Section 2:             editorial changes + addition of sodium excipient – harmonised text

Section 3:              powder description – harmonised text

Section 4.4:           sodium quantity clarification – harmonised text

Section 6.2:           administrative update – harmonised text

Sections 6.3:         Reconstituted storage and shelf life has been added on reconstitution and dilution + microbiological statements

Sections 6.4:         editorial changes update, reference to reconstituted storage conditions added – harmonised text

Section 6.5:           description update – harmonised text

Section 6.6:           instructions for constitution clarified by tables for powder for injection and powder for solution for infusion – harmonised text

Section 9:              editorial changes  update

SUMMARY OF PRODUCT CHARACTERISTICS CHANGES (Marked in red)

500mg (PA 1077/7/1)

1.       NAME OF THE MEDICINAL PRODUCT

Fortum 500mg Powder for Solution for Injection

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500mg of ceftazidime (as pentahydrate).

When reconstituted as directed, the reconstituted solution contains 500mg ceftazidime (as sodium salt).

Excipients: Contains approximately 26mg sodium per vial.

            For a full list of excipients, see section 6.1

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 6.6.

1.         NAME OF THE MEDICINAL PRODUCT

Fortum for Injection 500mg Powder for Solution for Injection

3.         PHARMACEUTICAL FORM

            Powder for solution for injection or infusion

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

4.4       Special Warnings and Special 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. Blood urea nitrogen levels are influenced by diet and by tissue breakdown, therefore renal function is more appropriately gauged by creatinine clearance. 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.

4.5                   Interactions with other Medicaments 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.

4.8       Undesirable Effects

            Local:

Repeated intravenous administration may induce thrombophlebitis. Local pain at the site of injection may follow intramuscular administration. As with other cephalosporins, there have been rare reports of toxic epidermal necrolysis.

            Hypersensitivity:

Maculopapular or urticarial rash, fever, pruritis, anaphylactic reactions and very rarely angioedema and anaphylaxis including bronchospasm and hypotension may occur.

As with other cephalosporins, there  have been rare reports of erythema multiform, Stevens-Johnson syndrome, and toxic epidermal necrolysis. 

Gastrointestinal:

Gastrointestinal upset including, diarrhoea; nausea; vomiting; abdominal pain, oral thrush; colitis have been reported. As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.

Genito-urinary:

Candidiasis and vaginitis have been reported.

Hepatobiliary tract and pancreas:

            Very rarely jaundice

            CNS:

Headache, dizziness, bad taste and paraesthesia have been reported. There have been reports of neurological sequelae including tremor, myoclonia, convulsions, and encephalopathy in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.

            Transient laboratory test changes:

Transient changes noted during ceftazidime therapy include eosinophilia, thrombocytosis and elevations in one or more of the hepatic enzymes, ALT (SGPT), AST (SGOT), LDH, GGT and alkaline phosphatase. As with other cephalosporins, transient elevations of blood urea, blood urea nitrogen and/or serum creatinine have been observed occasionally. Very rarely leucopenia, neutropenia, agranulocytosis, thrombocytopenia and lymphocytosis have been reported.

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 ¡Ý1/10,

common ¡Ý1/100 and <1/10,

uncommon ¡Ý1/1000 and<1/100,

rare ¡Ý1/10,000 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

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 the administration of these two agents.

Therefore it would be prudent to flush giving sets and i.v. lines between administration of these two agents.

6.6       Instructions for Use and Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

Fortum is compatible with most commonly used intravenous fluids.

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

All sizes of vials of Fortum for Injection 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.

Preparation of Solution

*Addition should be in 2 stages (see text).

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

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.

Ceftazidime at concentrations between 1 mg/ml and 40 mg/ml is compatible with:

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

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% Lignocaine Hydrochloride Injection.

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.

The contents of a 500 mg vial of Fortum for Injection, reconstituted with 1.5 ml Water for Injections, may be added to metronidazole injection (500 mg in 100 ml) and both retain their activity.

Preparation of solutions for IM or 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:

1.         Introduce the syringe needle through the vial closure and 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.         Insert a gas relief needle through the vial closure to relieve the internal pressure. With the gas relief in place, add the remainder of the diluent. 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

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

All sizes of vials of Fortum 500mg 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.

The contents of a 500 mg vial of Fortum for Injection, reconstituted with 1.5 ml Water for Injections, may be added to metronidazole injection (500 mg in 100 ml) and both retain their activity.

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).

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.