Amoxicillin + Clavulanic acid - Vial (Powder) Instructions for Use

Marketing Authorization Holder

Vial, LLC (Russia)

Manufactured By

NORTH CHINA PHARMACEUTICAL CORPORATION, Ltd. (China)

Packaging and Quality Control Release

NORTH CHINA PHARMACEUTICAL CORPORATION, Ltd. (China)

Or

KIROV PHARMACEUTICAL FACTORY, JSC (Russia)

ATC Code

J01CR02 (Amoxicillin and beta-lactamase inhibitor)

Active Substances

Clavulanic acid (Rec.INN registered by WHO)

Amoxicillin (Rec.INN registered by WHO)

Dosage Forms

	Amoxicillin + Clavulanic acid – Vial	Powder for preparation of solution for intravenous administration 500 mg+100 mg: vial 1 pc.
		Powder for preparation of solution for intravenous administration 1000 mg+200 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Vials (1) – cardboard packs.
Vials (10) – cardboard packs (12) – cardboard boxes.
Vials (10) – cardboard packs (50) – cardboard boxes.
Vials (10) – cardboard packs (60) – cardboard boxes.

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic with a beta-lactamase inhibitor

Pharmacotherapeutic Group

Antibiotic, semi-synthetic penicillin + beta-lactamase inhibitor

Pharmacological Action

Amoxicillin is a semi-synthetic aminopenicillin belonging to the group of beta-lactam antibiotics, possessing a broad spectrum of antibacterial activity against many gram-positive and gram-negative microorganisms.

Amoxicillin is destroyed by microbial enzymes (β-lactamases) and does not act on microorganisms that produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins, which has the ability to inactivate β-lactamases.

The presence of clavulanic acid protects Amoxicillin from the destructive action of β-lactamases and effectively expands the spectrum of activity of amoxicillin, which includes many bacteria usually resistant to amoxicillin, as well as to other penicillins and cephalosporins.

Amoxicillin+Clavulanic acid has a bactericidal effect in vivo on the following microorganisms: gram-positive aerobes: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes; gram-negative aerobes: Enterobacter species, Escherichia coli, Haemophilus influenzae, Klebsiella species, Moraxella catarrhalis.

Amoxicillin+Clavulanic acid has a bactericidal effect in vitro on the following microorganisms: gram-positive aerobes: Bacillus anthracis, Corynebacterium species, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Nocardia asteroids, coagulase-negative staphylococci including Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus spp. of the viridans group; gram-positive anaerobes: Clostridium spp., Peptococcus spp., Peptostreptococcus spp.; gram-negative aerobes: Bordetella pertussis, Brucella spp., Gardnerella vaginalis, Helicobacter pylori, Legionella spp., Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Salmonella spp., Shigella spp., Vibrio cholerae, Yersinia enterocolitica; gram-negative anaerobes: Bacteroides spp. (including Bacteroides fragilis), Fusobacterium species; others: Borrelia burgdorferi, Chlamydiae spp., Leptospira icterohaemorrhagiae, Treponema pallidum.

Pharmacokinetics

Amoxicillin and Clavulanic acid in combination do not affect each other’s pharmacokinetics.

C_max in plasma after a bolus injection of amoxicillin+clavulanic acid (1000 mg+200 mg) is 105 mg/l for amoxicillin and 28 mg/l for clavulanic acid; when administering 500 mg of amoxicillin and 100 mg of clavulanic acid – 32 mg/l and 10 mg/l, respectively.

The half-life of amoxicillin 1000 mg is 0.9 h, of clavulanic acid 200 mg is 0.9 h; when administering 500 mg of amoxicillin and 100 mg of clavulanic acid – 1 h and 1 h, respectively.

After IV administration, therapeutic concentrations of amoxicillin and clavulanic acid are achieved in the abdominal cavity, adipose and muscle tissues and interstitial fluid, in the skin, lungs and pleural fluid, in the gallbladder, as well as in synovial and peritoneal fluids, bile and pus.

Amoxicillin and Clavulanic acid cross the placental barrier and are excreted in low concentrations in breast milk.

Amoxicillin and Clavulanic acid bind to plasma proteins by 13-20%.

Amoxicillin is excreted mainly by the kidneys, whereas Clavulanic acid is excreted via both renal and extrarenal mechanisms.

Approximately 60-70% of amoxicillin and 40-65% of clavulanic acid are excreted by the kidneys unchanged within the first 6 hours after a single bolus injection of 1000 mg/200 mg.

Amoxicillin in an amount equivalent to 10-25% of the initial amoxicillin dose is excreted by the kidneys as inactive penicilloic acid.

Clavulanic acid undergoes intensive metabolism in the human body and is excreted by the kidneys and intestines.

