Treatment of single or multiple infections caused by susceptible organisms.

May be used alone as first choice drug before the results of sensitivity tests are available.

May be used in combination with an aminoglycoside or most other beta-lactam antibiotics.

May be used with an antibiotic against anaerobes when the presence of Bacteroides fragilis is suspected.

Susceptibility to FORTUM will vary with geography and time and local susceptibility data should be consulted where available (see Pharmacological properties, Pharmacodynamic effects).

Indications include:

-       severe infections e.g. - septicaemia, bacteraemia, peritonitis, meningitis

-       infections in immunosuppressed patients

-       infections in patients in intensive care, e.g. infected                                       burns

-       respiratory tract infections including lung infections in cystic fibrosis

-       ear, nose and throat infections

-       urinary tract infections

-       skin and soft tissue infections

-       gastrointestinal, biliary and abdominal infections

-       bone and joint infections

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

-       prophylaxis: prostatic surgery (transurethral resection).

Dosage depends upon the severity, sensitivity, site and type of infection and upon the age and renal function of the patient.

Use FORTUM injection by intravenous (i.v.) or deep intramuscular (i.m.) injection. Recommended i.m. 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.

• Adults

1 to 6 g/day in two or three divided doses by i.v. or i.m. injection.

Urinary tract and less severe infections:  – 1 g every 12 hours. 

Most infections:

–  1 g every 8 hours or 2 g every 12 hours.

Very severe infections particularly in immunocompromised patients including those with neutropenia:

–  2 g every eight or 12 hours, or 3 g every 12 hours.

Fibrocystic adults with pseudomonal lung infections:

 - 100 to 150 mg/kg/day in three divided doses.

In adults with normal renal function 9 g/day has been used without ill effect.

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

• Infants and children (greater than 2 months)

30 to 100 mg/kg/day in two or three divided doses.

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

• Neonates (0 to 2 months)

25 to 60 mg/kg/day in two divided doses.

In neonates, the serum half-life of ceftazidime can be three to four times that in adults.

• Elderly

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

• Renal Impairment

Ceftazidime is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function, the dosage should be reduced.

An initial loading dose of 1 g should be given. Maintenance doses should be based on creatinine clearance as shown in Table 1:

Table 1:    Recommended maintenance doses of FORTUM in renal insufficiency

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 40 mg/l.

In children 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 hours.

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

Peritoneal dialysis

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

In addition to i.v. use, FORTUM 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 arteriovenous 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 dosage recommended under impaired renal function.

For patients on venovenous haemofiltration and venovenous haemodialysis, follow the dosage recommendations in table 2 & 3.

Table 2:                  Continuous venovenous haemofiltration dosage guidelines for FORTUM

^a- Maintenance dose to be administered every 12 hours.

Table 3: FORTUM dosage guidelines during continuous venovenous haemodialysis

^a- Maintenance dose to be administered every 12 hours.

Before beginning treatment establish whether the 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 to FORTUM occurs discontinue the drug.  Serious hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine or other emergency measures.

Concurrent treatment with high doses of cephalosporins and nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Clinical experience has shown that this is not likely to be a problem with FORTUM at the recommended dose levels. There is no evidence that FORTUM adversely affects renal function at normal therapeutic doses.

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 in patients with renal impairment (see Dosage and Administration – Renal Impairment and Adverse Reactions).

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

Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further.

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

Each 1 g of ceftazidime contains 52 mg of sodium. The sodium content must be taken into account in patients requiring sodium restriction

Concurrent use of high doses with nephrotoxic drugs may adversely affect renal function (see Warnings and Precautions).

Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of FORTUM 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.

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

Ceftazidime does not interfere in the alkaline picrate assay for creatinine.

There is no experimental evidence of embryopathic or teratogenic effects, but as with all drugs, FORTUM should be administered with caution during the early months of pregnancy and early infancy.

Ceftazidime is excreted in human milk in small quantities and should be used with caution in breast-feeding.

