Florazid

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

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime (as ceftazidime pentahydrate) 1 g or 2 g;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to light yellow in color.

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 organisms (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 for susceptibility testing

Breakpoints for minimum inhibitory concentration (MIC) established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Bacterium	Breakpoints (mg/l)
	S	I	R
Enterobacteriaceae	≤ 1	2–4	> 4
Pseudomonas aeruginosa	≤ 8		> 8
Non-species related breakpoints2	≤ 4	8	> 8

S — susceptible, I — intermediate susceptibility, R — resistant.

• Breakpoint values refer to high-dose therapy (2 g × 3).

• Non-species-related breakpoints were primarily determined based on PK/PD data and are independent of the MIC distribution 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 information on microbial resistance should be obtained whenever possible, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the benefit of using the medicinal product questionable, 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 capable of developing 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*

Streptococcus pneumoniae**

Viridans group streptococci

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 is methicillin-susceptible and exhibits intrinsic low-level resistance to ceftazidime. All methicillin-resistant S. aureus strains are resistant to ceftazidime.

** Streptococcus pneumoniae strains showing intermediate susceptibility or resistance to penicillin are expected to exhibit at least reduced susceptibility to ceftazidime.

• High resistance rates have been observed in one or more areas/countries/regions within the EU.

Pharmacokinetics

Absorption

After intramuscular injection of 500 mg or 1 g of ceftazidime, 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, and 170 mg/L, respectively, are achieved. The pharmacokinetics of ceftazidime are linear within the single-dose range of 0.5–2 g following intravenous or intramuscular administration.

Distribution

Plasma protein binding is approximately 10%. Concentrations of ceftazidime 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, synovial, pleural, and peritoneal fluids. Ceftazidime rapidly crosses the placenta and is excreted in breast milk. The drug poorly penetrates the intact blood-brain barrier; in the absence of inflammation, concentrations in the central nervous system (CNS) are low. However, during meningitis, CNS concentrations of ceftazidime range from 4–20 mg/L or higher, reaching 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 in an active form in urine via glomerular filtration; about 80–90% of the administered dose is recovered in urine within 24 hours. Less than 1% is excreted in bile.

Special patient groups

Renal impairment

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

Hepatic impairment

Mild to moderate hepatic dysfunction does 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 renal function is normal (see section "Dosage and administration").

Elderly 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 in elderly patients (aged 80 years and above) is 3.5–4 hours, both after single-dose administration and after prolonged administration (over 7 days) at a dose of 2 g twice daily intravenously (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 administration of a 25–30 mg/kg dose. However, in patients aged 2 months and older, the elimination half-life falls within the adult range.

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 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 procedures (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 "Special precautions" and "Pharmacological properties").

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

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

Contraindications.

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

Hypersensitivity to other cephalosporin antibiotics.

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

Interaction with other medicinal products and other forms of 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 use of ceftazidime with chloramphenicol is considered, potential antagonism should be taken into account.

Like other antibiotics, ceftazidime may affect the 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's, Fehling's, 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 should be taken.

Prior to initiation of therapy, patients should be questioned about previous history of severe hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other beta-lactam antibiotics. The drug should be administered cautiously in patients who have experienced non-severe hypersensitivity reactions to other beta-lactam antibiotics.

Severe cutaneous adverse reactions (SCARs)

During treatment with ceftazidime, severe cutaneous adverse reactions have been reported with an "unknown" frequency, 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 lead to fatal outcomes.

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

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.

Spectrum of activity

Ceftazidime has a limited antibacterial spectrum. It is not suitable for monotherapy in certain types of infections unless the causative pathogen and its susceptibility to this drug are known 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.

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.

Pseudomembranous colitis

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported with antibiotic use. This should be considered in the diagnosis of patients who develop diarrhea during or after antibiotic administration. If prolonged and severe diarrhea or abdominal cramps occur, treatment should be discontinued immediately, further diagnostic evaluation performed, and specific therapy for Clostridium difficile initiated if necessary. Medicinal products that inhibit gastrointestinal motility should not be prescribed.

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 by the kidneys; therefore, the dose should be reduced 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 "Posology and method of administration" and "Undesirable effects").

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., Candida, Enterococci); in such cases, discontinuation of therapy or other necessary measures may be required. Close monitoring of the patient's condition is essential.

Effect on laboratory parameters

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

Ceftazidime does not interfere with creatinine determination using alkaline picrate.

A positive Coombs test has been observed in approximately 5% of patients receiving ceftazidime. This phenomenon may interfere with blood cross-matching tests.

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 direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition, or postnatal development. The drug should be administered to pregnant women only if the benefit outweighs the potential risk.

Breastfeeding

Ceftazidime is excreted in breast milk in small amounts, but no effects on breastfed infants are 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, the occurrence of adverse reactions such as dizziness may affect the ability to drive or operate machinery (see section "Undesirable effects").

Dosage and Administration.

Adults and children with body weight ≥ 40 kg

Table 1

Intermittent administration
Infection	Dose administered
respiratory tract infections in patients with cystic fibrosis	100–150 mg/kg body weight/day every 8 hours, up to a maximum of 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 at induction of anesthesia, 1 g at the time of catheter removal
chronic 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 lead to the occurrence of adverse reactions.

