Ceftazidime mdj

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFtazidime MJ (CEFtazidime MJ)

Composition:

Active substance: ceftazidime;

1 vial contains 1.0 g of sterile pentahydrate ceftazidime, calculated as anhydrous ceftazidime;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or yellowish-white crystalline powder.

Pharmacotherapeutic group.

Antibacterial agent for systemic use. Third-generation cephalosporins.

ATC code J01D D02.

Pharmacological Properties.

Pharmacodynamics.

Ceftazidime is a bactericidal cephalosporin antibiotic whose mechanism of action is related to inhibition of bacterial cell wall synthesis.

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

Susceptible microorganisms

Gram-positive aerobes: Streptococcus pyogenes, Streptococcus agalactiae.

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

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.

Gram-positive aerobes: Staphylococcus aureus, Streptococcus pneumoniae.

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 reach 46, 87, or 170 mg/L, respectively. Therapeutically effective concentrations persist in serum even 8–12 hours after intravenous or intramuscular administration. Plasma protein binding is approximately 10%. Concentrations exceeding the MIC (minimum inhibitory concentration) 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, and concentrations in the central nervous system (CNS) are low in the absence of inflammation. However, during meningitis, CNS concentrations of ceftazidime range from 4 to 20 mg/L or higher, which corresponds to therapeutic levels.

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

Ceftazidime may be used for prophylaxis of infectious complications during prostate surgery (transurethral resection).

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 microorganisms causing the infection are expected to fall outside the spectrum of ceftazidime activity.

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 medicinal product.

Hypersensitivity to cephalosporin antibiotics.

History of severe hypersensitivity (e.g., anaphylactic reactions) to other β-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 MDj with chloramphenicol is proposed, potential antagonism should be considered.

Like other antibiotics, Ceftazidime MDj may affect intestinal flora, leading to reduced enterohepatic 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

As with other β-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. In the event of severe hypersensitivity reactions, ceftazidime therapy should be discontinued immediately and appropriate emergency measures initiated.

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

Ceftazidime has a limited spectrum of antibacterial activity. It is not an appropriate agent for monotherapy of certain types of infections unless the causative organism is unknown and known to be susceptible to this drug, or there is a high likelihood that the probable pathogen will be susceptible to ceftazidime. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Furthermore, ceftazidime is susceptible to hydrolysis by certain extended-spectrum β-lactamases. Therefore, when selecting ceftazidime for therapy, information regarding the prevalence of microorganisms producing extended-spectrum β-lactamases should be taken into account.

Concomitant treatment with 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 observed. 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. Cases of neurological complications have been reported when the dose was not appropriately reduced (see sections "Dosage and administration" and "Side effects").

As with other broad-spectrum antibiotics, prolonged treatment with Ceftazidime MDj may result in overgrowth of organisms not susceptible to the drug (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other appropriate measures may be necessary. Careful patient monitoring 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. In cases of persistent or severe diarrhea, or if 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 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.

Ceftazidime MDj contains sodium, which should be taken into consideration 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 development, or postnatal development. The drug should be prescribed to pregnant women only if the expected benefit outweighs the potential risk.

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

Effect on ability to drive and use machines

No specific studies have been conducted. However, the occurrence of side effects such as dizziness may affect the ability to drive or operate machinery (see section "Side effects").

Method of administration and dosage.

Adults and children ≥ 40 kg

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 suppurative otitis media	1–2 g every 8 hours
malignant external otitis
Continuous infusion
Infection	Dose administered
febrile neutropenia	A loading dose of 2 g is administered, followed by continuous infusion of 4 g 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, 9 g per day has been used without adverse reactions.

Children < 40 kg

Infants and children > 2 months of age and body weight < 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/day
	chronic otitis media
	malignant external otitis
	neutropenia in children	150 mg/kg body weight/day in 3 divided doses, maximum 6 g/day
	respiratory tract infections in cystic fibrosis patients
	bacterial meningitis
	bacteremia*
	bone and joint infections	100–150 mg/kg body weight/day in 3 divided doses, maximum 6 g/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/day, up to a maximum of 6 g/day
	hospital-acquired pneumonia
	respiratory tract infections in cystic fibrosis patients
	bacterial meningitis
	bacteremia*
	bone and joint infections
	complicated skin and soft tissue infections
	complicated intra-abdominal infections
	peritonitis associated with continuous ambulatory peritoneal dialysis
Infants ≤ 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 ≤ 2 months of age, the serum half-life may be 2–3 times longer than in adults

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

Children

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

Elderly patients

Due to reduced ceftazidime clearance, in elderly patients with acute infections the daily dose 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 of the drug 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 glomerular filtration rate (GFR).

