Fortum® for Injection

Ceftazidime (as pentahydrate) (INN) Injection

Fortum for Injection: Vials contain 2g or 3g ceftazidime (as pentahydrate) with sodium carbonate (118mg per gram of ceftazidime).

Fortum Monovial in a vial containing 2g ceftazidime pentahydrate.

Sterile Powder for constitution for Injection

Single infections

Mixed infections caused by two or more susceptible organisms

Severe infections in general

Respiratory tract infections

Ear, nose and throat infections

Urinary tract infections

Skin and soft tissue infections

Gastrointestinal, biliary and abdominal infections

Bone and joint infections

Dialysis: infections associated with haemo - and peritoneal dialysis and with continuous ambulatory peritoneal dialysis (CAPD)

In meningitis it is recommended that the results of a sensitivity test are known before treatment with ceftazidime as a single agent. It may be used for infections caused by organisms resistant to other antibiotics including aminoglycosides and many cephalosporins. When appropriate, however, it may be used in combination with an aminoglycoside or other beta-lactam antibiotic for example, in the presence of severe neutropenia, or with an antibiotic active against anaerobes when the presence of bacteroides fragilis is suspected. In addition, ceftazidime is indicated in the perioperative prophylaxis of transurethral prostatectomy.

In vitro the activities of ceftazidime and aminoglycoside antibiotics in combination have been shown to be at least additive; there is evidence of synergy in some strains tested. This property may be important in the treatment of febrile neutropenic patients.

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

Ceftazidime is to be used by the parenteral route, the dosage depending upon the severity, sensitivity and type of infection and the age, weight and renal function of the patient.

Adults: The adult dosage range for ceftazidime is 1 to 6g per day 8 or 12 hourly (im or iv). In the majority of infections, 1g 8-hourly or 2g 12-hourly should be given. In urinary tract infections and in many less serious infections, 500mg or 1g 12-hourly is usually adequate. In very severe infections, especially immunocompromised patients, including those with neutropenia, 2g 8 or 12-hourly or 3g 12-hourly should be administered.

When used as a prophylactic agent in prostatic surgery 1g (from the 1g vial) should be given at the induction of anaesthesia. A second dose should be considered at the time of catheter removal.

Elderly: In view of the reduced clearance of ceftazidime in acutely ill elderly patients, the daily dosage should not normally exceed 3g, especially in those over 80 years of age.

Cystic fibrosis: In fibrocystic adults with normal renal function who have pseudomonal lung infections, high doses of 100 to 150mg/kg/day as three divided doses should be used. In adults with normal renal function 9g/day has been used.

Infants and children: The usual dosage range for children aged over two months is 30 to 100mg/kg/day, given as two or three divided doses.

Doses up to 150mg/kg/day (maximum 6g daily) in three divided doses may be given to infected immunocompromised or fibrocystic children or children with meningitis.

Neonates and children up to 2 months of age: Whilst clinical experience is limited, a dose of 25 to 60mg/kg/day given as two divided doses has proved to be effective. In the neonate the serum half-life of ceftazidime can be three to four times that in adults.

Dosage in impaired renal function: Ceftazidime is excreted by the kidneys almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function it is recommended that the dosage of ceftazidime should be reduced to compensate for its slower excretion, except in mild impairment, i.e. glomerular filtration rate (GFR) greater than 50ml/min. In patients with suspected renal insufficiency, an initial loading dose of 1g of ceftazidime may be given. An estimate of GFR should be made to determine the appropriate maintenance dose.

Renal impairment: For patients in renal failure on continuous arteriovenous haemodialysis or high-flux haemofiltration in intensive therapy units, it is recommended that the dosage should be 1g daily in divided doses. For low-flux haemofiltration it is recommended that the dosage should be that suggested under impaired renal function.

Recommended maintenance doses are shown below:

RECOMMENDED MAINTENANCE DOSES OF CEFTAZIDIME IN RENAL INSUFFICIENCY

* These values are guidelines and may not accurately predict renal function in all patients especially in the elderly in whom the serum creatinine concentration may overestimate renal function.

In patients with severe infections, especially in neutropenics, who would normally receive 6g of ceftazidime daily were it not for renal insufficiency, the unit dose given in the table above may be increased by 50% or the dosing frequency increased appropriately. In such patients it is recommended that ceftazidime serum levels should be monitored and trough levels should not exceed 40mg/litre.

When only serum creatinine is available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Males:

Females:

0.85 x above value.

To convert serum creatinine in µmol/litre into mg/dl divide by 88.4.

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

The serum half-life of ceftazidime during haemodialysis ranges from 3 to 5 hours. The appropriate maintenance dose of ceftazidime should be repeated following each haemodialysis period.

