Eurosidim

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROZIDIME (EUROZIDIME)

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime (as ceftazidime pentahydrate) 1.0 g;

Excipient: anhydrous sodium carbonate.

Pharmaceutical form. Powder for injection.

Main physicochemical properties: white or pale yellow powder.

Pharmacotherapeutic group. Antibacterials for systemic use. 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. It has high activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains resistant to gentamicin and other aminoglycosides. Ceftazidime is highly stable against the action of most β-lactamases produced by both Gram-positive and Gram-negative microorganisms. Ceftazidime demonstrates high in vitro activity and acts within a narrow MIC (minimum inhibitory concentration) range against most infectious agents. In vitro studies have shown an additive effect when ceftazidime is used in combination with aminoglycoside antibiotics, and synergy has been observed in experiments with certain strains.

In vitro studies have demonstrated that ceftazidime is active against the following microorganisms.

Acquired resistance to the antibiotic varies among different regions and may change over time, with significant differences observed even among individual strains. Local (regional) 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, 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, Klebsiella pneumoniae, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Morganella morganii, Escherichia coli.

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

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, respectively, are rapidly achieved in patients. Five minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g, mean serum concentrations of 46, 87, or 170 mg/L, respectively, are achieved. 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 of ceftazidime 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 placenta and is excreted into breast milk. The drug poorly penetrates the blood-brain barrier when intact; in the absence of inflammation, drug concentrations in the CNS are low. However, during meningitis, ceftazidime concentrations in the CNS reach 4–20 mg/L or higher, achieving therapeutic levels.

Ceftazidime is not metabolized in the body. After parenteral administration, high and sustained serum concentrations of ceftazidime are achieved. The elimination half-life is approximately 2 hours. The drug is excreted unchanged and in active form in urine via glomerular filtration; approximately 80–90% of the administered dose is excreted 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.

Ceftazidime may be used for 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, its antibacterial spectrum directed mainly against Gram-negative aerobes should be taken into account (see sections «Special precautions for use» and «Pharmacological properties»).

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

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

Contraindications.

Hypersensitivity to ceftazidime 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 use of ceftazidime with chloramphenicol is proposed, the possibility of antagonism should be considered.

Like other antibiotics, Eurozidim 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 occur with 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, cephalosporin antibiotics, 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.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections unless susceptibility of the causative organism to ceftazidime has been established or there is a high likelihood that the potential 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 certain extended-spectrum beta-lactamases. Therefore, when selecting ceftazidime for therapy, 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 reduced according to the degree of renal impairment. Careful monitoring of safety and efficacy is required in patients with impaired renal function. 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»).

This medicinal product contains 2.28 mmol (or 52.44 mg)/dose of sodium. Caution should be exercised when administering to patients on a sodium-restricted diet.

As with other broad-spectrum antibiotics, prolonged treatment with ceftazidime 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. Close clinical monitoring of the patient 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 prolonged and significant diarrhea occurs, or if abdominal cramps develop, 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 motility 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 treatment with ceftazidime. In such cases, periodic susceptibility testing should be performed.

Serious skin reactions (SSRs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported in association with ceftazidime therapy, with frequency unknown.

Patients should be informed of the signs and symptoms of these reactions, and careful monitoring for skin reactions should be performed during treatment. If signs or symptoms suggestive of these reactions occur, ceftazidime should be discontinued immediately, and alternative therapy should be considered.

If a serious reaction such as SJS, TEN, DRESS, or AGEP occurs during ceftazidime therapy, ceftazidime must not be re-administered to this patient.

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. Ceftazidime 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 effects on the breastfed infant are expected with therapeutic doses. Ceftazidime may be used during breastfeeding.

Fertility

There are no data on the effect of ceftazidime on fertility.

Ability to affect reaction speed when driving or operating machinery.

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 «Adverse reactions»).

Method of administration and dosage.

Adults and children ≥ 40 kg

Children < 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 Eurocidim 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 for elderly patients with acute infections generally should not exceed 3 g, especially 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 is recommended.

Renal impairment

Ceftazidime is eliminated 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 administration is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency – continuous infusion

Adults and children ≥ 40 kg body weight

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

Children < 40 kg

The safety and efficacy of administering Euzidim by continuous intravenous infusion in children with impaired renal function whose body weight is < 40 kg 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 ranges from 3 to 5 hours.

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

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis, including in standard regimens and 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 impairment 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 doses. For low-flux hemofiltration, doses should be adjusted as in renal impairment.

For patients undergoing veno-venous hemofiltration and veno-venous hemodialysis, dosing recommendations are provided in the tables.

Dosing recommendations for ceftazidime in patients undergoing prolonged veno-venous hemofiltration

The maintenance dose should be administered every 12 hours.