Recommended maintenance doses of ceftazidime in renal impairment – intermittent administration

Adults and children ≥ 40 kg body weight

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 may be correspondingly increased. In such patients, monitoring of ceftazidime serum levels is recommended.

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

Children < 40 kg

Creatinine clearance, ml/min**	Approximate serum creatinine level*, μmol/L (mg/dL)	Recommended individual dose mg/kg body weight	Dosing frequency (hours)
50-31	150-200 (1.7-2.3)	25	12
30-16	200-350 (2.3-4)	25	24
15-6	350-500 (4-5.6)	12.5	24
< 5	> 500 (> 5.6)	12.5	48

*This 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 kidney disease.

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

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

Recommended maintenance doses of ceftazidime in renal impairment – continuous infusion

Adults and children ≥ 40 kg body weight

Creatinine clearance, mL/min	Approximate serum creatinine level, µmol/L (mg/dL)	Dosing frequency (hours)
50–31	150–200 (1.7–2.3)	Administer a loading dose of 2 g followed by continuous infusion of 1 to 3 g every 24 hours
30–16	200–350 (2.3–4)	Administer a loading dose of 2 g 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 < 40 kg

The safety and efficacy of administering ceftazidime by continuous intravenous infusion to 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 ceftazidime must be administered by continuous intravenous infusion to 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 supplemental 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 doses. For low-flux hemofiltration, doses should be the same as those used for impaired renal function.

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

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

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

and the maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

Residual renal function (creatinine clearance, mL/min)	Maintenance 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 MDj 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 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 on the patient's age and renal function.

Acquired resistance to the antibiotic varies across different regions and may change over time, with significant differences possible among individual strains. Local (regional) data on antibiotic susceptibility should preferably be used, especially when treating severe infections.

Preparation instructions

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

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

Dose administered		Required amount of solvent (ml)	Approximate concentration (mg/ml)
250 mg	Intramuscular Intravenous bolus	1 2.5	210 90
500 mg	Intramuscular Intravenous bolus	1.5 5	260 90
1 g	Intramuscular Intravenous bolus Intravenous infusion	3 10 50*	260 90 20
2 g	Intravenous bolus Intravenous infusion	10 50*	170 40

* 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 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).

Ceftazidime for intramuscular administration 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 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 Ceftazidime MDJ 500 mg vial, dissolved in 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. Draw 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 (1 g and 2 g vials):

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 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. 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.

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

Side effects.

Infections and infestations: candidiasis (including vaginitis and aphthous stomatitis).

Blood and lymphatic system disorders: eosinophilia, thrombocytosis, leukopenia, neutropenia, thrombocytopenia, lymphocytosis, hemolytic anemia, agranulocytosis.

Immune system disorders: anaphylaxis (including bronchospasm and/or arterial hypotension).

Nervous system disorders: dizziness, headache, paresthesia.

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.

Cardiac disorders: phlebitis or thrombophlebitis at the injection site.

Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pain, colitis, taste disturbances.

As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis (see section "Special precautions").

Renal and urinary system disorders: interstitial nephritis, acute renal failure.

Hepatobiliary disorders: transient elevation of one or more liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase), jaundice.

Skin and subcutaneous tissue disorders: maculopapular rash, urticaria, pruritus, angioedema, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and administration site conditions: pain and/or inflammation at the site of intramuscular injection, fever.

Investigations: positive Coombs test; as with some other cephalosporins, transient increases in blood urea nitrogen, serum urea, 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.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a dry, dark place, out of reach of children.

The reconstituted solution may be stored for up to 24 hours at temperatures not exceeding 25 °C or for up to 7 days at temperatures up to 4 °C.

Incompatibilities.

Ceftazidime MDj is less stable in sodium bicarbonate injection solution 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 a ceftazidime solution. Therefore, infusion systems and intravenous catheters should be flushed between administration of these two drugs.

Packaging.

1 glass vial with a laminated rubber stopper covered with a protective cap, packed in a cardboard carton.

Prescription category.

Prescription only.

Manufacturer.

LABORATORIO FARMACEUTICO C.T. S.R.L.

Manufacturer's address and place of business.

VIA DANTE ALIGHIERI, 71-18038, SANREMO, (IM) ITALY.