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

Children with body weight < 40 kg

Table 2

Infants and children > 2 months of age and weighing < 40 kg	Infection	Usual dose
Intermittent administration
	complicated urinary tract infections	100–150 mg/kg body weight/day in 3 divided doses, maximum 6 g per day
	chronic otitis media
	malignant external otitis
	neutropenia in children	150 mg/kg body weight/day in 3 divided doses, maximum 6 g per day
	respiratory tract infections in patients with cystic fibrosis
	bacterial meningitis
	bacteraemia*
	bone and joint infections	100–150 mg/kg body weight/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	A loading dose of 60–100 mg/kg body weight is administered, followed by continuous infusion of 100–200 mg/kg body weight per day, up to a maximum of 6 g per day
	hospital-acquired pneumonia
	respiratory tract infections in patients with cystic fibrosis
	bacterial meningitis
	bacteraemia*
	bone and joint infections
	complicated skin and soft tissue infections
	complicated intra-abdominal infections
	peritonitis associated with continuous ambulatory peritoneal dialysis
Infants and children ≤ 2 months of age	Infection	Usual dose
Intermittent administration
	Most infections	25–60 mg/kg body weight/day in 2 divided doses1

1In infants and children aged ≤ 2 months, the serum half-life may be 2–3 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 administering ceftazidime by continuous intravenous infusion to infants and children aged ≤ 2 months have not been established.

Geriatric patients

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

Hepatic impairment

Dosage adjustment is not required for patients with mild to moderate hepatic impairment. Clinical studies in patients with severe hepatic impairment have not been conducted. Careful clinical monitoring of efficacy and safety 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 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 with body weight ≥ 40 kg

Table 3

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 such patients, monitoring of ceftazidime serum levels is recommended.

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

Children with body weight < 40 kg

Table 4

Creatinine clearance, ml/min**	Approximate serum creatinine level* in blood, µmol/l (mg/dl)	Recommended individual dose mg/kg body weight	Dosing interval, 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

* Serum creatinine levels calculated according to recommendations may not precisely correspond to the actual degree of renal function impairment in all patients with renal insufficiency.

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

Careful clinical monitoring of efficacy and safety during administration is recommended.

Recommended maintenance doses of ceftazidime in renal impairment – continuous infusion

Adults and children with body weight ≥ 40 kg

Table 5

Creatinine clearance, mL/min	Approximate serum creatinine level, µmol/L (mg/dL)	Dosing interval, hours
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 (4–5.6)	Not studied

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 ceftazidime 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 ceftazidime 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.

After each hemodialysis session, a maintenance dose of ceftazidime, as recommended in Tables 6 and 7 below, should be administered.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis, including in the standard regimen and during 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 used as for impaired renal function.

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

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

Table 6

Residual renal function (creatinine clearance, ml/min)	Maintenance dose (mg) according to ultrafiltration rate (ml/min)a
	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

The maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

Table 7

Residual renal function (creatinine clearance, mL/min)	Replacement 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

The maintenance dose should be administered every 12 hours.

Administration.

Ceftazidime 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.

Instructions for solution preparation

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

All 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 drug may be disregarded.

Table 8

Dosage and route of administration		Required amount of diluent (ml)	Approximate concentration (mg/ml)
1 g	Intramuscular Intravenous bolus Intravenous infusion	3 10 50*	260 90 20
2 g	Intravenous bolus Intravenous infusion	10 50*	170 40

*Reconstitution should be performed in two steps (see text).

The color of the solution varies from light yellow to amber depending on the concentration, diluent, and storage conditions. Provided 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 peritoneal dialysis fluid (lactate).

For intramuscular administration, ceftazidime may be reconstituted with 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 or 0.5% glucose solution; cefuroxime (cefuroxime sodium) 3 mg/mL in 0.9% sodium chloride injection; cloxacillin (cloxacillin sodium) 4 mg/mL in 0.9% sodium chloride injection; heparin 10 IU/mL or 50 IU/mL in 0.9% sodium chloride injection; potassium chloride 10 mEq/L or 40 mEq/L in 0.9% sodium chloride injection.

The contents of a 1 g Florazid vial, reconstituted with 1.5 mL of water for injections, may be added 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 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. Withdraw the entire solution into the syringe, ensuring the needle remains submerged in the solution throughout. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions for intravenous infusion (1 g and 2 g vials) in two steps

1. Insert the needle of the syringe through the vial stopper and add 10 mL of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Do not insert an air vent needle through the stopper until the drug is completely dissolved. Insert an air vent needle through the stopper into the vial to relieve internal pressure.
4. Add the resulting solution to an intravenous infusion system to achieve a total 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 8 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 of the solution 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 2–8 °C.

After dilution:

After dilution, the medicinal product maintains chemical and physical stability for 8 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 of the solution 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 2–8 °C.

Children.

May 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 and Precautions"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

The most commonly reported adverse reactions are 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 group, adverse reactions are listed in order of decreasing severity.

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

Infections and infestations

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

Blood and lymphatic system disorders

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

Immune system disorders

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

Nervous system disorders

Uncommon – dizziness, headache.
Frequency not known – neurological complications¹, 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 appropriately reduced doses of ceftazidime.

Vascular disorders

Common – phlebitis or thrombophlebitis at the infusion site.

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, polymorphic erythema, 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 (BUN), 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.

• Cases of neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment who did not receive appropriately reduced doses of ceftazidime.

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

Reporting of adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as 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

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. Prepared solution can be stored for up to 8 hours at a temperature not exceeding 25 °C and up to 24 hours at 2–8 °C.

Incompatibilities

Ceftazidime is less stable in solutions of sodium bicarbonate for injection than in other intravenous diluents 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 ceftazidime solution. Therefore, it is recommended to flush infusion systems and intravenous catheters between administration of these two drugs.

Packaging

Powder in a glass vial sealed with a rubber stopper and an aluminum cap with flip-off component. One vial per carton.

Prescription status

Prescription only.

Manufacturer

Ananta Medicare Limited.

Address of manufacturer and location of its operations

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorization Holder

Ananta Medicare Ltd.

Address of Marketing Authorization Holder and/or its representative

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.