Ceftazidime 2g Powder For Solution For Injection Or Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ceftazidime 2 g powder for solution for injection or infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 2 g of ceftazidime (as Ceftazidime pentahydrate)
Excipient: This medicinal product contains 4.6 mmol (104 mg) sodium per dose. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for solution for injection or infusion.
White to yellowish powder
4 CLINICAL PARTICULARS
4.1 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 (see sections 4.4 and 5.1).
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 regarding the appropriate use of antibacterial agents.
4.2 Posology and method of administration
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 8 h, maximum 1 9 g per day |
|
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 resection 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 8h |
|
Malignant otitis externa | |
|
Continuous Infusion | |
|
Infection |
Dose to be administered |
|
Febrile neutropenia |
Loading dose of 2 g followed by a 1 continuous infusion of 4 to 6 g every 24 h |
|
Nosocomial pneumonia | |
|
Broncho-pulmonary infections in cystic fibrosis | |
|
Bacterial meningitis | |
|
Bacteraemia* | |
|
Bone and joint infections | |
|
Complicated skin and soft tissue infections | |
|
Complicated intra-abdominal infections | |
|
Peritonitis associated with dialysis in patients on CAPD | |
|
1 In adults with normal renal function 9 g/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 | |||
|
Complicated urinary tract infections |
100-150 mg/kg/day in three divided doses, maximum 6 g/day | ||
|
Chronic suppurative otitis media | |||
|
Malignant otitis externa | |||
|
Neutropenic children |
150 mg/kg/day in three divided doses, maximum 6 g/day | ||
|
Broncho-pulmonary infections in cystic fibrosis | |||
|
Bacterial meningitis | |||
|
Bacteraemia* | |||
|
Bone and joint infections |
100-150 mg/kg/day in three divided | ||
|
Complicated skin and soft tissue infections | |||
|
Complicated intra-abdominal infections | |||
|
Peritonitis associated with dialysis in patients on CAPD | |||
|
Continuous Infusion | |||
|
Febrile neutropenia |
Loading dose of 60-100 mg/kg followed by a continuous infusion 100-200 mg/kg/day, maximum 6 g/day | ||
|
Nosocomial pneumonia | |||
|
Broncho-pulmonary infections in cystic fibrosis | |||
Peritonitis associated with dialysis in patients on CAPD
|
Neonates and infants < 2 months |
Infection |
Usual dose |
|
Intermittent Administration | ||
|
Most infections |
25-60 mg/kg/day in two divided doses | |
|
i 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. | ||
Bacterial meningitis Bacteraemia*
Bone and joint infections
Complicated skin and soft tissue infections
Complicated intra-abdominal infections
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 (see also section 5.2). 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 (see also section 4.4).
An initial loading dose of 1 g 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 |
Approx. serum creatinine |
Recommended unit dose |
Frequency of dosing |
|
(ml/min) |
pmol/l (mg/dl) |
of Ceftazidime (g) |
(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 |
|
<5 |
>500 |
0.5 |
48 |
|
(>5.6) |
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* pmol/l (mg/dl) |
Recommended individual dose mg/kg body weight |
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 |
|
<5 |
>500 (>56) |
12.5 |
48 |
|
* The serum creatinine values are guideline values t |
iat may not indicate exactly the same degree of | ||
|
reduction for all patients with reduced renal function. | |||
|
** Estimated based on body surface area, or measured. | |||
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 pmol/l (mg/dl) |
Frequency of dosing (hourly) |
|
50-31 |
150-200 |
Loading dose of 2 g followed |
|
(1.7-2.3) |
by 1 g to 3 g /24 hours | |
|
30-16 |
200-350 |
Loading dose of 2 g followed |
|
(2.3-4.0) |
by 1 g/24 hours | |
|
<15 |
>350 (>40) |
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 5 h.
Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the below table should be repeated.
Peritoneal 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 haemofiltration 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 below.
Table 5: Continuous veno-venous haemofiltration dose guidelines
|
Residual renal function (Creatinine Clearance ml/min) |
Maintenance dose (mg) for an ultrafiltration rate (ml/min) of1: | |||
|
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 |
1Maintenance dose should be administered every 12 hours.
Table 6: Continuous veno-venous haemodialysis dose guidelines
|
Residual renal function |
Maintenance dose (mg) for |
a dialysate in flow rate ofi: | ||||
|
(Creatinine Clearance |
1.0 litre/h |
2.0 litre/h | ||||
|
ml/min) |
Ultrafiltration rate |
Ultrafiltration rate | ||||
|
(litres/h) |
(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 |
|
1Maintenance dose should be administered every 12 |
lours. | |||||
Method of administration
Ceftazidime should be administered by intravenous injection or infusion, or by deep intramuscular injection. Recommended intramuscular injection sites are the upper
outer quadrant of the gluteus maximus or lateral part of the thigh. Ceftazidime solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids.
