Ceftazidime 2.0 g powder for solution for injection/infusion

1 vial with 2.5625 g of powder contains 2.3296 g of ceftazidime pentahydrate corresponding to 2.0 g of ceftazidime.

For excipients, see 6.1

Powder for solution for injection and infusion

White to cream-coloured powder

Ceftazidime is indicated for the parenteral treatment of the following infections when caused by pathogens susceptible to ceftazidime (see section 5.1)

- Respiratory tract infections, including lower respiratory tract infections in patients with cystic fibrosis

- Urinary tract infections: ceftazidime may also be used for peri-operative prophylaxis during trans-urethral prostatectomy

- Skin and soft tissue infections

- Biliary tract infections

- Intra-abdominal infections

- Bone and joint infections

- Infections associated with peritoneal dialysis and with continuous ambulatory peritoneal dialysis (CAPD)

- Meningitis due to aerobic gram-negative organisms

It is recommended that the results of bacterial cultures and susceptibility tests are known before commencing treatment. This is especially important if ceftazidime is to be used as monotherapy.

Ceftazidime should be used in combination with an additional antibacterial agent(s) when treating infections that are likely to be due to a mixture of susceptible and resistant bacterial species. For example, combination therapy with an antibacterial agent that is active against anaerobes should be considered when the infection is thought to be due to aerobic and anaerobic bacteria.

Ceftazidime may also be used in combination with another antibacterial agent (such as an aminoglycoside) to treat infections in patients with severe neutropenia.

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

Posology

The range of usual dose regimens in patients with normal renal function for the age groups defined is as follows:

¹ In acutely ill elderly patients the clearance of ceftazidime is usually decreased

² Plasma elimination half life of ceftazidime can be 3 to 4 times that of adults.

The duration of therapy depends on the patient response. In general treatment should be continued for at least 48 hours after clinical recovery.

Dosage in renal insufficiency: Ceftazidime is almost exclusively excreted by glomerular filtration and the dose should be reduced when the glomerular filtration rate (GFR) is less than 50 ml/min.

In adults with renal insufficiency, an initial loading dose of 1 g of ceftazidime may be given, followed by an appropriate maintenance dose as in the table:

Recommended maintenance doses of ceftazidime in adults with 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 renal insufficiency and 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 40 mg/litre.

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

In patients on haemodialysis: 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.

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.

In patients on peritoneal dialysis: Ceftazidime may also be used in patients who are undergoing peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD) at a dose adjusted according to renal function. In such patients, a loading dose of 1g of ceftazidime may be given, followed by 500 mg every 24 hours. In addition, for intra-peritoneal infections, ceftazidime can be incorporated into the dialysis fluid (usually 125 to 250 mg for 2 L of dialysis fluid).

Dosage in hepatic insufficiency: No dose adjustment is required unless there is concomitant renal insufficiency.

Method of 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. See section 6.6 for information on preparation of solutions for intravenous or intramuscular administrations.

Hypersensitivity to ceftazidime, to any of the cephalosporins or to sodium carbonate.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta-lactam drug.

Before therapy with ceftazidime is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other beta-lactam drugs. Ceftazidime is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug. Ceftazidime should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug.

Antibiotic-associated diarrhoea, colitis and pseudomembranous colitis have all been reported with the use of ceftazidime. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Ceftazidime should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted. Anti-peristaltics are contraindicated.

Ceftazidime should be used with caution in individuals with a previous history of gastro-intestinal disease, particularly colitis.

Ceftazidime has not been shown to be nephrotoxic. However, the total daily dosage should be reduced when ceftazidime is administered to patients with acute or chronic renal insufficiency in order to avoid potential clinical consequences, such as seizures (see section 4.2).

Cephalosporin antibiotics should be given with caution to patients receiving concurrent treatment with nephrotoxic drugs such as aminoglycoside antibiotics or potent diuretics (such as frusemide) as these combinations may have an adverse effect on renal function and have been associated with ototoxicity (see section 4.5).

