Norzidim

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

Composition:

Active substances:
1 vial (1 g/0.5 g) contains ceftazidime pentahydrate with sodium carbonate equivalent to ceftazidime – 1 g and sulbactam sodium equivalent to sulbactam – 0.5 g;

1 vial (2 g/1 g) contains ceftazidime pentahydrate with sodium carbonate equivalent to ceftazidime – 2 g and sulbactam sodium equivalent to sulbactam – 1 g;

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Combinations of antibacterial agents. ATC code J01RA.

Pharmacological Properties.

Pharmacodynamics. Ceftazidime is a third-generation cephalosporin antibiotic.

Ceftazidime has high affinity for the essential penicillin-binding protein (PBP) 3 of Gram-negative bacteria, and lower affinity for PBPs 1 (PBPs 1, 3 in E. coli; PBPs 1 and 3 in Ps. aeruginosa; and PBPs 3 in E. cloacae). The ability of ceftazidime to bind and inhibit penicillin-binding proteins of Gram-positive bacteria (1a, 1b, 2 – S. aureus, S. pneumoniae) is lower than its ability to inhibit PBPs of Gram-negative bacteria.

Ceftazidime demonstrates high resistance to hydrolysis by β-lactamases of both Gram-negative and Gram-positive bacteria, but it is susceptible to hydrolysis by extended-spectrum chromosomal and plasmid-mediated β-lactamases that degrade third-generation cephalosporins.

Sulbactam is a β-lactam ring derivative. Chemically, it is a penicillinate sulfone and a derivative of penicillin. It is an irreversible inhibitor of β-lactamases, effectively blocking both plasmid-mediated (including extended-spectrum) and chromosomal β-lactamases of class A, thereby preventing β-lactamase-mediated inactivation of cephalosporins. Sulbactam efficiently inhibits most β-lactamases produced by anaerobic microorganisms, including Bacteroides spp. Unlike tazobactam and clavulanic acid, sulbactam possesses intrinsic antibacterial activity against Neisseriaceae spp. (for N. gonorrhoeae, MIC90 is 0.39 µg/mL; for N. meningitidis, MIC90 ≤0.5 µg/mL), Acinetobacter spp. (for A. calcoaceticus, MIC90 is 0.19–1 µg/mL; for A. baumannii, 1–32 µg/mL), and certain anaerobes, including Bacteroides spp. (for B. fragilis, MIC90 is 6.25–12.5 µg/mL). Among all PBPs, sulbactam most effectively inhibits PBP-2.

When ceftazidime and sulbactam are used in combination, their combined effect against microorganisms is greater than that of ceftazidime alone. The spectrum of activity is broader, and activity against multidrug-resistant strains is enhanced. The increased efficacy is attributed to potentiation of ceftazidime's action at the target site.

Since ceftazidime preferentially inhibits PBP-3, the addition of sulbactam enhances ceftazidime's effect by blocking PBP-2 against various Gram-negative microorganisms, including Acinetobacter spp., Ps. aeruginosa, and B. fragilis. Another factor contributing to increased efficacy is sulbactam’s ability to inhibit both plasmid-mediated (broad- and extended-spectrum) and chromosomal class A β-lactamases.

In in vitro studies, the MIC90 of the ceftazidime/sulbactam combination against moderately sensitive or resistant strains is reduced by 4–16 times, and these strains are effectively suppressed by the combination.

For E. coli strains producing extended-spectrum β-lactamases and resistant to ceftazidime, the MIC90 of ceftazidime when used in combination with sulbactam is reduced by 8–16 times.

For E. coli and K. pneumoniae strains producing extended-spectrum β-lactamases and resistant to ceftazidime, the MIC90 of ceftazidime in combination with sulbactam is reduced by 16–128 times, rendering them susceptible to ceftazidime concentrations achieved in blood and tissues when ceftazidime/sulbactam is administered at standard therapeutic doses.

For A. baumannii strains, the MIC90 of ceftazidime in combination with sulbactam is reduced by 8 times, making them susceptible to ceftazidime concentrations achieved in blood and tissues with standard therapeutic dosing of ceftazidime/sulbactam.

