- Approval Id
- de78011f0a9f398f
- Drug Approval Emc Name
- Ceftazidime Venus Pharma 2 g powder for solution for injection/infusion
- Drug Name
- Ceftazidime Venus Pharma 2 g powder for solution for injection/infusion
- Company Name
- Synchrony Pharma Ltd
- Company Address
- 3 Bunhill Row, London, EC1Y 8YZ
- Company Website
- //www.cnx-therapeutics.com
- Company Telephone
- +44 (0)20 7821 2840
- Company Medical Info Direct Line
- +44 (0)20 7821 2840
- Company Medical Info Email
- medinfo@cnx-therapeutics.com
- Atc Code
- J01DD02
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Venus Pharma GmbH
Am-Bahnhof 1-3,
59368, Werne,
Germany
- Authorisation Number
- PL 34985/0013
- Authorisation Date
- 04/08/2021
- Instruction Authorisation Holder
- Venus Pharma GmbH
Am-Bahnhof 1-3,
59368, Werne,
Germany
- Instruction Authorisation Number
- PL 34985/0013
- Instruction Authorisation Date
- 04/08/2021
- Instruction Composition
- Each vial contains 2 g ceftazidime (as pentahydrate) with sodium carbonate (118 mg per gram of ceftazidime).
\*Excipient with known effect\*
Each vial contains 104 mg (4.6 mmol) of sodium per vial.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Powder for solution for injection/infusion
White to pale yellow powder
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Ceftazidime Venus Pharma 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 patient 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 transurethral 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 causive bacteria would not fall within its spectrum of activity.
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
\*\*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 9 g 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 |
| Per-operative prophylaxis for transurethral 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 8 h |
| Malignant otitis externa |
| \*Continuous infusion\* | |
| Infection | Dose to be administered |
| Febrile neutropenia | Loading dose of 2 g followed by a continuous infusion of 4 to 6 g every 24 h1 |
| 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 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 doses, maximum 6 g/day |
| 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 | |
| Bacterial meningitis | |
| Bacteraemia\\* | |
| Bone and joint infections | |
| Complicated skin and soft tissue infections | |
| Complicated intra-abdominal infections | |
| Peritonitis associated with dialysis in patients with CAPD | |
| Neonates and infants ≤ 2 months | Infection | Usual dose |
| \*Intermittent Administration\* | | |
| Most infections | | 25-60 mg/kg/day in two divided doses1 |
| 1 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 suspects to be associated with, any of the infections listed in section 4.1. | | |
\*\*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 Ml/min | Approx. serum creatinine µmol/l(mg/dl) | Recommended unit dose of Ceftazidime (g) | 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 |
| <5 | >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) | 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 (>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. | | | |
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 5 h.
Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the tables 5 & 6 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 250mg 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 tables 5 & 6 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 |
| 1 Maintenance dose to be administered every 12 h. | | | | |
\*\*Table 6: Continuous veno-venous haemodialysis dose guidelines\*\*
| | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Residual renal function (creatinine clearance in ml/min) | Maintenance dose (mg) for a dialysate in flow rate of 1: | | | | | |
| 1.0 litre/h | | | 2.0 litre/h | | |
| Ultrafiltration rate (litre/h) | | | Ultrafiltration rate (litre/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 |
| 1 Maintenance dose to be administered every 12 h. | | | | | | |
\*\*Method of administration\*\*
The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.
Ceftazidime Venus Pharma 2 g should be administered by intravenous injection or infusion. Ceftazidime Venus Pharma 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.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
\*\*Hypersensitivity\*\*
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.
\*\*Spectrum of activity\*\*
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.
\*\*Pseudomembranous colitis\*\*
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 life-threatening. 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.
\*\*Renal function\*\*
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 section 4.2 and 4.8).
\*\*Overgrowth of non-susceptible organisms\*\*
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.
\*\*Test and assay interactions\*\*
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).
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.
\*\*Sodium content\*\*
Important information about one of the ingredients of Ceftazidime Venus Pharma:
Ceftazidime Venus Pharma 2 g contains 104 mg sodium per gram, equivalent to 5.2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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 a 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 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 (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 eosinphilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or uticarcial rash, pain and/or inflammation following intramuscular injection and positive Coomb's test.
