Cefazolin 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFAZOLIN 500 CEFAZOLIN 1000 (CEFAZOLIN 500) (CEFAZOLIN 1000)

Composition:

Active substance: cefazolin;

Each vial contains cefazolin in the form of cefazolin sodium 0.5 g or 1 g.

Each set for preparation of solution for intramuscular and intravenous injections contains:

1 vial: cefazolin (in the form of cefazolin sodium) — 0.5 g or 1 g.

1 ampoule of 5 ml or 10 ml solvent: water for injections.

Pharmaceutical form. Powder for injection solution.

Main physicochemical properties: crystalline powder or mass of white or almost white color.

Solvent: water for injections, solvent for parenteral administration.

Main physicochemical properties: colorless transparent liquid.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. First-generation cephalosporins. ATC code J01D B04.

Pharmacological properties.

Pharmacodynamics.

Cefazolin is a semi-synthetic first-generation cephalosporin antibiotic intended for parenteral administration. Its antimicrobial mechanism of action is associated with inhibition of the enzyme transpeptidase, thereby blocking muropeptide biosynthesis in the bacterial cell wall. Cefazolin is a broad-spectrum antibiotic active against many Gram-positive and Gram-negative microorganisms. The drug is active against the following Gram-positive microorganisms: Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (methicillin-resistant staphylococci are also resistant to cefazolin), ß-hemolytic streptococci group A, and other streptococcal strains (many enterococcal strains are resistant to the drug), Streptococcus (Diplococcus) pneumoniae, Corynebacterium diphtheriae, Bacillus anthracis; as well as the following Gram-negative microorganisms: Escherichia coli, Proteus mirabilis, Klebsiella spp., Enterobacter aerogenes, Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Shigella spp., Salmonella spp., Treponema spp., Leptospira spp. Most indole-positive strains of Proteus (Proteus vulgaris), as well as Enterobacter cloacae, Morganella morganii, Providencia rettgeri, Serratia, Pseudomonas spp., Acinetobacter spp., and anaerobic cocci Peptococcus, Peptostreptococcus, including B. fragilis, are resistant to cefazolin. Rickettsiae, viruses, fungi, and protozoa are not susceptible to the drug.

Breakpoints for susceptibility testing. Breakpoints for minimum inhibitory concentration (MIC), as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

1. Isolates susceptible to cefadroxil and/or cephalexin may be reported as "susceptible, increased exposure" (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, which have no breakpoints and should not be used for the treatment of staphylococcal infections. For orally administered agents, adequate concentrations at the site of infection should be ensured. If susceptibility to cefotaxime and ceftriaxone is reported for methicillin-susceptible staphylococci, they should be reported as "susceptible, increased exposure" (I). Some methicillin-resistant S. aureus strains are susceptible to ceftaroline and ceftobiprole.
3. Susceptibility of group A, B, C, and G streptococci to cephalosporins is determined based on susceptibility to benzylpenicillin.

Pharmacokinetics.

After intramuscular administration, the drug is rapidly absorbed; approximately 90% of the administered dose binds to plasma proteins. Maximum plasma concentration after intramuscular injection is achieved within 1 hour and ranges from 37 to 64 µg/mL. After intravenous administration, maximum drug concentration is reached immediately after infusion and amounts to 185 µg/mL.

Therapeutic plasma concentration lasts 8–12 hours. The drug penetrates well into tissues and body fluids, crosses inflamed synovial membranes into joints and into the peritoneal cavity. Cefazolin readily crosses the placental barrier. The drug is minimally metabolized in the liver and excreted into bile. A substantial portion of the administered dose (approximately 60–90%) is excreted within the first 6 hours (70–95% within 24 hours). Cefazolin is excreted unchanged in urine. A small amount of the drug may pass into breast milk.

Elimination half-life is approximately 2 hours after intramuscular administration and 1.8 hours after intravenous administration. In renal impairment, the elimination half-life ranges from 3 to 42 hours.

Clinical characteristics.

Indications.

Infectious-inflammatory diseases 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 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 — risk of bleeding increases. When high doses of oral anticoagulants (e.g., warfarin or heparin) are used 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 health status. Such 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 agents, 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 carefully monitored. Renal function may be impaired due to tubular secretion blockade of 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 and typhoid vaccine; therefore, such combinations are not recommended. An interval of at least 24 hours should be maintained between administration of the last dose of the antibiotic and a live vaccine.

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

Special precautions for use.

Before starting each new course of treatment with cefazolin, it is necessary to determine whether the patient has previously experienced hypersensitivity reactions 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, in some cases with fatal outcomes.

There is a possibility of cross-allergic reactions between penicillins and cephalosporins. Severe hypersensitivity reactions (including anaphylaxis) have been reported.

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

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

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

Antibacterial therapy, particularly 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 must be considered in all patients who develop diarrhea during or after cefazolin administration. Cefazolin therapy should be discontinued in cases of severe diarrhea and/or bloody diarrhea, and appropriate treatment initiated.

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

Cautious administration is required 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 also recommended 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 increased to avoid toxic effects.

