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GlaxoSmithKline (Ireland) Ltd

Stonemason's Way, Rathfarnham, Dublin 16,
Telephone: +353 1 495 5000
Fax: +353 1 495 5105
Medical Information Direct Line: 1 800 244 255
Medical Information Facsimile: +353 1 495 5242


Summary of Product Characteristics last updated on medicines.ie: 21/08/2009
SPC Fortum 1g Powder for Solution - For injection or Infusion, vial - For Infusion, monovial



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1. NAME OF THE MEDICINAL PRODUCT
Fortum 1g Powder for Solution– For Injection or Infusion, vial

- For Infusion, monovial


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1g of Ceftazidime (as pentahydrate).

When reconstituted as directed, the reconstituted solution contains 1g ceftazidime (as sodium salt).

Excipients: Contains approximately 52.5mg sodium per vial.

For a full list of excipients, see section 6.1


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3. PHARMACEUTICAL FORM

Powder for solution for injection or infusion

A white to cream powder in a clear glass vial with a rubber closure.

Fortum may be supplied with a transfer set. The transfer set is specifically designed for connection to an infusion bag via the additive port. Presentations containing this delivery system will be marketed as Fortum Monovial.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Ceftazidime is a broad-spectrum bactericidal cephalosporin with resistance to most beta-lactamases for use in the treatment of serious single or mixed infections due to susceptible micro-organisms.

The drug may be used pending sensitivity test results, however in meningitis, results should be known before ceftazidime is used.

This antibiotic may be used in combination with an aminoglycoside such as gentamicin or tobramycin or with other beta-lactam antibiotics. A synergism exists.


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4.2 Posology and method of administration

The dosage depends upon the severity, sensitivity and type of infection and the age, weight and renal function of the patient.

In the presence of normal renal function:

Adults: The usual total daily dose is 1-6g in 2 or 3 divided doses by intravenous or deep intramuscular injection.

In cystic fibrosis with pseudomonal lung infections, daily doses of 100 to 150mg/kg (in 3 divided doses) may be used (i.e. up to 9g daily).

Children over the age of 2 months: The usual total daily dose is 30 to 100 mg/kg bodyweight in divided doses. In immuno-compromised or fibrocystic children or children with meningitis, doses of up to 50 mg/kg thrice daily to a maximum of 6 g daily may be given.

Neonates and infants up to 2 months of age: Experience in this group is limited, doses of 25 to 60 mg/kg/day given in 2 divided doses may be used.

Dosage in adults with impaired renal function:

The following is offered as a guide for maintenance dosage of ceftazidime following an initial loading dose of 1g.

Creatinine clearance ml/min

Approx. Serum creatinine micromol/l (mg/dl)

Recommended Unit dose of ceftazidime (g)

Frequency of dosing (hourly)

50-31

150-200

1.0

12

 

(1.7-2.3)

 

 

30-16

200-350

1.0

24

 

(2.3-4.0)

 

 

15-6

350-500

0.5

24

 

(4.0-5.6)

 

 

<5

>500

0.5

48

 

(>5.6)

 

 

In patients with severe infections, the unit dose should be increased by 50%, or the dosing frequency increased. In such patients the ceftazidime serum levels should be monitored and trough levels should not exceed 40mg/l.

In children the creatinine clearance should be adjusted for body surface area or lean body mass and the dosing frequency reduced as in adults.

Haemodialysis:

The serum half-life during haemodialysis ranges from 3 to 5 hours.

Following each haemodialysis period the maintenance dose of ceftazidime recommended in the above table should be repeated.

Peritoneal dialysis

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

For patients in renal failure on continuous arteriovenous haemodialysis or high-flux haemofiltration in intensive therapy units; 1g daily either as a single dose or in divided doses. For low-flux haemofiltration follow the dosage recommended under impaired renal function.

