.g., cephalosporin, carbapenem, or monobactam) in medical history.

History of jaundice or liver function disorders caused by amoxicillin/clavulanic acid (see section "Adverse reactions").

Interaction with other medicinal products and other types of interactions.

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent use of Clavam may lead to prolonged elevated blood levels of amoxicillin, but not clavulanic acid.

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

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

There are isolated reports of increased international normalized ratio (INR) in patients receiving acenocoumarol or warfarin and taking amoxicillin. If such concomitant use is necessary, prothrombin time or INR should be closely monitored, and treatment with the drug may need to be discontinued if necessary. Additionally, dose adjustment of oral anticoagulants may be required (see sections "Special precautions for use" and "Adverse reactions").

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

In patients receiving mycophenolate mofetil, initiation of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite, mycophenolic acid, by approximately 50%. This change in pre-dose levels may not reflect changes in total exposure to mycophenolic acid. Therefore, dose adjustment of mycophenolate mofetil is usually not required in the absence of clinical signs of transplant dysfunction. However, clinical monitoring should be performed during and immediately after antibiotic treatment.

Special precautions for use.

Before initiating therapy with Clavam, it is necessary to determine whether there is a history of hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents (see sections "Contraindications" and "Adverse reactions").

Severe, and sometimes even fatal, cases of hypersensitivity (anaphylactic reactions) have been observed in patients receiving penicillin therapy. These reactions are most likely to occur in individuals with a history of hypersensitivity to penicillins. If allergic reactions occur, therapy with the drug should be discontinued and appropriate alternative treatment initiated.

If the 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.

The drug should be discontinued if infectious mononucleosis is suspected, as the development of a measles-like rash associated with this disease may be related to amoxicillin administration.

Concomitant use of allopurinol during amoxicillin treatment may increase the incidence of skin-related 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 "Adverse reactions"). In such cases, treatment must be discontinued, and subsequent administration of amoxicillin is contraindicated.

The drug 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. Symptoms of the disease may appear during or immediately after treatment, but in some cases may develop several weeks after completion of therapy. These events are usually reversible. Fatal cases have been reported extremely rarely and always occurred in patients with severe underlying diseases or in those receiving concomitant medications with hepatotoxic potential (see section "Adverse reactions").

Antibiotic-associated colitis has been reported with the use of nearly all antibacterial agents, with severity ranging from mild to life-threatening (see section "Adverse reactions"). Therefore, it is important to consider this possibility if patients develop diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Clavam therapy should be immediately discontinued, medical advice should be sought, and appropriate treatment initiated. In cases of antibiotic-associated colitis, drugs that inhibit intestinal motility are contraindicated.

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

Occasionally, patients receiving Clavam 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 "Adverse reactions" 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, mainly after parenteral administration, may very rarely occur in patients with reduced urine output. Therefore, when high doses of amoxicillin are used, adequate fluid intake and monitoring of urine output are recommended to reduce the possibility of amoxicillin crystalluria (see section "Overdose").

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

There have been reports of false-positive Aspergillus antigen test results in patients receiving amoxicillin/clavulanic acid (using the Bio-Rad Laboratories Platelia 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 Clavam may cause non-specific binding of IgG and albumin to erythrocyte membranes, which may result in 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 of the solutions.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies do not provide sufficient evidence to conclude on any direct or indirect adverse effects on pregnancy, embryonal/fetal development, delivery, or postnatal development. Limited data on the use of amoxicillin/clavulanic acid in pregnant women do not indicate an increased risk of congenital malformations. However, in pregnant women with premature rupture of membranes, prophylactic use of amoxicillin/clavulanic acid has been associated with an increased risk of neonatal necrotizing enterocolitis. The 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 are available on the effects of clavulanic acid on infants). Diarrhea and fungal mucosal infections in the infant may occur during breastfeeding, which may necessitate discontinuation of breastfeeding. Amoxicillin/clavulanic acid should be prescribed during breastfeeding only after the physician has evaluated the benefit-risk ratio.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted to assess the ability to influence reaction speed when driving or operating machinery. However, adverse reactions such as allergic reactions, dizziness, and seizures may affect the ability to drive or operate machinery.

Dosage and Administration

The doses are expressed as amoxicillin/clavulanic acid content, unless otherwise specified for individual components.

When selecting the dose of Clavam for treating a specific infection, the following factors should be considered: the likely pathogens and their expected susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use"); severity and site of infection; age, body weight, and renal function of the patient, as described below.

Alternative dosage forms of the drug may be used if necessary (e.g., those with higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid).

