Zacef

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

Composition:

Active substance:
ceftazidime;

1 vial contains 1 g of ceftazidime (as sterile ceftazidime pentahydrate, calculated as 100% dry ceftazidime);

Excipient:
sodium carbonate.

Pharmaceutical form.
Powder for solution for injection.

Main physicochemical properties:
crystalline powder of white or white with a creamy shade.

Pharmacotherapeutic group.
Antibacterials for systemic use. Other
β-lactam antibiotics. Third-generation cephalosporins. Ceftazidime.

ATC code
J01D D02.

Pharmacological Properties.

Pharmacodynamics.

Ceftazidime is a bactericidal cephalosporin antibiotic whose mechanism of action is related to inhibition of bacterial cell wall synthesis. It exhibits high activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains resistant to gentamicin and other aminoglycosides. It is highly stable against the action of most β-lactamases produced by both Gram-positive and Gram-negative microorganisms. Ceftazidime demonstrates high activity in vitro and acts within a narrow range of minimum inhibitory concentrations (MIC) against the majority of infectious agents.

Ceftazidime is active against the following microorganisms:

Gram-negative:

Pseudomonas aeruginosa, Pseudomonas spp. (including Ps. pseudomallei), Escherichia coli, Klebsiella spp. (including Klebsiella pneumoniae), Proteus mirabilis, Proteus vulgaris, Morganella morganii (Proteus morganii), Proteus rettgeri, Providencia spp., Enterobacter spp., Citrobacter spp., Serratia spp., Salmonella spp., Shigella spp., Yersinia enterocolitica, Pasteurella multocida, Acinetobacter spp., Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae (including ampicillin-resistant strains), Haemophilus parainfluenzae (including ampicillin-resistant strains);

Gram-positive:

Staphylococcus aureus (methicillin-susceptible strains), Staphylococcus epidermidis (methicillin-susceptible strains), Micrococcus spp., Streptococcus pyogenes (β-hemolytic group A streptococci), Streptococcus group B (Streptococcus agalactiae), Streptococcus pneumoniae, Streptococcus mitis, Streptococcus spp. (excluding Streptococcus faecalis);

Anaerobic:

Peptococcus spp., Peptostreptococcus spp., Streptococcus spp., Propionibacterium spp., Clostridium perfringens, Fusobacterium spp., Bacteroides spp. (many strains of Bacteroides fragilis are resistant).

Ceftazidime is inactive in vitro against methicillin-resistant staphylococci, Streptococcus faecalis and many other enterococci, Listeria monocytogenes, Campylobacter spp., and Clostridium difficile.

Pharmacokinetics.

In patients, after intramuscular injection of 500 mg and 1 g of ceftazidime, mean peak serum concentrations of 18 mg/L and 37 mg/L are rapidly achieved, respectively. Within 5 minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g of ceftazidime, mean serum concentrations reach 46 mg/L, 87 mg/L, and 170 mg/L, respectively. Therapeutically effective concentrations persist in serum even 8–12 hours after intravenous or intramuscular administration. Plasma protein binding is approximately 10%. Concentrations of ceftazidime exceeding the MIC for most common pathogenic microorganisms are achieved in the following tissues and fluids: bone, heart, bile, sputum, intraocular fluid, synovial, pleural, and peritoneal fluids. Ceftazidime rapidly crosses the placenta and is excreted into breast milk. The drug poorly penetrates the intact blood-brain barrier; in the absence of inflammation, drug concentrations in the CNS are low. However, during meningitis, ceftazidime concentrations in the CNS reach 4–20 mg/L or higher, corresponding to therapeutic levels.

Ceftazidime is not metabolized in the body. After parenteral administration, high and sustained serum concentrations of ceftazidime are achieved. The elimination half-life is approximately 2 hours. The drug is excreted unchanged and in active form in urine via glomerular filtration; approximately 80–90% of the dose is eliminated within 24 hours. In patients with impaired renal function, ceftazidime elimination is reduced, and therefore dosage adjustment is required. Less than 1% of the drug is excreted in bile, significantly limiting the amount reaching the intestinal tract.