For patients on venous haemofiltration and venovenous haemodialysis, follow the dosage recommendations in the tables below:

Continuous venovenous haemofiltration dosage guidelines for ceftazidime

Residual renal function (creatinine clearance ml/min)

Maintenance dose (mg) for a ultrafiltration rate (ml/min) ofa

 

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

a Maintenance dose to be administered every 12 hours

Ceftazidime dosage guidelines during continuous venovenous haemodialysis

Residual renal function (creatinine clearance ml/min)

Maintenance dose (mg) for a dialysate inflow rate ofa

 

1.0 litre/h

2.0 litres / 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

Dosage in the elderly:

The daily dosage should usually not exceed 3g especially in those over 80 years, bearing in mind the reduced renal clearance in this group when acutely ill.


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4.3 Contraindications

Ceftazidime is contraindicated in patients with known hypersensitivity to cephalosporins or penicillins.


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4.4 Special warnings and precautions for use

Cross-resistance and cross-sensitisation may exist between penicillins and cephalosporins.

Before beginning treatment establish whether a patient has a history of hypersensitivity reactions to ceftazidime, cephalosporins, penicillins or other drugs.

Special care is indicated in patients who have experienced an allergic reaction to penicillins or other beta-lactams. If an allergic reaction occurs discontinue the drug. Serious hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine or other emergency measures.

Prolonged use of an anti-infective may result in the development of superinfection due to organisms resistant to that anti-infective.

As with other extended-spectrum cephalosporins and penicillins, some initially susceptible strains of Enterobacter spp. and Serratia spp. may develop resistance during ceftazidime therapy. When clinically appropriate during therapy of such infections, periodic susceptibility testing should be considered.

Use of this anti-infective in the presence of renal insufficiency requires careful monitoring of dosage to avoid excessive accumulation in blood. The maximum dose should be limited to 2 g in 24 hours in patients with oliguria or creatinine clearance of 50-31 ml/min. The reason being that blood urea nitrogen levels are influenced by diet and tissue break down, therefore renal function is more appropriately gauged by creatinine clearance.

Ceftazidime is eliminated via the kidneys, therefore the dosage should be reduced according to the degree of renal impairment. Neurological sequelae have occasionally been reported when the dose has not been reduced appropriately (see Dosage in Impaired Renal Function).

A positive Coombs' may occur.


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4.5 Interaction with other medicinal products and other forms of interaction

Ceftazidime may interfere with tests for glucose using copper reagents, but does not affect enzyme-based tests for glycosuria, nor the alkaline picrate assay for creatinine.

Concurrent use at high doses with nephrotoxic drugs including frusemide, and some aminoglycosides may increase the risk of renal toxicity. Kidney function should be monitored carefully.

Ceftazidime at high doses may increase the activity of hepatic mixed function oxidases and hence affect the activity of drugs dependent on this metabolic system. No such effects have so far been recorded at therapeutic doses.

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.


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4.6 Pregnancy and lactation

Pregnancy: There is no evidence of embryo toxicity or teratogenicity in animal studies, but there is no experience of safety in use during human pregnancy. Ceftazidime should therefore only be used during pregnancy if considered essential by the physician.

Lactation: Ceftazidime is excreted in breast milk and should be used with caution in nursing mothers.


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4.7 Effects on ability to drive and use machines

None reported.


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4.8 Undesirable effects

Data from large clinical trials (internal and published) were used to determine the frequency of very common to 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.

The following convention has been used for the classification of frequency:-

very common ≥1/10,

common ≥1/100 and <1/10,

uncommon ≥1/1000 and<1/100,

rare ≥1/10,000 and <1/1000,

very rare <1/10,000.

Infections and infestations

Uncommon:

Candidiasis ( including vaginitis and oral thrush)

Blood and lymphatic system disorders

Common:

Eosinophilia and thrombocytosis.

Uncommon:

Leucopenia, neutropenia, and thrombocytopenia,

Very Rare:

Lymphocytosis, haemolytic anaemia and agranulocytosis.

Immune system disorders

Very Rare:

Anaphylaxis (including bronchospasm and/or hypotension).