The standard recommended route of administration is by intravenous intermittent injection or intravenous continuous infusion. Intramuscular administration should only be considered when the intravenous route is not possible or less appropriate for the patient.
The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to ceftazidime, to any other cephalosporin or to any of the excipients listed in section 6.1.
History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).
4.4 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 must be initiated.
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 may range in severity from mild to lifethreatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftazidime (see 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 impairment 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 (see sections 4.2 and 4.8).
Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. 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
(falsepositive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).
Ceftazidime does not interfere in the alkaline picrate assay for creatinine.
The development of a positive Coombs’ test associated with the use of ceftazidime in about 5% of patients may interfere with the cross-matching of blood.
Important information about one of the ingredients of Ceftazidime Kabi:
Ceftazidime 2 g contains 104 mg of sodium per vial.
This should be considered for patients who are on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been conducted with probenecid and furosemide.
Concurrent use of high doses with nephrotoxic medicinal products may adversely affect renal function (see section 4.4).
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.
4.6 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 (see section 5.3).
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.
4.7 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 (see section 4.8).
4.8 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: (>1/10)
Common:
Uncommon:
Rare:
Very rare: Unknown
(>1/100 to <1/10)
(>1/1000 to <1/100)
(>1/10000 to <1/1000)
(< 1/10000)
(cannot be estimated from the available data)
|
System Organ |
Common |
Uncommon |
Very rare |
Unknown |
|
Class | ||||
|
Infections and infestations |
Candidiasis (including vaginitis and oral thrush) | |||
|
Blood and lymphatic system |
Eosinophilia Thrombocytosis |
Neutropenia Leucopenia Thrombocytopenia |
Agranulocytosis Haemolytic anaemia Lymphocytosis | |
|
disorders |
|
Immune system |
Anaphylaxis (including bronchospasm and/or hypotension) (see section 4.4) | |||
|
disorders | ||||
|
Nervous system |
Headache Dizziness |
Neurological sequelae4 Paraesthesia | ||
|
disorders | ||||
|
Vascular disorders |
Phlebitis or thrombophlebitis with intravenous administration | |||
|
Gastrointestinal disorders |
Diarrhoea |
Antibacterial agent-associated diarrhoea and colitis2 (see section 4.4) Abdominal pain Nausea Vomiting |
Bad taste | |
|
Hepatobiliary |
Transient elevations in one or more hepatic enzymes3 |
Jaundice | ||
|
disorders | ||||
|
Skin and subcutaneous tissue disorders |
Maculopapular or urticarial rash |
Pruritus |
Toxic epidermal necrolysis Stevens-johnson syndrome Erythema multiforme Angioedema | |
|
Renal and urinary |
Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine |
Interstitial nephritis Acute renal failure | ||
|
disorders | ||||
|
General disorders and administration site conditions |
Pain and/or inflammation after intramuscular injection |
Fever | ||
|
Investigations |
Positive Coombs' test4 | |||
|
'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. 2Diarrhoea and colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis. 3ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase. 4A positive Coombs test develops in about 5% of patients and may interfere with blood cross matching. | ||||
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 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 (see sections 4.2 and 4.4).
Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 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 ceftazidime 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 |
< 81 |
- |
> 8 |
|
Non-species related breakpoints2 |
< 4 |
8 |
> 8 |
S=susceptible, I=intermediate, R=resistant.
'The breakpoints relate to high dose therapy (2 g x 3).
2Non-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.
Commonly Susceptible Species_
Gram positive aerobes
Streptococcus pyogenes
Streptococcus agalactiae_
Gram-negative aerobes
Citrobacter koseri Escherichia coli Haemophilus influenzae Moraxella catarrhalis Neisseria meningitidis Proteus mirabilis 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:
Fusobacterium 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 suseptibility 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.
5.2 Pharmacokinetic properties
Absorption
After intramuscular administration of 500 mg and 1 g 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 2 g 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 peritoneal 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 CSF 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 2 h. Ceftazidime is excreted unchanged into the urine by glomerular filtration; approximately 80 to 90% of the dose is recovered in the urine within 24 h. 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 (see section 4.2).
Hepatic impairment
The presence of mild to moderate hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days, provided renal function was not impaired (see section 4.2).
Elderly
The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination half-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.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeat dose toxicity, genotoxicity, toxicity to reproduction. Carcinogenicity studies have not been performed with ceftazidime.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Carbonate anhydrous
6.2 Incompatibilities
Ceftazidime should not be mixed with solutions with a pH above 7.5 for example sodium bicarbonate solution for injection. Ceftazidime and aminoglycosides should not be mixed in the solution for injection because of the risk for precipitation.