Dosage recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration

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

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

Instructions for preparation

Eurosidim is compatible with most commonly used intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see «Incompatibility»).

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

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

The solution color varies from light yellow to amber depending on concentration, solvent, and storage conditions. When recommendations are followed, the drug's activity does not depend on 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 mg/mL to 0.25 mg/mL is compatible with intraperitoneal dialysis fluid (lactate).

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

The efficacy of both drugs is preserved when mixing ceftazidime at a concentration 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 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.

Preparation of solutions for intramuscular or intravenous bolus injection:

1. Insert the needle of the syringe through the vial stopper and add the recommended volume of solvent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Invert the vial. With the plunger fully depressed, insert the needle into the vial. Withdraw the entire solution into the syringe, keeping the needle submerged in the solution at all times. Small bubbles of carbon dioxide gas may be disregarded.

Preparation of solutions for intravenous infusion:

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

1. Remove the syringe needle and shake the vial until a clear solution is obtained.
2. 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.
3. 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 very important 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 «Dosage and Administration» and «Special Warnings»). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

Adverse effects were 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.

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.

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 related to Clostridium difficile and may present as pseudomembranous colitis (see section «Special precautions for use»).

Frequency not known – taste disturbances.

Renal and urinary disorders

Very rare – interstitial nephritis, acute renal failure.

Uncommon – transient increase in blood urea levels.

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 (AGEP).

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 elevations 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.

Shelf life: 3 years.

Reconstituted solution:

Solution for intravenous use:

The reconstituted solution may be stored for up to 24 hours in a refrigerator at a temperature of 2–8 °C.

Infusion solution:

The reconstituted solution may be stored for up to 24 hours in a refrigerator at a temperature of 2–8 °C and up to 8 hours at a temperature not exceeding 25 °C.

Solution for intramuscular use:

The solution should be prepared immediately before use and administered promptly.

Storage conditions:

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities:

Eurozidime is less stable in sodium bicarbonate injection solution than in other intravenous solutions. Therefore, sodium bicarbonate is not recommended as a solvent.

Eurozidime 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 administration of these two drugs.

Packaging: 1 or 10 vials with powder in a cardboard box.

Prescription status: Prescription only.

Manufacturer:

S.C.S. DOBFAR S.P.A.

Manufacturer's address and place of business:

Via Alessandro Fleming, 2, Verona (VR), 37135, Italy.

INSTRUCTIONS

for medical use of the medicinal product

EUROZIDIME

(EUROZIDIME)

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime (as ceftazidime pentahydrate) 1.0 g;

Excipient: sodium carbonate anhydrous.

Pharmaceutical form. Powder for injection.

Main physicochemical properties: white or pale yellow powder.

Pharmacotherapeutic group. Antibacterials for systemic use. 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. It exhibits high activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains resistant to gentamicin and other aminoglycosides. Ceftazidime is highly stable against the action of most β-lactamases produced by both Gram-positive and Gram-negative microorganisms. In vitro, ceftazidime demonstrates high activity and acts within a narrow range of MIC (minimum inhibitory concentration) against most infectious agents. In vitro studies have shown an additive effect when ceftazidime is used in combination with aminoglycoside antibiotics, and synergy has been observed in experiments with certain strains.

In vitro studies have demonstrated that ceftazidime is active against the following microorganisms.

Acquired resistance to the antibiotic varies by region and may change over time, and significant differences may exist among individual strains. Local (regional) data on antibiotic susceptibility should be used whenever possible, 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, Klebsiella pneumoniae, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Morganella morganii, Escherichia coli.

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

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, respectively, are rapidly achieved in patients. 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, respectively, are achieved. 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 of ceftazidime 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 placenta and is excreted into breast milk. The drug poorly penetrates the blood-brain barrier when intact; in the absence of inflammation, drug concentrations in the CNS are low. However, during meningitis, ceftazidime concentrations in the CNS reach 4–20 mg/L or higher, achieving therapeutic levels.

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

Ceftazidime may be used for 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, its antibacterial spectrum, primarily directed against Gram-negative aerobes, should be taken into account (see sections «Special precautions» and «Pharmacological properties»).

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

The drug should be prescribed in accordance with current official 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.

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

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

Like other antibiotics, Eurozidim 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; however, a slight interference may occur with 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 starting therapy, patients should be assessed for a history of severe hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, 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.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections until it has been established that the causative pathogen is susceptible to ceftazidime or there is a high likelihood that the likely pathogen will be susceptible to ceftazidime. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Furthermore, ceftazidime is susceptible to hydrolysis by certain extended-spectrum beta-lactamases. 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 reduced according to the degree of renal impairment. Careful monitoring of safety and efficacy is required in patients with impaired renal function. 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»).

This medicinal product contains 2.28 mmol (or 52.44 mg) of sodium per dose. Caution should be exercised when administering to patients on a sodium-restricted diet.