Nervous system disorders

Uncommon:

Headache and dizziness

Very Rare:

Paraesthesia

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.

Vascular disorders

Common:

Thrombophlebitis with IV administration

Gastrointestinal disorders

Common:

Diarrhoea

Uncommon:

Nausea, vomiting, abdominal pain, and colitis

Very Rare:

Bad taste

As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.

Hepatobiliary disorders

Common:

Transient elevations in one or more of the hepatic enzymes, ALT (SGPT), AST (SOGT), LDH, GGT and alkaline phosphatase.

Very Rare:

Jaundice.

Skin and subcutaneous tissue disorders

Common:

Maculopapular or urticarial rash

Uncommon:

Pruritus

Very Rare:

Angioedema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

General disorders and administration site conditions

Common:

Pain and/or inflammation after IM injection.

Uncommon:

Fever

Investigations

Uncommon:

As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen and/or serum creatinine have been observed.


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4.9 Overdose

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Serum levels of ceftazidime are reduced by haemodialysis or peritoneal dialysis.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Ceftazidime is bactericidal in action. It acts by inhibiting cell wall synthesis. A wide range of pathogenic strains and isolates are susceptible to ceftazidime in vitro, including strains resistant to gentamicin and other aminoglycosides. Ceftazidime is highly stable to most clinically important beta-lactamases produced by both Gram-positive and Gram-negative organisms, therefore it is active against many ampicillin- and cephalothin-resistant strains.

Ceftazidime is not active in vitro against the following organisms: Methicillin-resistant staphylococci, Streptococcus faecalis and many other Enterococci, Listeria monocytogenes, Campylobacter spp., or Clostridium difficile.


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5.2 Pharmacokinetic properties

Ceftazidime is a broad-spectrum cephalosporin, resistant to most beta-lactamases, not absorbed by the oral route and intended only for parenteral use. The drug is only weakly protein bound (10%), and is excreted unchanged (has a half-life of 1-2 hours) almost exclusively via glomerular filtration. Therapeutically effective levels of drug persist for 8-12 hours.

In the neonate the biological half-life may be up to six hours. In patients with renal insufficiency, i.e. with a creatinine clearance less than 50 ml/min.

Frequency of dosage must be extended and dosage reduced to compensate for slower excretion.

After parenteral administration effective levels of drug are reached in most tissues including bone, bile, aqueous humour, synovial and serous fluids. The drug crosses the placenta and is excreted in breast milk. It penetrates the intact blood brain barrier poorly but gives therapeutic levels in CSF if the meninges are inflamed.


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5.3 Preclinical safety data

No additional data.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Anhydrous Sodium Carbonate


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6.2 Incompatibilities

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

Ceftazidime and aminoglycosides should not be mixed in the same giving set or syringe.

Precipitation has been reported with vanomycin added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these agents.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.


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6.3 Shelf life

Shelf life of powder: 2 years.

Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours when stored at 2-8°C and protected from light. From a microbiological point of view, the product 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 2-8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.


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6.4 Special precautions for storage

Do not store above 25°C. Keep the vial in the outer carton in order to protect from light.


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6.5 Nature and contents of container

Fortum is supplied in individually cartoned, soda glass or neutral glass (Type II or I) clear glass vials with a bromobutyl rubber closure and a flip off aluminium overseal.

The monovial transfer set consists of a stainless steel needle which is embedded in a polymer resin capsule needle guard with a low density polyethylene overcap. The transfer set is connected to the vial by a bromobutyl rubber sealing ring.

Not all product presentations may be marketed.