As with other cephalosporins, prolonged use of ceftazidime may result in the overgrowth of non-susceptible organisms, such as enterococci and Candida spp.

During long-term treatment with ceftazidime, it is recommended that blood counts and tests for renal and hepatic function should be performed at regular intervals.

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.

The sodium content of the medicinal product (13 mg sodium per dose for 250 mg Ceftazidime, 26 mg sodium per dose for 500 mg Ceftazidime, 52 mg sodium per dose for 1 g Ceftazidime and 104 mg sodium per dose for 2.0 g Ceftazidime) should be taken into account when prescribing to patients requiring sodium restriction.

Nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics or potent diuretics, such as furosemide (frusemide). Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

In vitro, chloramphenicol has been shown to be antagonistic with respect to ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of ceftazidime with chloramphenicol (or other bacteriostatic agents: e.g. tetracycline or sulfonamides) 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.

Pregnancy

Reproduction studies have not revealed any evidence of impaired fertility or harm to the foetus due to ceftazidime. However animal reproduction studies are not always predictive of human response. Therefore Ceftazidime should only be used during pregnancy after careful assessment of the risk/benefit relationship, especially during the first trimester.

Lactation

Ceftazidime is excreted in human milk in low concentrations. Consequently, there is a risk of diarrhoea, induction of hypersensitivity and fungus infections of the mucous membranes in the infant. Ceftazidime should be administered to breastfeeding women only if clearly needed.

No studies have been performed on the effects on the ability to drive and use machines. The possibility that dizziness and convulsions may occur should be taken into account when driving or operating machinery.

The most common adverse reactions during ceftazidime treatment are local reactions following intravenous injection, allergic reactions, and effects on the gastro-intestinal tract.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: 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), not known (cannot be estimated from the available data)

An overdose of ceftazidime may be associated with pain, inflammation and phlebitis at the injection site.

Overdose or the administration of inappropriately large doses in the presence of renal insufficiency can lead to neurological sequelae including dizziness, paraesthesiae, headache, encephalopathy, convulsion and coma.

Laboratory abnormalities that may occur after an overdose include elevations in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leucopenia and prolongation of the prothrombin time.

General symptomatic and supportive measures should be instituted, together with specific measures to control any seizures. In cases of severe overdose, especially in a patient with renal failure, combined haemodialysis and haemoperfusion may be considered if response to more conservative therapy fails.

ATC code: JOIDD02

Pharmacotherapeutic group: Third-generation cephalosporins

Mode of Action

Ceftazidime is a semi-synthetic antibacterial agent of the cephalosporin class. Like other ß-lactam drugs, ceftazidime exerts antibacterial activity by binding to and inhibiting the action of certain bacterial cell wall synthetic enzymes, namely the penicillin binding proteins. This inhibition of one or more of essential penicillin binding proteins results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

Susceptibility

According to the National Committee for Clinical Laboratory Standards Guidelines (NCCLS, 2001), the MIC breakpoints for sensitive, intermediately sensitive or resistant organisms are as follows:

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 the agent in at least some types of infections is questionable.

+ Based on published data from several different sources

* Shows some in-vitro activity against methicillin-susceptible strains but should not be relied upon to treat staphylococcal infections.

# Shows some in-vitro activity against penicillin-susceptible strains but should not be relied upon to treat pneumococcal infections.

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 certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally-encoded (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

- drug efflux pumps

More than one of these mechanisms of resistance may co-exist in a single bacterial cell. Depending on the mechanism(s) present, bacteria may express cross-resistance to several or all other beta-lactams and/or antibacterial drugs of other classes.

The approximate Cmax ceftazidime after different doses and modes of administration to subjects with normal renal function were as follows:

In general, plasma concentrations at 8 hours after intravenous or intramuscular administration of 500 mg or more ceftazidime are in excess of 2 mg/l. Following multiple intravenous doses of 1g and 2g every 8 hours for 10 days, there was no evidence of accumulation of ceftazidime in the serum of individuals with normal renal function.

Distribution

Less than 10% of ceftazidime is protein bound and the degree of protein binding is independent of concentration.

Concentrations of ceftazidime in excess of the minimum inhibitory levels of common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, 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 20 mg/l or more are achieved in the CSF when the meninges are inflamed.

Elimination

Approximately 80% to 90% of a dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period, resulting in high urinary concentrations.

In subjects with normal renal function, the half-life of ceftazidime is approximately 2 hours after intravenous or intramuscular administration.

The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals who received 2g intravenously every 8 hours for 5 days. Therefore, dosage adjustment is not required for patients with hepatic dysfunction, unless renal function is also impaired.

Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse micronucleus test and an Ames test were both negative for mutagenic effects.

Sodium Carbonate anhydrous

Ceftazidime should not be mixed with solutions with a pH above 7.5 for example sodium bicarbonate solution for injection. Ceftazidime and aminoglycosides should not be mixed in the solution for injection because of the risk for precipitation.

Cannulae and catheters for intravenous use should be flushed with physiological salt-solution between administrations of ceftazidime and vancomycin to avoid precipitation.

2 years

Reconstituted solution: The product should be used immediately.

Keep the container in the outer carton

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 to 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions

Nature

20 ml vials of clear glass hydr. class III Ph. Eur. and 50 ml vials of clear glass hydr. class II Ph. Eur. with rubber stopper and flip-off crimp seal

Content

individual pack for 1 vial

hospital pack for 5/10/25/50 vials

Not all pack sizes may be marketed.

Intramuscular administration:

Ceftazidime should be reconstituted with Water for Injections PhEur or 0.5% or 1% Lidocaine Hydrochloride Injection BP as indicated in the table below. The Product Information for Lidocaine should be consulted before reconstitution of ceftazidime with lidocaine.

Intravenous administration:

For direct intermittent intravenous administration, reconstitute ceftazidime with Water for Injections PhEur (see table below). Slowly inject the solution directly into the vein over a period of up to 5 minutes or give through the tubing of a giving set.

For intravenous infusion, reconstitute the 1 g or 2 g infusion vial with 40 ml Water for Injections PhEur or one of the compatible intravenous fluids. Alternatively, reconstitute the 250 mg, 500 mg, 1 g or 2 g vial and add an appropriate quantity of the resulting solution to an IV container with one of the compatible intravenous fluids. Intermittent intravenous infusion with a Y-type giving set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.

Preparation of Solutions of Ceftazidime

*Note: Addition should be in 2 stages (see 'Instructions for reconstitution' below)

When ceftazidime is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, follow the recommended techniques of reconstitution described below.

Instructions for reconstitution:

For 250 mg im/IV, 500 mg im/IV, 1 g im/IV and 2 g IV vials

1. Inject the diluent and shake well to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Invert the vial and completely depress the syringe plunger prior to insertion.

4. Insert the needle through the vial stopper. Be sure the needle remains within the solution and withdraw contents of the vial in the usual manner. Pressure in the vial may aid withdrawal.

5. The withdrawn solution may contain carbon dioxide bubbles, which should be expelled from the syringe before injection.

For 1 g and 2 g infusion vials

1. Inject 10ml of the diluent and shake to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Insert a vent needle to release pressure before adding additional diluent to the vial. Add diluent and then remove the vent needle.

4. Additional pressure that may develop in the vial, especially after storage, should be relieved prior to administration to the patient.

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.

Single use only.

Unused solution should be discarded.

Only clear solutions practically free from particles should be used.

Free from bacterial endotoxins.

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

At ceftazidime concentrations between 25 mg/ml and 263 mg/ml the Ceftazidime Sandoz powders for injection/infusion may be mixed in commonly used solutions for infusion:

0.9% sodium chloride solution (physiological saline solution),

5% glucose solution,

0.9% sodium chloride + 5% glucose solution,

Ringer Lactate Solution

When reconstituted for intramuscular use, the Ceftazidime Sandoz powder for injection/infusion can also be diluted with 1% lidocaine solutions.

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 04416/0563

10^th September 2003 / 15^th July 2008

09/04/2011