Cefazolin

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

Composition:

Active substance: cefazolin;

1 vial contains cefazolin sodium equivalent to cefazolin 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to almost white crystalline hygroscopic powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. First-generation cephalosporins.

ATC code J01D B04.

Pharmacological properties.

Pharmacodynamics.

Cefazolin is a semi-synthetic antibiotic of the first-generation cephalosporins for parenteral administration. Its antimicrobial action mechanism is associated with inhibition of the transpeptidase enzyme 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-positive microorganisms, including both penicillinase-producing and non-producing strains. It is 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.

It is active against gram-positive microorganisms, particularly Staphylococcus spp., Streptococcus spp. (including Streptococcus pneumoniae), Corynebacterium diphtheriae, Bacillus anthracis. Most indole-positive Proteus strains (Proteus vulgaris), as well as Enterobacter cloacae, Morganella morganii, Providencia rettgeri, Serratia spp., Pseudomonas spp., Acinetobacter spp., anaerobic cocci Peptococcus spp., Peptostreptococcus spp., including B. fragilis, are resistant to cefazolin.

It has no effect on rickettsiae, viruses, fungi, or protozoa.

Breakpoints in susceptibility testing.

Breakpoints for minimal inhibitory concentration (MIC) have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

1. Isolates susceptible to cefadroxil and/or cephalexin may be categorized as "susceptible-dose dependent" (I) to cefazolin.
2. Susceptibility of staphylococci to cephalosporins is determined based on susceptibility to cefoxitin, except for cefixime, ceftazidime, ceftazidime-avibactam, cefditoren, and ceftolozane-tazobactam, for which there are no established MIC breakpoints and which should not be used for treatment of staphylococcal infections. For orally administered agents, sufficient concentration of the active substance at the site of infection should be ensured. If susceptibility to cefotaxime and ceftriaxone is determined for methicillin-susceptible staphylococci, they should be classified as "susceptible-dose dependent" (I). Some methicillin-resistant S. aureus strains are susceptible to ceftaroline and ceftobiprole (see notes 6/D and 8/F).
3. Susceptibility of group A, B, C, and G streptococci to cephalosporins is determined based on their susceptibility to benzylpenicillin.
4. IE – Insufficient evidence to establish clinically relevant breakpoints for a specific microorganism.

Pharmacokinetics.

Studies have shown that after intravenous administration of cefazolin for injection to healthy volunteers, mean serum concentrations reached a peak of approximately 185 µg/mL and were about 4 µg/mL at 8 hours after a 1 g dose. The serum half-life of cefazolin is approximately 1.8 hours following intravenous administration. In studies involving healthy volunteers receiving continuous intravenous infusion at a rate of 3.5 mg/kg over one hour (approximately 250 mg) and 1.5 mg/kg over the next 2 hours (approximately 100 mg), cefazolin achieved a steady-state serum level of approximately 28 µg/mL by the third hour. Studies in hospitalized patients with infections have shown that cefazolin achieves mean peak serum levels approximately equivalent to those observed in healthy volunteers.

Biliary concentrations of cefazolin in patients without obstructive biliary disease may reach or exceed serum levels by up to fivefold. However, in patients with obstructive biliary disease, biliary concentrations of cefazolin are significantly lower than serum concentrations (<1 µg/mL).

In synovial fluid, cefazolin levels become comparable to serum levels approximately 4 hours after administration.

Cefazolin rapidly crosses the placenta. Cefazolin is present in breast milk at very low concentrations. Cefazolin is excreted unchanged in urine. Within the first 6 hours, approximately 60% of the administered dose is excreted in urine, increasing to 70–80% within 24 hours.

In patients undergoing peritoneal dialysis (2 L/h), after 24 hours of dialysate containing 50 mg/L and 150 mg/L cefazolin, mean serum levels were approximately 10 µg/mL and 30 µg/mL, respectively. Mean peak levels were 29 µg/mL (range 13–44 µg/mL) with 50 mg/L (3 patients); and 72 µg/mL (range 26–142 µg/mL) with 150 mg/L (6 patients). Intraperitoneal administration of cefazolin for injection is generally well tolerated. Controlled studies in healthy adult volunteers receiving 1 g four times daily for 10 days, with monitoring of CBC, AST, ALT, bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, revealed no clinically significant changes related to cefazolin administration.

