Cefazolin

INSTRUCTION for medical use of the medicinal product CEFALOLIN (CEFAZOLIN)

Composition:

Active substance: cefazolin;

1 vial contains sterile sodium cefazolin salt, calculated as cefazolin – 0.5 g or 1 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white powder, highly hygroscopic.

Pharmacotherapeutic group. Antimicrobial agents for systemic use, other β-lactam antibiotics. First-generation cephalosporins. ATC code J01D B04.

Pharmacological Properties.

Pharmacodynamics.

Cefazolin is a semi-synthetic antibiotic of the first-generation cephalosporins intended for parenteral administration. Its antimicrobial action mechanism is associated with inhibition of the enzyme transpeptidase and blockade of muropeptide biosynthesis in the bacterial cell wall. The drug has a broad spectrum of bactericidal activity and is effective against most Gram-negative and Gram-positive microorganisms, including those producing and non-producing penicillinase. Highly active against most Gram-negative microorganisms: Escherichia coli, Proteus mirabilis, Salmonella spp., Shigella spp., Klebsiella spp. (including Klebsiella pneumoniae), Enterobacter spp., Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, Treponema spp., Leptospira spp. Active against Gram-positive microorganisms, particularly Staphylococcus spp., Streptococcus spp. (including Streptococcus pneumoniae), Corynebacterium diphtheriae, Bacillus anthracis. Most indole-positive strains of Proteus (Proteus vulgaris), as well as Enterobacter cloacae, Morganella morganii, Providencia rettgeri, Serratia spp., Pseudomonas spp., Acinetobacter spp., and anaerobic cocci Peptococcus spp., Peptostreptococcus spp., including B. fragilis, are resistant to cefazolin. The drug has no effect on rickettsiae, viruses, fungi, or protozoa.

Pharmacokinetics.

Cefazolin is rapidly absorbed after intramuscular administration, with peak plasma concentrations reached within 60 minutes after injection, ranging from 37 to 64 mcg/mL. After intravenous administration, maximum drug concentration is achieved immediately and amounts to 185 mcg/mL. Bactericidal blood concentrations persist for 8–12 hours. The drug penetrates well into tissues and body fluids and reaches therapeutic concentrations in mucous membranes, sputum, bone tissue, and cerebrospinal fluid; it crosses the placental barrier and penetrates into breast milk in very low concentrations. Approximately 90% of the drug binds to plasma proteins. It is excreted unchanged in urine (approximately 90%). The drug undergoes minimal metabolism in the liver and is excreted in bile. Elimination half-life is about 2 hours after intramuscular administration and 1.8 hours after intravenous administration. In case of impaired renal function, the elimination half-life ranges from 3 to 42 hours.

Clinical characteristics.

Indications. Infections caused by microorganisms sensitive to cefazolin:

• respiratory tract infections;
• urinary and genital system infections;
• skin and soft tissue infections;
• bone and joint infections;
• sepsis;
• endocarditis;
• biliary tract infections.

Prophylaxis of surgical infections.

Contraindications. Hypersensitivity to cephalosporin antibiotics or other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interaction.

Antibiotics.

An antagonistic effect with bacteriostatic-acting antibiotics (e.g., tetracyclines, sulfonamides, erythromycin, chloramphenicol) has been observed in vitro; therefore, the possibility of such interaction should be considered when combining cefazolin with these antibiotics.

Like other antibiotics, cefazolin may reduce the therapeutic efficacy of BCG vaccine and typhoid vaccine; therefore, such combinations are not recommended. An interval of at least 24 hours should be maintained between administration of the last antibiotic dose and live vaccines.

Probenecid. Concomitant administration of probenecid reduces renal clearance of cefazolin, promoting its accumulation and prolonged elevation of serum drug concentrations.

Vitamin K. Some antibiotics, such as cefamandole, cefazolin, and cefotetan, may affect vitamin K metabolism, particularly in cases of vitamin K deficiency. In such situations, additional vitamin K administration may be required.

Anticoagulants. Cephalosporins may very rarely cause disturbances in blood coagulation. When high doses of oral anticoagulants (e.g., warfarin or heparin) are administered concomitantly, blood coagulation parameters should be monitored. Numerous cases of enhanced anticoagulant effects have been reported in patients receiving antibiotics. Risk factors include presence of infection or inflammation, advanced age, and poor general health status. Such disturbances occur more frequently with antibiotics such as fluoroquinolones, macrolides, co-trimoxazole, and certain cephalosporins.

