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 continuous ambulatory peritoneal dialysis (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 causative 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

Peri-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 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 doses, maximum 6 g/day

Complicated skin and soft tissue infections

Complicated intraabdominal 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 on 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 suspected 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 tables 3 & 4 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 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 of1:

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 2 g should be administered by intravenous injection or infusion. 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.

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 Clostridioides 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:

This medicinal product contains 100 mg sodium per vial, equivalent to 5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This should be particularly taken into account for those who are on a controlled sodium diet.

This medicinal product is administered only after reconstitution - see section 6.6.

The sodium content of the diluent should be taken into account when calculating the total sodium content of the prepared dilution of the product. For detailed information on the sodium content of the solution used to dilute the product, please refer to the product characteristics of the diluent used.

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. 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 eosinophilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or urticarial 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 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <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

Hepatobiliary disorders

Transient elevations in one or more hepatic enzymes3

Jaundice

Skin and subcutaneous tissue disorders

Maculopapular or urticarial rash

Pruritus

Toxic epidermal necrolysis

Stevens-Johnson 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 Clostridioides 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.

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.