FORTUM 1 GRAM

Israel - English - Ministry of Health

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Active ingredient:
CEFTAZIDIME AS PENTAHYDRATE
Available from:
GLAXO SMITH KLINE (ISRAEL) LTD
ATC code:
J01DD02
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJ/INF
Composition:
CEFTAZIDIME AS PENTAHYDRATE 1 G/VIAL
Administration route:
I.M, I.V
Prescription type:
Required
Manufactured by:
GLAXO SMITH KLINE MANUFACTURING SPA,ITALY
Therapeutic group:
CEFTAZIDIME
Therapeutic area:
CEFTAZIDIME
Therapeutic indications:
Fortum 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 trans-urethral resection of the prostate (TURP).The selection of ceftazidime should take into account its antibacterial spectrum, which is mainly restric
Authorization number:
046 44 23497 05
Authorization date:
2013-02-28

ל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

.102.50

.102.50

.102.50

ךיראת

:

71.5.71

תילגנאב רישכת םש

םושירה רפסמו

:

23499)

-

40

-

23497); Fortum 2 gram (046

-

44

-

Fortum 1 gram (046

םושירה לעב םש

:

GlaxoSmithKline (ISRAEL) Ltd

! דבלב תורמחהה טורפל דעוימ הז ספוט

ןולעב ןולעב ןולעב אפורל אפורל אפורל

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Undesirable effects

Skin

and

subcutaneous

tissue disorders

Common - Maculopapular or

urticarial rash

Uncommon - Pruritus

Very rare

Unknown

-

Toxic epidermal

necrolysis Stevens-Johnson

syndrome Erythema

multiforme Angioedema

Skin

and

subcutaneous

tissue

disorders

Common - Maculopapular or

urticarial rash

Uncommon - Pruritus

Very rare

Unknown

-

Toxic epidermal

necrolysis Stevens-Johnson

syndrome Erythema multiforme

Angioedema

Drug Reaction with Eosinophilia

Systemic

Symptoms

(DRESS)

There have been rare reports where

DRESS has been associated with

ceftazidime.

תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ .בוהצ עקר לע

עבצב )ןולעב( ונמוס תורמחה רדגב םניאש םייוניש קורי

Page 1 of 19

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in May 2017

Fortum

1 gram

Fortum

2 gram

1.

NAME OF THE MEDICINAL PRODUCT

Fortum 1 gram

Fortum 2 gram

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Fortum 1 gram: Vials contain 1g ceftazidime (as pentahydrate) with sodium carbonate

(118mg per gram of ceftazidime).

Fortum 2 gram: Vials contain 2g ceftazidime (as pentahydrate) with sodium carbonate

(118mg per gram of ceftazidime).

3.

PHARMACEUTICAL FORM

Fortum 1 gram - Powder for solution for injection or infusion

Fortum 2 gram - Powder for solution for injection or infusion

CLINICAL PARTICULARS

4.1

Therapeutic indications

Fortum 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.

Page 2 of 19

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 day

Febrile neutropenia

2 g every 8 h

Nosocomial pneumonia

Bacterial meningitis

Bacteraemia*

Bone and joint infections

1-2 g every 8 h

Complicated skin and soft tissue

infections

Complicated intra-abdominal

infections

Peritonitis associated with dialysis in

patients on CAPD

Complicated urinary tract infections

1-2 g every 8 h or 12 h

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

Nosocomial pneumonia

Page 3 of 19

Broncho-pulmonary infections in

cystic fibrosis

Loading dose of 2 g followed by a

continuous infusion of 4 to 6 g every

24 h

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

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

Nosocomial

pneumonia

Page 4 of 19

Broncho-pulmonary

infections in cystic

fibrosis

mg/kg/day, maximum 6

g/day

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 doses

In neonates and infants ≤ 2 months, the serum half life of ceftazidime can be

three to four times that in adults.

*Where associated with, or suspects to be associated with, any of the infections

listed in section 4.1.

Paediatric population

The safety and efficacy of Fortum 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 Fortum in renal impairment –

intermittent infusion

Adults and children ≥ 40 kg

Page 5 of 19

Creatinine

clearance

ml/min

Approx. serum

creatinine

mol/l(mg/dl)

Recommended

unit dose of Fortum

Frequency of dosing

(hourly)

50-31

150-200

(1.7-2.3)

30-16

200-350

(2.3-4.0)

15-6

350-500

(4.0-5.6)

<5

>500

(>5.6)

In patients with severe infections the unit dose should be increased by 50% or the

dosing frequency increased. In children the creatinine clearance should be adjusted

for body surface area or lean body mass.

