Ceftazidime astra

INSTRUCTIONS for medical use of the medicinal product Ceftazidime Astra

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime pentahydrate equivalent to ceftazidime 1000 mg;

Excipient: sodium carbonate anhydrous.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder, white to cream-colored.

Pharmacotherapeutic group. Antibacterial agent for systemic use. Third-generation cephalosporins. ATC code J01D D02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftazidime inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This leads to disruption of cell wall (peptidoglycan) biosynthesis, resulting in lysis and death of bacterial cells.

PK/PD relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic (PK-PD) index correlating with in vivo efficacy is the percentage of the dosing interval during which the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftazidime for specific target species (i.e., % T > MIC).

Mechanism of resistance

Bacterial resistance to ceftazidime may be due to one or more of the following mechanisms:

• hydrolysis by beta-lactamases. Ceftazidime can be effectively hydrolyzed by extended-spectrum beta-lactamases (ESBLs), including the SHV ESBL family and AmpC enzymes, which may be inducible or stably derepressed in certain aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftazidime;
• impermeability of the outer membrane, limiting ceftazidime access to penicillin-binding proteins in Gram-negative organisms;
• bacterial efflux pumps.

Clinical breakpoints

Minimum inhibitory concentration (MIC) clinical breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

Bacterium	Breakpoints (mg/l)
	Susceptible	Intermediate	Resistant
Enterobacteriaceae	≤ 1	2–4	> 4
Pseudomonas aeruginosa	≤ 8		> 8
Non-species related breakpoints2	≤ 4	8	> 8

• The breakpoint values refer to high-dose therapy (2 g × 3).
  • Species-unrelated breakpoint values were primarily established based on PK/PD data and do not depend on the distribution of MICs of specific bacterial species. They are intended for application only to species not mentioned in the table.

Microbiological susceptibility

The prevalence of acquired resistance in individual species may vary geographically and over time; therefore, local data on microbial resistance should be taken into account, especially when treating severe infections. If necessary, expert advice should be sought when local resistance prevalence renders the benefit of the medicinal product doubtful, at least for certain types of infections.

Susceptible species

Gram-positive aerobes Streptococcus pyogenes Streptococcus agalactiae

Gram-negative aerobes Citrobacter koseri Haemophilus influenzae Moraxella catarrhalis Neisseria meningitidis Pasteurella multocida Proteus mirabilis Proteus spp. (other) Providencia spp.

Species that may develop resistance

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

Gram-positive aerobes Staphylococcus aureus* Staphylococcus pneumoniae** Viridans group streptococcus

Gram-positive anaerobes Clostridium perfringens Peptostreptococcus spp.

Gram-negative anaerobes Fusobacterium spp.

Resistant microorganisms

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

Gram-positive anaerobes Clostridium difficile

Gram-negative anaerobes Bacteroides spp. (most strains of Bacteroides fragilis are resistant)

Others Chlamydia spp. Mycoplasma spp. Legionella spp.

* Staphylococcus aureus methicillin-susceptible strains have intrinsic low-level resistance to ceftazidime. All methicillin-resistant S. aureus are resistant to ceftazidime. ** Streptococcus pneumoniae strains exhibiting intermediate susceptibility or resistance to penicillin can be expected to have at least reduced susceptibility to ceftazidime. + High resistance rates have been observed in one or more areas/countries/regions within the EU.

Pharmacokinetics.

Absorption

In patients, following intramuscular injection of ceftazidime 500 mg and 1 g, mean peak serum concentrations of 18 and 37 mg/L are rapidly achieved, respectively. Within 5 minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g, mean serum concentrations of 46, 87, and 170 mg/L are achieved, respectively. The pharmacokinetics of ceftazidime are linear within the single dose range of 0.5–2 g following either intravenous or intramuscular administration.