Data from sponsored and unsponsored 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 ≥1/100 and <1/10
Uncommon ≥1/1,000 and <1/100
Rare ≥1/10,000 and <1/1000
Very rare <1/10,000
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\*\* | | | | Anaphylaxis (including bronchospasm and/or hypotension) (see section 4.4) |
| \*\*Nervous system disorders\*\* | | Headache Dizziness | | Neurological sequelae1 Paraesthesia |
| \*\*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 |
| \*\*Heptobiliary disorders\*\* | Transient elevations in one or more hepatic enzymes3 | | | Jaundice |
| \*\*Skin and subcutaneous tissue disorders\*\* | Maculopapular or urticarial rash | Pruritus | | Toxic epidermal necrolysis StevensJohnson syndrome Erythema multiforme Angioedema Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)4 |
| \*\*Renal and urinary disorders\*\* | | Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine | Interstitial nephritis Acute renal failure | |
| \*\*General disorders and administration site conditions\*\* | Pain and/or inflammation after intramuscular injection | Fever | | |
| \*\*Investigations\*\* | Positive Coombs' test5 | | | |
1 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.
2 Diarrhoea and colitis may be associated with \*Clostridium difficile\* and may present as pseudomembranous colitis.
3 ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase.
4 There have been rare reports where DRESS has been associated with ceftazidime.
5 A 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 or search for MHRA Yellow Card in the Google Play or Apple App store.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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-bacterials 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
1 The breakpoints relate to high dose therapy (2 g x 3).
2 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.
| |
| --- |
| \*\*Commonly Susceptible Species\*\* |
| \*\*Gram-positive aerobes:\*\* \*Streptococcus pyogenes\* \*Streptococcus agalactiae\* |
| \*\*Gram-negative aerobes:\*\* \*Citrobacter koseri\* \*Haemophilus influenza\* \*Moraxella catarrhalis\* \*Neisseria menigitidis\* \*Pasteurella multocida\* \*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\* \*Escherichia coli\* \*Klebsiella pneumonia\* \*Klebsiella spp (other)\* \*Pseudomonas aeruginosa\* \*Serratia spp\* \*Morganella morganii\* |
| \*\*Gram-positive aerobes:\*\* \*Staphylococcus aureus£\* |
| \*Staphylococcus pneumoniae££\* \*Viridans group streptococcus\* |
| \*\*Gram-positive anaerobes:\*\* \*Clostridium perfringens\* \*Peptostreptococcus spp.\* |
| \*\*Gram-negative anaerobes\*\* \*Fusobacterium spp.\* |
| \*\*Inherently resistant organisms\*\* |
| \*\*Gram-positive aerobes:\*\* Enterococcus spp 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-resistance \*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. |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 170mg/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.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Sodium carbonate (anhydrous sterile)6.2 Incompatibilities
Ceftazidime is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. It is not recommended as a diluent. Ceftazidime and aminoglycosides should not be mixed in the same giving set or syringe. Precipitation has been reported with vancomycin added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.6.3 Shelf life
2 years
\*\*After reconstitution:\*\*
Chemical and physical in-use stability has been demonstrated for 6 days at 2 to 8°C and 9 hours at 25°C.
From a microbiological point of view, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
\*\*After dilution:\*\*
Chemical and physical in-use stability has been demonstrated for 6 days at 2 to 8°C and 9 hours at 25°C.
From a microbiological point of view, the reconstituted and diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
\*\*Reconstituted Solutions\*\*
Constituted solutions may be stored in the refrigerator (2 - 8°C) for up to 24 hours.6.4 Special precautions for storage
This medical product does not require any special storage condition.
Keep vials in the outer carton to protect from light.
For storage conditions after reconstitution see section 6.3.6.5 Nature and contents of container
Ceftazidime Venus Pharma 2 g powder for solution for injection/infusion is packaged in 20 ml clear glass vials with a 20 mm grey butyl rubber plug and a 20 mm flip-off aluminium seal.
Available in packs of 1, 5 or 10 vials.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
All sizes of vials of Ceftazidime Venus Pharma 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 7 and table 8 for addition volumes and solution concentrations, which may be useful when fractional doses are required.
