ZOIDIM

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

Composition:

Active substance: ceftazidime;

One vial contains ceftazidime pentahydrate equivalent to ceftazidime 1000 mg;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white crystalline powder.

Pharmacotherapeutic group.

Antibacterial agent for systemic use. Third-generation cephalosporins.

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.

Acquired resistance to the antibiotic varies across different regions and may change over time, with significant differences observed among individual strains. It is advisable to use local (regional) data on antibiotic susceptibility and prevalence of microorganisms producing extended-spectrum beta-lactamases, especially when treating severe infections.

Susceptible microorganisms

Gram-positive aerobes: Streptococcus pyogenes, Streptococcus agalactiae.

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

Strains with possible acquired resistance

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

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus pneumoniae, Viridans group streptococcus.

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 500 mg and 1 g, 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 the drug, mean serum concentrations of 46 mg/L, 87 mg/L, or 170 mg/L are achieved, respectively. Therapeutically effective concentrations persist in serum for up to 8–12 hours after both intravenous and intramuscular administration. Plasma protein binding is approximately 10%. Effective concentrations exceeding the 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 placental barrier and is excreted into breast milk. The drug poorly penetrates the intact blood-brain barrier; in the absence of inflammation, CNS concentrations are low. However, during meningitis, ceftazidime concentrations in the CNS 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 administered dose is recovered in urine within 24 hours. In patients with impaired renal function, ceftazidime elimination is reduced, and dosage adjustment is required. Less than 1% of the administered dose is excreted in bile, significantly limiting the amount of drug 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.

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

Ceftazidime may be used for prophylaxis of urinary tract infections 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" and "Pharmacological properties").

Ceftazidime should be used 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 on the use of antibacterial agents.

Contraindications.

Hypersensitivity to ceftazidime or to any of the excipients of the medicinal product.

Hypersensitivity to other 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 interactions.

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

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

Like other antibiotics, Zoidim may affect intestinal 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 be observed when using copper reduction methods (Benedict, Fehling, Clinitest).

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

Special precautions.

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 should be initiated.

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

Severe skin adverse reactions (SSARs), 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. These reactions may be life-threatening or fatal and occur with an "unknown" frequency.

Patients should be informed about the signs and symptoms of these reactions, and careful monitoring for skin reactions is required.

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

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

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections unless it has been established that the causative pathogen is susceptible to the drug, or there is a high likelihood that the probable pathogen will be susceptible to ceftazidime. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Additionally, ceftazidime is susceptible to hydrolysis by extended-spectrum beta-lactamases (ESBLs). Therefore, when selecting ceftazidime for treatment, 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 agents 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 adjusted 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 "Adverse reactions").

As with other broad-spectrum antibiotics, prolonged treatment with Zoidim may result in overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci). In such cases, discontinuation of therapy or other necessary measures may be required. Continuous monitoring of the patient's condition is essential.

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

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.

Important information about excipients.

Zoidim contains 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 any direct or indirect harmful effects on pregnancy, embryonal or postnatal development. The drug should be prescribed during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Data on effects on fertility are lacking.

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Method of administration and dosage.

Adults and children ≥ 40 kg

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

Children < 40 kg

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

Children

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

Geriatric patients

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

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. Careful clinical monitoring of efficacy and safety 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 loading dose should be 1 g. The maintenance dose should be based on creatinine clearance.

Recommended maintenance doses of ceftazidime in renal impairment – intermittent administration

Adults and children ≥ 40 kg body weight

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 < 40 kg

*This is the serum creatinine level calculated according to recommendations and 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 selection should be cautious. Careful clinical monitoring of the efficacy and safety of the drug is recommended.

Children < 40 kg

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

If administration of the drug by continuous intravenous infusion is required in children with renal impairment, 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 (see table below), should be administered after each hemodialysis session.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis, including continuous ambulatory peritoneal dialysis.

In addition to intravenous administration, ceftazidime can 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 per day as a single dose or divided doses. For low-flux hemofiltration, doses should be adjusted as in renal impairment.

For patients undergoing venovenous hemofiltration and venovenous hemodialysis, dosing recommendations are provided in the tables.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

and 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

Zoetim 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 disease, sensitivity, location and type of infection, as well as the patient's age and renal function.

Preparation instructions

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

Vials are produced under reduced pressure. During dissolution of the drug, carbon dioxide is released and the pressure inside the vial increases. Small bubbles of carbon dioxide in the dissolved drug can be disregarded.

*Note. Reconstitution should be carried out in two steps (see text).

The solution color varies from light yellow to amber depending on concentration, diluent, and storage conditions. Provided the 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; 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% dextran 70 and 0.9% sodium chloride solution; 6% dextran 70 and 5% glucose solution.

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

For intramuscular administration, ceftazidime can be reconstituted with 0.5% or 1% lidocaine hydrochloride solution.

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

Preparation of solutions 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, ensuring the needle remains submerged in the solution at all times. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions 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 needle through the stopper until the drug is fully dissolved. After complete dissolution, insert an air needle through the stopper into the vial to relieve internal pressure.
4. Add the resulting solution to an intravenous infusion system to achieve a total solution volume of at least 50 mL and administer by intravenous infusion over 15–30 minutes.

Note. To ensure sterility of the product, it is essential not to insert an air needle through the stopper before the drug is completely dissolved.

After reconstitution

After reconstitution, the medicinal product maintains chemical and physical stability for 6 days at 4°C and for 9 hours at 25°C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, responsibility for the duration and conditions of storage prior to use rests with the user. If reconstitution was not performed under controlled and validated aseptic conditions, the solution should be stored for no longer than 24 hours at a temperature of 2–8°C.

After dilution

After dilution, the medicinal product maintains chemical and physical stability for 6 days at 4°C and for 9 hours at 25°C.

From a microbiological standpoint, the solution should be used immediately after reconstitution and dilution. If not used immediately, responsibility for the duration and conditions of storage prior to use rests with the user.

If reconstitution was not performed under controlled and validated aseptic conditions, the solution must be stored for no longer than 24 hours at a temperature of 2–8°C.

Children.

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

Overdose.

Symptoms.

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 "Special precautions" and "Dosage and administration").

Treatment.

Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

Adverse reactions have been classified by frequency of occurrence – from very common to uncommon, and by organ systems: 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 (cannot be estimated from available data).

Infections and infestations

Uncommon – candidiasis (including vaginitis and candidal stomatitis).

Blood and lymphatic system disorders

Common – eosinophilia and thrombocytosis.

Uncommon – leukopenia, neutropenia, and thrombocytopen游戏副本