Distribution

Plasma protein binding is approximately 10%. Ceftazidime concentrations exceeding the minimum inhibitory concentration (MIC) for most common pathogenic microorganisms are achieved in various tissues and body fluids, including bone, heart, bile, sputum, intraocular fluid, synovial fluid, pleural fluid, and peritoneal fluid. Ceftazidime rapidly crosses the placenta and is excreted into breast milk. The drug poorly penetrates the intact blood-brain barrier, and concentrations in the central nervous system (CNS) are low in the absence of inflammation. However, during meningitis, ceftazidime concentrations in the CNS range from 4 to 20 mg/L or higher, which corresponds to therapeutic levels.

Biotransformation

Ceftazidime is not metabolized in the body.

Elimination

After parenteral administration, plasma levels decline with a half-life of approximately 2 hours. Ceftazidime is excreted unchanged and in active form in the urine via glomerular filtration; about 80–90% of the administered dose is excreted in the urine within 24 hours. Less than 1% of the drug is excreted in bile.

Special patient groups

Renal impairment

In patients with impaired renal function, elimination of ceftazidime is reduced; therefore, the dose should be adjusted (see section "Dosage and administration").

Hepatic impairment

Mild to moderate hepatic dysfunction did not affect the pharmacokinetics of ceftazidime in patients receiving the drug at a dose of 2 g intravenously every 8 hours for 5 days, provided that renal function was not impaired (see section "Dosage and administration").

Geriatric patients

The observed reduction in clearance in elderly patients is primarily due to age-related decline in renal clearance of ceftazidime. The mean elimination half-life of the drug in elderly patients (aged 80 years) is 3.5–4 hours, both after single-dose administration and after multiple dosing (for 7 days) at 2 g twice daily administered intravenously (as bolus).

Children

The elimination half-life of ceftazidime is prolonged in premature and full-term neonates, ranging from 4.5 to 7.5 hours after a dose of 25–30 mg/kg. However, in patients aged 2 months and older, the elimination half-life falls within the adult range.

Clinical characteristics.

Indications.

To be used for the 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.

For the 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 urinary tract infections during prostate surgery (transurethral resection).

When prescribing ceftazidime, consideration should be given to its antibacterial spectrum, which primarily includes Gram-negative aerobes (see sections «Special precautions for use» 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 used 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 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.

Interaction studies have been conducted only with probenecid and furosemide.

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 use of chloramphenicol with ceftazidime is considered, potential antagonism should be taken into account.

Like other antibiotics, ceftazidime 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 for use.

Hypersensitivity reactions

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, cephalosporin antibiotics, or other beta-lactam antibiotics. Caution should be exercised when prescribing the drug to patients who have experienced mild hypersensitivity reactions to other beta-lactam antibiotics.

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 ceftazidime therapy. These reactions may be life-threatening or fatal, and their frequency is classified as "unknown".

Patients should be informed about the signs and symptoms and closely monitored for skin reactions.

If signs or symptoms suggesting such 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 activity

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections, except when the causative pathogen has been identified and is known to be susceptible to ceftazidime, or when there is a high likelihood of susceptibility. 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 (ESBLs). Therefore, when selecting ceftazidime for therapy, local information regarding the prevalence of ESBL-producing microorganisms should be taken into account.

Pseudomembranous colitis

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported with antibiotic use. It is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy (see section "Adverse reactions"). In such cases, discontinuation of ceftazidime and initiation of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit intestinal peristalsis should not be administered.

Renal function

Concomitant administration of high doses of cephalosporins and nephrotoxic agents, such as aminoglycosides or potent diuretics (e.g., furosemide), may adversely affect renal function. Ceftazidime is eliminated via the kidneys, and dosage should be adjusted according to the degree of renal impairment. Careful clinical monitoring of safety and efficacy is recommended in patients with impaired renal function. Cases of neurological complications have been reported when the dose was not appropriately reduced (see sections "Dosage and administration" and "Adverse reactions").