Table 7: Powder for Solution for Injection
| | | | |
| --- | --- | --- | --- |
| Presentation | | Amount of diluent to be added (ml) | Approximate concentration (mg/ml) |
| 1 g | | | |
| | Intramuscular Intravenous bolus | 3 ml 10 ml | 260 90 |
| 2 g | | | |
| | Intravenous bolus | 10 ml | 170 |
Note:
• The resulting volume of the solution of ceftazidime in reconstitution medium is increased due to the displacement factor of the drug product resulting in the listed concentrations in mg/ml presented in the above table.
Table 8: Powder for Solution for Infusion
| | | | |
| --- | --- | --- | --- |
| Presentation | | Amount of diluent to be added (ml) | Approximate concentration (mg/ml) |
| 1 g | | | |
| | Intravenous infusion | 50 ml\\* | 20 |
| 2 g | | | |
| | Intravenous infusion | 50 ml\\* | 40 |
\\* Addition should be in two stages.
Note:
• The resulting volume of the solution of ceftazidime in reconstitution medium is increased due to the displacement factor of the drug product resulting in the listed concentrations in mg/ml presented in the above table.
Solution is clear with the defined concentration, diluents and storage conditions used.
Ceftazidime at concentrations between 1 mg/ml and 40 mg/ml is compatible with:
• sodium chloride 9 mg/ml (0.9%) solution for injection
• M/6 sodium lactate injection
• 5% dextrose injection
• 0.9% sodium chloride and 5% dextrose injection
• 10% dextrose injection
Ceftazidime at concentrations detailed in Table 7 may be constituted for intramuscular use with 0.5% or 1% Lidocaine Hydrochloride Injection.
\*\*Preparation of solution for bolus injection\*\*
1. Insert the syringe needle through the vial closure and inject the recommended volume of diluent. The vacuum may assist entry of the diluent. Remove the syringe needle.
2. Shake to dissolve: carbon dioxide is released and a clear solution will be obtained in about 1 to 2 minutes.
3. Invert the vial. With the syringe plunger fully depressed, insert the needle through the vial closure and withdraw the total volume of solution into the syringe (the pressure in the vial may aid withdrawal). Ensure that the needle remains within the solution and does not enter the head space. The withdrawn solution may contain small bubbles of carbon dioxide; they may be disregarded.
These solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids. Ceftazidime is compatible with the intravenous fluids listed above.
\*\*Preparation of solutions for iv infusion from ceftazidime injection in standard vial presentation (mini-bag or burette-type set):\*\*
Prepare using a total of 50 ml of compatible diluents (listed above), added in TWO stages as below.
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 the gas relief needle is not inserted through the vial closure before the product has dissolved.
Any residual antibiotic solution should be discarded.
For single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Each vial contains 2 g ceftazidime (as pentahydrate) with sodium carbonate (118 mg per gram of ceftazidime).
\*Excipient with known effect\*
Each vial contains 104 mg (4.6 mmol) of sodium per vial.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Powder for solution for injection/infusion
White to pale yellow powder
## Clinical Particulars
4.1 Therapeutic indications
Ceftazidime Venus Pharma 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 patient 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 transurethral 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 causive bacteria would not fall within its spectrum of activity.
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
\*\*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 9 g 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 |
| Per-operative prophylaxis for transurethral 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 8 h |
| Malignant otitis externa |
| \*Continuous infusion\* | |
| Infection | Dose to be administered |
| Febrile neutropenia | Loading dose of 2 g followed by a continuous infusion of 4 to 6 g every 24 h1 |
| 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 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 doses, maximum 6 g/day |
| 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 | |
| Bacterial meningitis | |
| Bacteraemia\\* | |
| Bone and joint infections | |
| Complicated skin and soft tissue infections | |
| Complicated intra-abdominal infections | |
| Peritonitis associated with dialysis in patients with CAPD | |
| Neonates and infants ≤ 2 months | Infection | Usual dose |
| \*Intermittent Administration\* | | |
| Most infections | | 25-60 mg/kg/day in two divided doses1 |
| 1 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 suspects to be associated with, any of the infections listed in section 4.1. | | |
\*\*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 Ml/min | Approx. serum creatinine µmol/l(mg/dl) | Recommended unit dose of Ceftazidime (g) | 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 |
| <5 | >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) | 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 (>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. | | | |
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 5 h.
Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the tables 5 & 6 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 250mg 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 tables 5 & 6 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 |
| 1 Maintenance dose to be administered every 12 h. | | | | |
\*\*Table 6: Continuous veno-venous haemodialysis dose guidelines\*\*
| | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Residual renal function (creatinine clearance in ml/min) | Maintenance dose (mg) for a dialysate in flow rate of 1: | | | | | |
| 1.0 litre/h | | | 2.0 litre/h | | |
| Ultrafiltration rate (litre/h) | | | Ultrafiltration rate (litre/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 |
| 1 Maintenance dose to be administered every 12 h. | | | | | | |
\*\*Method of administration\*\*
The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.
Ceftazidime Venus Pharma 2 g should be administered by intravenous injection or infusion. Ceftazidime Venus Pharma 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.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
\*\*Hypersensitivity\*\*
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.
\*\*Spectrum of activity\*\*
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.
\*\*Pseudomembranous colitis\*\*
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 life-threatening. 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.
\*\*Renal function\*\*
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 section 4.2 and 4.8).
\*\*Overgrowth of non-susceptible organisms\*\*
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.
\*\*Test and assay interactions\*\*
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).
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.
\*\*Sodium content\*\*
Important information about one of the ingredients of Ceftazidime Venus Pharma:
Ceftazidime Venus Pharma 2 g contains 104 mg sodium per gram, equivalent to 5.2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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 a 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 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 (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 eosinphilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or uticarcial rash, pain and/or inflammation following intramuscular injection and positive Coomb's test.
Data from sponsored and unsponsored 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 ≥1/100 and <1/10
Uncommon ≥1/1,000 and <1/100
Rare ≥1/10,000 and <1/1000
Very rare <1/10,000
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\*\* | | | | Anaphylaxis (including bronchospasm and/or hypotension) (see section 4.4) |
| \*\*Nervous system disorders\*\* | | Headache Dizziness | | Neurological sequelae1 Paraesthesia |
| \*\*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 |
| \*\*Heptobiliary disorders\*\* | Transient elevations in one or more hepatic enzymes3 | | | Jaundice |
| \*\*Skin and subcutaneous tissue disorders\*\* | Maculopapular or urticarial rash | Pruritus | | Toxic epidermal necrolysis StevensJohnson syndrome Erythema multiforme Angioedema Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)4 |
| \*\*Renal and urinary disorders\*\* | | Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine | Interstitial nephritis Acute renal failure | |
| \*\*General disorders and administration site conditions\*\* | Pain and/or inflammation after intramuscular injection | Fever | | |
| \*\*Investigations\*\* | Positive Coombs' test5 | | | |
1 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.
2 Diarrhoea and colitis may be associated with \*Clostridium difficile\* and may present as pseudomembranous colitis.
3 ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase.
4 There have been rare reports where DRESS has been associated with ceftazidime.
5 A 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 or search for MHRA Yellow Card in the Google Play or Apple App store.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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-bacterials 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
1 The breakpoints relate to high dose therapy (2 g x 3).
2 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.
| |
| --- |
| \*\*Commonly Susceptible Species\*\* |
| \*\*Gram-positive aerobes:\*\* \*Streptococcus pyogenes\* \*Streptococcus agalactiae\* |
| \*\*Gram-negative aerobes:\*\* \*Citrobacter koseri\* \*Haemophilus influenza\* \*Moraxella catarrhalis\* \*Neisseria menigitidis\* \*Pasteurella multocida\* \*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\* \*Escherichia coli\* \*Klebsiella pneumonia\* \*Klebsiella spp (other)\* \*Pseudomonas aeruginosa\* \*Serratia spp\* \*Morganella morganii\* |
| \*\*Gram-positive aerobes:\*\* \*Staphylococcus aureus£\* |
| \*Staphylococcus pneumoniae££\* \*Viridans group streptococcus\* |
| \*\*Gram-positive anaerobes:\*\* \*Clostridium perfringens\* \*Peptostreptococcus spp.\* |
| \*\*Gram-negative anaerobes\*\* \*Fusobacterium spp.\* |
| \*\*Inherently resistant organisms\*\* |
| \*\*Gram-positive aerobes:\*\* Enterococcus spp 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-resistance \*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. |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 170mg/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.
## Pharmaceutical Particulars
6.1 List of excipients
Sodium carbonate (anhydrous sterile)6.2 Incompatibilities
Ceftazidime is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. It is not recommended as a diluent. Ceftazidime and aminoglycosides should not be mixed in the same giving set or syringe. Precipitation has been reported with vancomycin added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.6.3 Shelf life
2 years
\*\*After reconstitution:\*\*
Chemical and physical in-use stability has been demonstrated for 6 days at 2 to 8°C and 9 hours at 25°C.
From a microbiological point of view, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
\*\*After dilution:\*\*
Chemical and physical in-use stability has been demonstrated for 6 days at 2 to 8°C and 9 hours at 25°C.
From a microbiological point of view, the reconstituted and diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
\*\*Reconstituted Solutions\*\*
Constituted solutions may be stored in the refrigerator (2 - 8°C) for up to 24 hours.6.4 Special precautions for storage
This medical product does not require any special storage condition.
Keep vials in the outer carton to protect from light.
For storage conditions after reconstitution see section 6.3.6.5 Nature and contents of container
Ceftazidime Venus Pharma 2 g powder for solution for injection/infusion is packaged in 20 ml clear glass vials with a 20 mm grey butyl rubber plug and a 20 mm flip-off aluminium seal.
Available in packs of 1, 5 or 10 vials.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
All sizes of vials of Ceftazidime Venus Pharma 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 7 and table 8 for addition volumes and solution concentrations, which may be useful when fractional doses are required.
Table 7: Powder for Solution for Injection
| | | | |
| --- | --- | --- | --- |
| Presentation | | Amount of diluent to be added (ml) | Approximate concentration (mg/ml) |
| 1 g | | | |
| | Intramuscular Intravenous bolus | 3 ml 10 ml | 260 90 |
| 2 g | | | |
| | Intravenous bolus | 10 ml | 170 |
Note:
• The resulting volume of the solution of ceftazidime in reconstitution medium is increased due to the displacement factor of the drug product resulting in the listed concentrations in mg/ml presented in the above table.
Table 8: Powder for Solution for Infusion
| | | | |
| --- | --- | --- | --- |
| Presentation | | Amount of diluent to be added (ml) | Approximate concentration (mg/ml) |
| 1 g | | | |
| | Intravenous infusion | 50 ml\\* | 20 |
| 2 g | | | |
| | Intravenous infusion | 50 ml\\* | 40 |
\\* Addition should be in two stages.
Note:
• The resulting volume of the solution of ceftazidime in reconstitution medium is increased due to the displacement factor of the drug product resulting in the listed concentrations in mg/ml presented in the above table.
Solution is clear with the defined concentration, diluents and storage conditions used.
Ceftazidime at concentrations between 1 mg/ml and 40 mg/ml is compatible with:
• sodium chloride 9 mg/ml (0.9%) solution for injection
• M/6 sodium lactate injection
• 5% dextrose injection
• 0.9% sodium chloride and 5% dextrose injection
• 10% dextrose injection
Ceftazidime at concentrations detailed in Table 7 may be constituted for intramuscular use with 0.5% or 1% Lidocaine Hydrochloride Injection.
\*\*Preparation of solution for bolus injection\*\*
1. Insert the syringe needle through the vial closure and inject the recommended volume of diluent. The vacuum may assist entry of the diluent. Remove the syringe needle.
2. Shake to dissolve: carbon dioxide is released and a clear solution will be obtained in about 1 to 2 minutes.
3. Invert the vial. With the syringe plunger fully depressed, insert the needle through the vial closure and withdraw the total volume of solution into the syringe (the pressure in the vial may aid withdrawal). Ensure that the needle remains within the solution and does not enter the head space. The withdrawn solution may contain small bubbles of carbon dioxide; they may be disregarded.
These solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids. Ceftazidime is compatible with the intravenous fluids listed above.
\*\*Preparation of solutions for iv infusion from ceftazidime injection in standard vial presentation (mini-bag or burette-type set):\*\*
Prepare using a total of 50 ml of compatible diluents (listed above), added in TWO stages as below.
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 the gas relief needle is not inserted through the vial closure before the product has dissolved.
Any residual antibiotic solution should be discarded.
For single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