These dosage forms may be administered at a maximum daily dose of 3000 mg of amoxicillin and 600 mg of clavulanic acid. If a higher dose of amoxicillin is required, another dosage form of the drug should be prescribed to avoid excessively high daily doses of clavulanic acid.

The duration of treatment is determined individually by the physician. Some infections (e.g., osteomyelitis) require prolonged treatment. The duration of treatment should not exceed 14 days unless the response to therapy and clinical condition have been re-evaluated (see section "Special Warnings and Precautions for Use").

Dosage for adults and children with body weight ≥ 40 kg

Standard dose: 1000/200 mg every 8 hours.

Prophylaxis of postoperative 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 formulation of Clavam).

For surgical procedures lasting more than 1 hour, the recommended dose is 1000/200 mg to 2000/200 mg administered at induction of anesthesia, followed by 1000/200 mg every 8 hours, up to three doses 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.

Dosage for children with body weight < 40 kg

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

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

Elderly 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

Hepatic impairment

Caution is required in dosing, with continuous monitoring of liver function.

The drug should be administered by intravenous injection (bolus) or by intermittent infusion (drip). Clavam must not be administered intramuscularly.

For children under 3 months of age, Clavam should be administered only as intravenous infusion.

Treatment may be initiated with 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).

A transient pink discoloration may appear during dissolution, which disappears.

The solution should be administered within 20 minutes after reconstitution.

Preparation of solution for intravenous infusion

The solution prepared as described above, 500/100 mg, should be immediately added to 50 ml of infusion fluid, and 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 preparation, the solution 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.

The drug can be diluted with 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.

If a more concentrated solution is prepared, the stability period increases proportionally.

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

Unused solution should be disposed of according to current regulations.

Children.

Can be administered to children from the first days of life.

Overdose.

Overdose may be accompanied by gastrointestinal symptoms and disturbances of water and electrolyte balance. These disorders are treated symptomatically, with special attention to correction of water and electrolyte balance. Seizures may occur in patients with renal impairment and in those receiving high doses of the drug.

Amoxicillin crystalluria may occur, which sometimes may lead to renal failure (see section "Special Instructions"). There have been reports of amoxicillin precipitation in the urinary catheter when high-dose intravenous administration of the drug was used. The patency of the catheter should be checked regularly (see section "Special Instructions").

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: Eosinophilia, thrombocytosis, reversible leukopenia (including neutropenia) and thrombocytopenia, bone marrow hypoplasia, reversible agranulocytosis, hemolytic anemia, prolonged bleeding time and prothrombin index.

Immune system disorders: Angioedema; anaphylaxis/shock; serum sickness-like syndrome (urticaria or skin rashes accompanied by arthritis, arthralgia, myalgia, fever, and bronchospasm), allergic vasculitis.

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

Vascular disorders: Thrombophlebitis at the injection site.

Gastrointestinal disorders: Diarrhea, nausea, vomiting, dyspepsia, abdominal pain, stomatitis, black hairy tongue, candidiasis, antibiotic-associated colitis (including pseudomembranous colitis and hemorrhagic colitis). The likelihood of occurrence is significantly lower with parenteral administration of the drug.

Hepatobiliary disorders: Transient elevations in serum transaminases, lactate dehydrogenase, and alkaline phosphatase; hepatic dysfunction, cholestatic jaundice, cholestatic hepatitis, hepatitis. These reactions have been reported with other penicillins and cephalosporins.

Hepatitis occurs predominantly in males and elderly patients, and its occurrence may be associated with prolonged treatment. Symptoms may appear during or immediately after therapy, but in some cases may occur several weeks after completion of treatment. These reactions are usually reversible. Fatal cases are extremely rare 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.

If any allergic dermatitis occurs, treatment should be discontinued.

Renal and urinary disorders: Interstitial nephritis, hematuria, crystalluria (see section "Overdose").

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Incompatibilities.

The drug should not be mixed with blood products, other protein-containing solutions, including protein hydrolysates, or with fat emulsions for intravenous use.

If Clavam is administered simultaneously with an aminoglycoside, the antibiotics should not be mixed in the same syringe, intravenous solution container, or other vessels, as the activity of the aminoglycoside may be lost.

Packaging. Powder 500 mg/100 mg or 1000 mg/200 mg in a vial. One vial per cardboard pack.

Prescription category. Prescription only.

Manufacturer. Alkem Laboratories Ltd.

Manufacturer's address and place of business.

167 Mahatma Gandhi, Udio Nagar, Dabhel, Daman, 396210, India.