FORTUM 1 G POWDER FOR SOLUTION FOR INJECTION OR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Fortum 1 g powder for solution for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1 g ceftazidime (as pentahydrate) with sodium carbonate (118 mg per gram of ceftazidime).

Excipient with known effect

Each vial contains 52 mg (2.3 mmol) of sodium per vial.

For the full list of excipients, see section 6.1.

Powder for solution for injection or infusion Vials containing white to cream sterile powder.

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 patients on CAPD.

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

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

Ceftazidime may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing trans-urethral resection of the prostate (TURP).

The selection of ceftazidime should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram negative bacteria (see sections 4.4 and 5.1).

Ceftazidime should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum of activity.

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

4.2. Posology and Method of Administration

Posology

Table 1: Adults and children > 40 kg

Table 2: Children < 40 kg

1In 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

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

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

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 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

| 1 Maintenance dose to be administered every 12 h

Table 6: Continuous veno-venous haemodialysis dose guidelines

'‘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.

4.3. Contra-indications

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 Fortum: 1 g powder for solution for injection

Fortum 1 g contains 52 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.

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

5   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:

S=Susceptible, I=Intermediate, R=Resistant

1The breakpoints relate to high dose therapy (2 g x 3).

2Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes.

Microbiological Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftazidime in at least some types of infections is questionable.

Commonly Susceptible Species__________­____________

Gram-positive aerobes:

Streptococcus pyogenes

Streptococcus agalactiae___________­______________________

Gram-negative aerobes:

Citrobacter koseri

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.

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 170 mg/l, respectively. The kinetics of ceftazidime are linear within the single dose range of 0.5 to 2 g following intravenous or intramuscular dosing.

Distribution

The serum protein binding of ceftazidime is low at about 10%. Concentrations in excess of the MIC for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids. Ceftazidime crosses the placenta readily, and is excreted in the breast milk. Penetration of the intact blood-brain barrier is poor, resulting in low levels of ceftazidime in the CSF in the absence of inflammation. However, concentrations of 4 to 20 mg/l or more are achieved in the CSF when the meninges are inflamed.

Biotransformation

Ceftazidime is not metabolised.

Elimination

After parenteral administration plasma levels decrease with a half-life of about 2 h. Ceftazidime is excreted unchanged into the urine by glomerular filtration; approximately 80 to 90 % of the dose is recovered in the urine within 24 h. Less than 1% is excreted via the bile.

Special patient populations

Renal impairment

Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced (see section 4.2).

Hepatic impairment

The presence of mild to moderate hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days, provided renal function was not impaired (see section 4.2).

Elderly

The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination halflife 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

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium carbonate (anhydrous sterile)

6.2 Incompatibilities

Fortum is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. It is not recommended as a diluent. Fortum 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

3 years

After reconstitution:

Chemical and physical in-use stability has been demonstrated for 6 days at 4°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 4°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.

6.4 Special precautions for storage

Store below 25°C.

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

Fortum 1 g powder for solution for injection or infusion is packaged in clear Ph.Eur.Type III glass 17 ml, 26 ml, 60 ml or 77 ml vial with a bromobutyl rubber plug and a flip-off type aluminium overseal.

Packs of 1, 5, 10, 50 or 100 vials

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 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

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

* 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.

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

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 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.

Glaxo Operations UK Ltd

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

Trading as

GlaxoSmithKline UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 00004/0293

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 17 October 1983

Date of latest renewal: 17 January 2011