Nephrotoxic agents. A nephrotoxic effect of antibiotics (e.g., aminoglycosides, colistin, polymyxin B), iodinated contrast agents, platinum-containing compounds, high-dose methotrexate, certain antiviral agents (e.g., acyclovir, foscarnet), pentamidine, cyclosporine, tacrolimus, and diuretics (e.g., furosemide) cannot be excluded. If these medicinal products are used concomitantly with cefazolin, renal function parameters should be carefully monitored.

Ethanol. Disulfiram-like reactions may occur.

Oral contraceptives. Cefazolin may reduce the efficacy of oral contraceptives. For this reason, additional contraceptive methods are recommended during cefazolin therapy.

Special precautions.

Hypersensitivity.

Before initiating treatment, ensure that the patient has no history of hypersensitivity reactions to cephalosporins, penicillins, or other drugs. Cefazolin should be administered with caution to patients predisposed to allergic reactions. Cross-allergic reactions between penicillins and cephalosporins are possible. As with other beta-lactam antibacterial agents, severe hypersensitivity reactions, in some cases fatal, have been reported. In case of pronounced hypersensitivity reactions, cefazolin should be discontinued immediately and appropriate therapy initiated. Prior to starting therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to cefazolin, other cephalosporins, or other beta-lactam antibiotics. Caution should be exercised when administering cefazolin to patients who have previously experienced hypersensitivity reactions to other beta-lactam antibiotics.

Antibiotic-associated pseudomembranous colitis.

If a patient develops severe or persistent diarrhea, the possibility of antibiotic-associated pseudomembranous colitis should be considered. The severity of pseudomembranous colitis may range from mild to life-threatening; therefore, this diagnosis should be considered in all patients who develop diarrhea during or after cefazolin therapy. If severe diarrhea or bloody diarrhea occurs, cefazolin treatment should be discontinued and appropriate therapy initiated.

Antiperistaltic agents are contraindicated. Without appropriate treatment, toxic megacolon, peritonitis, or shock may develop.

Renal function impairment.

For patients with renal impairment, the dose and/or dosing interval may require adjustment depending on the degree of renal dysfunction. When prescribing cefazolin to patients with impaired renal function, the daily dose should be reduced or the interval between doses increased to avoid toxicity.

In cases of renal insufficiency with glomerular filtration rate below 55 mL/min, accumulation of cefazolin should be considered. Although cefazolin rarely causes renal function impairment, renal function should be monitored, especially in critically ill patients receiving maximum therapeutic doses and in patients also receiving other nephrotoxic drugs, such as aminoglycosides or potent diuretics (e.g., furosemide). Administration of high doses of cefazolin in patients with renal insufficiency is associated with an increased risk of seizures.

Intrathecal administration.

The drug is not intended for intrathecal administration. Serious central nervous system toxicity (including seizures) has been reported following intrathecal injection of cefazolin.

Bacterial resistance and superinfection.

Prolonged use of cefazolin may lead to overgrowth of resistant organisms. Therefore, patients should be closely monitored for the development of superinfection. If superinfection occurs, appropriate therapy should be initiated.

Coagulation disorders.

Coagulation disorders may occur rarely during treatment with cefazolin. The risk is higher in patients with vitamin K deficiency or other conditions predisposing to coagulation disorders (parenteral nutrition, malnutrition, hepatic or renal dysfunction, thrombocytopenia). Coagulation disorders may also be associated with underlying conditions (e.g., hemophilia, peptic ulcer) that cause or exacerbate bleeding. Coagulation should be monitored in patients with the aforementioned conditions. If coagulation parameters worsen, vitamin K (10 mg weekly) should be administered.

Laboratory test results.

Urinary glucose tests performed using Benedict's or Fehling's solutions may yield false-positive results in patients receiving cefazolin. Cefazolin does not interfere with enzymatic tests used to measure urinary glucose. Direct and indirect Coombs' test results may also be falsely positive, for example in newborns whose mothers received cephalosporins.

Each 0.5 g / 1 g vial contains 24.13 mg / 48.27 mg of sodium, respectively. This should be taken into account if the patient is on a sodium-restricted diet.

Use during pregnancy or breastfeeding. Animal studies have shown no effect of cefazolin on fertility.

Pregnancy. Animal studies have shown no direct or indirect reproductive toxicity.

Due to the lack of experience with cefazolin use during pregnancy and because cefazolin crosses the placental barrier, especially during the first trimester of pregnancy, cefazolin should not be administered during pregnancy.

Breastfeeding. Cefazolin is excreted in small amounts in breast milk; therefore, adverse effects in the infant are not expected. However, if the infant develops diarrhea or Candida fungal infection, breastfeeding should be discontinued or cefazolin treatment stopped.

Ability to affect reaction speed when driving or operating machinery. Cefazolin does not affect the ability to drive or operate machinery. However, certain adverse effects (see section "Adverse reactions") may impair the ability to drive or operate machinery.

