Zedan

INSTRUCTIONS for medical use of the medicinal product ZEDAN

Composition:

Active substance: ceftazidime;

One vial contains ceftazidime pentahydrate equivalent to ceftazidime 1000 mg;

Excipient: sodium carbonate anhydrous.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: almost white or yellowish powder.

Pharmacotherapeutic group. Antibacterials for systemic use. Third-generation cephalosporins. ATC code J01DD02.

Pharmacological properties.

Pharmacodynamics.

Ceftazidime is a bactericidal cephalosporin antibiotic whose mechanism of action is related to inhibition of bacterial cell wall synthesis.

Acquired resistance to the antibiotic varies across regions and over time, and may differ significantly among individual strains. Local data on antibiotic susceptibility should be consulted, especially when treating severe infections.

Susceptible microorganisms

Gram-positive aerobes: Streptococcus pyogenes, Streptococcus agalactiae.

Gram-negative aerobes: Citrobacter koseri, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Proteus mirabilis, Proteus spp., Providencia spp.

Strains capable of developing resistance

Gram-negative aerobes: Acinetobacter baumannii, Burkholderia cepacia, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Morganella morganii.

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus pneumoniae.

Gram-positive anaerobes: Clostridium perfringens, Peptococcus spp., Peptostreptococcus spp.

Gram-negative anaerobes: Fusobacterium spp.

Resistant microorganisms

Gram-positive aerobes: Enterococcus spp., including E. faecalis and E. faecium, Listeria spp.

Gram-positive anaerobes: Clostridium difficile.

Gram-negative anaerobes: Bacteroides spp., including B. fragilis.

Others: Chlamydia spp., Mycoplasma spp., Legionella spp.

Pharmacokinetics.

After intramuscular injection of 1 g, a mean peak concentration of 37 mg/L is rapidly achieved in patients. Within 5 minutes after intravenous bolus administration of 1 g, mean serum concentrations of 87 mg/L are reached. Therapeutically effective concentrations persist in serum for up to 8–12 hours after both intravenous and intramuscular administration. Plasma protein binding is approximately 10%. Concentrations exceeding the minimum inhibitory concentration (MIC) for most common pathogenic microorganisms are achieved in tissues and body fluids such as bone, heart, bile, sputum, intraocular fluid, synovial fluid, pleural fluid, and peritoneal fluid. Ceftazidime rapidly crosses the placenta and is excreted in breast milk. The drug poorly penetrates the intact blood-brain barrier; in the absence of inflammation, drug concentrations in the central nervous system (CNS) are low. However, during meningitis, CNS concentrations of ceftazidime reach 4–20 mg/L or higher, achieving therapeutic levels.

Ceftazidime is not metabolized in the body. After parenteral administration, high and sustained serum concentrations are achieved. The elimination half-life is approximately 2 hours. The drug is excreted unchanged, in active form, in urine via glomerular filtration; approximately 80–90% of the dose is recovered in urine within 24 hours. In patients with impaired renal function, elimination of ceftazidime is reduced, and 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 dialysis in patients undergoing continuous ambulatory peritoneal dialysis.

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

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

Zedan can be used for prophylaxis of infectious complications during prostate surgery (transurethral resection).

When prescribing ceftazidime, it should be borne in mind that its antibacterial activity is primarily directed against gram-negative aerobes (see sections «Special precautions for use» and «Pharmacological properties»).

Zedan 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 activity.

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

Contraindications.

Hypersensitivity to ceftazidime or to any of the excipients of the drug.

Hypersensitivity to cephalosporin antibiotics.

History of severe hypersensitivity (e.g., anaphylactic reactions) to other beta-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of high doses of the drug with nephrotoxic medicinal products may adversely affect renal function (see section «Special precautions for use»).

Chloramphenicol is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown; however, if concomitant administration of the drug with chloramphenicol is proposed, the possibility of antagonism should be considered.

Like other antibiotics, ceftazidime may affect the gut flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

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

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

Special precautions for use.

As with other beta-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. If severe hypersensitivity reactions occur, ceftazidime therapy should be discontinued immediately and appropriate emergency measures initiated.

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

Zedan has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections, except when the causative pathogen is known to be susceptible to this drug or when there is a high probability that the 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. In addition, ceftazidime is susceptible to hydrolysis by certain extended-spectrum beta-lactamases. Therefore, when selecting ceftazidime for treatment, local information regarding the prevalence of microorganisms producing extended-spectrum beta-lactamases should be taken into account.