Overgrowth of non-susceptible microorganisms

As with other broad-spectrum antibiotics, prolonged treatment with ceftazidime may result in overgrowth of non-susceptible microorganisms (e.g., Enterococci, fungi); in such cases, discontinuation of therapy or other appropriate measures may be required. Close monitoring of the patient is essential.

Effects on laboratory parameters

Ceftazidime does not interfere with enzymatic methods for glucose in urine, but may slightly interfere with copper reduction methods (Benedict, Fehling, Clinitest), potentially leading to false-positive results.

Ceftazidime does not interfere with creatinine measurement using the alkaline picrate method.

A positive Coombs test has occurred in approximately 5% of patients receiving ceftazidime. This phenomenon may interfere with blood compatibility testing.

Sodium content

The medicinal product contains sodium (1 vial with 1 g ceftazidime contains 52 mg (2.3 mmol) of sodium), which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding

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

Fertility

No data are available.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. However, certain adverse reactions (e.g., dizziness) may occur, which could affect the ability to drive or operate machinery (see section "Adverse reactions").

Dosage and Administration.

Adults and children with body weight ≥ 40 kg

Intermittent administration
Infection	Dose administered
Respiratory tract infections in patients with cystic fibrosis	100–150 mg/kg body weight per day every 8 hours, maximum 9 g per day1
Febrile neutropenia	2 g every 8 hours
Hospital-acquired pneumonia
Bacterial meningitis
Bacteremia*
Bone and joint infections	1–2 g every 8 hours
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis
Complicated urinary tract infections	1–2 g every 8 or 12 hours
Prophylaxis of infectious complications during prostate surgery (transurethral resection)	1 g during anesthesia induction and a second dose at the time of catheter removal
Chronic suppurative otitis media	1–2 g every 8 hours
Malignant external otitis
Continuous infusion
Infection	Dose administered
Febrile neutropenia	A loading dose of 2 g is administered, followed by continuous infusion of 4 to 6 g every 24 hours1
Hospital-acquired pneumonia
Respiratory tract infections in patients with cystic fibrosis
Bacterial meningitis
Bacteremia*
Bone and joint infections
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis
1 In adult patients with normal renal function, administration of 9 g per day did not cause adverse reactions. * If associated or suspected to be associated with infections listed in the section "Indications".

Children with body weight < 40 kg

Infants and children older than 2 months of age with body weight < 40 kg

Infection	Usual dose
Intermittent administration
Complicated urinary tract infections	100–150 mg/kg body weight per day in 3 divided doses, maximum 6 g per day
Chronic suppurative otitis media
Malignant external otitis
Neutropenia in children	150 mg/kg body weight per day in 3 divided doses, maximum 6 g per day
Respiratory tract infections in patients with cystic fibrosis
Bacterial meningitis
Bacteremia*
Bone and joint infections	100–150 mg/kg body weight per day in 3 divided doses, maximum 6 g per day
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis
Continuous infusion
Febrile neutropenia	An initial loading dose of 60–100 mg/kg body weight followed by continuous infusion of 100–200 mg/kg body weight per day, maximum up to 6 g per day
Hospital-acquired pneumonia
Respiratory tract infections in patients with cystic fibrosis
Bacterial meningitis
Bacteremia*
Bone and joint infections
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis

Infants and children aged ≤ 2 months

Infection	Usual dose
Intermittent administration
Most infections	25–60 mg/kg body weight per day in 2 doses1
1 In neonates and children aged ≤ 2 months, the serum half-life may be 3–4 times longer than in adults. * If associated or suspected to be associated with the infections listed in the section "Indications".

Children

The safety and efficacy of the medicinal product administered by continuous intravenous infusion in infants and children aged ≤ 2 months have not been established.

Geriatric patients

Due to reduced ceftazidime clearance, the daily dose in elderly patients should not exceed 3 g, particularly 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 (see section "Pharmacokinetics"). Careful clinical monitoring of the safety and efficacy of the medicinal product is recommended.