Administration and Dosage

Cefazolin should be administered intramuscularly or intravenously (by infusion or bolus injection). Cefazolin must not be administered intrathecally.

Dosage. The usual daily dose of cefazolin for adults is 1–4 g; the maximum daily dose is 6 g. The single dose for adults in infections caused by gram-positive microorganisms is 0.25–0.5 g every 8 hours. For moderate respiratory tract infections caused by pneumococci and urinary tract infections, the drug should be administered at 1 g every 12 hours. In pneumococcal pneumonia, the dose is 0.5 g every 12 hours. For infections caused by susceptible gram-negative microorganisms, administer 0.5–1 g every 6–8 hours. In severe infections (sepsis, endocarditis, peritonitis, destructive pneumonia, acute hematogenous osteomyelitis, complicated urological infections), administer 1–1.5 g every 6–8 hours.

For prophylaxis of postoperative infectious complications in adults, cefazolin should be administered intramuscularly or intravenously:

• 1 g dose 0.5–1 hour before the start of surgery;
• for prolonged surgeries (2 hours or longer) — an additional 0.5–1 g during surgery;
• after surgery — 0.5–1 g every 6–8 hours for the first 24 hours.

In certain cases (e.g., open-heart surgery, joint prosthesis implantation), prophylactic use of cefazolin may continue for 3–5 days postoperatively.

Children aged 1 month and older. Administer the drug at a dose of 25–50 mg/kg/day, divided into 3–4 doses; in severe infections, administer 90–100 mg/kg/day (maximum dose). The average duration of treatment is 7–10 days.

Adult patients with impaired renal function: dosage regimen should be adjusted according to creatinine clearance. After an initial loading dose appropriate to the severity of infection, the following recommendations may be applied. For creatinine clearance:

• ≥55 mL/min — no dose adjustment required;
• 35–54 mL/min — single dose unchanged, but the interval between doses should be at least 8 hours;
• 11–34 mL/min — reduce the standard single dose by half, with dosing intervals of 12 hours;
• <10 mL/min — administer ¼ of the therapeutic dose every 18–24 hours.

Elderly patients: dosage as for adults (provided normal renal function).

Renal impairment in children. Initially administer the usual single dose, then adjust subsequent doses according to the degree of renal insufficiency. In children with moderate renal impairment (creatinine clearance 40–70 mL/min), administer 60% of the daily dose twice daily every 12 hours; with creatinine clearance 20–40 mL/min — 25% of the daily dose twice daily every 12 hours; in severe renal impairment (creatinine clearance 5–20 mL/min) — 10% of the average daily dose every 24 hours. All recommended doses should be administered after an initial loading dose. The average duration of treatment is 7–10 days.

Administration method.

Cefazolin is a sterile powder for injection solution and must be reconstituted before administration. Cefazolin dissolves easily in the following diluents: water for injection, 0.5% lidocaine solution, 0.9% sodium chloride solution, Ringer's solution.

Freshly prepared solutions are recommended. After dilution with the above-mentioned solvents, a clear solution ranging from pale yellow to yellow is formed.

Preparation of injection and infusion solutions.

For intramuscular injection. Dissolve 1 g of Cefazolin in 4 mL of one of the following compatible diluents, shaking thoroughly until complete dissolution:

• water for injection;
• 0.9% sodium chloride solution;
• 0.5% lidocaine solution.

Administer deeply into the upper outer quadrant of the gluteus maximus muscle.

For intravenous bolus injection.

Dissolve cefazolin in one of the following compatible diluents:

• water for injection;
• 0.9% sodium chloride solution.

Lidocaine solution must not be administered intravenously.

Use 4 mL of compatible diluent per 1 g of cefazolin. Cefazolin should be injected slowly over approximately 3–5 minutes. The solution should be administered by direct intravenous injection into a vein or via an infusion line when a compatible infusion solution is being administered.

If administration of 2 g of cefazolin is required, intravenous infusion over approximately 30–60 minutes is recommended.

For intravenous infusion.

Cefazolin should first be dissolved in one of the compatible diluents for intravenous injection.

Further dilution should be performed in one of the following compatible diluents:

• 0.9% sodium chloride solution;
• Ringer's solution;
• water for injection.

Dilution of the drug for intravenous infusion:

Add the recommended volume of solvent and shake well until the contents of the vial are completely dissolved.

Only freshly prepared solutions should be used for intravenous infusion. The solution should be inspected visually before use. Use only clear solutions without any particles.

The solution is intended for single use only. Any unused solution should be discarded.