Clinical characteristics.

Indications.

Treatment of the following infections in adults and children, including newborns:

• hospital-acquired pneumonia;

• respiratory tract infections in patients with cystic fibrosis;

• bacterial meningitis;

• chronic suppurative otitis media;

• malignant external otitis;

• complicated urinary tract infections;

• complicated skin and soft tissue infections;

• complicated intra-abdominal infections;

• bone and joint infections;

• peritonitis associated with peritoneal dialysis in patients undergoing continuous ambulatory peritoneal dialysis.

Treatment of bacteremia arising in patients as a result of any of the above infections.

Ceftazidime may be used for the treatment of patients with neutropenia and fever resulting from bacterial infection.

Ceftazidime may be used for prophylaxis of infectious complications during prostate surgery (transurethral resection).

When prescribing ceftazidime, its antibacterial spectrum, primarily directed against Gram-negative aerobes, should be taken into account (see sections "Special precautions for use" and "Pharmacological properties").

Ceftazidime should be administered in combination with other antibacterial agents if it is expected that some of the microorganisms causing the infection are not covered by the spectrum of ceftazidime.

The drug should be prescribed in accordance with current official recommendations for the use of antibacterial agents.

Contraindications.

• Hypersensitivity to ceftazidime pentahydrate or to any of the excipients of the drug.
• Hypersensitivity to cephalosporin antibiotics.
• History of severe hypersensitivity (e.g., anaphylactic reactions) to other β-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

• Nephrotoxic agents:* Concomitant treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g.,
• furosemide* ) may adversely affect renal function. If combination therapy is necessary, renal function should be monitored throughout the treatment course (also see section "Incompatibilities").

Chloramphenicol in vitro is an antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown, but when administering Zacef together with chloramphenicol , antagonism should be considered as a possibility.

Coumarins: Concomitant use may enhance their anticoagulant effect.

Like other antibiotics, ceftazidime may affect the intestinal flora, leading to reduced reabsorption of estrogens and reduced efficacy of combined oral contraceptives . Therefore, alternative non-hormonal methods of contraception are recommended.

Probenecid: slows down the excretion of ceftazidime, promoting its accumulation and prolonged elevation of plasma concentrations.

Typhoid vaccine: the use of antibacterial agents should be avoided for 3 days before and after administration of the oral typhoid vaccine.

Ceftazidime does not interfere with enzymatic methods for glucose in urine testing; however, a slight interference may be observed when using copper reduction methods (Benedict, Fehling, Clinitest).

Ceftazidime does not interfere with the alkaline picrate method for creatinine determination.

Special precautions for use.

Hypersensitivity

As with other β-lactam antibiotics, severe and sometimes fatal hypersensitivity reactions have been reported. If an allergic reaction occurs, the drug must be discontinued immediately. Severe hypersensitivity reactions may require administration of adrenaline, antihistamines, corticosteroids, and other emergency measures.

Prior to initiating therapy, patients should be questioned about previous hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, penicillins, or other β-lactam antibiotics. The drug should be administered with caution in patients who have had mild hypersensitivity reactions to other β-lactam antibiotics.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported during treatment with ceftazidime with an incidence of "unknown". These reactions may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of skin reactions, and closely monitored for the development of such signs and symptoms.

If signs or symptoms suggestive of these reactions occur, ceftazidime should be discontinued immediately and alternative therapy considered.

If a serious reaction such as SJS, TEN, DRESS, or AGEP develops during ceftazidime treatment, ceftazidime therapy must never be restarted.

Spectrum of antibacterial activity

Ceftazidime has a limited spectrum of antibacterial activity. It is not suitable for use as monotherapy for certain types of infections, except when the causative pathogen has been documented and is known to be susceptible to this drug, or when there is a high probability that the most likely pathogen will be susceptible to ceftazidime. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, or bone and joint infections. Furthermore, ceftazidime is susceptible to hydrolysis by certain extended-spectrum β-lactamases. Therefore, when selecting ceftazidime for treatment, information regarding the prevalence of microorganisms producing extended-spectrum β-lactamases should be taken into account.