Dosage in peritoneal dialysis: Ceftazidime may also be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD). As well as using ceftazidime intravenously, it can be incorporated into the dialysis fluid (usually 125 to 250mg for 2L of dialysis fluid).

Administration: Ceftazidime may be given intravenously or by deep intramuscular injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh.

Ceftazidime is contraindicated in patients with known hypersensitivity to cephalosporin antibiotics.

Hypersensitivity reactions:

As with other beta-lactam antibiotics, before therapy with ceftazidime is instituted, careful inquiry should be made for 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 beta-lactams. Ceftazidime should be given only with special caution to patients with type I or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious hypersensitivity reactions may require adrenaline (epinephrine), hydrocortisone, antihistamine or other emergency measures.

Renal function:

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with nephrotoxic drugs, e.g. aminoglycoside antibiotics, or potent diuretics such as furosemide, as these combinations are suspected of affecting renal function adversely. Clinical experience with ceftazidime has shown that this is not likely to be a problem at the recommended dose levels. There is no evidence that ceftazidime adversely affects renal function at normal therapeutic doses: however, as for all antibiotics eliminated via the kidneys, it is necessary to reduce the dosage according to the degree of reduction in renal function to avoid the clinical consequences of elevated antibiotic levels, e.g. neurological sequelae, which have occasionally been reported when the dose has not been reduced appropriately (see 4.2 Dosage in Impaired Renal Function and 4.8 Undesirable Effects).

Overgrowth of non-susceptible organisms:

As with other broad spectrum antibiotics, prolonged use of ceftazidime may result in the overgrowth of non-susceptible organisms (e.g. Candida, Enterococci and Serratia spp) which may require interruption of treatment or adoption of appropriate measures. Repeated evaluation of the patient's condition is essential.

Ceftazidime does not interfere with enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed. 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.

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. Therefore, alternative non-hormonal methods of contraception are recommended.

There is no experimental evidence of embryopathic or teratogenic effects attributable to ceftazidime but, as with all drugs, it should be administered with caution during the early months of pregnancy and in early infancy. Use in pregnancy requires that the anticipated benefit be weighed against the possible risks.

Ceftazidime is excreted in human milk in low concentrations and consequently caution should be exercised when ceftazidime is administered to a nursing mother.

None 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 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

Blood and lymphatic system disorders

Immune system disorders

Nervous system disorders

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

Gastrointestinal disorders

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

Renal and urinary disorders

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

General disorders and administration site conditions

Investigations

Overdosage can lead to neurological sequelae including encephalopathy, convulsions and coma.

Serum levels of ceftazidime can be reduced by dialysis.

ATC classification

Pharmacotherapeutic group: cephalosporins ATC code: J01DD02

Mode 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.

Mechanism of Resistance

Ceftazidime is effectively stable to hydrolysis by most classes of beta-lactamases, including penicillinases and cephalosporinases but not extended spectrum beta-lactamases.

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 certain of the extended-spectrum beta-lactamases (ESBLs) including the SHV plasmid mediated ESBLs and by the chromosomally-encoded (AmpC) enzyme 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

- drug efflux pumps.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

- Enterobacteriaceae: S =< 1 mg/l and R > 8 mg/l

- Pseudomonas aeruginosa: S =< 8 mg/l and R > 8 mg/l

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.

Ceftazidime administered by the parenteral route reaches high and prolonged serum levels in man. After intramuscular administration of 500mg and 1g serum mean peak levels of 18 and 37mg/litre respectively are rapidly achieved. Five minutes after an intravenous bolus injection of 500mg, 1g or 2g, serum mean levels are respectively 46, 87 and 170mg/litre.

Therapeutically effective concentrations are still found in the serum 8 to 12 hours after both intravenous and intramuscular administration. The serum half-life is about 1.8 hours in normal volunteers and about 2.2 hours in patients with apparently normal renal function. The serum protein binding of ceftazidime is low at about 10%.

Ceftazidime is not metabolised in the body and is excreted unchanged in the active form into the urine by glomerular filtration. Approximately 80 to 90% of the dose is recovered in the urine within 24 hours. Less than 1% is excreted via the bile, significantly limiting the amount entering the bowel.

Concentrations of ceftazidime in excess of the minimum inhibitory levels for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial and pleural and peritoneal fluids. Transplacental transfer of the antibiotic readily occurs. Ceftazidime penetrates the intact blood brain barrier poorly and low levels are achieved in the csf in the absence of inflammation. Therapeutic levels of 4 to 20mg/litre or more are achieved in the csf when the meninges are inflamed.

No additional data of relevance.

Sodium carbonate (anhydrous sterile)

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.