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 and to other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions.

When cefazolin is used concomitantly with:

probenecid – excretion of cefazolin is slowed, promoting its accumulation and prolonged elevation of drug concentration in blood;

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 administration of vitamin K may be required;

anticoagulants – increased risk of bleeding. When high doses of oral anticoagulants (e.g., warfarin or heparin) are used concomitantly, 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. These disturbances occur more frequently with antibiotics such as fluoroquinolones, macrolides, co-trimoxazole, and certain cephalosporins;

nephrotoxic agents – nephrotoxic effects 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 closely monitored. Renal function may be impaired due to tubular secretion blockade by cefazolin – in such cases, the dose of the drug should be reduced and blood urea nitrogen and creatinine levels should be monitored throughout treatment;

ethanol – disulfiram-like reactions are possible.

Cefazolin should not be used concomitantly with antibacterial agents having a bacteriostatic mechanism of action (tetracyclines, sulfonamides, erythromycin, chloramphenicol). Like other antibiotics, cefazolin may reduce the therapeutic efficacy of BCG vaccine, 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 a live vaccine;

oral contraceptives – cefazolin may reduce the efficacy of oral contraceptives. For this reason, additional contraceptive methods are recommended during treatment with cefazolin.

Special precautions for use.

When prescribing cefazolin, official recommendations for antibiotic therapy and recommendations for prevention of antibiotic resistance should be followed.

Hypersensitivity. Before starting each new course of treatment with cefazolin, it is necessary to ascertain whether the patient has a history of hypersensitivity reactions to cefazolin, cephalosporins, penicillins, other β-lactam antibiotics, or other medicinal products.

As with other β-lactam antibacterial agents, severe hypersensitivity reactions, in some cases fatal, have been reported.

Cross-allergic reactions between penicillins and cephalosporins are possible. Severe hypersensitivity reactions (including anaphylaxis) have been reported with both drugs.

Antibiotics should be prescribed cautiously in patients with a history of any type of allergic reaction, especially to medicinal products.

As with other cephalosporins, the possibility of severe acute allergic reactions, including anaphylactic shock, cannot be excluded, even if the detailed history does not indicate such reactions. In the event of such reactions, epinephrine (adrenaline), glucocorticoids, and other emergency measures should be administered.

Cephalosporins may be absorbed on the surface of erythrocyte membranes and interact with antibodies directed against the drug. This may lead to a false-positive Coombs test (e.g., in children whose mothers were treated with cefazolin), and very rarely to the development of hemolytic anemia. In such a reaction, cross-reactivity with penicillins may occur.

Antibiotic-associated colitis / overgrowth of resistant microorganisms. Treatment with antibacterial medicinal products, especially in severe diseases in elderly patients, in debilitated patients, and in children, may lead to the development of antibiotic-associated diarrhea and colitis, including pseudomembranous colitis. The severity of pseudomembranous colitis may range from mild to life-threatening; therefore, it is important to consider this diagnosis in all patients who develop diarrhea during or after cefazolin administration. Thus, in the event of diarrhea during or after cefazolin treatment, these diagnoses, including pseudomembranous colitis, must be ruled out. Cefazolin should be discontinued in cases of severe and/or bloody diarrhea, and appropriate therapy initiated. Medicinal products that inhibit peristalsis should not be used. Without adequate treatment, toxic megacolon, peritonitis, and shock may develop.

Patients with a history of gastrointestinal disorders, especially colitis, should be treated with caution. Prolonged use of antibacterial medicinal products may lead to overgrowth of resistant microorganisms and fungi and to the development of superinfection, requiring appropriate measures, including periodic testing of microbial sensitivity to the drug.

Renal impairment. In patients with renal impairment, doses and/or intervals between administrations of the drug may need to be adjusted depending on the degree of renal function impairment. When prescribing cefazolin to patients with impaired renal function, the daily dose should be reduced or the interval between administrations prolonged to avoid toxic effects.

In cases of renal impairment with a glomerular filtration rate of less than 55 mL/min, accumulation of cefazolin should be considered. Although cefazolin is rarely a cause of renal function impairment, renal function should be monitored, especially in critically ill patients receiving maximum doses of the drug and in patients receiving concomitant therapy with other potentially nephrotoxic medicinal products (including aminoglycosides, potent diuretics).