Cannulae and catheters for intravenous use should be flushed with physiological salt-solution between administrations of ceftazidime and vancomycin to avoid precipitation.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
3 years.
Reconstituted solution: Chemical and physical in use stability has been demonstrated up to 6 h at 25°C and 12 h at 5°C after reconstitution of the product with water for injection, 1 % lidocain solution, 0.9 % sodium chloride solution, ringer lactate and 10 % glucose solution. From a microbiological point of view, the product should be used immediately
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
Do not store above 25°C.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Ceftazidime 2 g powder for solution for injection or infusion
Nature: Colourless type II glass bottles closed with type I rubber stoppers covered with aluminium caps and plastic flip off caps.
Contents: Each pack contains:
1 x 50 ml bottle
10 x 50 ml bottles
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Intravenous use - injection
For direct intermittent intravenous administration, ceftazidime should be reconstituted with Water for Injections (see table below). The solution has to be injected slowly directly into the vein over a period up to 5 minutes or given through the tubing of a giving set.
Intramuscular use (for 500 mg and 1000mg):
Ceftazidime should be reconstituted with Water for Injections or Lidocaine Hydrochloride 10 mg/ml (1%) solution for injection as indicated in the table below. Information for Lidocaine should be consulted before reconstitution of ceftazidime with lidocaine.
Intravenous use - infusion (see section 4.2):
For intravenous infusion, the content of the 2 g infusion vial should be reconstituted with 10 ml of water for injections (for bolus) and 50 ml of water for injections (intravenous infusion) or one of the compatible intravenous fluids. Administer by intravenous infusion over 15-30 minutes. Intermittent intravenous infusion with a Y-type giving set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.
All sizes of vials of Ceftazidime are supplied under reduced pressure. As the product dissolves, carbon dioxide is released and a positive pressure develops. Small bubbles of carbon dioxide in the constituted solution may be ignored.
Instructions for constitution
See table for addition volumes and solution concentrations, which may be useful when fractional doses are required.
|
Vial size |
Amount of diluent to |
Approximate | |
|
be added (ml) |
concentration (mg/ml) | ||
|
500 mg powder for solution for injection | |||
|
500 mg |
Intramuscular |
1.5 ml |
260 |
|
Intravenous bolus |
5 ml |
90 | |
|
1 g powder for solution for injection | |||
|
1 g |
Intramuscular |
3 ml |
260 |
|
Intravenous bolus |
10 ml |
90 | |
|
2 g powder for solution for injection or infusion | |||
|
2 g |
Intravenous bolus |
10 ml |
170 |
|
Intravenous infusion |
50 ml* |
40 | |
|
* Addition s |
hould be in 2 stages | ||
Compatible intravenous fluids:
At ceftazidime concentrations between 40 mg/ml and 170 mg/ml, the Ceftazidime powders for injection may be mixed in commonly used solutions for infusion:
- sodium chloride 9 mg/ml (0.9%) solution (physiological saline solution),
- Ringer Lactate Solution
- Glucose 100 mg/ml (10%) solution
When reconstituted for intramuscular use, the Ceftazidime powder for injection can also be diluted with lidocaine 10 mg/ml (1%) solutions.
When ceftazidime is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, the recommended techniques of reconstitution described below should be followed.
Instructions for reconstitution:
For 2g infusion vials
Preparation of solutions for iv infusion from ceftazidime injection in standard vial presentation (minibag or burette-type set):
1. Introduce the syringe needle through the vial closure and inject 10 ml of diluent.
2. Withdraw the needle and shake the vial to give a clear solution.
3. Do not insert a gas relief needle until the product has dissolved. Insert a gas relief needle through the vial closure to relieve the internal pressure.
4. Transfer the reconstituted solution to final delivery vehicle (e.g. mini-bag or burette-type set) making up a total volume of at least 50 ml and administer by intravenous infusion over 15 to 30 min.
NOTE: To preserve product sterility, it is important that a gas relief needle is not inserted through the vial closure before the product has dissolved.
The dilution is to be made under aseptic conditions.
Single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Only clear solutions practically free from particles should be used.
Free from bacterial endotoxins.
Solutions range from light yellow to amber depending on concentration, diluent and storage conditions used. Within the stated recommendations, product potency is not adversely affected by such color variations.
7 MARKETING AUTHORISATION HOLDER
Fresenius Kabi Limited Cestrian Court Eastgate Way Manor Park Runcorn Cheshire WA7 1NT UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 08828/0195
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/10/2013
10 DATE OF REVISION OF THE TEXT
22/10/2013