Renal impairment

Ceftazidime is eliminated unchanged by the kidneys. Therefore, the dose should be reduced in patients with impaired renal function (see section "Dosage and administration").

The initial loading dose should be 1 g. The maintenance dose should be determined according to creatinine clearance.

Recommended maintenance doses of ceftazidime in renal impairment: intermittent administration

Adults and children with body weight ≥ 40 kg

Creatinine clearance, mL/min	Approximate serum creatinine level, µmol/L (mg/dL)	Recommended single dose of ceftazidime, g	Dosing interval, hours
50–31	150–200 (1.7–2.3)	1	12
30–16	200–350 (2.3–4)	1	24
15–6	350–500 (4–5.6)	0.5	24
< 5	> 500 (> 5.6)	0.5	48

For patients with severe infections, the single dose may be increased by 50% or the frequency of administration correspondingly increased.

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

Children with body weight < 40 kg

Creatinine clearance, ml/min**	Approximate serum creatinine* level, µmol/L (mg/dL)	Recommended individual dose, mg/kg body weight	Dosing frequency, hours
50–31	150–200 (1.7–2.3)	25	12
30–16	200–350 (2.3–4)	25	24
15–6	350–500 (4–5.6)	12.5	24
< 5	> 500 (> 5.6)	12.5	48
* This serum creatinine level is calculated according to recommendations and may not exactly correspond to the level of reduced kidney function in all patients with renal impairment. ** Creatinine clearance calculated based on body surface area, or measured.

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

Recommended maintenance doses of ceftazidime in renal insufficiency: continuous infusion

Adults and children with body weight ≥ 40 kg

Creatinine clearance, mL/min	Approximate serum creatinine level, µmol/L (mg/dL)	Dose
50–31	150–200 (1.7–2.3)	A loading dose of 2 g is administered, followed by continuous infusion of 1 to 3 g every 24 hours
30–16	200–350 (2.3–4)	A loading dose of 2 g is administered, followed by continuous infusion of 1 g every 24 hours
≤ 15	> 350 (> 4)	Not studied

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

Children with body weight < 40 kg

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

A maintenance dose of ceftazidime, as recommended in the tables 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 daily, administered either as a single dose or divided doses. For low-flux hemofiltration, doses should be adjusted as for impaired renal function.

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

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

Residual renal function (creatinine clearance, ml/min)	Maintenance dose (mg) according to ultrafiltration rate (ml/min)а
	5	16.7	33.3	50
0	250	250	500	500
5	250	250	500	500
10	250	500	500	750
15	250	500	500	750
20	500	500	500	750
а The maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

Residual renal function (creatinine clearance, mL/min)	Supplemental dose (mg) for dialysate at flow rate (mL/min)a
	1 L/h			2 L/h
	Ultrafiltration rate (L/h)			Ultrafiltration rate (L/h)
	0.5	1	2	0.5	1	2
0	500	500	500	500	500	750
5	500	500	750	500	500	750
10	500	500	750	500	750	1000
15	500	750	750	750	750	1000
20	750	750	1000	750	750	1000
a The supplemental dose should be administered every 12 hours.

Introduction

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

The medicinal product should be administered by intravenous 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.

Solutions of ceftazidime may be administered directly into the vein or into the intravenous infusion system, if the patient is receiving parenteral fluids.

Standard recommended methods are intermittent intravenous administration or continuous intravenous infusion.

Intramuscular administration should be used only when the intravenous route is not feasible or less suitable for the patient.

Preparation of injection solution

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

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

Dose administered		Required amount of solvent (ml)	Approximate concentration (mg/ml)
1 g	Intramuscular Intravenous bolus Intravenous infusion	3 10 50*	260 90 20

*Reconstitution should be performed in two steps (see below, "Preparation of solution for intravenous infusion").

The solution color varies from light yellow to amber depending on concentration, diluent, and storage conditions. Provided the recommended procedures are followed, the efficacy of the drug is not affected by variations in color.