Indications

Bacterial infections caused by microorganisms sensitive to the drug

• Infections of the lower respiratory tract (exacerbation of chronic bronchitis, lobar pneumonia and bronchopneumonia);
• Infections of the ENT organs (otitis media, sinusitis, recurrent tonsillitis);
• Infections of the urinary tract (including cystitis, urethritis, pyelonephritis);
• Infections of the pelvic organs (including salpingitis, salpingo-oophoritis, endometritis, septic abortion, pelvic peritonitis, postpartum sepsis);
• Infections of the skin and soft tissues (phlegmon, wound infection, erysipelas, impetigo, abscesses);
• Infections of bones and joints (including chronic osteomyelitis);
• Sexually transmitted infections (gonorrhea, chancroid);
• Other infectious diseases: septicemia, peritonitis, intra-abdominal sepsis, postoperative infections.

Prevention of postoperative infections during surgical interventions on the gastrointestinal tract, pelvic organs, head and neck, heart, kidneys, biliary tract, as well as during implantation of artificial joints.

ICD codes

Dosage Regimen

The drug is administered intravenously.

The dosage regimen depends on the patient’s age, body weight and renal function, as well as the severity of the infection.

The minimum course of antibacterial therapy is 5 days. The maximum duration of therapy can be 14 days, after which its effectiveness and tolerability should be assessed.

Doses are given based on the content of amoxicillin/clavulanic acid.

Adults and children over 12 years of age with body weight over 40 kg

Standard dose: 1000 mg/200 mg every 8 h.

Severe infections 1000 mg/200 mg every 4-6 h.

Prophylaxis in surgery

Procedures lasting less than 1 h: 1000 mg/200 mg during induction anesthesia

Procedures lasting more than 1 h: up to 4 doses of 1000 mg/200 mg within 24 h.

Patients with impaired renal function

Dose adjustment is based on the maximum recommended dose of amoxicillin.

Patients on hemodialysis

Dose adjustment is based on the maximum recommended dose of amoxicillin. Initially, a dose of 1000 mg/200 mg is administered, then 500 mg/100 mg every 24 h and additionally 500 mg/100 mg at the end of the hemodialysis session (to compensate for the decrease in plasma levels of amoxicillin and clavulanic acid).

Prevention of postoperative infections during surgical interventions on the gastrointestinal tract, pelvic organs, head and neck, heart, kidneys, biliary tract, as well as during implantation of artificial joints.

Patients with impaired liver function

Treatment should be carried out with caution: regular monitoring of liver function should be performed.

Children

For children under 12 years of age with body weight less than 40 kg the dose is calculated based on body weight.

Under 3 months with body weight less than 4 kg 25 mg/5 mg/kg every 12 h.

Under 3 months with body weight more than 4 kg 25 mg/5 mg/kg every 8 h.

In children under 3 months of age, the drug should be administered only by slow infusion over 30-40 minutes.

From 3 months to 12 years

25 mg/5 mg/kg every 6-8 h depending on the severity of the infection.

Children with impaired renal function

Dose adjustment is based on the maximum recommended dose of amoxicillin.

Children on hemodialysis

Dose adjustment is based on the maximum recommended amoxicillin content. 25 mg/5 mg/kg every 24 h and additionally 12.5 mg/2.5 mg/kg at the end of the hemodialysis session (to compensate for the decrease in serum levels of amoxicillin and clavulanic acid) and then 25 mg/5 mg/kg/day;

Children with impaired liver function

Treatment should be carried out with caution; regular monitoring of liver function should be performed.

Method of administration

Bolus administration

The powder is dissolved with water for injections.

The drug can be administered as a slow IV injection lasting 3-4 minutes directly into a vein or through a catheter.

The resulting solution must be administered within 20 minutes after preparation.

Infusion administration

The drug is administered intravenously by drip over 30-40 minutes, having first dissolved the powder in the volume of water for injections indicated in the table above, the resulting solution is added to 100 ml of solvent.

Adverse Reactions

From the digestive system diarrhea, nausea, vomiting, dyspeptic disorders, colitis (including pseudomembranous and hemorrhagic).

From the liver and biliary tract moderate increase in AST and ALT activity, hepatitis, cholestatic jaundice (when used together with other penicillins and cephalosporins), increase in alkaline phosphatase activity and/or bilirubin concentration.

From the kidneys and urinary tract interstitial nephritis, crystalluria, hematuria.

From the nervous system dizziness, headache, convulsions (may occur in patients with impaired renal function when taking high doses of the drug), insomnia, agitation, anxiety, behavior change, reversible hyperactivity.

From the hematopoietic and lymphatic system reversible leukopenia (including neutropenia), thrombocytopenia, reversible agranulocytosis and hemolytic anemia, prolongation of prothrombin time and bleeding time, eosinophilia, thrombocytosis, anemia.

Superinfection candidiasis of the skin and mucous membranes.

Local reactions in some cases – phlebitis at the site of IV administration.

Allergic reactions skin rash, itching, urticaria, multiform exudative erythema, angioedema, anaphylactic reactions, serum sickness-like syndrome, allergic vasculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis.

Contraindications

• Infectious mononucleosis;
• History of episodes of jaundice or impaired liver function as a result of using amoxicillin/clavulanic acid;
• Hypersensitivity to amoxicillin and clavulanic acid;
• Hypersensitivity to penicillins, cephalosporins, other beta-lactam antibiotics.