As with other broad-spectrum antibiotics, prolonged treatment with ceftazidime may lead to overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other necessary measures may be required. Close clinical monitoring of the patient 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 prolonged and severe diarrhea occurs, or if abdominal cramps develop, treatment should be discontinued immediately, further investigations performed, and specific treatment for Clostridium difficile initiated if necessary. Medicinal products 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.

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), which may be life-threatening or result in fatal outcomes, have been reported in association with ceftazidime therapy, with unknown frequency.

Patients should be informed of the signs and symptoms of these reactions and closely monitored for skin reactions during treatment. If signs or symptoms suggestive of these reactions occur, ceftazidime should be discontinued immediately, and alternative therapy considered.

If a patient develops a serious reaction such as SJS, TEN, DRESS, or AGEP during ceftazidime therapy, ceftazidime must not be re-administered to this patient.

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, the delivery process, or postnatal development. Ceftazidime should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding

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

Fertility

There are no data on the effect of ceftazidime on fertility.

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage.

Adults and children ≥ 40 kg

Children < 40 kg

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

Children

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

Geriatric patients

Due to the reduced clearance of ceftazidime, for elderly patients with acute infections, the daily dose should generally not exceed 3 g, especially 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. Close clinical monitoring of efficacy and safety of treatment 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 may be 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 correspond to 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 ≥ 40 kg body weight

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

Children < 40 kg

The safety and efficacy of Euzidim 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 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 ranges from 3 to 5 hours.

A maintenance dose of ceftazidime, as recommended in the 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 into several doses. For low-flux hemofiltration, doses should be adjusted as in renal impairment.

For patients undergoing veno-venous hemofiltration and veno-venous hemodialysis, dosage recommendations are provided in the tables.

Dosing recommendations for ceftazidime in patients undergoing prolonged veno-venous hemofiltration

The maintenance dose should be administered every 12 hours.

Dosage recommendations for ceftazidime in patients undergoing long-term venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration

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

Acquired resistance to the antibiotic varies in different regions and may change over time, and may differ significantly between individual strains. It is advisable to use local (regional) data on antibiotic sensitivity, especially when treating severe infections.

Instructions for Preparation

Eurocidim is compatible with most commonly used intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see «Incompatibility»).

Vials are manufactured under reduced pressure. As the drug dissolves, carbon dioxide is released and the pressure inside the vial increases. Small bubbles of carbon dioxide in the dissolved preparation can be disregarded.

Note. Dissolution 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 that the recommendations are followed, the drug's activity 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 mg/mL to 0.25 mg/mL is compatible with intraperitoneal dialysis fluid (lactate).

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

The efficacy of both agents is maintained when ceftazidime at a concentration of 4 mg/mL is mixed with the following substances: hydrocortisone (hydrocortisone sodium phosphate) 1 mg/mL in 0.9% sodium chloride 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.

Preparation of solutions for intramuscular or intravenous bolus injection:

1. Insert the needle of the syringe 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. Draw the entire solution into the syringe, keeping the needle submerged in the solution at all times. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions for intravenous infusion:

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

1. Remove the syringe needle and shake the vial until a clear solution is obtained.
2. 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.
3. 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 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 Warnings and Precautions for Use»). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Side effects

Adverse reactions have been classified according to frequency of occurrence – from very common to rare – and by organ systems: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000; very rare < 1/10,000; frequency not known.

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.

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 related to Clostridium difficile and may present as pseudomembranous colitis (see section «Special precautions for use»).

Frequency not known – taste disturbances.

Renal and urinary disorders

Very rare – interstitial nephritis, acute renal failure.

Uncommon – transient increase in blood urea levels.

Hepatobiliary disorders

Common – transient increase in 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 (AGEP).

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 some 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.

Shelf life: 3 years.

Reconstituted solution:

Intravenous solution:

The reconstituted solution may be stored for up to 24 hours in a refrigerator at 2–8 °C.

Infusion solution:

The reconstituted solution may be stored for up to 24 hours in a refrigerator at 2–8 °C and up to 8 hours at temperatures not exceeding 25 °C.

Intramuscular solution:

The solution should be prepared immediately before use and administered promptly.

Storage conditions:

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Incompatibilities:

Eurosidim is less stable in sodium bicarbonate injection solution than in other intravenous solutions. Therefore, sodium bicarbonate is not recommended as a solvent.

Eurosidim 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 administration of these two drugs.

Packaging: 1 or 10 vials with powder in a cardboard box.

Prescription status: Prescription only.

Manufacturer:

S.S. Doffa S.p.A.

Manufacturer's address and place of business:

Nucleo Industriale S. Atto (loc. S. Nicola a Tordino) - 64100, Teramo (TE), Italy.