Unlike ceftazidime, which lacks clinically significant activity against anaerobes, the ceftazidime/sulbactam combination is highly effective against anaerobic bacteria.

For various clinical isolates of Bacteroides spp. resistant to ceftazidime, the MIC90 of ceftazidime in combination with sulbactam is reduced by 32–128 times, rendering them susceptible to ceftazidime concentrations achieved in blood and tissues with standard therapeutic dosing.

For Prevotella spp. strains resistant to ceftazidime, the MIC90 of ceftazidime in combination with sulbactam is reduced by 32 times, and the MIC50 is reduced by 8 times, making them susceptible to ceftazidime concentrations achieved in blood and tissues with standard therapeutic dosing.

The in vitro activity of the ceftazidime/sulbactam combination against Gram-positive flora is enhanced compared to ceftazidime alone; however, due to ceftazidime's moderate intrinsic activity against Gram-positive organisms, the MIC against staphylococci is reduced by 2–4 times.

Norzidim is active against the following microorganisms:

Gram-positive microorganisms:
Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, coagulase-negative staphylococci, Streptococcus pneumoniae, Streptococcus pyogenes (β-hemolytic group A streptococci), Streptococcus agalactiae (β-hemolytic group B streptococci), and other β-hemolytic streptococci (groups C, G, F).

Most enterococcal strains (Enterococcus faecalis, Enterococcus faecium) are resistant to Norzidim.

Methicillin-resistant staphylococci are resistant to Norzidim, as are most cephalosporin antibiotics.

Anaerobes:
Gram-positive cocci (including Peptococcus spp.).
Gram-positive rods (including Clostridium spp., Eubacterium spp., and Lactobacillus spp.).

Gram-negative aerobes:
Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli; Klebsiella spp., including K. pneumoniae, K. oxytoca, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Acinetobacter baumannii; Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including β-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); N. meningitidis; Pantoea agglomerans (formerly Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

Gram-negative anaerobes:
Bacteroides spp., including Bacteroides fragilis, B. melaninogenicus, and other anaerobic microorganisms from the abdominal cavity, pelvis, and oral cavity belonging to the genus Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

Norzidim, as a combination of sulbactam and ceftazidime, is active against all microorganisms susceptible to ceftazidime. Due to sulbactam’s intrinsic activity and the synergistic effect between ceftazidime and sulbactam, Norzidim’s activity significantly exceeds that of ceftazidime alone against Acinetobacter spp. (Acinetobacter calcoaceticus subsp. anitratus, lwoffi; Acinetobacter baumannii), Neisseriaceae spp., and anaerobes (including B. fragilis). Sulbactam potentiates ceftazidime’s activity against Enterobacteriaceae producing extended-spectrum β-lactamases (which degrade third-generation cephalosporins). The ceftazidime/sulbactam combination demonstrates higher activity against P. aeruginosa than ceftazidime alone. Due to the presence of sulbactam, Norzidim is more active against Staphylococcus spp.

Pharmacokinetics. Pharmacokinetic parameters: Cmax, µg/mL, and T1/2, hours.

Plasma protein binding of ceftazidime is 21 (±6)%. Sulbactam protein binding in blood is 38–40% and is independent of sulbactam concentration in blood. Renal excretion of ceftazidime within 24 hours after intramuscular administration is approximately 80%, and after intravenous administration, approximately 90% of the administered dose. For sulbactam, urinary excretion within 24 hours is approximately 71–85% of the administered dose. Tmax after intramuscular administration is about 2 hours for ceftazidime and slightly over 1 hour for sulbactam.

Table 3

Norzidim 1500 mg
	Intravenous infusion, 30 min		Intramuscular
	Ceftazidime 1000	Sulbactam 500	Ceftazidime 1000	Sulbactam 500
Cmax, mcg/ml	86 (±13)	23.3 (±3.5)	36–41 (±4.4)	14.2±3.7
T1/2, hours	1.95 (±0.25)	0.96 ± 0.2	2.1±0.42	1.16 ± 0.21

Table 4

Norzidim 3000 mg
	Intravenous, 20 min infusion
	Ceftazidime 2000	Sulbactam 1000
Cmax, mcg/ml	233 (±54.1)	52.21 ± 14.76
AUC0-∞, h x mcg/ml	334.2 (±40)	67.95 ± 14.41
T1/2, h	1.6 (±0.25)	0.93 ± 0.15

Clinical characteristics.

