Cefazolin-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFASOLIN-DARNITSA (CEFAZOLIN-DARNITSA)

Composition:

Active substance: cefazolin;

One vial contains sodium cefazolin equivalent to 0.5 g or 1 g of cefazolin.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or almost white powder. Highly hygroscopic.

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 the biosynthesis of muropeptide in the bacterial cell wall. Cefazolin is a broad-spectrum antibiotic active against many Gram-positive and Gram-negative microorganisms. The drug is effective against the following Gram-positive microorganisms: Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis (methicillin-resistant staphylococci are also resistant to cefazolin), β-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 Proteus strains (including Proteus vulgaris), as well as Enterobacter cloacae, Morganella morganii, Providencia rettgeri, Serratia, Pseudomonas spp., Acinetobacter spp., and anaerobic cocci such as Peptococcus, Peptostreptococcus, including B. fragilis, are resistant to cefazolin. Rickettsiae, viruses, fungi, and protozoa are not susceptible to the drug.

Pharmacokinetics.

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

Therapeutic blood concentrations last for 8–12 hours. The drug penetrates well into tissues and body fluids, crosses the inflamed synovial membrane into joints, and enters the peritoneal cavity. Cefazolin readily crosses the placental barrier. The drug undergoes minimal metabolism in the liver and is excreted with bile. A substantial portion of the administered dose (approximately 60–90%) is excreted within the first 6 hours; by 24 hours, 70–95% is eliminated unchanged in the urine. A small amount of the drug may pass into breast milk.

The 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.

Prophylaxis of surgical infections.

Contraindications.

Hypersensitivity to cephalosporin antibiotics and other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interactions.

When Cefazolin-Darnytsia is used concomitantly with:

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

anticoagulants (e.g., warfarin, heparin) − increased risk of bleeding. Coagulation parameters should be monitored during concomitant use of cefazolin with anticoagulants at high doses. 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;

Vitamin K: some cephalosporins, such as cefazolin, may lead to impaired vitamin K metabolism, especially in cases of its deficiency, which may require additional vitamin K administration;

aminoglycosides and loop diuretics (furosemide, ethacrynic acid), other nephrotoxic medicinal products (including colistin, polymyxin B, vancomycin) − increased risk of nephrotoxicity; kidney function is impaired due to blockade of tubular secretion of cefazolin, in which case the drug dose should be reduced and treatment conducted under monitoring of blood urea nitrogen and serum creatinine levels. Concomitant use with nephrotoxic medicinal products should be avoided;

ethanol − disulfiram-like reactions are possible.

Cefazolin should not be used together with antibacterial medicinal products having a bacteriostatic mechanism of action (tetracyclines, sulfonamides, erythromycin, chloramphenicol).

Cefazolin solution must not be mixed in the same container with other antibiotics.

Cross-reactivity between cefazolin and penicillin-group medicinal products may occur.

Hormonal contraceptives − as with other antibiotics, effectiveness of hormonal contraceptives may be reduced; therefore, additional (non-hormonal) contraceptive methods are recommended during treatment.

Like other antibiotics, cefazolin may reduce the therapeutic effect of the 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 a live vaccine.

Laboratory tests: false-positive results in glucosuria tests are possible when non-enzymatic methods using Benedict's or Fehling's solutions or Clinitest tablets are used; cefazolin does not affect enzymatic methods for measuring glucose in urine. Direct and indirect Coombs' tests may yield false-positive results.

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 determine whether the patient has a history of hypersensitivity reactions to cefazolin, cephalosporins, penicillins, other *β*-lactam antibiotics, or other medicinal products.

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 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 if the detailed medical history does not indicate such reactions. In case 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 development of hemolytic anemia. Cross-reactivity with penicillins may occur in such cases.

Antibiotic-associated colitis/overgrowth of resistant microorganisms. Treatment with antibacterial medicinal products, especially in severe diseases in elderly patients, immunocompromised patients, and children, may lead to 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, if diarrhea occurs during or after cefazolin treatment, these diagnoses, including pseudomembranous colitis, must be ruled out. Cefazolin therapy should be discontinued in cases of severe and/or bloody diarrhea, and appropriate treatment initiated. Antiperistaltic agents should not be used. 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 resistant microorganisms and fungi, resulting in superinfection, which requires appropriate management, including periodic monitoring of microbial sensitivity to the drug.

Renal impairment. In patients with renal impairment, dosage and/or dosing interval 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 dosing interval extended to avoid toxic effects.

In cases of renal impairment with glomerular filtration rate below 55 mL/min, accumulation of cefazolin should be considered. Although cefazolin rarely causes renal dysfunction, 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 (e.g., aminoglycosides, potent diuretics).

Administration of high doses of cefazolin in patients with renal impairment may be associated with 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 setting of renal dysfunction.

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

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

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

The drug is contraindicated during pregnancy.

If cefazolin use is necessary, 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

Before starting therapy, it is necessary to rule out the presence of hypersensitivity to the antibiotic by performing a skin test.