Use with caution:severe hepatic insufficiency, gastrointestinal diseases (including a history of colitis associated with the use of penicillins), chronic renal failure.

Use in Pregnancy and Lactation

Use of the drug during pregnancy is only possible in cases where the intended benefit to the mother outweighs the potential risk to the fetus. If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Treatment should be carried out with caution; liver function should be regularly monitored.

Use in Renal Impairment

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

Patients on hemodialysis

Dosage adjustment is based on the maximum recommended dose of amoxicillin. Initially, a dose of 1000 mg/200 mg is administered, followed by 500 mg/100 mg every 24 hours and an additional 500 mg/100 mg at the end of the hemodialysis session (to compensate for the decrease in plasma levels of amoxicillin and clavulanic acid).

Pediatric Use

For children under 12 years of age weighing less than 40 kg, the dose is calculated based on body weight.

Younger than 3 months weighing less than 4 kg 25 mg/5 mg/kg every 12 h.

Younger than 3 months weighing more than 4 kg 25 mg/5 mg/kg every 8 h.

In children under 3 months of age, the drug should be administered only by slow infusion over 30-40 minutes.

From 3 months to 12 years

25 mg/5 mg/kg every 6-8 h depending on the severity of the infection.

Children with renal impairment

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

Children on hemodialysis

Dosage adjustment is based on the maximum recommended amoxicillin content. 25 mg/5 mg/kg every 24 hours and an additional 12.5 mg/2.5 mg/kg at the end of the hemodialysis session (to compensate for the decrease in serum levels of amoxicillin and clavulanic acid) and then 25 mg/5 mg/kg/day;

Children with hepatic impairment

Treatment should be carried out with caution; liver function should be regularly monitored.

Special Precautions

During course treatment, it is necessary to monitor the state of the hematopoietic organs, liver, and kidneys. When prescribed to patients with sepsis, a bacteriolysis reaction (Jarisch-Herxheimer reaction) may develop.

In patients with hypersensitivity to penicillins, cross-allergic reactions with cephalosporin antibiotics are possible.

If it is necessary to administer large doses of the drug parenterally to patients on a low-salt diet, the presence of the sodium ion in the drug should be taken into account.

Amoxicillin and Clavulanic acid can provoke nonspecific binding of immunoglobulins and albumins to the erythrocyte membrane, which may be the cause of a false-positive Coombs test.

If there are high concentrations of amoxicillin in the urine, it may precipitate in urinary catheters at room temperature. The patency of such catheters should be checked regularly. Crystalluria, which occurred as a result of taking Amoxicillin-containing drugs, in some cases led to renal failure.

Effect on ability to drive vehicles and mechanisms

Given the likelihood of developing side effects from the central nervous system, caution should be exercised when driving a car and working with machinery.

Overdose

Gastrointestinal disorders and disturbances in water-electrolyte balance may occur. These manifestations of overdose should be treated symptomatically, with particular attention paid to normalizing the water-electrolyte balance. Amoxicillin+Clavulanic acid is removed by hemodialysis.

Drug Interactions

Bactericidal antibiotics (including aminoglycosides, cephalosporins, vancomycin, rifampicin) have a synergistic effect; bacteriostatic drugs (macrolides, chloramphenicol, lincosamides, tetracyclines, sulfonamides) have an antagonistic effect.

Reduces the effectiveness of oral contraceptives, drugs in the metabolism of which para-aminobenzoic acid is formed, ethinyl estradiol – the risk of breakthrough bleeding.

Diuretics, allopurinol, phenylbutazone, NSAIDs and other drugs that block tubular secretion increase the concentration of amoxicillin.

Allopurinol increases the risk of skin rash.

When used concomitantly with methotrexate, the toxicity of methotrexate increases.

Concomitant use with disulfiram should be avoided.

Probenecid reduces the excretion of amoxicillin, increasing its serum concentration.

Taking the drug leads to a high content of amoxicillin in the urine, which can lead to false-positive results when determining glucose in the urine (for example, Benedict’s test, Fehling’s test). In this case, it is recommended to use the glucose-oxidase method for determining the concentration of glucose in the urine.

Pharmaceutical incompatibility

Pharmaceutically incompatible with solutions containing blood, proteins, lipids.

When used concomitantly with aminoglycosides, antibiotics should not be mixed in the same syringe and in the vial for intravenous fluids, since under such conditions aminoglycosides lose their activity.

The drug solution should not be mixed with solutions of glucose, dextran, or sodium bicarbonate.

Do not mix in a syringe or infusion vial with other drugs.

Rare cases of increased international normalized ratio (INR) in patients with the combined use of acenocoumarol or warfarin and amoxicillin are described in the literature. If it is necessary to prescribe the drug concomitantly with anticoagulants, prothrombin time or INR should be carefully monitored when prescribing or discontinuing the drug.

Storage Conditions

Store in a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.