Indications.

For the treatment of the following infections in adults and children aged 1 year and older:

• Hospital-acquired pneumonia;
• Respiratory tract infections in patients with cystic fibrosis;
• Bacterial meningitis;
• Chronic otitis media;
• Malignant external otitis;
• Complicated urinary tract infections;
• Complicated skin and soft tissue infections;
• Complicated intra-abdominal infections;
• Bone and joint infections;
• Peritonitis associated with dialysis in patients undergoing continuous ambulatory peritoneal dialysis.

For the treatment of bacteremia arising in patients as a result of any of the above-mentioned infections.

Ceftazidime may be used for the treatment of patients with neutropenia and fever due to bacterial infection.

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

When prescribing ceftazidime, it should be taken into account that its antibacterial activity 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 some of the microorganisms causing the infection are not covered by the spectrum of ceftazidime.

The medicinal product 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 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.

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

Like other antibiotics, Norzidim may affect the intestinal flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Norzidim does not affect the results of enzymatic methods for detecting glucosuria; however, a slight interference with test results may occur when using copper reduction methods (Benedict, Fehling, Clinistix).

Ceftazidime does not affect the results of creatinine determination by the alkaline picrate method.

Alcohol

Reactions such as facial flushing, increased sweating, headache, and tachycardia have been reported when alcohol is consumed during and within 5 days after treatment with cephalosporins. Patients should be cautious about consuming alcoholic beverages while taking Norzidim. When using artificial nutrition (oral or parenteral), solutions containing ethanol should not be used.

Interaction with substances used in laboratory tests

False-positive glucose reactions in urine may occur when using Benedict's or Fehling's solution.

Special precautions for use.

Hypersensitivity. There have been reports of severe, and sometimes fatal, anaphylactic reactions in patients receiving therapy with β-lactams or cephalosporins. The occurrence of such reactions is more likely in individuals with a history of hypersensitivity to multiple allergens. If allergic reactions occur, the drug must be discontinued immediately and appropriate treatment initiated.

Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other beta-lactam antibiotics. The drug should be administered with caution in patients who have experienced mild hypersensitivity reactions to other beta-lactam antibiotics.

Severe anaphylactic reactions require immediate emergency treatment, including administration of epinephrine. Oxygen therapy, intravenous corticosteroids, and securing airway patency, including intubation, may be indicated as needed.

General warnings.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections, except when the causative pathogen is known to be susceptible to ceftazidime or when there is a high probability of susceptibility. This is particularly important when treating patients with bacteremia, bacterial meningitis, skin and soft tissue infections, or bone and joint infections. Furthermore, ceftazidime is susceptible to hydrolysis by certain extended-spectrum beta-lactamases. Therefore, when prescribing ceftazidime, one must consider the prevalence of microorganisms producing extended-spectrum beta-lactamases.

As with other antibiotics, treatment with ceftazidime may lead to vitamin K deficiency in some patients. The mechanism is likely related to suppression of normal gut flora responsible for vitamin K synthesis. Thus, at-risk patients include those with poor nutrition, malabsorption (e.g., due to biliary fibrosis), and those on prolonged parenteral (intravenous) nutrition. In such patients, prothrombin time should be monitored. Similar monitoring is recommended for patients receiving anticoagulant therapy. In these cases, supplementation with exogenous vitamin K should be considered.

As with other antibiotics, prolonged ceftazidime therapy may lead to overgrowth of resistant microorganisms. Close monitoring of patients during treatment is required.

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported with antibiotic use. Therefore, this diagnosis should be considered in patients who develop diarrhea during or after antibiotic therapy. If diarrhea is persistent and severe, or if abdominal cramps occur, treatment should be discontinued immediately, further evaluation performed, and specific therapy for Clostridium difficile initiated as needed. Medications 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 ceftazidime therapy. In such cases, periodic susceptibility testing should be performed.

Clinicians should be prepared for potential adverse effects on renal, hepatic, and hematopoietic systems, as observed with other systemic agents. This is particularly important in neonates, especially preterm infants, and other young children.