Fortum Monovial - Two years for the unconstituted product and 24 hours for the constituted product when stored below 30°C and protected from light.

Three years when stored below 25°C and protected from light.

The unconstituted product should be stored below 30°C and protected from light. Constituted solutions may be stored in the refrigerator (2 - 8°C) for up to 24 hours.

Individually cartoned vials containing 2g ceftazidime (as pentahydrate) for intravenous use in packs of 1 or 5.

Individually cartoned Monovials containing 2g (as pentahydrate) for intravenous infusion.

Individually cartoned vials containing 2g ceftazidime (as pentahydrate) for intravenous infusion in packs of 1 or 5.

Individually cartoned vials containing 3g ceftazidime (as pentahydrate) for intravenous and intravenous infusion use.

Not all pack sizes may be marketed.

Instructions for constitution: See table for addition volumes and solution concentrations, which may be useful when fractional doses are required.

PREPARATION OF SOLUTION

*Note: Addition should be in two stages.

‡Note: Use Sodium Chloride Injection 0.9%, Dextrose Injection 5% or other approved diluent (see pharmaceutical precautions) as Water for Injections produces hypotonic solutions at this concentration.

All sizes of vials as supplied are under reduced pressure. As the product dissolves, carbon dioxide is released and a positive pressure develops. For ease of use, it is recommended that the following techniques of reconstitution are adopted.

250mg i.m./i.v., 500mg i.m./i.v., 1g i.m./i.v., and 2g and 3g i.v. bolus vials:

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.

2g and 3g i.v. infusion vials:

This vial may be constituted for short intravenous infusion (e.g. up to 30 minutes) as follows (mini-bag or burette-type set):

Prepare using a total of 50ml (for 2g vials) and 75ml (for 3g vials) of compatible diluent, added in TWO stages as below:-

1. Insert the syringe needle through the vial closure and inject 10ml of diluent for 2g vial and 15ml for 3g vial. The vacuum may assist entry of the diluent. Remove the syringe needle.

2. Shake to dissolve: carbon dioxide is released and a clear solution obtained in about 1 to 2 minutes.

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 a least 50ml (75ml for the 3g vial), and administer by intravenous infusion over 15-30 minutes.

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.

Fortum Monovial:

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

The 2g presentation must be constituted in not less than 100mL infusion bag.

1) Peel off 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 constitution, 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 the steps 4 to 7 to rinse the inside of the vial. Dispose of the empty Monovial safely. Check that the powder is completely dissolved and that the bag has no leaks.

Fortum Monovial is for i.v. infusion only.

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.

Vials of Fortum for Injection and Fortum Monovials as supplied are under reduced pressure; a positive pressure is produced on constitution due to the release of carbon dioxide.

Vials of Fortum for Injection should be stored at a temperature below 25°C.

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

In keeping with good pharmaceutical practice, it is preferable to use freshly constituted solutions of Fortum for Injection. If this is not practicable, satisfactory potency is retained for 24 hours in the refrigerator (2 - 8°C) when prepared in Water for Injection BP or any of the injections listed below.

At ceftazidime concentrations between 1mg/ml and 40mg/ml in:

0.9% Sodium Chloride Injection BP

M/6 Sodium Lactate Injection BP

Compound Sodium Lactate Injection BP (Hartmann's Solution)

5% Dextrose Injection BP

0.225% Sodium Chloride and 5% Dextrose Injection BP

0.45% Sodium Chloride and 5% Dextrose Injection BP

0.9% Sodium Chloride and 5% Dextrose Injection BP

0.18% Sodium Chloride and 4% Dextrose Injection BP

10% Dextrose Injection BP

Dextran 40 Injection BP 10% in 0.9% Sodium Chloride Injection BP

Dextran 40 Injection BP 10% in 5% Dextrose Injection BP

Dextran 70 Injection BP 6% in 0.9% Sodium Chloride Injection BP

Dextran 70 Injection BP 6% in 5% Dextrose Injection BP

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

At concentrations of between 0.05mg/ml and 0.25mg/ml in Intraperitoneal Dialysis Fluid (Lactate) BPC 1973.

When reconstituted for intramuscular use with: 0.5% or 1% Lidocaine Hydrochloride Injection BP

When admixed at 4mg/ml with (both components retain satisfactory potency):

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

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

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

Heparin 10u/ml or 50u/ml in 0.9% Sodium Chloride Injection BP

Potassium Chloride 10mEq/L or 40 mEq/L in 0.9% Sodium Chloride Injection BP

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.

Glaxo Operations UK Ltd

Greenford

Middlesex

UB6 OHE

Trading as

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

PL 00004/0294

18 May 2001

31^st July 2009

11. Legal Status

POM