Ceftazidime-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTAZIDIME-VISTA (CEFTAZIDIME-VISTA)

Composition:

active substance: ceftazidime;

1 vial contains 1.164 g of ceftazidime pentahydrate, equivalent to 1 g of ceftazidime;

excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or pale yellow powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-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 the inhibition of bacterial cell wall synthesis.

Acquired resistance to the antibiotic varies among different regions and may change over time, with significant differences observed in individual strains. It is advisable to use local data on antibiotic susceptibility and the 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, 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, or 170 mg/L are achieved, respectively. Therapeutically effective concentrations persist in serum for up to 8–12 hours after intravenous or intramuscular administration. Plasma protein binding is approximately 10%. Therapeutic 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 into 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, 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 and in active form via the urine by 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 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 resulting from bacterial infection.

Ceftazidime may be used for prophylaxis of urinary tract infections during urological surgery (transurethral resection of the prostate).

When prescribing ceftazidime, consideration should be given to its antibacterial spectrum, which is primarily directed against Gram-negative aerobes (see sections "Pharmacological properties" and "Special instructions").

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

The drug should be prescribed in accordance with current official guidelines 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

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 instructions").

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

Special precautions for use

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, and careful monitoring for skin reactions is required.

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.

As with other beta-lactam antibiotics, severe and sometimes fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, ceftazidime therapy should be stopped immediately and appropriate emergency measures 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 in patients with a history of non-severe hypersensitivity reactions to other beta-lactam antibiotics.

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 ceftazidime, or there is a high likelihood that the probable pathogen will be susceptible. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Furthermore, ceftazidime is susceptible to hydrolysis by extended-spectrum beta-lactamases (ESBLs). Therefore, when selecting ceftazidime for treatment, information regarding the prevalence of ESBL-producing microorganisms should be taken into account.

Cases of pseudomembranous colitis, ranging from mild to life-threatening in severity, have been reported with antibiotic use. It is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. Treatment should be discontinued immediately, further diagnostic evaluation performed, and specific therapy for Clostridium difficile initiated if necessary. Antiperistaltic agents should not be prescribed.

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 by the kidneys; therefore, the dose should be adjusted according to the degree of renal impairment. Patients with renal impairment require close medical supervision regarding the safety and efficacy of ceftazidime therapy. Cases of neurological complications have been reported when the dose was not appropriately reduced in patients with renal impairment (see sections "Dosage and administration" and "Adverse reactions").

Prolonged use of the medicinal product Ceftazidime-Vista may result in overgrowth of nonsusceptible microorganisms (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other necessary interventions may be required. Close monitoring of the patient is essential.

Ceftazidime does not interfere with enzymatic tests for glucosuria but may cause minor interferences (false-positive results) when using copper reduction methods (e.g., Benedict's, Fehling's, Clinitest).

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

A positive Coombs test occurs in approximately 5% of patients, which may interfere with blood group determination.

The medicinal product Ceftazidime-Vista contains sodium (one vial with 1 g of ceftazidime contains 52.44 mg (2.28 mmol) 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 any direct or indirect harmful effects on pregnancy, embryonal/fetal 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 human milk in small amounts, but with therapeutic doses, effects on the breastfed infant are not expected. Ceftazidime may be used during breastfeeding.

Ability to affect the speed of reactions while 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").

Method of Administration and Dosage

Table 1

Adults and children with body weight ≥ 40 kg

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

Table 2

Children<40 kg

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

Children

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

Geriatric patients

Due to reduced ceftazidime clearance, the total daily dose should not exceed 3 g in elderly patients with acute infections, 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. Close 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

Table 3

Adults and children with body weight ≥ 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 serum ceftazidime levels is recommended.

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

Table 4

Children with body weight < 40 kg

* Serum creatinine level calculated according to recommendations, which may not accurately 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 the drug's efficacy and safety is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency – continuous infusion

Table 5

Adults and children with body weight ≥ 40 kg

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

Children with body weight < 40 kg

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

If children with impaired renal function require administration of the drug by continuous intravenous infusion, 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 tables 6–7 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 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, dosing should follow recommendations for impaired renal function.

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

Table 6

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

The maintenance dose should be administered every 12 hours.

Table 7

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration

The medicinal product Ceftazidime-Vista 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.

Solutions of ceftazidime may be administered directly into the vein or into the 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.

Instructions for solution preparation

The medicinal product Ceftazidime-Vista is compatible with most intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see section "Incompatibility").

Vials are manufactured 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 preparation can be disregarded.

Table 8

Note. Reconstitution for the preparation of intravenous infusion should be carried out in two steps (see below in the text).

The color of the solution varies from pale yellow to amber depending on concentration, diluent, and storage conditions. Provided the recommendations are followed, the drug's activity is not affected by variations in its color.

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% 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 (lactate).

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

The efficacy of both drugs is maintained when mixing ceftazidime at a concentration of 4 mg/mL with the following substances: hydrocortisone (sodium hydrocortisone 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 IU/mL or 50 IU/mL in 0.9% sodium chloride injection solution; potassium chloride 10 mEq/L or 40 mEq/L in 0.9% sodium chloride injection solution.

The contents of one vial of Ceftazidime-Vista 1 g, reconstituted with 3 mL of water for injections, can be added in a volume of 1.5 mL to a metronidazole solution (500 mg in 100 mL), with both drugs retaining their activity.

Preparation of solutions for intramuscular or intravenous bolus injection:

1. Insert the syringe needle through the vial stopper and inject 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 g vial) in two steps:

1. Insert the syringe needle through the vial stopper and inject 10 mL of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Do not insert the air vent needle through the stopper until the drug is completely dissolved. Insert the air vent needle through the stopper into the vial to relieve internal pressure.
4. Add the resulting solution to an intravenous infusion system, ensuring a total solution volume of at least 50 mL, and administer via intravenous infusion over 15–30 minutes.

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

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 conditions of storage prior to use 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 conditions of storage prior to use 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.

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

Adverse Reactions

Adverse reactions have been classified according to their 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 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.

Cases of 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 injection site.

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

Uncommon – transient increase in blood urea levels.
Very rare – interstitial nephritis, acute renal failure.

Hepatobiliary disorders

Common – transient elevation of one or more liver enzymes (ALT, AST, LDH, 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, toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

General disorders and administration site conditions

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

Investigations

Common – positive Coombs test.
Uncommon – as with other cephalosporins, transient increases in blood urea, blood urea nitrogen, and/or serum creatinine have occasionally been observed.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.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.

Incompatibilities

Ceftazidime-Vista is less stable in sodium bicarbonate injection solution than in other intravenous infusion solutions; therefore, sodium bicarbonate injection solution 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, infusion systems and intravenous catheters should be flushed between administrations of these two drugs.

Packaging
1 g of powder in a vial, 1 or 10 vials per cardboard box.

Prescription status
Prescription only.

Manufacturer

ACS DOBFAR S.P.A.

Manufacturer's address and location of operations

NUCLEO INDUSTRIALE S. ATTO (LOC. S. NICOLO' A TORDINO),
64100 TERAMO (TE), ITALY

or

VIA ALESSANDRO FLEMING, 2, VERONA (VR), 37135, ITALY.