Serious skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported during ceftazidime therapy. These reactions may be life-threatening or fatal and are reported with a frequency of "unknown."

Patients should be informed about the signs and symptoms of these reactions and closely monitored for skin-related adverse events.

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 occurs during ceftazidime therapy, re-administration of ceftazidime is absolutely contraindicated.

Use in renal impairment. In patients with varying degrees of renal dysfunction, the total clearance of sulbactam administered as Norzidim correlates closely with creatinine clearance. In patients with severe renal impairment, a significant increase in the half-life of sulbactam is observed. Hemodialysis significantly affects the half-life, total clearance, and volume of distribution of sulbactam. No significant changes in the pharmacokinetics of ceftazidime have been observed in patients with renal insufficiency.

Concurrent administration of high-dose cephalosporins and nephrotoxic agents, such as aminoglycosides or potent diuretics (e.g., furosemide), may adversely affect renal function. However, clinical experience with ceftazidime has shown that this is unlikely when recommended dosages are followed. There is no evidence that ceftazidime adversely affects renal function at standard therapeutic doses.

Ceftazidime is primarily excreted by the kidneys; therefore, dosage adjustment is necessary according to the degree of renal impairment. Neurological complications have been reported when dosage was not appropriately reduced (see sections "Dosage and administration" and "Adverse reactions").

Use in hepatic impairment. Ceftazidime is significantly excreted in bile. In patients with liver disease and/or biliary obstruction, the plasma half-life of ceftazidime is typically prolonged, and urinary excretion is increased. Even in cases of severe hepatic impairment, therapeutic concentrations of ceftazidime are detected in bile, and the plasma elimination half-life is increased 2- to 4-fold.

Dosage adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or concomitant renal impairment.

Use in elderly patients. Prolonged elimination half-life, reduced total clearance, and increased volume of distribution have been observed for both sulbactam and ceftazidime compared to data obtained in younger volunteers. Sulbactam pharmacokinetics correlate directly with renal function, while ceftazidime pharmacokinetics correlate with hepatic function.

The drug contains sodium, which should be considered when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

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

Ceftazidime and sulbactam are excreted in small amounts in breast milk; therefore, the drug should be administered with caution to breastfeeding mothers.

Ability to affect reaction speed when driving or operating machinery.

Due to the potential for nervous system-related adverse reactions, caution should be exercised when driving or operating potentially hazardous machinery.

Method of administration and dosage.

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. A skin test for hypersensitivity to the antibiotic is mandatory.

Adults

The standard dose of Norzidim for adults is 3 to 9 g per day (i.e. 2 to 6 g of ceftazidime per day), given in equally divided doses administered 2–3 times daily by intravenous or intramuscular injection.

Adults and children with body weight ≥ 40 kg

Intermittent administration
Infection	Dose
Respiratory tract infections in patients with cystic fibrosis	100–150 mg/kg body weight per day every 8 hours, maximum 9 g per day1
Febrile neutropenia	2 g every 8 hours
Hospital-acquired pneumonia
Bacterial meningitis
Bacteremia*
Bone and joint infections	1–2 g every 8 hours
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis
Complicated urinary tract infections	1–2 g every 8 or 12 hours
Prophylaxis of infectious complications during prostate surgery (transurethral resection)	1 g 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
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 of the drug per day did not cause adverse reactions.

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

Children from 1 year of age

45–150 mg/kg of Norzidim in 2–3 doses (equivalent to ceftazidime 30–100 mg/kg body weight per day and sulbactam 15–50 mg/kg body weight per day). For children with immunodeficiency, cystic fibrosis, or meningitis, a dosage of up to 225 mg/kg/day of Norzidim is recommended (equivalent to ceftazidime 150 mg/kg body weight per day and sulbactam 75 mg/kg body weight per day). Maximum dose – 9 g of Norzidim per day in 3 doses.

