Cefazolin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFZOLIN (Cefazolin)

Composition:

Active substance: cefazolin;

1 vial contains cefazolin (as cefazolin sodium) 1.0 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white 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 intended for parenteral administration. Its antimicrobial action mechanism is associated with inhibition of the enzyme transpeptidase, resulting in blockade of mukopeptide biosynthesis in the bacterial cell wall.

The drug has a broad spectrum of bactericidal activity and is effective against most Gram-positive and Gram-negative 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 also active against Gram-positive microorganisms, particularly Staphylococcus spp., Streptococcus spp. (including Streptococcus pneumoniae), Corynebacterium diphtheriae, and 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., 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 reaches 185 mcg/mL. Bactericidal concentrations in the blood are maintained 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 appears in breast milk in very low concentrations. Approximately 90% of the drug is protein-bound in plasma. It is excreted unchanged in urine (approximately 90%). A small portion is metabolized in the liver and excreted in bile.

The elimination half-life is approximately 2 hours after intramuscular administration and 1.8 hours after intravenous administration. In cases 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.

Prevention of surgical infections.

Contraindications.

Hypersensitivity to cephalosporin antibiotics and to other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interaction.

When cefazolin is used concomitantly with:

probenecid – excretion of cefazolin is slowed, promoting its accumulation and prolonged elevation of drug concentration in the 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 drugs (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 of cefazolin – in such cases, the dose 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 bacteriostatic antibacterial agents (tetracyclines, sulfonamides, erythromycin, chloramphenicol). Like other antibiotics, cefazolin may reduce the therapeutic effect of
BCG vaccine , typhoid vaccine ; therefore, this combination is not recommended. An interval of at least 24 hours should be maintained between administration of the last dose of antibiotic 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

Before starting each new course of treatment with cefazolin, it is necessary to determine whether the patient has had hypersensitivity reactions in the past to cefazolin, cephalosporins, penicillins, other β-lactam antibiotics, or other medicinal products. As with other β-lactam antibacterial agents, severe hypersensitivity reactions have been reported, including cases with fatal outcomes.

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

Antibiotics should be administered cautiously to patients with a history of any type of allergic reactions, particularly to medicinal products.

As with other cephalosporins, the possibility of severe acute allergic reactions, including anaphylactic shock, cannot be excluded—even in the absence of relevant data in the detailed patient history. In the event of such reactions, epinephrine (adrenaline), glucocorticoids, and other emergency measures should be administered immediately.

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 result (e.g., in children whose mothers were treated with cefazolin) and, very rarely, to the development of hemolytic anemia. Cross-reactivity with penicillins may occur in such cases.

Antibacterial therapy, especially in severe diseases, elderly individuals, debilitated patients, and children, may lead to antibiotic-associated diarrhea and colitis, including pseudomembranous colitis. 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 treatment. Cefazolin therapy should be discontinued in cases of severe and/or bloody diarrhea, and appropriate therapy should be initiated.

The use of agents that inhibit peristalsis is contraindicated. Without adequate treatment, toxic megacolon, peritonitis, and shock may develop.

Cautious administration is recommended in patients with a history of gastrointestinal disorders, particularly colitis. Prolonged use of antibacterial agents may lead to overgrowth of non-susceptible microorganisms and fungi, resulting in superinfection, which requires appropriate intervention.

Cautious administration is advised in patients with impaired renal function, as well as in patients with epilepsy or central nervous system disorders. Treatment of patients with impaired renal function should be conducted in a hospital setting; the daily dose should be reduced or the interval between drug administrations extended to avoid toxic effects.

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

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

Intrathecal administration of the drug is not recommended. Severe toxic reactions affecting the central nervous system, including seizures, have been reported following this route of administration, as well as with overdose in the setting of renal dysfunction.

Impairment of blood coagulation may occur in isolated cases during cefazolin therapy. During prolonged treatment, regular monitoring of blood parameters, liver function, and kidney function is recommended.

In patients with impaired vitamin K synthesis or deficiency (e.g., due to chronic liver or kidney disease, in elderly patients, or following prolonged antibiotic therapy), as well as in patients previously treated with anticoagulants, prothrombin time should be monitored.

Coagulation disorders may also be associated with concomitant conditions (e.g., hemophilia, peptic ulcer of the stomach or duodenum) that cause or exacerbate bleeding. In patients with the aforementioned conditions, blood coagulation should be monitored. If coagulation parameters deteriorate, vitamin K (10 mg per week) should be administered.

Laboratory tests for glucose in urine using Benedict's or Fehling's solutions may yield false-positive results in patients receiving cefazolin. Cefazolin does not affect the results of enzymatic tests used to measure urinary glucose. Direct and indirect Coombs tests may also yield false-positive results, for example in newborns whose mothers received cephalosporins.

Only clear, freshly prepared solutions of the drug should be used.

Use during pregnancy or breastfeeding

Cefazolin should not be administered during pregnancy.

If it is necessary to use the drug, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

Until the individual patient's response to the drug is known, patients should refrain from driving or operating machinery, considering that neurological adverse effects such as dizziness and seizures may occur during treatment.

Method of Administration and Dosage.

Cefazolin is administered intramuscularly and intravenously (by infusion and bolus injection). Cefazolin must not be administered intrathecally.