Children < 40 kg

Creatinine

clearance

(ml/min)**

Approx. serum

creatinine

mol/l(mg/dl)

Recommended

individual dose

mg/kg body weight

Frequency of dosing

(hourly)

50-31

150-200

(1.7-2.3)

30-16

200-350

(2.3-4.0)

15-6

350-500

(4.0-5.6)

12.5

<5

>500

(>5.6)

12.5

*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 Fortum 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

Not evaluated

Page 6 of 19

(>4.0)

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

is advised.

Children < 40 kg

The safety and effectiveness of Fortum 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 250 mg for 2 litres of dialysis solution).

For patients in renal failure on continuous arterio-venous haemodialysis or high-flux

haemofiltration in intensive therapy units: 1 g daily either as a single dose or in

divided doses. For low-flux haemofiltration, follow the dose recommended under

renal impairment.

For patients on veno-venous haemofiltration and veno-venous haemodialysis, follow

the dosage recommendations in the tables 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) of

16.7

33.3

Maintenance dose to be administered every 12 h.

Table 6: Continuous veno-venous haemodialysis dose guidelines

Page 7 of 19

Residual

renal

function

(creatinine

clearance

in ml/min)

Maintenance dose (mg) for a dialysate in flow rate of

1.0 litre/h

2.0 litre/h

Ultrafiltration rate (litre/h)

Ultrafiltration rate (litre/h)

1000

1000

1000

1000

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.

Fortum 1 g 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. Fortum 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.

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

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.

Page 8 of 19

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.

Page 9 of 19

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 Fortum:

1 g powder for solution for injection or infusion.

Fortum 1 g contains 52 mg of sodium per vial.

2 g powder for solution for injection or infusion.

Fortum 2 g contains 104 mg of sodium per vial.

This should be considered for patients who are on a controlled sodium diet.

4.5.

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been conducted with 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.

In common with other antibiotics, ceftazidime may affect the gut flora, leading to

lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

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).

Fortum 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

Page 10 of 19

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

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

sequelae

Paraesthesia

Vascular

disorders

Phlebitis or

thrombophlebitis

with intravenous

administration

Page 11 of 19

Gastrointest

inal

disorders

Diarrhoea

Antibacterial

agent-associated

diarrhoea and

colitis

(see section

4.4)

Abdominal pain

Nausea

Vomiting

Bad taste

Heptobiliar

y disorders

Transient

elevations in one

or more hepatic

enzymes

Jaundice

Skin and

subcutaneou

s tissue

disorders

Maculopapular or

urticarial rash

Pruritus

Toxic epidermal

necrolysis

Stevens-Johnson

syndrome

Erythema

multiforme

Angioedema

Drug Reaction

with

Eosinophilia and

Systemic

Symptoms

(DRESS)

Renal and

urinary

disorders

Transient

elevations of blood

urea, blood urea

nitrogen and/or

serum creatinine

Interstitial

nephritis

Acute

renal

failure

General

disorders

administrati

on site

conditions

Pain and/or

inflammation

after

intramuscular

injection

Fever

Investigatio

Positive Coombs’

test

There have been reports of neurological sequelae including tremor, myoclonia, convulsions,

encephalopathy and coma in patients with renal impairment in whom the dose of Fortum has not been

appropriately reduced.

Diarrhoea and colitis may be associated with

Clostridium difficile

and may present as

pseudomembranous colitis.

ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase.

There have been rare reports where DRESS has been associated with ceftazidime.

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. Any suspected adverse events should be reported to the Ministry of Health

Page 12 of 19

according to the National Regulation by using an online form

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffec

tMedic@moh.gov.il.

Additionally, you should also report to GSK Israel (il.safety@gsk.com).

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

unbound

concentration

remains

above

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

Page 13 of 19

Minimum inhibitory concentration (MIC) breakpoints established by the European

Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Organism

Breakpoints (mg/L)

Enterobacteriaceae

≤1

>4

Pseudomonas

aeruginosa

≤8

>8

Non-species related

breakpoints

2

≤4

>8

S=Susceptible, I=Intermediate, R=Resistant

The breakpoints relate to high dose therapy (2 g x 3).

Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are

independent of MIC distributions of specific species. They are for use only for species not mentioned in

the table or footnotes.

Microbiological Susceptibility

The prevalence of acquired resistance may vary geographically and with time for

selected species and local information on resistance is desirable, particularly when

treating severe infections. As necessary, expert advice should be sought when the local

prevalence of resistance is such that the utility of ceftazidime in at least some types of

infections is questionable.

Page 14 of 19

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.