Children with body weight < 40 kg

Children older than 1 year with body weight < 40 kg
Intermittent administration
Infection		Dose
Complicated urinary tract infections		100–150 mg/kg body weight per day in 3 divided doses, maximum 6 g per day
Chronic otitis media
Malignant external otitis
Neutropenia in children		150 mg/kg body weight per day in 3 divided doses, maximum 6 g per day
Respiratory tract infections in patients with cystic fibrosis
Bacterial meningitis
Bacteremia*
Bone and joint infections		100–150 mg/kg body weight per day in 3 divided doses, maximum 6 g per day
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis
Continuous infusion
Infection		Dose
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
Bacteremia*
Bone and joint infections
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
Peritonitis associated with continuous ambulatory peritoneal dialysis

• If this is related or suspected to be related to infections listed in the section "Indications".

Elderly patients

Due to reduced clearance in elderly patients with acute infections, exceeding the daily dose of 4.5 g of Norzidim is not recommended, especially for patients over 80 years of age.

Dosing in renal impairment

Ceftazidime and sulbactam are primarily excreted by the kidneys in unchanged form. Therefore, dosage reduction is necessary for patients with impaired renal function.

The initial dose should be 1.5 g of Norzidim. Maintenance dosing should be based on glomerular filtration rate. Since the elimination half-life of ceftazidime is approximately twice that of sulbactam, dosage adjustments of Norzidim in renal impairment should be determined according to the allowable dose corresponding to a given glomerular filtration rate, as indicated by creatinine clearance.

Recommended doses of Norzidim in renal insufficiency

Adults and children with body weight ≥ 40 kg

Creatinine clearance, mL/min	Serum creatinine level, µmol/L (mg/dL)	Recommended initial dose of Norzidim (g) for the given creatinine clearance	Recommended corresponding maintenance single dose of Norzidim, g	Dosing interval (hr)
> 50	<150 (<1.7)	Normal dose	Normal dose	Normal regimen
50–31	150–200 (1.7–2.3)	1.0	1.5	12
30–16	200–350 (2.3–4.0)	0	1.5	24
15–6	350–500 (4.0–5.6)	0.5	0.75	24
< 5	> 500 (> 5.6)	0.5	0.75	48

For patients with severe and very severe infections, the single dose may be increased by 50% or the frequency of administration correspondingly increased. In such patients, serum levels should be monitored and must not exceed 40 mg/L.

Children with body weight < 40 kg

Creatinine clearance, mL/min**	Approximate serum creatinine level*, µmol/L (mg/dL)	Recommended individual dose, mg/kg body weight	Dosing 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

*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 use is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency: continuous infusion

Adults and children with body weight ≥ 40 kg

Creatinine clearance, mL/min	Approximate serum creatinine level, µmol/L (mg/dL)	Administration frequency, 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

Dosing should be administered with caution. Careful clinical monitoring of efficacy and safety of use is recommended.

Children with body weight < 40 kg

The safety and efficacy of the drug 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 the drug needs to 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 during hemodialysis ranges from 3 to 5 hours.

After each hemodialysis session, a recommended maintenance dose of Norzidim should be administered.

Peritoneal dialysis

Norzidim can be used during peritoneal dialysis under standard regimens and during long-term ambulatory peritoneal dialysis.

In addition to intravenous administration, Norzidim can be added to dialysis fluid (typically 187.5 to 375 mg of Norzidim per 2 L of dialysis fluid).

For patients with renal insufficiency undergoing prolonged arteriovenous hemodialysis or high-flux hemofiltration in intensive care units, the recommended dose is 1.5 g of Norzidim per day as a single dose. For low-flux hemofiltration, doses should be administered as for impaired renal function.

Dosing recommendations for patients undergoing venovenous hemofiltration and venovenous hemodialysis are provided in the tables below.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

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

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

Norzidim is administered intravenously 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.

Norzidim solutions may be administered directly into the vein or into an intravenous infusion system if the patient is receiving parenteral fluids.

Preparation instructions

Norzidim is compatible with most commonly used intravenous infusion solutions.

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

Table 2

Dose administered		Required amount of diluent (ml)	Approximate volume of solution after reconstitution	Approximate concentration of ceftazidime/sulbactam (mg/ml)
750 mg	Intramuscularly Intravenously	1.75 5	2.0 5.2	250/125 95/50
1.5 g	Intramuscularly Intravenously	3.0 10	4.0 11.0	250/125 90/45
3 g	Intravenously	10.0	12.0	165/80

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

Sodium bicarbonate for injection should not be used as a solvent (see “Incompatibility”).

