Document: leaflet MAH GENERIC_PL 24598-0005 change

• leaflet MAH GENERIC_PL 04569-0977
• leaflet MAH GENERIC_PL 24598-0005

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Technical Information Leaflet

Ceftazidime 1 g Powder for Solution for Injection Ceftazidime 2 g Powder for Solution for Injection or Infusion

Ceftazidime

This leaflet provides Technical Information for the healthcare professional. There is a separate Patient Information Leaflet.

1. NAME OF THE MEDICINAL PRODUCT

Ceftazidime 1 g Powder for Solution for Injection. Ceftazidime 2 g Powder for Solution for Injection or Infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ceftazidime 1 g Powder for Solution for Injection - Each vial contains 1.165g of ceftazidime pentahydrate (equivalent to 1g of ceftazidime) with 0.118 g sodium carbonate. Ceftazidime 2 g Powder for Solution for Injection or Infusion - Each vial contains 2.330 g of ceftazidime pentahydrate (equivalent to 2g of ceftazidime) with 0.236 g sodium carbonate. For full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injection/infusion.

Ceftazidime 1 g Powder for Solution for Injection - A white to almost white coloured powder for solution for injection.

Ceftazidime 2 g Powder for Solution for Injection or Infusion - A white to almost white coloured powder for solution for injection or infusion.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Ceftazidime is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms (see section 5. 1) and when parenteral therapy is required:

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

-    Meningitis due to aerobic gram-negative organisms

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

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 (1.7 - 2.3)	1	12
30 - 16	200 - 350 (2.3 - 4.0)	1	24
15 - 6	350 - 500 (4.0 - 5.6)	0.5	24
< 5	>500 (>5.6)	0.5	48

' 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 those patients with neutropenia, who would normally receive 6 g 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 the serum concentration of ceftazidime should be monitored and that trough concentrations should not exceed 40 mg/l.

When only serum creatinine is available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance. To convert serum creatinine in mol/l into mg/dl divide by 88.4. The serum creatinine should represent a steady state of renal function:

Males: Creatinine clearance (ml/min) = Weight (kg) x (140 - age in years)    Females: 0.85 x above value

72 x serum creatinine (mg/dl)

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

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.

Hepatic impairment: No dosage adjustment is required in patients with hepatic impairment.

Dosage in 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 lg of ceftazidime may be given, followed by 500mg 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).

Method of Administration Intravenous injection or infusion

After reconstitution of the solution according to the directions provided (see Section 6.6), ceftazidime may be administered intravenously.

Intramuscular injection

After reconstitution of the solution according to the directions provided (see Section 6.6), ceftazidime may be administered 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.

4.3    Contraindications

Hypersensitivity to ceftazidime or to any of the cephalosporins.

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

4.4    Special warnings and precautions for use

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. 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 furosemide) 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.

This vial contains 4.52mmol of sodium in total. The sodium content should be taken into consideration when prescribing to patients requiring sodium restriction.

4.5    Interaction with other medicinal products and other forms of interaction

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.

Laboratory Tests: 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. Ceftazidime does not interfere with enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's test, Fehling's test, Clinitest) may be observed. Ceftazidime does not interfere in the alkaline picrate assay for creatinine.

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.

4.6    Pregnancy and Lactation

Pregnancy: Reproduction studies have not revealed any evidence of impaired fertility or harm to the foetus due to ceftazidime. However, as animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed

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

Investigations
Laboratory test changes noted transiently during ceftazidime therapy include: eosinophilia, positive Coombs' test, haemolytic anaemia, thrombocytosis and elevations in one or more of the hepatic enzymes, ALT (SGPT), AST (SGOT), LDH, GGT and alkaline phosphatase.	Very rare (<1/10,000)

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

General properties: Pharmacotherapeutic group: Third generation cephalosporins (ATC code: J01DD02)

Mode of Action: Ceftazidime is a semi-synthetic bactericidal antibacterial agent of the cephalosporin class. Like other beta-lactam drugs, Ceftazidime exerts antibacterial activity by binding to and inhibiting the action of certain bacterial cell wall synthetic enzymes (transpeptidases). Inhibition of one or more of these essential penicillin-binding proteins results in the interruption of cell wall biosynthesis at the final stage of peptidoglycan production, resulting in bacterial cell lysis and death.

Mechanisms of 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.

Breakpoints: Clinical MIC breakpoints to separate susceptible (S) pathogens from resistant (R) pathogens according to EUCAST are:

-    Enterobacteriaceae: S<1.0 mg/l; R>8 mg/l.

-    Pseudomonas spp.: S<8 mg/l; R>8 mg/l.

-    Non-species related breakpoints: S<4 mg/l; R>8 mg/l.