Children

Cefazolin should not be administered to premature infants or newborns under 1 month of age, as there is currently insufficient data on the use of the drug in these age groups.

Overdose. Symptoms: dizziness, paresthesia, and headache. Allergic reactions may occur in patients with chronic renal insufficiency. Neurotoxic effects are possible, including increased seizure susceptibility, generalized seizures, vomiting, and tachycardia. Laboratory abnormalities may include elevated levels of creatinine, blood urea nitrogen, liver enzymes, and bilirubin; positive Coombs test; thrombocytosis/thrombocytopenia; eosinophilia; leukopenia; and prolonged prothrombin time.

Treatment: discontinue the drug. If necessary, administer anticonvulsant and desensitizing therapy. In cases of severe overdose, supportive therapy and monitoring of hematological, renal, hepatic, and coagulation functions are recommended until the patient's condition stabilizes. The drug can be removed from the body by hemodialysis; peritoneal dialysis is less effective.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000).

Infections and infestations

Uncommon: oral fungal infections.

Rare: genital fungal infections, vaginitis. Prolonged use of cefazolin may lead to overgrowth of resistant microorganisms. Catarrh.

Blood and lymphatic system disorders

Changes in blood cell counts such as leukopenia, granulocytopenia, neutropenia, thrombocytopenia, leukocytosis, granulocytosis, monocytosis, lymphocytopenia, basophilia, and eosinophilia have been observed. These changes are rare and reversible.

Very rare: coagulation disorders, bleeding.

Immune system disorders

Uncommon: fever.

Very rare: anaphylactic shock (laryngeal edema with airway constriction, rapid heartbeat, dyspnea, hypotension, swollen tongue, anal pruritus, genital pruritus, facial swelling).

Metabolism and nutrition disorders

Rare: hyperglycemia, hypoglycemia.

Nervous system disorders

Uncommon: seizures.

Rare: dizziness.

Vascular disorders

Uncommon: thrombophlebitis.

Respiratory system disorders

Rare: pleural effusion, dyspnea or respiratory distress, cough.

Gastrointestinal disorders

Common: nausea, vomiting, diarrhea.

Rare: anorexia.

Very rare: pseudomembranous colitis (if diarrhea occurs during antibiotic therapy, appropriate treatment should be initiated immediately).

Hepatobiliary disorders

Rare: transient increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transferase, bilirubin and/or lactate dehydrogenase levels, transient hepatitis, and transient cholestatic jaundice.

Skin and subcutaneous tissue disorders

Common: rash.

Uncommon: erythema, erythema multiforme, urticaria, angioneurotic edema.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome.

Renal and urinary disorders

Rare: nephrotoxicity, interstitial nephritis, nephropathy, proteinuria, transient increase in blood urea nitrogen (BUN), usually in patients receiving other potentially nephrotoxic drugs.

Reproductive system disorders

Very rare: vulvar and vaginal pruritus.

General disorders and administration site conditions

Common: pain at injection site, sometimes with induration.

Rare: malaise, fatigue, chest pain. If severe diarrhea occurs during cefazolin treatment, consult a physician immediately, as diarrhea may be a symptom of a serious condition (pseudomembranous colitis) requiring urgent treatment. Patients should not attempt self-treatment to reduce intestinal motility.

Prolonged use of cephalosporins may lead to overgrowth of resistant organisms, particularly Enterobacter, Citrobacter, Pseudomonas, Enterococcus, Candida. This may result in superinfection or potential colonization with resistant bacteria or yeasts.

Investigations

Elevated levels of AST, ALT, blood urea, and alkaline phosphatase without clinical signs of kidney or liver damage. Animal studies have shown potential nephrotoxicity of cefazolin. Although this effect has not been demonstrated in humans, the possibility should be considered, especially in patients receiving high doses over prolonged periods. Interstitial nephritis and nephropathy have been reported rarely. Patients who developed these conditions were also receiving concomitant therapies. The role of cefazolin in the development of interstitial nephritis and other nephropathies has not been established.

The following adverse effects have been reported: decreased hemoglobin and/or hematocrit levels, anemia, agranulocytosis, aplastic anemia, pancytopenia, and hemolytic anemia.

During cephalosporin therapy, the following adverse effects have been observed: persistent nightmares, dizziness, hyperactivity, nervousness or anxiety, insomnia, somnolence, weakness, hot flushes, blurred vision, confusion, and increased cerebral epileptogenic activity.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibility. Cefazolin solution should not be mixed with other medicinal products in the same syringe or infusion system, especially with antibiotics. Use only the solvents specified in the section "Administration and dosage" for reconstitution.

Packaging. 0.5 g or 1 g in vials; 10 vials with powder in a blister pack, 1 blister pack per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.