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

Preparation of solutions for injection and infusion.

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

For intravenous bolus injection: dissolve a 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 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, or Ringer's injection solution with or without lactate. Administer over 20–30 minutes (administration rate: 60–80 drops/min). Vials should be shaken vigorously during dilution until complete dissolution. Daily doses for intravenous administration remain the same as for intramuscular administration.

Dosage.

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

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

• at a dose of 1000 mg 0.5–1 hour before the start of surgical intervention;
• during prolonged surgeries (2 hours or more) – an additional dose of 500–1000 mg during the surgery;
• after surgery – 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, dosage regimen should be adjusted according to creatinine clearance. After the 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 – single standard dose should be halved, with dosing intervals of 12 hours;
• less than 10 mL/min – administer half the therapeutic dose every 18–24 hours.

Elderly patients: dosage 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.

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.

The drug should not 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 insufficiency, neurotoxic effects may develop, 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

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Eye disorders:
Color vision impairment.

Respiratory, thoracic and mediastinal disorders:
Cough, rhinitis, chest pain, dyspnea, pleural effusion, interstitial pneumonia, respiratory failure.

Gastrointestinal disorders:
Anorexia, nausea, vomiting, abdominal pain, diarrhea, flatulence, symptoms of pseudomembranous colitis (if diarrhea occurs during or after antibiotic therapy, appropriate treatment should be initiated immediately).

These may occur during or after treatment. With prolonged use, gastrointestinal dysbiosis and candidiasis (including candidal stomatitis) may develop.

Hepatobiliary disorders:
In isolated cases, transient elevations in ALT, AST, and alkaline phosphatase levels have been observed, as well as transient hepatitis, cholestatic jaundice, and hyperbilirubinemia.

Renal and urinary disorders:
Renal function impairment (transient increases in blood urea nitrogen, hypercreatinemia, proteinuria) without clinical signs of renal failure. Rare cases of interstitial nephritis, possibly with pyuria and eosinophiluria, and other renal function disorders (renal papillary necrosis, toxic nephropathy, papillary necrosis, renal failure) have been reported, usually in patients concurrently receiving other potentially nephrotoxic agents.

Animal studies have shown cefazolin to be a potentially nephrotoxic substance. Although nephrotoxicity has not been demonstrated in humans, it should be considered as a possibility, especially in patients receiving high doses over prolonged periods. The role of cefazolin in the development of interstitial nephritis or other nephropathies has not been definitively established.

Nervous system disorders:
General weakness, headache, dizziness, increased fatigue, paresthesia, insomnia/somnolence, hyperactivity, increased excitability (nervousness), anxiety, nightmares, vertigo, hot flashes, confusion, epileptogenic activity, seizures (usually with inappropriately high doses in the presence of renal dysfunction).

Cardiac disorders:
Tachycardia, arterial hypertension.

Blood and lymphatic system disorders:
Cases of leukopenia/leukocytosis, granulocytosis/granulocytopenia, agranulocytosis, monocytosis, neutropenia, lymphopenia, hemolytic anemia, aplastic anemia, thrombocytopenia/thrombocytosis, hypoprothrombinemia, reduced hemoglobin and/or hematocrit, prolonged prothrombin time, coagulopathy and hemorrhage, pancytopenia, basophilia, and eosinophilia have been reported. These adverse reactions are usually reversible and resolve upon discontinuation of therapy.

Immune system disorders:
Hypersensitivity reactions, including drug fever, angioneurotic edema, anaphylactic shock, exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), eosinophilia, arthralgia, serum sickness, bronchospasm, facial swelling, anal pruritus, genital pruritus, interstitial pneumonia/pneumonitis.

Hypersensitivity reactions may occur to any component of the medicinal product, cephalosporin-class antibiotics, penicillins, or other β-lactam antibiotics (monobactams and carbapenems), or to any excipient, including L-arginine.

Skin and subcutaneous tissue disorders:
Pallor, hemorrhages, skin rash, pruritus, skin hyperemia, dermatitis, urticaria, local increase in vascular permeability leading to angioneurotic edema, including of joints and mucous membranes.

General disorders and administration site conditions:
Pain, induration, swelling at the injection site. Cases of phlebitis have been observed following intravenous administration. In isolated cases, anogenital pruritus, genital candidiasis, and vaginitis may occur. With prolonged use, superinfection caused by organisms resistant to the drug may develop.

Investigations:
Hypoglycemia/hyperglycemia. Positive Coombs test.

Shelf life. 3 years.

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

Incompatibilities.
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.
0.5 g or 1 g of powder in a vial; 1, 5, or 40 vials per package.
1 vial containing 0.5 g of powder and 1 ampoule of solvent (Water for Injections-Darnytsia, 5 ml in ampoule) per package.
1 vial containing 1 g of powder and 1 ampoule of solvent (Water for Injections-Darnytsia, 10 ml in ampoule) per package.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsa".

Manufacturer's address and place of business.
13, Boryspilska Street, Kyiv, 02093, Ukraine.