The use of high doses of cefazolin in patients with renal impairment may be associated with the risk of seizures.

Dose adjustment is not required for geriatric patients with normal renal function.

Intrathecal administration of the drug is not recommended. Reports of severe toxic reactions affecting the central nervous system, including seizures, have been associated with this route of administration as well as with overdose in the presence of renal dysfunction.

During prolonged cefazolin therapy, regular monitoring of blood counts and liver and kidney function parameters is recommended.

Coagulation disorders. Cefazolin may rarely cause coagulation disorders. Therefore, prothrombin time should be monitored in patients with conditions that may lead to bleeding (e.g., gastrointestinal ulcers), in patients with coagulation defects (inherited: e.g., hemophilia; acquired: e.g., thrombocytopenia), in patients with impaired synthesis or deficiency of vitamin K (e.g., chronic liver or kidney disease, advanced age, malnutrition, prolonged antibiotic therapy), and in patients who have undergone prolonged anticoagulant therapy prior to cefazolin administration. If indicated, exogenous vitamin K (10 mg per week) should be administered.

Effect on laboratory test results. During cefazolin therapy, false-positive results in non-enzymatic glucosuria tests may occur. The drug does not affect the results of enzymatic glucosuria tests.

Sodium. The medicinal product contains sodium, which should be taken into account in patients on a sodium-controlled diet.

Only clear, freshly prepared solutions of the drug are suitable for use. Cefazolin solution must not be mixed in the same container with other antibiotics.

Use during pregnancy or breastfeeding.

Low concentrations of cefazolin have been detected in breast milk.

Use during pregnancy and breastfeeding is justified only when the expected benefit to the mother outweighs the potential risk to the fetus or infant.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of nervous system adverse reactions such as dizziness and seizures, driving or operating machinery should be avoided during treatment.

Administration and Dosage

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

Preparation of Injection and Infusion Solutions

For intramuscular administration, the contents of a 500 mg (1000 mg) vial should be dissolved in 2–3 mL (4–5 mL) of 0.9% sodium chloride solution or sterile water for injection, shaking thoroughly until complete dissolution. The solution should be injected deeply into the upper outer quadrant of the gluteal muscle.

For intravenous bolus injection, a single dose should be dissolved in 10 mL of 0.9% sodium chloride solution or sterile water for injection and administered slowly over 3–5 minutes.

For intravenous infusion, 500 mg or 1000 mg of the drug should be diluted in 50–100 mL of water for injection or 0.9% sodium chloride solution, or in one of the following solutions: 5% glucose solution, 10% glucose solution, 5% glucose solution in sodium lactate infusion solution, 0.9% sodium chloride solution with 5% glucose solution for intravenous infusion, 0.45% sodium chloride solution with 5% glucose solution for intravenous infusion, 5% sodium lactate solution, or 10% invert sugar solution in water for injection, Ringer's injection solution with or without lactate. The infusion should be administered over 20–30 minutes (administration rate − 60–80 drops/min). Vials should be shaken vigorously until complete dissolution. Daily doses for intravenous administration remain the same as for intramuscular administration.

The freshly prepared solution (333 mg/mL) is yellow, clear, and maintains its physical and chemical stability for 24 hours at room temperature.

Dosage

The usual daily dose for adults is typically 1000–4000 mg, with a maximum daily dose of 6000 mg.

*In rare cases, doses up to 12 grams of injectable cefazolin per day have been used.

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

• at a dose of 1000 mg 0.5–1 hour before the start of surgery;
• during prolonged surgeries (2 hours or more) − an additional 500–1000 mg during the operation;
• after surgery − at a dose of 500–1000 mg every 6–8 hours during the first 24 hours.

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

In adult patients with impaired renal function, the dosing 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.

With creatinine clearance:

• 55 mL/min or higher − 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 − the standard single dose should be halved, with dosing intervals of 12 hours;
• less than 10 mL/min − half the therapeutic dose every 18–24 hours.

Elderly patients: dosing as in adults (provided normal renal function).

Children aged 1 month and older: the drug should be administered at a dose of 25–50 mg/kg/day (in severe cases – up to 100 mg/kg/day), divided into 3–4 doses.

Maximum daily dose for children – 100 mg/kg body weight.

In children with impaired renal function, dose adjustment should be based on creatinine clearance.