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 to <1/10, uncommon ≥1/1,000 to <1/100,

rare ≥1/10,000 to <1/1,000, 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 FORTUM has not been appropriately reduced.

Vascular disorders

              Common:                        Phlebitis or thrombophlebitis with i.v. 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 (See Warnings and Precautions).

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

General disorders and administration site conditions

A positive Coombs test develops in about 5% of patients and may interfere with blood cross-matching.

To report any side effect(s):

Kingdom of Saudi Arabia

-National Pharmacovigilance centre (NPC)

•       Fax: +966-11-205-7662

•       Call NPC at +966-11-2038222, Ext: 2317-2356-2353-2340

•       Reporting hotline: 19999

•       E-mail: npc.drug@sfda.gov.sa

•       Website: www.sfda.gov.sa/npc

-GlaxoSmithKline - Head Office, Jeddah

•       Tel:  00966(012)6536666

•       Mobile: +966-56-904-9882

•       Email: saudi.safety@gsk.com 

•       Website: https://gskpro.com/en-sa/

•       P.O Box 55850, Jeddah 21544, Saudi Arabia.

Symptoms and Signs

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

Treatment

Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.

Mechanism of Action

Ceftazidime is bactericidal in action. It acts by inhibiting bacterial cell wall synthesis.

Pharmacodynamic Effects

The prevalence of acquired resistance is geographically and time dependent and for select species may be very high.  Local information on resistance and prevalence of extended spectrum beta lactamase (ESBLs) producing organisms is desirable, particularly when treating severe infections.  

Absorption

After i.m. administration of 1 g, peak levels of  37 mg/1, are achieved rapidly.  Five minutes after i.v. bolus injection of 1 g or 2 g, serum levels are, respectively, 87 and 170 mg/l. Distribution

Therapeutically effective concentrations are still present in the serum 8 to 12 hours after either i.v. or i.m. administration.  Serum protein binding is 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 cerebral spinal fluid (CSF) in the absence of inflammation. However, therapeutic levels of 4 to 20 mg/l or more are achieved in the CSF when the meninges are inflamed.

Metabolism

Ceftazidime is not metabolised in the body.

Elimination

Parenteral administration produces high and prolonged serum levels, which decrease with a half-life of about 2 hours. Ceftazidime is excreted unchanged, in 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, which limits the amount entering the bowel.

Special Patient Populations

Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced (see Dosage and Administration - Renal Impairment, Warnings and Precautions). 

No additional data of relevance.

Sodium carbonate (anhydrous).

FORTUM is less stable in Sodium Bicarbonate Injection than in other i.v. 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 FORTUM in solution. Therefore, it would be prudent to flush giving sets and i.v. lines between administration of these two agents.

Fortum dry powder should be stored below 30°C, protected from light

The recommended periods of storage after reconstitution are:

6 hours below 25°C

3 days in a refrigerator (4°C)

FORTUM Vials are available in Carton packs each containing 1 or 5 vials.

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

Not all pack sizes may be marketed.

FORTUM for injection/infusion is compatible with most commonly used i.v. fluids.  However, Sodium Bicarbonate Injection is not recommended as a diluent (see Incompatibilities).

All sizes of vials of FORTUM Injection 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.

Table 4:          Instructions for reconstitution 

# NOTE: Addition should be in two stages (see text)

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 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).

FORTUM may be constituted for i.m. use with 0.5% or 1% Lidocaine Hydrochloride Injection.

Both components retain satisfactory potency when ceftazidime at 4 mg/ml is mixed 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/l or 40 mEq/l in 0.9% Sodium Chloride Injection.

The contents of a 500 mg vial of FORTUM for injection, constituted 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 i.m. or i.v. 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 i.v. infusion from FORTUM injection (mini-bag or burette-type set)

Prepare using a total of 50 ml (for 1 g and 2 g vials) of compatible diluent, added in TWO stages as below.

1 g and 2 g vials for i.v. infusion:

1.             Introduce the syringe needle through the vial closure and inject 10 ml of diluent for the 1 g and 2 g vials.

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 minutes.

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.

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