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6.6 Special precautions for disposal and other handling

Preparation of Solution

Vial Size

Route of administration

Diluent

Amount of Diluent to be added

Approximate Concentration (mg/ml)

1g Vial

intramuscular

Water for Injection or 0.5% or 1% Lignocaine Hydrochloride Injection

3 ml

260

1g Vial

intravenous bolus

Water for Injection

10 ml

90

1g Vial

Intravenous infusion

See list of compatible infusion fluids

50ml in 2 stages. Dissolve contents of the vial in 10ml. Add the 10ml of solution to 40ml*

20

1g Monovial

intravenous infusion

See list of compatible infusion fluids

50 ml infusion bag

20

1g Monovial

intravenous infusion

See list of compatible infusion fluids

100 ml infusion bag

10

1 g Monovial is not currently marketed

* Addition of diluent should be added in 2 stages (see preparation of solutions for IV infusion)

Vials of Fortum do not contain any preservatives and should be used as single-dose preparations.

All sizes of vials of Fortum 1g as supplied are 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.

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

Fortum may be constituted for intramuscular use with 0.5% or 1% Lignocaine Hydrochloride Injection.

Fortum is compatible with most commonly used intravenous fluids. However, Sodium Bicarbonate Injection is not recommended as a diluent (see 6.2 Incompatibilities).

Both components retain satisfactory potency when ceftazidime at 4 mg/ml is admixed with:

Hydrocortisone (hydrocortisone sodium phosphate) 1 mg/ml in 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

Cefuroxime (cefuroxime sodium) 3 mg/ml in 0.9% Sodium Chloride Injection.

Cloxacillin (cloxacillin sodium) 4 mg/ml in 0.9% Sodium Chloride Injection.

Heparin 10 IU/ml or 50 IU/ml in 0.9% Sodium Chloride Injection.

Potassium Chloride 10 mEq/I or 40 m Eq/I in 0.9% Sodium Chloride 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 between 1 mg/ml and 40 mg/ml is compatible with the following infusion bags:

0.9% Sodium Chloride 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 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

Preparation of solutions for IM and IV bolus injection:

 1. Introduce the syringe needle through the vial closure and inject the recommended volume of diluent.

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

3. Invert the vial. With the syringe piston fully depressed, insert the needle into the solution. Withdraw the total volume of solution into the syringe ensuring that the needle remains in the solution. Small bubbles of carbon dioxide may be disregarded.

Preparation of solutions for IV infusion:

Prepare using a total of 50ml of compatible diluent added in TWO stages as below:

 1. Introduce the syringe needle through the vial closure and inject 10ml of diluent.

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

3. Do no insert a gas relief needle until the product has dissolved. When dissolution is complete, insert a gas relief needle through the vial closure to relieve the internal pressure.

4. With the gas relief in place, add the remainder of the diluent (40ml). Remove both gas relief needle and syringe needle; shake the vial and set up for infusion use in the normal way.

Note: To preserve product sterility, it is important that a gas relief needle is not inserted through the vial closure before the product has dissolved.

Preparation of solution for intravenous infusion using 1g Monovial:

The contents of the Monovial are added to 50 or 100ml infusion bags containing 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, or another compatible fluid.

 1. Peel of the removable top part of the label and remove the cap.

2. Insert the needle of the Monovial into the additive port of the infusion bag.

3. To activate, push the plastic needle holder of the Monovial down onto the vial shoulder until a "click" is heard.

4. Holding it upright, fill the vial to approximately two-thirds capacity by squeezing the bag several times.

5. Shake the vial to reconstitute the Fortum.

6. On reconstitution, the Fortum will effervesce slightly.

7. With the vial uppermost, transfer the reconstituted Fortum into the infusion bag by squeezing and releasing the bag.

8. Repeat steps 4 to 7 to rinse the inside of the vial. Dispose of the empty Monovial safely. Check that the powder has dissolved, and that the bag has no leaks.


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7. MARKETING AUTHORISATION HOLDER

GlaxoSmithKline (Ireland) Limited,

Stonemasons Way,

Rathfarnham,

Dublin 16


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1077/7/2


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24th September 1984

Date of last renewal: 1st June 2008


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10. DATE OF REVISION OF THE TEXT

July 2009



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Active Ingredients

 
   Ceftazidime Pentahydrate