In renal insufficiency with a glomerular filtration rate of less than 55 mL/min, the possibility of cefazolin accumulation 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 taking other nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g., furosemide). The use of high doses of cefazolin in patients with renal insufficiency is associated with a risk of seizures.

Dose adjustment in elderly patients with normal renal function is not required.

Intrathecal administration of the drug is not recommended. Reports have described severe toxic reactions affecting the central nervous system, including seizures, following this route of administration, as well as after overdose in the context of renal dysfunction.

Coagulation disorders may occur in isolated cases during cefazolin therapy. During prolonged treatment, regular monitoring of blood counts, 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 after prolonged antibiotic therapy), and in patients previously treated with anticoagulants prior to cefazolin administration, 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. Coagulation should be monitored in patients with the aforementioned conditions. If coagulation parameters worsen, 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 glucose in urine. Results of direct and indirect Coombs tests may also be falsely positive, for example in newborns whose mothers received cephalosporins.

Sodium. The medicinal product contains sodium, which should be taken into account if the patient is on a sodium-restricted 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.

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 during treatment, nervous system disturbances such as dizziness and seizures may occur.

Administration and Dosage

Cefazolin is administered intramuscularly and 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. Shake thoroughly until complete dissolution. Inject deeply into the upper outer quadrant of the gluteal muscle.

For intravenous bolus injection, the single dose of the drug 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, dissolve 500 mg or 1000 mg 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. Administer over 20–30 minutes (infusion rate of 60–80 drops/min). Shake the vial vigorously during dilution until complete dissolution. Daily doses for intravenous administration remain the same as for intramuscular administration.

Dosage. The average daily dose of cefazolin for adults is usually 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.

For infections caused by susceptible gram-negative microorganisms, the drug is administered at 0.5–1 g every 6–8 hours.

For 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 0.5–1 hour before the start of surgery;
• for prolonged surgeries (2 hours or more) — 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 prostheses), prophylactic use of cefazolin may continue for 3–5 days after surgery.

For 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) is administered. The average duration of treatment is 7–10 days.

For 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.

Based on creatinine clearance and serum creatinine concentration, respectively:

• 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 dosing interval of 12 hours;
• <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.

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 an initial loading dose. The average duration of treatment is 7–10 days.

Children. The drug is not to be used in children under 1 month of age and in premature infants.

Overdose.

Symptoms: dizziness, paresthesia, and headache; allergic reactions may occur. In patients with chronic renal failure, neurotoxic effects may develop, including increased seizure susceptibility, generalized seizures, vomiting, and tachycardia. Laboratory abnormalities may 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.

Side effects.

Immune system disorders: rash, itching, skin redness, 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: 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, 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 and 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 elevations in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, bilirubin, and/or lactate dehydrogenase have been observed; 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, excitement, hyperactivity, convulsions, persistent nightmares, insomnia, somnolence, weakness, hot flashes, blurred vision, confusion, and increased cerebral epileptogenic activity.

Injection site reactions: 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 cavity mycosis, genital mycosis may occur. Prolonged use may lead to superinfection caused by organisms resistant to the drug. Long-term use of cephalosporins may promote overgrowth of resistant microorganisms, particularly Enterobacter, Citrobacter, Pseudomonas, Enterococcus, Candida.

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

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

Cefazolin, powder for solution for injection — 3 years.

Water for injections — 4 years.

The shelf life is determined by the component of the medicinal product (powder or solvent) with the earlier expiration date.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Reconstituted solution: store at 2–8 °C.

Incompatibility.

The medicinal product should not be mixed with other medicinal products.

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

Packaging.

For the manufacturer Private Joint-Stock Company "Lekhim-Kharkiv":

0.5 g of powder in a vial;
1, 10, or 50 vials with powder in a carton;
1 vial with powder and 1 ampoule of solvent (Water for injections, 5 ml in an ampoule) in a blister, 1 blister in a carton;
or 1 g of powder in a vial;
1, 5, or 50 vials with powder in a carton;
1 vial with powder and 1 ampoule of solvent (Water for injections, 10 ml in an ampoule) in a blister, 1 blister in a carton.

For the manufacturer LLC "Lekhim-Obukhiv":

0.5 g of powder in a vial;
50 vials with powder in a carton;
1 vial with powder and 1 ampoule of solvent (Water for injections, 5 ml in an ampoule) in a blister; 1 blister in a carton;
1 vial with powder in a blister; 1 blister in a carton;
5 vials with powder in a blister; 2 blisters in a carton;
or 1 g of powder in a vial;
1 vial with powder in a blister; 1 blister in a carton;
5 vials with powder in a blister; 1 blister in a carton;
50 vials with powder in a carton;
1 vial with powder and 1 ampoule of solvent (Water for injections, 10 ml in an ampoule) in a blister; 1 blister in a carton.

Prescription status. Prescription only.

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

Manufacturer's address and place of business.

Ukraine, 61115, Kharkiv region, city of Kharkiv, Severyna Pototskoho Street, 36.

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