Preparation of Injection and Infusion Solutions.

For intramuscular injection: dissolve the contents of the vial in 4–5 mL of sterile water for injection or 0.9% sodium chloride solution, shaking thoroughly until complete dissolution. Administer deeply into the upper outer quadrant of the gluteal muscle.

For intravenous bolus injection: dissolve the single dose of the drug in 10 mL of 0.9% sodium chloride solution or sterile water for injection and administer slowly over 3–5 minutes.

For intravenous infusion: dissolve 0.5–1 g of the drug 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 in sodium lactate infusion solution, 0.9% sodium chloride with 5% glucose for intravenous infusion, 0.45% sodium chloride with 5% glucose for intravenous infusion, 5% sodium lactate solution, or 10% invert sugar solution in water for injection, Ringer's injection solution with or without lactate. Infuse over 20–30 minutes (administration rate of 60–80 drops/min). Shake vials vigorously until complete dissolution. Daily doses for intravenous administration remain the same as for intramuscular administration.

Dosage.

The usual daily dose of cefazolin in adults is 1–4 g, with a maximum daily dose of 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 is administered at 1 g every 12 hours. In infections caused by susceptible gram-negative microorganisms, the drug is administered at 0.5–1 g every 6–8 hours. In severe infections (sepsis, endocarditis, peritonitis, destructive pneumonia, acute hematogenous osteomyelitis, complicated urological infections), the drug is administered at 1–1.5 g every 6–8 hours.

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

• at a dose of 1 g 0.5–1 hour before the start of surgery;
• during prolonged operations (2 hours or longer) – an additional 0.5–1 g during the operation;
• 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 after surgery.

In children aged 1 month and older: the drug is administered at a dose of 20–50 mg/kg/day, divided into 3–4 doses; in severe infections, 90–100 mg/kg/day (maximum dose). The average duration of treatment is 7–10 days.

Adult patients with impaired renal function: initially administer the drug at a dose of 0.5 g, then adjust the treatment regimen by reducing the dose and increasing the intervals between doses according to the recommendations below.

Depending on creatinine clearance and serum creatinine concentration:

• 55 mL/min and <1.5 mg% – no dose adjustment required;

• 35–54 mL/min and 1.6–3 mg% – single dose unchanged, but the interval between doses should be at least 8 hours;
• 11–34 mL/min and 3.1–4.5 mg% – reduce the standard single dose by half, with a 12-hour interval between doses;
• <10 mL/min and >4.6 mg% – administer half the therapeutic dose every 12–18 hours.

In children with impaired renal function: initially administer the usual single dose, then adjust subsequent doses according to the degree of renal impairment. 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; with severe renal impairment (creatinine clearance 5–20 mL/min) – 10% of the average daily dose every 24 hours. All recommended doses are 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 or to premature infants, 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 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 and monitoring of hematological, renal, hepatic, and coagulation functions are recommended 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, pruritus, erythema, dermatitis, urticaria, drug fever, angioneurotic edema, anaphylactic shock (laryngeal edema with airway narrowing, rapid heartbeat, dyspnea, hypotension, swollen tongue, anal pruritus, genital pruritus, facial swelling), exudative multiform erythema, Stevens–Johnson syndrome, Lyell’s syndrome, eosinophilia, arthralgia, serum sickness, bronchospasm.

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

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; prolonged use may lead to dysbiosis, candidiasis of the gastrointestinal tract (including candidal stomatitis). If diarrhea occurs during antibiotic therapy, appropriate treatment should be initiated immediately.

Hepatobiliary disorders: in isolated cases, transient increases in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, bilirubin and/or lactate dehydrogenase have been observed; transient hepatitis and cholestatic jaundice.

Renal and urinary 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 disorders (nephropathy, renal papillary necrosis, renal failure), proteinuria have been reported.

Vascular disorders: thrombophlebitis.

Nervous system disorders: headache, dizziness, paresthesia, nervousness or anxiety, excitation, hyperactivity, seizures, intrusive dreams, insomnia, somnolence, fatigue, hot flashes, blurred vision, confusion, and increased cerebral epileptogenic 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 pruritus, genital candidiasis and vaginitis, oral mycosis, genital mycosis may occur. Prolonged use may lead to superinfection caused by drug-resistant pathogens. Prolonged administration of cephalosporins may result in overgrowth of resistant organisms, particularly Enterobacter, Citrobacter, Pseudomonas, Enterococcus, Candida.

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

Shelf life.

Cefazolin, powder for injection solution 1.0 g – 2 years.

Water for injections, solvent for parenteral use, 10 ml in ampoule – 4 years.

Storage conditions.

Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.

Incompatibility.

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

Packaging.
1 g of powder in a vial; 1, 5, or 50 vials per carton; or 1 or 5 vials per blister, 1 blister per carton; 1 vial and 1 ampoule of solvent (water for injections, 10 ml per ampoule) in a blister, 1 blister per carton.

Prescription status.

Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhim-Kharkiv". LLC "Lekhim-Obukhiv".

Manufacturer's address and location of business activity.

Ukraine, 61115, Kharkiv region, Kharkiv city, Severin Pototskoho Street, 36.

Ukraine, 08700, Kyiv region, Obukhiv city, Kyivska Street, 126 A.