Each vial contains:

Ceftazidime (as pentahydrate buffered with sodium carbonate) ......................... 250 mg, 500 mg, 1 g, or 2 g

CEFIDIME 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.

CEFIDIME may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

CEFIDIME may be used in the peri-operative prophylaxis of urinary tract infections in patients undergoing transurethral resection of the prostate (TURP).

The selection of CEFIDIME should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram negative bacteria.

CEFIDIME 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.

Dosage:

Table 1: 

Adults and Children ≥ 40 kg:

Table 2: 

Children < 40 kg:

Pediatric population:

The safety and efficacy of CEFIDIME administered as continuous infusion to neonates and infants ≤ 2 months has not been established.

Elderly:

In view of the age-related reduced clearance of CEFIDIME in elderly patients, the daily dose should not normally exceed 3 g in those over 80 years of age.

Hepatic impairment:

Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment. There are no study data in patients with severe hepatic impairment. Close clinical monitoring for safety and efficacy is advised.

Renal impairment:

CEFIDIME is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function, the dosage should be reduced.

An initial loading dose of 1 g should be given. Maintenance doses should be based on creatinine clearance:

Table 3: Recommended Maintenance Doses of CEFIDIME in Renal Impairment – Intermittent Infusion:

Adults and Children ≥ 40 kg:

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:

^* 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 CEFIDIME in Renal Impairment – Continuous Infusion:

Adults and Children ≥ 40 kg:

Caution is advised in dose selection. Close clinical monitoring for safety and efficacy is advised.

Children < 40 kg: 

The safety and effectiveness of CEFIDIME 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 hours.

Following each haemodialysis period, the maintenance dose of CEFIDIME recommended in Tables 5 and 6  should be repeated.

Peritoneal dialysis:

CEFIDIME may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD).

In addition to intravenous use, CEFIDIME can be incorporated into the dialysis fluid (usually 125-250 mg for 2 litres of dialysis solution).

For patients with 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: 

Table 6: Continuous Veno-venous Haemodialysis Dose Guidelines: 

Administration:

The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.

CEFIDIME 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.

CEFIDIME 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.

Hypersensitivity to the active substance, to other cephalosporins or to any of the excipients.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other beta-lactam medicinal products.

Special caution is required to determine any other type of previous hypersensitivity reactions to penicillin or to other beta-lactam medicinal products because patients hypersensitive to these medicines may be hypersensitive to CEFIDIME as well (cross-allergy).

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with CEFIDIME 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 CEFIDIME 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 CEFIDIME for treatment.

Antibacterial agent-associated colitis and pseudomembranous 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 CEFIDIME. Discontinuation of therapy with CEFIDIME 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 of CEFIDIME 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.

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 (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.

Important information about one of the ingredients of CEFIDIME: 

CEFIDIME contains sodium; this should be considered for patients who are on a controlled sodium diet.

Special Precautions for Disposal and Other Handling: 

All sizes of CEFIDIME Vials of 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.

^* Note: Addition should be in two stages.

Solutions range in colour from light yellow to amber depending on concentration, diluents and storage conditions used. Within the stated recommendations, product potency is not adversely affected by such colour variations.

CEFIDIME 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.

Compound sodium lactate injection (Hartmann's solution).

5% dextrose injection 0.225% Sodium chloride and 5% Dextrose injection.

0.45% Sodium chloride and 5% Dextrose injection.

0.9% Sodium chloride and 5% Dextrose injection.

0.18% Sodium chloride and 4% Dextrose injection.

10% Dextrose injection.

Dextran 40 injection 10% in 0.9% Sodium chloride injection.

Dextran 40 injection 10% in 5% Dextrose injection.

Dextran 70 injection 6% in 0.9% Sodium chloride injection.

Dextran 70 injection 6% in 5% Dextrose injection.

CEFIDIME at concentrations between 0.05 mg/ml and 0.25 mg/ml is compatible with Intra-peritoneal Dialysis Fluid (Lactate).

CEFIDIME 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 1-2 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. CEFIDIME is compatible with the most commonly used intravenous fluids.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction studies have only been conducted with probenecid and furosemide.

Concurrent use of high doses with nephrotoxic medicinal products may adversely affect renal function.

Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of ceftazidime with chloramphenicol is proposed, the possibility of antagonism should be considered.

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.

CEFIDIME should be prescribed to pregnant women only if the benefit outweighs the risk.

Lactation: 

Ceftazidime is excreted in human milk in small quantities but at therapeutic doses of ceftazidime, no effects on the breastfed infant are anticipated. CEFIDIME can be used during breastfeeding.

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.

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 Coombs test.

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).

Infections and Infestations: 

Uncommon: Candidiasis (including vaginitis and oral thrush).

Blood and Lymphatic system disorders: 

Common: Eosinophilia, thrombocytosis.

Uncommon: Neutropenia, leucopenia, thrombocytopenia.

Unknown: Agranulocytosis, haemolytic anaemia, lymphocytosis

Immune system disorders: 

Unknown: Anaphylaxis (including bronchospasm and/or hypotension).

Nervous system disorders: 

Uncommon: Headache, dizziness.

Unknown: Neurological sequelae¹, paraesthesia.

Vascular disorders: 

Common: Phlebitis or thrombophlebitis with intravenous administration.

Gastrointestinal disorders: 

Common: Diarrhoea.

Uncommon: Antibacterial agent-associated diarrhoea and colitis², abdominal pain, nausea, vomiting.

Unknown: Bad taste.

Heptobiliary disorders: 

Common: Transient elevations in one or more hepatic enzymes³.

Unknown: Jaundice.

Skin and Subcutaneous tissue disorders: 

Common: Maculopapular or urticarial rash.

Uncommon: Pruritus.

Unknown: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme, angioedema.

Renal and Urinary disorders: 

Uncommon: Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine.

Very rare: Interstitial nephritis, acute renal failure.

General disorders and Administration site conditions: 

Common: Pain and/or inflammation after intramuscular injection.

Uncommon: Fever.

Investigations: 

Common: Positive Coombs test⁴.

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 A positive Coombs test develops in about 5% of patients and may interfere with blood cross matching.

Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma.

Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.

Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.

Pharmacodynamic properties: 

Pharmacotherapeutic group:  Anti-bacterials for systemic use. Third-generation cephalosporins.

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:

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.

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 influenzae, Moraxella catarrhalis, Neisseria menigitidis, Pasteurella multocida, Proteus mirabilis, Proteus spp (other), Providencia spp..

Gram-negative aerobes: 

Acinetobacter baumannii⁺, Burkholderia cepacia, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae.

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 is 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.

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.

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.

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 3.5-4 hours following single or 7 days repeat BID dosing of 2 g IV bolus injections in elderly patients 80 years or older.

Pediatric 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.

Store at a temperature not exceeding 30^°C, and to be used directly after reconstitution.

CEFIDIME 250 mg Vials: Box containing 1 vial  + 1 ampoule of Sterile Water for Injection solvent.

CEFIDIME 500 mg Vials: Box containing 1 vial  + 1 ampoule of Sterile Water for Injection solvent.

CEFIDIME 1 g Vials: Box containing 1 vial + 1 ampoule of Sterile Water for Injection solvent.

CEFIDIME 2 g Vials: Box containing 1 vial  + 2 ampoules of Sterile Water for Injection solvent.