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 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.

Page 15 of 19

Inherently resistant organisms

Gram-positive aerobes:

Enterococcus spp

including

Enterococcus faecalis

Enterococcus faecium

Listeria spp

Gram-positive anaerobes:

Clostridium difficile

Gram-negative anaerobes

Bacteroides

spp. (many strains of

Bacteroides fragilis

are resistant).

Others:

Chlamydia

Mycoplasma

Legionella

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

5.2.

Pharmacokinetic properties

Absorption

After intramuscular administration of 500 mg and 1 g of ceftazidime, peak plasma

levels of 18 and 37 mg/l respectively are achieved rapidly. Five minutes after

intravenous bolus injection of 500 mg, 1 g or 2 g, plasma levels are 46, 87 and 170

mg/l, respectively. The kinetics of ceftazidime are linear within the single dose range

of 0.5 to 2 g following intravenous or intramuscular dosing.

Distribution

The serum protein binding of ceftazidime is low at about 10%. Concentrations in

excess of the MIC for common pathogens can be achieved in tissues such as bone,

heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids.

Ceftazidime crosses the placenta readily, and is excreted in the breast milk.

Penetration of the intact blood-brain barrier is poor, resulting in low levels of

ceftazidime in the CSF in the absence of inflammation. However, concentrations of 4

to 20 mg/l or more are achieved in the CSF when the meninges are inflamed.

Biotransformation

Ceftazidime is not metabolised.

Elimination

After parenteral administration plasma levels decrease with a half-life of about 2 h.

Ceftazidime is excreted unchanged into the urine by glomerular filtration;

approximately 80 to 90 % of the dose is recovered in the urine within 24 h. Less than

1 % is excreted via the bile.

Special patient populations

Renal impairment

Page 16 of 19

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 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 when vancomycin has been added to ceftazidime in

solution. It is recommended that giving sets and intravenous lines are flushed

between administration of these two agents.

6.3.

Shelf life

The expiry date of the product is indicated on the label and packaging.

6.4.

Special precautions for storage

Page 17 of 19

The unconstituted product should be stored below 25

C and protected from light.

Constituted solutions may be stored in the refrigerator (2 - 8

C) for up to 24 hours.

6.5.

Nature and contents of container

Type III glass vials with a bromobutyl rubber plug closure and an aluminium

overseal.

Individually cartoned vials containing 1g ceftazidime (as pentahydrate) for

intramuscular or intravenous use in packs of 1 or 5.

Individually cartoned vials containing 2g ceftazidime (as pentahydrate) for

intravenous use in pack of 1.

Not all pack sizes may be marketed.

6.6.

Special precautions for disposal and other handling

All sizes of vials of Fortum are supplied under reduced pressure. As the product

dissolves, carbon dioxide is released and a positive pressure develops. Small bubbles

of carbon dioxide in the constituted solution may be ignored.

Instructions for constitution

See table for addition volumes and solution concentrations, which may be useful

when fractional doses are required.

Vial size

Amount of diluent

to be added (ml)

Approximate

concentration (mg/ml)

1 g powder for solution for injection or infusion

Intramuscular

Intravenous bolus

Intravenous infusion

3 ml

10 ml

50 ml*

2 g powder for solution for injection or infusion

Intravenous bolus

Intravenous infusion

10 ml

50 ml

*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.

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

compound sodium lactate injection (Hartmann's solution)

5% dextrose injection

Page 18 of 19

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

Ceftazidime at concentrations between 0.05 mg/ml and 0.25 mg/ml is compatible

with Intra-peritoneal Dialysis Fluid (Lactate).

Ceftazidime may be constituted for intramuscular use with 0.5% or 1% Lidocaine

Hydrochloride Injection.

Preparation of solution for bolus injection

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.

Shake to dissolve: carbon dioxide is released and a clear solution will be obtained

in about 1 to 2 minutes.

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 most commonly used intravenous fluids.

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 (for 1 g and 2 g vials) of compatible diluents, added in

TWO stages as below.

Introduce the syringe needle through the vial closure and inject

10 ml of diluent for the vial.

Withdraw the needle and shake the vial to give a clear solution.

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.

Transfer the reconstituted solution to final delivery vehicle (e.g. mini-bag or

burette-type set) making up a total volume of a 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 is dissolved,

Page 19 of 19

7.

Manufacturer

GlaxoSmithKline Manufacturing S.p.A., Verona, Italy.

8.

License Holder and Importer

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

9.

License Number

Fortum 1gram 046-44-23497

Fortum 2 gram 046-40-23499

For DR v3.1

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