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% dextran 40 and 0.9% sodium chloride solution; 10% dextran 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 mg/mL to 0.25 mg/mL is compatible with peritoneal dialysis fluid (lactate).

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

Preparation of solution for intramuscular or intravenous bolus injection:

1. Insert the needle of the syringe through the stopper of the vial 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 may be disregarded.

Preparation of solution for intravenous infusion (1 g vials) in two steps:

1. Insert the needle of the syringe through the stopper of the vial 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. Add the resulting solution to an intravenous infusion system to achieve a final solution volume of at least 50 mL, and administer by intravenous infusion over 15–30 minutes.

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

The medicinal product is intended for single use only.

Any unused portions of the medicinal product or waste should be disposed of in accordance with local requirements.

Children.

Can be used in 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 "Dosage and administration" and "Special precautions"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

The most commonly reported adverse reactions include eosinophilia, thrombocytosis, phlebitis or thrombophlebitis at the site of intravenous administration, diarrhea, transient elevation of liver enzymes, maculopapular rash or urticaria, pain and/or inflammation at the site of intramuscular injection, and positive Coombs test.

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse effects are classified by organ systems and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations

Uncommon – candidiasis (including vaginal candidiasis and candidal stomatitis).

Blood and lymphatic system disorders

Common – eosinophilia, thrombocytosis.
Uncommon – neutropenia, leukopenia, thrombocytopenia.
Frequency not known – agranulocytosis, hemolytic anemia, lymphocytosis.

Immune system disorders

Frequency not known – anaphylaxis (including bronchospasm and/or arterial hypotension) (see section "Special precautions for use").

Nervous system disorders

Uncommon – headache, dizziness.
Frequency not known – neurological complications¹, paresthesia.

Vascular disorders

Common – phlebitis or thrombophlebitis at the site of infusion.

Gastrointestinal disorders

Common – diarrhea.
Uncommon – antibiotic-associated diarrhea and colitis² (see section "Special precautions for use"), abdominal pain, nausea, vomiting.
Frequency not known – taste disturbances.

Hepatobiliary disorders

Common – transient elevation of one or more liver enzymes³.
Frequency not known – jaundice.

Skin and subcutaneous tissue disorders

Common – maculopapular rash or urticaria.
Uncommon – pruritus.
Frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioneurotic edema, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)⁴, acute generalized exanthematous pustulosis (AGEP).

Renal and urinary disorders

Uncommon – transient increase in blood urea, blood urea nitrogen, and/or serum creatinine levels.
Very rare – interstitial nephritis, acute renal failure.

General disorders and administration site conditions

Common – pain and/or inflammation at the site of intramuscular injection.
Uncommon – fever.

Investigations

Common – positive Coombs test⁵.

¹ 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.
² Diarrhea and colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.
³ Alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP).
⁴ Rare cases of DRESS syndrome associated with ceftazidime have been reported.
⁵ Positive Coombs test occurs in approximately 5% of patients and may interfere with blood cross-matching tests.

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/.

Shelf life

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

Storage conditions

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

Keep out of reach of children.

After reconstitution:

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

From a microbiological standpoint, the solution should be used immediately. If not used immediately, responsibility for the duration and storage conditions prior to administration lies 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 to 8 °C.

After dilution:

After dilution, the medicinal product maintains chemical and physical stability for up to 6 days at 4 °C and for up to 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 storage conditions prior to administration lies with the user. If dilution 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 to 8 °C, protected from light.

Incompatibilities

Ceftazidime is less stable in solutions of injectable sodium bicarbonate than in other intravenous solutions and therefore is not recommended as a solvent.

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

Vial with powder. Pack of 1 or 10 vials per carton.

Prescription status

Prescription only.

Manufacturer

LLC "ASTRAFARM" (packaging from in bulk form by Hebei Huamin Pharmaceutical Co., Ltd., China).

Manufacturer's address and place of business

6, Kyivska St., city of Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine