Zibec Powder for Inj
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Zibec
Manufacturer
Distributor
Composition:
Each vial contains Ceftazidime USP …..1g
(As Ceftazidime pentahydrate)
A blend of Sterile ceftazidime pentahydrate & Sterile Sodium Carbonate
Pharmaceutical form
Powder for Injection (PI)
Clinical Particulars
Therapeutic Indications
Ceftazidime is indicated for the treatment of the infections listed below in adults and children including neonates (from birth).
- Nosocomial pneumonia
- Broncho-pulmonary infections in cystic fibrosis
- Bacterial meningitis
- Chronic suppurative otitis media
- Malignant otitis externa
- Complicated urinary tract infections
- Complicated skin and soft tissue infections
- Complicated intra-abdominal infections
- Bone and joint infections
- Peritonitis associated with dialysis in patients on CAPD.
Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.
Ceftazidime may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
Ceftazidime may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing trans-urethral resection of the prostate (TURP).
The selection of ceftazidime should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram-negative bacteria.
Ceftazidime should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum of activity.
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.
Posology & Method of administration
Method of Administration: Intramuscular/Intravenous
Table 1: Adults and children ≥40 kg
| Intermittent Administration | |
| Infection | Dose to be administered |
| Broncho-pulmonary infections in cystic fibrosis | 100 to 150 mg/kg/day every 8h, maximum 9g per day1 |
| Febrile neutropenia | 2 g every 8 h |
| Nosocomial pneumonia | |
| Bacterial meningitis | |
| Bacteraemia* | |
| Bone and joint infections | 1-2 g every 8 h |
| Complicated skin and soft tissue infections | |
| Complicated intra-abdominal infections | |
| Peritonitis associated with dialysis in patients on CAPD | |
| Complicated urinary tract infections | 1-2 g every 8 h or 12 h |
| Peri-operative prophylaxis for transuretheral resections of prostate (TURP) | 1 g at induction of anaesthesia, and a second dose at catheter removal |
| Chronic suppurative otitis media | 1 g to 2 g every 8 h |
| Malignant otitis externa | |
| In adults with normal renal function 9g/day has been used without adverse effects.
*When associated with, or suspected to be associated with, any of the infections listed in section 4.1. |
|
Table 2: Children < 40 kg
| Infants and toddlers>2 months and children <40 kg | Infection | Usual dose |
| Intermittent Administration | ||
| Infants and toddlers>2 months and children <40 kg | Complicated urinary tract infections | 100-150 mg/kg/day in three divided doses, maximum 6 g/day |
| Malignant otitis externa | ||
| Neutropenic children | 150 mg/kg/day in three divided doses, maximum 6g/day | |
| Broncho-pulmonary infections in cystic fibrosis | ||
| Bacterial meningitis | ||
| Bacteraemia* | ||
| Bone and joint infections | 100-150 mg/kg/day in three divided doses, maximum 6 g/day | |
| Complicated skin and soft tissue infections | ||
| Complicated intra-abdominal infections | ||
| Peritonitis associated with dialysis in patients on CAPD | ||
| Neonates and infants ≤ 2 months | Most infections | 25-60 mg/kg/day in two divided doses |
| In Neonates and infants ≤ 2 months, the serum half-life of ceftazidime can be three to four times that in adults.
*Where associated with or suspected to be associated with any of the infections listed in section 4.1. |
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Paediatric population
The safety and efficacy of Ceftazidime administered as continuous infusion to neonates and infants ≤ 2 months has not been established.
Elderly
In view of the age related reduced clearance of ceftazidime in elderly patients, the daily dose should not normally exceed 3 g in those over 80 years of age.
Hepatic impairment
Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment. There are no study data in patients with severe hepatic impairment. Close clinical monitoring for safety and efficacy is advised.
Renal impairment
Ceftazidime is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function, the dosage should be reduced.
An initial loading dose of 1g should be given. Maintenance doses should be based on creatinine clearance:
Table 3: Recommended maintenance doses of Ceftazidime in renal impairment-intermittent infusion
Adults and children ≥ 40 kg
| Creatinine clearance (ml/min) | Approx. serum creatinine µmol/l (mg/dl) | Approximate Available Volume (ml) | Frequency of dosing (hourly) |
| 50-31 | 150-200 (1.7-2.3) | 1 | 12 |
| 30-16 | 200-350 (2.3-4.0) | 1 | 24 |
| 15-6 | 350-500 (4.0-5.6) | 0.5 | 24 |
| <15 | >500 (>5.6) | 0.5 | 48 |
In patients with severe infections the unit dose should be increased by 50% or the dosing frequency increased.
In children the creatinine clearance should be adjusted for body surface area or lean body mass.
Children < 40 kg
| Creatinine clearance (ml/min) | Approx. serum creatinine µmol/l (mg/dl) | Approximate Available Volume (ml) | Frequency of dosing (hourly) |
| 50-31 | 150-200 (1.7-2.3) | 25 | 12 |
| 30-16 | 200-350 (2.3-4.0) | 25 | 24 |
| 15-6 | 350-500 (4.0-5.6) | 12.5 | 24 |
| <15 | >500 (>5.6) | 12.5 | 48 |
| • The serum creatinine values are guideline values that may not indicate exactly the same degree of reduction for all patients with reduced renal function.
* Estimated based on body surface area, or measured |
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Close clinical monitoring for safety and efficacy is advised.
Table 4: Recommended maintenance doses of Ceftazidime in renal impairment – continuous infusion
Adults and children ≥40 kg
| Creatinine Clearance (ml/min) | Approx. serum creatinine µmol/l (mg/dl) | Frequency of dosing (hourly) |
| 50-31 | 150-200 (1.7-2.3) | Loading dose of 2 g followed by 1 g to 3 g/24 hours |
| 30-16 | 200-350 (2.3-4.0) | Loading dose of 2 g followed by 1 g/24 hours |
| ≤15 | >350 (>4.0) | Not evaluated |
Caution is advised in dose selection. Close clinical monitoring for safety and efficacy is advised.
Children <40 kg
The safety and effectiveness of Ceftazidime administered as continuous infusion in renally impaired children < 40 kg has not been established. Close clinical monitoring for safety and efficacy is advised.
If continuous infusion is used in children with renal impairment, the creatinine clearance should be adjusted for body surface area or lean body mass.
Haemodialysis
The serum half-life during haemodialysis ranges from 3 to 5h.
Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the below table should be repeated.
Pentoneal dialysis
Ceftazidime may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD).
In addition to intravenous use, ceftazidime can be incorporated into the dialysis fluid (usually 125 to 250 mg for 2 litres of dialysis solution).
For patients in renal failure on continuous arterio-venous haemodialysis or high-flux haemofitlration in intensive therapy units: 1 g daily either as a single dose or in divided doses. For low-flux haemofiltration, follow the dose recommended under renal impairment.
For patients on veno-venous haemofiltration and veno-venous haemodialysis, follow the dosage recommendations in the tables
Table 5: Continuous veno-venous haemofiltration dose guidelines
| Residual renal function (creatinine clearance ml/min) | Maintenance dose (mg) for an ultrafitration rate (ml/min) of : | |||
| 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 |
| * Maintenance dose to be administered every 12h. | ||||
Table 6: Continuous veno-venous haemodialysis dose guidelines
| Residual renal function (creatinine clearance in m/min) | Maintenance dose (mg) for an ultrafiltration rate (mImin) of: | |||||
| 1.0 litre/h | 2.0 litre/h | |||||
| Ultrafiltration rate (litre/h) | Ultrafiltration rate (litres/h) | |||||
| 0.5 | 1.0 | 2.0 | 0.5 | 1.0 | 2.0 | |
| 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 |
| Maintenance dose to be administered every 12 h. | ||||||
Contraindications
Hypersensitivity to ceftazidime, to any other cephalosporin or to any of the excipients
History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems)
Special warnings and precautions for use
As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with ceftazidime must be discontinued immediately and adequate emergency measures Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftazidime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.
Ceftazidime has a limited spectrum of antibacterial activity. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with ceftazidime. This particularly applies when considering the treatment of patients with bacteraemia and when treating bacterial meningitis, skin and soft tissue infections and bone and joint infections. In addition, ceftazidime is susceptible to hydrolysis by several of the extended spectrum beta lactamases (ESBLs). Therefore, information on the prevalence of ESBL producing organisms should be taken into account when selecting ceftazidime for treatment.
Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including ceftazidime, and mar range in severity from mid to life-threatening. Therefore, it is important to consider the diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftazidime (se section 4.8). Discontinuation of therapy with ceftazidime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.
Ceftazidime is eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment. Patients with renal impaiment should be closely monitored for both safety and efficacy. Neurological sequelae have occasionally been reported when the dose has not been reduced in patients with renal impairment.
Prolonged use may result in the overgrowth of non-susceptible organisms (eg. Enterococci, fungi) which may require interruption of treatment or other appropriate measures. Repeated evaluation of the patient’s condition is essential.
Ceftazidime does not interfere with enzyme-based tests for glycosuria, but slight interference (false-positive) may occur with copper reduction methods (Benedict’s, Fehling’s, Clinitest).
Interaction with other medicinal products and other interactions
Interaction studies have only been conducted with probenecid and furosemide.Concurrent use of high doses with nephrotoxic medicinal products may adversely affect renal function.
Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of ceftazidime with chloramphenicol is proposed, the possibility of antagonism should be considered.
Fertility, pregnancy and lactation
Pregnancy
There are limited amounts of data from the use of ceftazidime in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Ceftazidime should be prescribed to pregnant women only if the benefit outweighs the risk.
Breast feeding
Ceftazidime is excreted in human milk in small quantities but at therapeutic doses of ceftazidime no effects on the breast-fed infant are anticipated. Ceftazidime can be used during breast-feeding.
Fertility
No data are available.
Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines.
Undesirable Effects
The most common adverse reactions are eosinophilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or urticarcial rash, pain and/or inflammation following intramuscular injection and positive Coomb’s test.
Data from sponsored and un-sponsored clinical trials have been used to determine the frequency of common and uncommon undesirable effects. The frequencies assigned to all other undesirable effects were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following convention has been used for the classification of frequency: Very common (21/10); Common (≥1/100 to <1/10); Uncommon (≥ 1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000) and Unknown (cannot be estimated from the available data).
| System organ class | Common) | Uncommon | Very rare | Unknown |
| Infections and infestations | Candidiasis (including vaginitis and oral thrush) | |||
| Blood and lymphatic system disorders | Eosinophilia Thrombocytosis | Neutropenia
Leucopenia Thrombocytopenia |
Agranulocytosis
Haemolytic anaemia Lymphocytosis |
|
| Immune system disorders | Eosinophilia Thrombocytosis | Neutropenia
Leucopenia Thrombocytopenia |
Anaphylaxis (including
bronchospasm and/or hypotension) (see section 4.4) |
|
| Nervous system disorders | Headache
Dizziness |
Neurological sequelae
Paraesthesia |
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| Vascular disorders | Phlebitis or thrombophlebitis with intravenous administration | |||
| Gastrointestinal disorders | Antibacterial agent-associated diarrhoea and colitis Abdominal pain Nausea
Vomiting |
Bad taste | ||
| Hepatobiliary disorders | Transient elevations in one or more hepatic enzymes | Jaundice | ||
| Skin and subcutaneous tissue disorders | Maculopapular or urticarial rash | Pruritus | Toxic epidermal necrolysis Stevens-johnson syndrome
Erythema multiforme Angioedema |
|
| Renal and urinary disorders | Transient elevating
urea nitrogen and/ or serum creatinine |
of blood urea, blood Interstitial nephritis
Acute renal failure |
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| General disorders and administration site conditions | Pain and/or inflammation after intramuscular injection | Fever | ||
| Investigations | Positive Coombs test |
There have been reports of neurological sequelae including tremor, myoclonia, convulsions, encephalopathy, and coma in patients with renal impairment in whom the dose of Ceftazidime has not been appropriately reduced.
*Diarrhoea and colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.
ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase.
A positive Coombs test develops in about 5% of patients and may interfere with blood cross matching
Overdose
Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma.
Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.
Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.
Pharmacological Properties
Pharmacodynamic Properties
Pharmacotherapeutic group: Antibacterials for systemic use. Third-generation cephalosporins
ATC code: J01DD02.
Mechanism of action: Ceftazidime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.
PK/PD relationship: For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftazidime for individual target species (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 may be efficiently hydrolysed by extended-spectrum beta-lactamases (ESBLs), including the SHV family of ESBLs, and AmpC enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species Reduced affinity of penicillin-binding proteins for ceftazidime
- Outer membrane impermeability, which restricts access of ceftaidime to penicillin binding proteins in Gram-negative organisms
- Bacterial efflux pumps.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
| Organism | Breakpoints (mg/L) | ||
| S | I | R | |
| Enterobacteriaceae | ≤ 1 | 2-4 | >4 |
| Pseudomonas aeruginosa | ≤8 | – | >8 |
| Non-species related breakpoints | ≤4 | 8 | >8 |
S=susceptible, I=intermediate, R=resistant.
‘The breakpoints relate to high dose therapy (2 g x 3).
*Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes.
Microbiological Susceptibility:
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftazidime in at least some types of infections is questionable.
| Gram-positive aerobes:
Streptococcus pyogenes; Streptococcus agalactiae |
| Gram-negative aerobes:
Escherichia coli Haemophilus influenzae Moraxella catarrhalis Neisseria meningitidis Proteus spp. (other) Providencia spp. |
| Species for which acquired resistance may be a problem |
| Gram-negative aerobes:
Acinetobacter baumannii+ Burkholderia cepacia Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Klebsiella pneumoniae Klebsiella spp. (other) 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:
Fusobactenum spp. |
| Inherently resistant organisms |
| Gram-positive aerobes:
Enterococci including Enterococcus faecalis and Enterococcus faecium; Listeria spp. |
| Gram-positive anaerobes:
Clostridium difficile |
| Gram-negative anaerobes:
Bacteroides spp. (many strains of Bacteroides fragilis are resistant). |
| Others:
Chlamydia spp. Mycoplasma spp. Legionella spp. ‘S. aureus that is methicillin-susceptible are considered to have inherent low susceptibility to ceftazidime. All methicillin-resistant S. aureus are resistant to ceftazidime. “S. pneumoniae that demonstrate intermediate susceptibility or are resistant to penicillin can be expected to demonstrate at least reduced susceptibility to ceftazidime. + High rates of resistance have been observed in one or more areas/countries/regions within the EU. |
Pharmacokinetic Properties
Absorption
After intramuscular administration of 500 mg and 1g of ceftazidime, peak plasma levels of 18 and 37 mg/l, respectively, are achieved rapidly. Five minutes after intravenous bolus injection of 500 mg, 1 g or 2 g, plasma levels are 46, 87 and 170 mg/l, respectively. The kinetics of ceftazidime are linear within the single dose range of 0.5 to 2g following intravenous or intramuscular dosing.
Distribution
The serum protein binding of ceftazidime is low at about 10%. Concentrations in excess of the MIC for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and pentoneal fluids. Ceftazidime crosses the placenta readily, and is excreted in the breast milk. Penetration of the intact blood-brain barrier is poor, resulting in low levels of ceftazidime in the CS in the absence of inflammation. However, concentrations of 4 to 20 mg/l or more are achieved in the CSF when the meninges are inflamed.
Biotransformation
Ceftazidime is not metabolised.
Elimination
After parenteral administration plasma levels decrease with a half-life of about 2h. Ceftazidime is excreted unchanged into the urine by glomerular filtration; approximately 80 to 90% of the dose is recovered in the urine within 24h. Less than 1% is excreted via the bile.
Special patient populations
Renal impairment
Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced.
The presence of mild to moderate hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2g intravenously every 8 hours for 5 days, provided renal function was not impaired.
The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination hail-life ranged from 3.5 to 4 hours following single or 7 days repeat BID dosing of 2 g IV bolus injections in elderly patients 80 years or older.
Paediatric population
The half-life of ceftazidime is prolonged in preterm and term neonates by 4.5 to 7.5 hours after doses of 25 to 30 mg/kg. However, by the age of 2 months the half-life is within the range for adults.
Preclinical Safety data
Non-clinical data reveal no special hazard for humans.
Shelf life
24 months from date of manufacture
Special precautions for Storage
Store in dry place at temperature below 30°C.
Keep out of the sight and reach of children.
Instructions for use
For IM, 3 ml of SWFI and For IV 10 ml of SWFI.
Nature and Contents of container
One vial in a carton with SWFI and pack insert.
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Updated on 9/Feb/2024