Renal function impairment

Concomitant treatment with high doses of cephalosporins and nephrotoxic agents such as aminoglycosides or potent diuretics (e.g., furosemide) may adversely affect renal function. This is unlikely when recommended dosages are followed. There are no data on a negative effect of ceftazidime on renal function when administered at usual therapeutic doses.

Ceftazidime is eliminated by the kidneys; therefore, the dose should be reduced according to the degree of renal impairment. Cases of neurological complications have been reported when the dose was not appropriately reduced.

Overgrowth of non-susceptible microorganisms

As with other broad-spectrum antibiotics, prolonged treatment with Zacef may result in overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci). In such cases, treatment should be discontinued and other necessary measures taken. It is essential to monitor the patient’s condition continuously.

As with other cephalosporins and penicillins, some previously susceptible strains of Enterobacter spp. and Serratia spp. may become resistant during treatment with ceftazidime. In such cases, periodic susceptibility testing should be performed.

Pseudomembranous colitis

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported with the use of antibiotics. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. If prolonged and severe diarrhea occurs, or if abdominal cramps develop, treatment should be discontinued immediately, further investigations performed, and specific therapy for Clostridium difficile initiated as needed. Medicinal products that inhibit intestinal peristalsis should not be prescribed.

Sodium content

Zacef contains sodium: 1 vial with 1 g of ceftazidime contains approximately 51 mg of sodium, which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Data on ceftazidime use in pregnant women are limited. Animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonal or postnatal development. The drug should be administered during pregnancy only if the potential benefit justifies the possible risk.

Ceftazidime is excreted in breast milk in small amounts, but no effect on the breastfed infant is expected when therapeutic doses are used. Ceftazidime may be used during breastfeeding.

Ability to influence reaction speed when driving or operating machinery

The possibility of dizziness and seizures occurring in some patients should be considered. Therefore, caution should be exercised when driving or operating other potentially hazardous machinery requiring heightened attention and rapid psychomotor responses during treatment.

Method of administration and dosage.

The dosage depends on the severity of the disease, sensitivity, location and type of infection, as well as on the patient's age and renal function.

Adults and children ≥ 40 kg Table 1

Children < 40 kg Table 2

*If this is associated or suspected to be associated with infections listed in the section "Indications".

Children

The safety and efficacy of the use of Zacef by continuous intravenous infusion in infants and children ≤ 2 months of age have not been established.

Elderly patients

Due to reduced ceftazidime clearance, the daily dose in elderly patients with acute infections, particularly those aged 80 years and older, should not exceed 3 g.

Hepatic impairment

Dosage adjustment is not required in patients with mild to moderate hepatic impairment. Clinical studies in patients with severe hepatic impairment have not been conducted. Close clinical monitoring of efficacy and safety of the drug is recommended in these patients.

Renal impairment

Ceftazidime is eliminated unchanged by the kidneys; therefore, the dose should be reduced in this patient group.

The initial dose should be 1 g. Maintenance dosing should be based on glomerular filtration rate.

Recommended maintenance doses of ceftazidime in renal impairment –

intermittent administration

Adults and children ≥ 40 kg body weight Table 3

For patients with severe infections, the single dose may be increased by 50% or, correspondingly, the frequency of administration may be increased. In such patients, monitoring of ceftazidime serum levels is recommended.

In children, creatinine clearance values should be adjusted according to body surface area or body weight.

Children < 40 kg Table 4

*this is the serum creatinine level calculated according to recommendations and may not precisely correspond to the degree of renal function impairment in all patients with renal insufficiency;

**creatinine clearance is estimated based on body surface area or measured directly.

Careful clinical monitoring of patients is recommended to assess the efficacy and safety of the drug.

Recommended maintenance doses of ceftazidime in renal insufficiency – continuous infusion

Adults and children ≥ 40 kg body weight Table 5

Dose selection should be cautious. Careful clinical monitoring of patients is recommended for both efficacy and safety of the drug administration.

Children < 40 kg

The safety and efficacy of the drug Zacef administered by continuous intravenous infusion in children with impaired renal function and body weight < 40 kg have not been established. Careful clinical monitoring of patients is recommended.

If continuous intravenous infusion of the drug is required in children with impaired renal function, creatinine clearance should be adjusted according to the child's body surface area or body weight.

Hemodialysis

The serum half-life of ceftazidime during hemodialysis is 3–5 hours.

A maintenance dose of ceftazidime, as recommended in Table 7 below, should be administered after each hemodialysis session.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis and continuous ambulatory peritoneal dialysis using the standard regimen.

In addition to intravenous administration, ceftazidime can be added to the dialysis fluid (usually 125 mg to 250 mg per 2 L of dialysis solution).

For patients with renal insufficiency undergoing prolonged arteriovenous hemodialysis or high-flux hemofiltration in intensive care units, the recommended dose is 1 g per day as a single dose or divided into several doses. For low-flux hemofiltration, doses should be adjusted according to renal function impairment guidelines.

For patients undergoing venovenous hemofiltration and venovenous hemodialysis, dosing recommendations are provided in Tables 6 and 7.

Table 6

Dosing recommendations for ceftazidime in patients undergoing prolonged
venovenous hemofiltration

*Note. The maintenance dose should be administered every 12 hours.

Table 7

Dosing recommendations for ceftazidime in patients undergoing prolonged
hemodialysis

* The maintenance dose should be administered every 12 hours.

Administration

Zacef must be administered intravenously or by deep intramuscular injection. Recommended sites for intramuscular administration are the upper outer quadrant of the gluteus maximus muscle or the lateral part of the thigh.

Ceftazidime solutions may be administered directly into the vein or into an intravenous infusion system, if the patient is receiving parenteral fluids.

The dosage depends on the severity of the infection, the susceptibility, location, and type of infection, as well as the patient's age and renal function.

Acquired resistance to the antibiotic varies among different regions and may change over time, with significant differences possible among individual strains. It is advisable to use local data on antibiotic susceptibility, especially when treating severe infections.

Instructions for preparation

Zacef is compatible with most commonly used intravenous infusion solutions; however, sodium bicarbonate for injection should not be used as a solvent (see section "Incompatibilities").

Table 8

*Note. Dissolution should be carried out in two stages (see text).

The solution color varies from light yellow to amber depending on concentration, diluent, and storage conditions. When recommendations are followed, the drug's efficacy is not affected by variations in its coloration.

Ceftazidime at concentrations from 1 mg/mL to 40 mg/mL is compatible with the following solutions: 0.9% sodium chloride solution; Hartmann's solution; 5% glucose solution; 0.225% sodium chloride solution in 5% glucose solution; 0.45% sodium chloride solution in 5% glucose solution; 0.9% sodium chloride solution in 5% glucose solution; 0.18% sodium chloride solution in 4% glucose solution; 10% glucose solution; 10% dextran 40 in 0.9% sodium chloride solution; 10% dextran 40 in 5% glucose solution; 6% dextran 70 in 0.9% sodium chloride solution; 6% dextran 70 in 5% glucose solution.

Ceftazidime at concentrations from 0.05 mg/mL to 0.25 mg/mL is compatible with peritoneal dialysis fluid (lactate).

Ceftazidime for intramuscular injection should be dissolved in 0.5% or 1% lidocaine solution.

The efficacy of both agents is maintained when ceftazidime at a concentration of 4 mg/mL is mixed with the following substances: hydrocortisone (hydrocortisone sodium phosphate) 1 mg/mL in 0.9% sodium chloride solution or 0.5% glucose solution; cefuroxime (cefuroxime sodium) 3 mg/mL in 0.9% sodium chloride solution; cloxacillin (cloxacillin sodium) 4 mg/mL in 0.9% sodium chloride solution; heparin 10 IU/mL or 5 IU/mL in 0.9% sodium chloride solution; potassium chloride 10 mEq/L or 40 mEq/L in 0.9% sodium chloride solution.

Preparation of solutions for intramuscular or intravenous bolus injection

Insert the syringe needle through the vial stopper and add the recommended volume of diluent.

Remove the syringe needle and shake the vial until a clear solution is obtained.

Invert the vial. With the syringe plunger fully depressed, insert the needle into the vial. Withdraw the entire solution into the syringe, keeping the needle tip submerged in the solution at all times.

Preparation of solutions for intravenous infusion

Insert the syringe needle through the vial stopper and add 10 mL of diluent.

Remove the syringe needle and shake the vial until a clear solution is obtained.

Do not insert an air vent needle through the stopper until the drug is completely dissolved. Insert an air vent needle through the stopper into the vial to relieve internal pressure.

Without removing the air vent needle, adjust the total volume to 50 mL. Remove the air vent needle, shake the vial, and set up the infusion system as usual.

Note. To ensure sterility of the preparation, it is essential not to insert the air vent needle through the stopper before the drug is fully dissolved.

Children.

Can be used in children from the first days of life.

Overdose.

Symptoms:
Neurological complications such as encephalopathy, seizures, and coma may occur. Symptoms of overdose may appear in patients with renal impairment if the dose is not appropriately reduced. Serum ceftazidime concentrations can be reduced by hemodialysis or peritoneal dialysis.

Treatment:
Symptomatic.

Adverse Reactions

Infections and infestations:
Candidiasis (including vaginitis and candidal stomatitis).

Immune system:
Anaphylaxis (including bronchospasm and/or arterial hypotension).

Blood and lymphatic system:
Eosinophilia, thrombocytosis, leukopenia, neutropenia, thrombocytopenia, lymphocytosis, hemolytic and aplastic anemias, agranulocytosis, hemorrhages.

Nervous system:
Dizziness, headache, paresthesia. Neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment who did not receive an appropriately reduced dose of ceftazidime.

Vascular disorders:
Phlebitis or thrombophlebitis at the injection site.

Gastrointestinal tract:
Diarrhea, nausea, vomiting, abdominal pain, colitis (including pseudomembranous colitis, which may be associated with Clostridium difficile), taste disturbances.

Urinary system:
Interstitial nephritis, acute renal failure.

Hepatobiliary system:
Transient elevations in liver enzymes (ALT, AST, LDH, GGT, alkaline phosphatase), jaundice.

Skin and subcutaneous tissue:
Maculopapular rash, urticaria, pruritus, angioneurotic edema, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP).

General disorders and administration site conditions:
Pain and/or inflammation at the site of intramuscular injection, drug fever.

Psychiatric disorders:
Confusion, hallucinations.

Laboratory findings:
Positive Coombs test (observed in approximately 5% of patients, which may interfere with blood grouping). As with other cephalosporins, transient increases in plasma levels of urea, blood urea nitrogen, and/or creatinine have occasionally been observed.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after the medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aіsf.dec.gov.ua.

Shelf life.
3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

The reconstituted solution remains stable for 10 hours at 25 °C, for 24 hours at temperatures not exceeding 18 °C, and for 7 days at temperatures up to 4 °C.

From a microbiological standpoint, the reconstituted solution should be used immediately. If this is not possible, storage for up to 24 hours at 2–8 °C is permitted.

Incompatibilities.

Ceftazidime is less stable in sodium bicarbonate injection solution than in other intravenous diluents and therefore is not recommended as a solvent.

Ceftazidime and aminoglycosides should not be mixed in the same infusion system or syringe.

Precipitation may occur if vancomycin is added to a ceftazidime solution. Therefore, infusion systems and intravenous catheters should be flushed between administration of these two agents.

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

Packaging.
1 g in a vial. 1 vial per pack; 1 vial per carton; 5 vials per cassette, 1 cassette per case.

Prescription category.
Prescription only.

Manufacturer.

Public Joint-Stock Company “Scientific and Production Center “Boryspil Chemical-Pharmaceutical Plant”.

Location and address of manufacturer’s place of business.

Ukraine, 03134, Kyiv, Miru St., 17.