Concomitant administration of high doses of cephalosporins and nephrotoxic drugs, such as aminoglycosides or potent diuretics (e.g., furosemide), may adversely affect renal function. Clinical experience with ceftazidime has shown that this phenomenon is unlikely when recommended dosages are followed. There are no data indicating that ceftazidime adversely affects renal function 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 (see sections "Dosage and administration" and "Side effects").

As with other broad-spectrum antibiotics, prolonged use of this drug may result in overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other interventions may be necessary. Careful patient monitoring is essential.

Cases of pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with antibiotic use. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. If diarrhea is persistent and severe, or if abdominal cramps occur, therapy should be discontinued immediately, further diagnostic evaluation performed, and specific treatment for Clostridium difficile initiated if necessary. Medications that inhibit intestinal peristalsis should not be administered.

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

The product contains sodium (1 g of ceftazidime contains 52 mg of sodium), which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Data on the use of Zedan in pregnant women are limited. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonal or postnatal development. The drug should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Effect on ability to drive and use machines.

No specific studies have been conducted. However, the occurrence of adverse reactions such as dizziness may affect the ability to drive or operate machinery (see section "Side effects").

Method of administration and dosage.

Adults and children with body weight ≥ 40 kg

*If this is associated or there is suspicion of association with infections listed in the section "Indications".

Children with body weight <40 kg

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

Children

The safety and efficacy of administering Zedan by continuous intravenous infusion in infants and children aged ≤ 2 months have not been established.

Older patients

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

Hepatic impairment

Dosage adjustment is not required for patients with mild to moderate hepatic impairment. Clinical studies in patients with severe hepatic impairment have not been conducted. Careful clinical monitoring of efficacy and safety of use is recommended.

Renal impairment

Ceftazidime is excreted unchanged by the kidneys. Therefore, the dose should be reduced in patients with impaired renal function.

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

Recommended maintenance doses of ceftazidime in renal impairment: intermittent administration

Adults and children with body weight ≥ 40 kg

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

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

Children with body weight < 40 kg

*This is the serum creatinine level calculated according to recommendations, and it may not precisely reflect the degree of renal function impairment in all patients with renal insufficiency.

** Creatinine clearance calculated based on body surface area or measured.

Careful clinical monitoring of efficacy and safety of use is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency: continuous infusion

Adults and children with body weight ≥ 40 kg

Dose adjustment should be performed with caution. Careful clinical monitoring of efficacy and safety of use is recommended.

Children with body weight < 40 kg

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

If administration of the drug by continuous intravenous infusion 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 to 5 hours.

After each hemodialysis session, a maintenance dose of ceftazidime as recommended in the table below should be administered.

Peritoneal dialysis

Zedan can be used during peritoneal dialysis, both in standard regimens and in continuous ambulatory peritoneal dialysis.

In addition to intravenous administration, ceftazidime may be added to the dialysis fluid (usually 125 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 daily as a single dose or divided into several doses. For low-flux hemofiltration, doses should be adjusted as in renal impairment.

Dosing recommendations for patients undergoing venovenous hemofiltration and venovenous hemodialysis are provided in the tables below.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

The maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration.

Zedan should be administered intravenously by injection or infusion, 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 dose depends on the severity of the infection, the susceptibility, site, and type of infection, as well as the patient's age and renal function.

Acquired resistance to the antibiotic varies across different regions and may change over time, with significant differences observed among individual strains. Local antibiotic susceptibility data should be used whenever possible, especially when treating severe infections.

Preparation of injection solution

Zedan is compatible with most intravenous infusion solutions. However, sodium bicarbonate injection should not be used as a solvent (see section "Incompatibility").

All vial sizes are manufactured under reduced pressure. As the drug dissolves, carbon dioxide is released and pressure inside the vial increases. Small carbon dioxide bubbles in the reconstituted solution can be disregarded.

*Dissolution should be carried out in two steps (see below).

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 to 40 mg/mL is compatible with the following solutions: 0.9% sodium chloride solution; M/6 sodium lactate solution; Hartmann’s solution; 5% glucose solution; 0.225% sodium chloride and 5% glucose solution; 0.45% sodium chloride and 5% glucose solution; 0.9% sodium chloride and 5% glucose solution; 0.18% sodium chloride and 4% glucose solution; 10% glucose solution; 10% glucose, 40%, and 0.9% sodium chloride solution; 10% glucose, 40%, and 5% glucose solution; 6% dextrin, 70%, and 0.9% sodium chloride solution; 6% dextrin, 70%, and 5% glucose solution.

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

For intramuscular administration, ceftazidime can be dissolved in 0.5% or 1% lidocaine hydrochloride solution.

The efficacy of both drugs is preserved when mixing ceftazidime at a dose of 4 mg/mL with the following substances: hydrocortisone (hydrocortisone sodium phosphate) 1 mg/mL in 0.9% sodium chloride injection solution or 0.5% glucose solution; cefuroxime (cefuroxime sodium) 3 mg/mL in 0.9% sodium chloride injection solution; cloxacillin (cloxacillin sodium) 4 mg/mL in 0.9% sodium chloride injection solution; heparin 10 or 50 IU/mL in 0.9% sodium chloride injection solution; potassium chloride 10 or 40 mEq/L in 0.9% sodium chloride injection solution.

Preparation of solution for intramuscular or intravenous bolus injection:

1. Insert the syringe needle through the vial stopper and add the recommended volume of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. 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. Small bubbles of carbon dioxide gas may be disregarded.

Preparation of solution for intravenous infusion:

1. Insert the syringe needle through the vial stopper and add 10 mL of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. 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.
4. 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.

The prepared solution may be stored for 24 hours at temperatures below 25°C or for 7 days at temperatures up to 4°C.

Children.

Can be administered to children from the first days of life.

Overdose.

Overdose may lead to neurological complications such as encephalopathy, seizures, and coma. Symptoms of overdose may occur in patients with renal impairment if the dose is not appropriately reduced (see sections "Method of administration and dosage" and "Special instructions"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse reactions.

Adverse effects have been classified by organs and systems, and by frequency of occurrence: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10000 and < 1/1000; very rare: < 1/10000; frequency not known.

Infections and infestations

Uncommon — candidiasis (including vaginal vaginitis and aphthous stomatitis).

Blood and lymphatic system disorders

Common — eosinophilia and thrombocytosis.

Uncommon — leukopenia, neutropenia, and thrombocytopenia.

Frequency not known — lymphocytosis, hemolytic anemia, and agranulocytosis.

Immune system disorders

Frequency not known — anaphylaxis (including bronchospasm and/or arterial hypotension).

Nervous system disorders

Uncommon — dizziness, headache.

Frequency not known — paresthesia.

Neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment who did not receive appropriate dose reduction of ceftazidime.

Vascular disorders

Common — phlebitis or thrombophlebitis at the site of administration.

Gastrointestinal disorders

Common — diarrhea.

Uncommon — nausea, vomiting, abdominal pain, and colitis.

As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis (see section "Special precautions").

Frequency not known — taste disturbances.

Renal and urinary disorders

Very rare — interstitial nephritis, acute renal failure.

Hepatobiliary disorders

Common — transient elevation of one or more liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), alkaline phosphatase).

Frequency not known — jaundice.

Skin and subcutaneous tissue disorders

Common — maculopapular rash or urticaria.

Uncommon — pruritus.

Frequency not known — angioneurotic edema, polymorphic erythema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

General disorders and administration site conditions

Common — pain and/or inflammation at the site of intramuscular injection.

Uncommon — fever.

Laboratory findings

Common — positive Coombs test.

Uncommon — transient increase in blood urea, blood urea nitrogen, and/or serum creatinine.

A positive Coombs test occurs in approximately 5% of patients and may interfere with blood grouping.

Shelf life.

3 years (from the date of manufacture of the bulk form).

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Incompatibilities.

Ceftazidime is less stable in sodium bicarbonate injection solution than in other intravenous solutions; therefore, sodium bicarbonate is not recommended as a solvent.

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

Cases of precipitate formation have been observed when vancomycin was added to a ceftazidime solution. Therefore, it is recommended to flush infusion systems and intravenous catheters between administration of these two drugs.

Packaging. 1 or 25 vials with powder in a cardboard box.

Prescription category. Prescription only.

Manufacturer. LLC "AVANT" (packaging of the bulk form produced by NSPC Hebei Huamin Pharmaceutical Company Limited, China).

Manufacturer's address. 14 Anton Tsydyka Street, Kyiv, Ukraine, 03057.

Date of last review.