With creatinine clearance:

• 40–70 mL/min − 60% of the daily dose, administered at 12-hour intervals;
• 20–40 mL/min − 25% of the daily dose, administered at 12-hour intervals;
• 5–20 mL/min − 10% of the average daily dose every 24 hours.

All recommended doses should be administered after the initial loading dose.

The average duration of treatment is 7–10 days.

Children.

Do not administer to children under 1 month of age and to premature infants, as there is currently insufficient data on the use of the medicinal product in these age groups.

Overdose.

Symptoms: dizziness, paresthesia, and headache; allergic reactions may occur. In patients with chronic renal insufficiency, neurotoxic manifestations may develop, including increased seizure susceptibility, generalized seizures, vomiting, and tachycardia. Possible laboratory abnormalities include elevated creatinine, blood urea nitrogen, liver enzymes, and bilirubin levels; 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 is recommended, along with monitoring of hematological, renal, hepatic, and coagulation functions until the patient's condition stabilizes. The drug is eliminated from the body by hemodialysis; peritoneal dialysis is less effective.

Adverse Reactions.

Immune system disorders: rash, itching, skin redness, dermatitis, urticaria, drug fever, angioneurotic edema, anaphylactic shock (laryngeal edema with airway narrowing, rapid heartbeat, dyspnea, low blood pressure, swollen tongue, anal itching, genital itching, facial swelling), exudative multiform erythema, Stevens–Johnson syndrome, Lyell’s syndrome, eosinophilia, arthralgia, serum sickness, bronchospasm.

Blood and lymphatic system disorders: cases of leukopenia, granulocytopenia, agranulocytosis, neutropenia, leukocytosis, monocytosis; lymphopenia, hemolytic anemia, aplastic anemia, thrombocytopenia/thrombocytosis, hypoprothrombinemia, decreased hematocrit, prolonged prothrombin time, pancytopenia, basophilia, eosinophilia. Coagulation disorders, hemorrhages.

Respiratory system disorders: pleural effusion, dyspnea or respiratory distress, cough.

Gastrointestinal disorders: anorexia, nausea, vomiting, abdominal pain, diarrhea, flatulence, symptoms of pseudomembranous colitis which may occur during or after treatment; with prolonged use, dysbiosis and candidiasis of the gastrointestinal tract (including candidal stomatitis) may develop. If diarrhea occurs during antibiotic therapy, appropriate treatment should be initiated immediately.

Hepatobiliary disorders: in isolated cases, transient elevations in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, bilirubin and/or lactate dehydrogenase levels have been observed, as well as transient hepatitis and cholestatic jaundice.

Renal and urinary system disorders: impaired renal function (transient increase in blood urea nitrogen, hypercreatinemia) without clinical signs of renal failure.

Rare cases of interstitial nephritis and other renal function disorders (nephropathy, renal papillary necrosis, renal failure), proteinuria have been reported.

Vascular disorders: thrombophlebitis.

Nervous system disorders: headache, dizziness, paresthesia, nervousness or anxiety, agitation, hyperactivity, seizures, intrusive dreams, insomnia, somnolence, weakness, hot flushes, blurred vision, confusion, and increased epileptogenic brain activity.

Local reactions at injection site: pain, induration, swelling at the injection site; cases of phlebitis have been observed following intravenous administration.

Other adverse effects: general weakness, malaise, fatigue, chest pain, pallor, tachycardia, hemorrhages.

In isolated cases, anogenital itching, genital candidiasis and vaginitis, oral cavity mycosis, genital mycosis may occur. With prolonged use, superinfection caused by drug-resistant pathogens may develop. Prolonged use of cephalosporins may lead to overgrowth of resistant microorganisms, particularly Enterobacter, Citrobacter, Pseudomonas, Enterococcus, Candida.

Positive Coombs test.

Elevated levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and alkaline phosphatase without clinical signs of kidney or liver damage.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Incompatibilities.

Cefazolin solution should not be mixed with other medicinal products in the same syringe or infusion system, especially with antibiotics.

Packaging. 1 or 10 vials with powder in a cardboard box.

Prescription status. Prescription only.

Manufacturer. NSPS Hebei Huamin Pharmaceutical Company Limited.

Manufacturer's address and location of operations.

No. 98 Huan Road, Economic and Technological Development Zone, Shijiazhuang, Hebei 052165, China.