The solution color varies from light yellow to amber depending on concentration, solvent, and storage conditions. Provided the recommendations are followed, the drug's efficacy is not affected by variations in its coloration.

Norzidim at concentrations from 1 mg/mL to 40 mg/mL is compatible with the following solutions: 0.9% sodium chloride solution; Hartmann's solution; 5% glucose solution; 0.225% sodium chloride in 5% glucose solution; 0.45% sodium chloride in 5% glucose solution; 0.9% sodium chloride in 5% glucose solution; 0.18% sodium chloride in 4% glucose solution; 10% glucose solution; 10% dextran 40 in 0.9% sodium chloride solution; 10% dextran 40 in 5% glucose solution; 6% dextran 70 in 0.9% sodium chloride solution; 6% dextran 70 in 5% glucose solution.

At concentrations from 0.05 mg/mL to 0.25 mg/mL, it is compatible with peritoneal dialysis fluid (lactate).

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

Heparin 10 IU/mL or 5 IU/mL in 0.9% sodium chloride solution; potassium chloride 10 mEq/L or 40 mEq/L in 0.9% sodium chloride solution.

The contents of a 500 mg Norzidim vial, dissolved in 1.5 mL of water for injections, may be added to metronidazole solution (500 mg in 100 mL), with both drugs retaining their activity.

Preparation of solutions for intramuscular or intravenous bolus injection:

• Insert the syringe needle through the vial stopper and add the recommended volume of solvent.
• Remove the syringe needle and shake the vial until a clear solution is obtained.
• 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 throughout. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions for intravenous infusion (1,000 mg + 500 mg vials):

• Insert the syringe needle through the vial stopper and add 10 mL of solvent.
• Remove the syringe needle and shake the vial until a clear solution is obtained.
• Insert an air vent needle through the stopper into the vial to increase pressure.
• Without removing the air vent needle, add an additional 10 mL of solvent.
• Draw the resulting solution into a syringe and transfer it into the infusion solution vial to be used for infusion.

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.

Children.

Norzidim may be administered to children according to the information provided in the section “Dosage and Administration”.

Overdose.

Overdose may lead to neurological complications such as encephalopathy, seizures, and coma. Symptoms of overdose may occur in patients with renal insufficiency if the dose is not appropriately reduced (see sections “Dosage and Administration” and “Special Warnings and Precautions for Use”). Drug concentration in serum can be reduced by hemodialysis or peritoneal dialysis. Treatment is symptomatic.

Adverse Reactions

Adverse effects have been classified by organ systems and frequency of occurrence: very common — ≥ 1/10; common — ≥ 1/100 and < 1/10; uncommon — ≥ 1/1000 and < 1/100; rare — ≥ 1/10,000 and < 1/1000; very rare — < 1/10,000; frequency not known.

Infections and infestations:

Uncommon – candidiasis (including vaginal vaginitis and aphthous 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).

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.

Vascular system disorders:

Common – phlebitis or thrombophlebitis at the injection site;

Frequency not known – vasculitis, arterial hypotension.

Gastrointestinal disorders:

Common – diarrhea;

Uncommon – nausea, vomiting, abdominal pain, and colitis;

Frequency not known – taste disturbances.

As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.

Hepatobiliary disorders:

Common – transient elevation of one or more liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (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, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP).

General disorders and administration site conditions:

Common – pain and/or inflammation at the site of intravenous injection;

Uncommon – fever.

Renal and urinary disorders:

Very rare – interstitial nephritis, acute renal failure, hematuria.

Laboratory findings:

Common – positive Coombs test;

Uncommon – as with some other cephalosporins, transient increases in blood urea, blood urea nitrogen, and/or serum creatinine have 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 in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

Norzidim is less stable in sodium bicarbonate injection solution than in other intravenous diluents. Therefore, it is not recommended as a solvent.

Norzidim and aminoglycosides should not be mixed in the same infusion system or syringe.

Precipitation may occur when Norzidim is mixed with vancomycin. Therefore, it is recommended to use separate infusion systems for administration of these drugs or to flush infusion systems and intravenous catheters between administration of these two agents.

Packaging.

Powder in a vial, 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer's address and location of its operations.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.