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

Commonly susceptible species

Gram-positive micro-organisms: Streptococcus pyogenes, Streptococcus agalactiae

Gram-negative micro-organisms: Haemophilus influenza, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Providencia species Species for which acquired resistance may be a problem:

Gram-negative micro-organisms: Acinetobacter spp., Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Inherently resistant organisms:

Gram-positive micro-organisms: Enterococcus species, Staphylococcus species, Coagulase negative*, Staphylococcus aureus*, Streptococcus milleri, Streptococcus pneumoniae#, Viridans Streptococci

Anaerobes: Bacteroides species, Clostridium species, Fusobacterium species, Peptostreptococcus species Others: Chlamydia species, Campylobacter species, Legionella species, Mycobacterium species, Mycoplasma species + 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.

5.2    Pharmacokinetic properties

Absorption: Ceftazidime administered by the parenteral route reaches high and prolonged serum concentrations in man. After intramuscular administration of 500 mg and 1 g serum mean peak concentrations of 18 and 37 mg/l respectively are rapidly achieved. Five minutes after an intravenous bolus injection of 500 mg, 1 g or 2 g, serum mean concentrations are respectively 46, 87 and 170 mg/l. 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%. Metabolism: Ceftazidime is not metabolised in the body and is excreted unchanged in the active form into the urine by glomerular filtration.

Distribution: Concentrations of ceftazidime in excess of the minimum inhibitory concentrations 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 concentrations are achieved in the cerebrospinal fluid in the absence of inflammation. Therapeutic concentrations of 4 - 20 mg/l or more are achieved in the cerebrospinal fluid when the meninges are inflamed.

Excretion: Excretion is almost exclusively by the kidney. Approximately 80 - 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.

5.3    Preclinical safety data: No additional data of relevance.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients: Sodium carbonate.

6.2    Incompatibilities

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. Solutions containing ceftazidime should not be mixed with or added to solutions containing other agents than listed below (see section 6.6).

6.3    Shelf life

Unopened vial: Three years.

Reconstituted solution: Chemical and physical stability has been demonstrated in the following conditions:

-    for 24 hours at 25°C and for 7 days at 5±3°C when dissolved in 10 or 3 ml of WFI.

-    for 6 hours    at 25°C and for 36 hours at    5+3°C when dissolved in 0.5% or 1 % Lidocaine HCI injection.

-    for 6 hours    at 25°C and for 24 hours at    5+3°C when dissolved in all the solutions studied (see table in Section 6.6).

From a microbiological point of view, unless the method of opening/reconstitution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, the 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 opening, reconstitution, and dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Unopened vial: Store below 25°C. Keep the vial in the outer carton.

Reconstituted solution: Store below 2 - 8°C. See section 6.3 for further information on shelf life of reconstituted solutions.

6.5    Nature and contents of container

Ceftazidime 1g: Type III glass vials with rubber (Type I) closures sealed with aluminium caps. The vials are placed in cartons. Boxes of one, five, ten, twenty or fifty vials.

Ceftazidime 2g: Type I glass vials with rubber (Type I) closures sealed with aluminium caps. The vials are placed in cartons. Boxes of one, five, ten, twenty or fifty vials.

Not all pack sizes may be marketed.

6.6    Instructions for use and handling

The use of freshly prepared solutions is recommended (see section 6.3). The reconstituted solution should be clear. Do not use if particles are present. Ceftazidime solutions range from a light yellow to amber solution depending on the concentration, diluent and storage conditions used. Within the stated recommendations, variations in the intensity of the colour will not affect the potency of the drug.

Ceftazidime 1g

Each 1 g vial contains 52 mg (2.26 mmol) of sodium. 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.

1g Intramuscular/Intravenous injection:

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.

Intramuscular injection: Ceftazidime 1 g Powder for Solution for Injection should be dissolved in 3 ml of 0.5% or 1.06% Lidocaine Hydrochloride BP. The resulting solution contains approximately 260 mg/ml ceftazidime. Solutions in Lidocaine should not be administered intravenously.

Intravenous injection: Ceftazidime 1 g Powder for Solution for Injection should be dissolved in 10 ml of Water for Injections Ph. Eur. The resulting solution contains approximately 90 mg/ml ceftazidime.

Ceftazidime 2g

Each 2 g vial contains 104 mg (4.52 mmol) of sodium. 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.

2 g Intravenous bolus injection:

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.

2 g Intravenous infusion:

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

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

3. Insert a gas relief needle through the vial closure to relieve the internal pressure and, with the gas relief in position, add a further 40ml of diluent. Remove the 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.

Intravenous bolus injection: Ceftazidime 2 g Powder for Solution for Injection or Infusion should be dissolved in 10 ml of Water for Injections Ph. Eur. The resulting solution contains approximately 170 mg/ml ceftazidime.

Intravenous infusion: Ceftazidime 2 g Powder for Solution for Injection or Infusion should be dissolved in 50 ml of diluent by the technique recommended above. Sodium Chloride Injection 0.9%, Dextrose Injection 5% or other approved diluent (see below) must be used as Water for Injections Ph. Eur produces hypotonic solutions at this concentration. The resulting solution contains approximately 40 mg/ml ceftazidime.

Reconstitution Diluent: At Ceftazidime concentration 1 mg/ml - 40 mg/ml: 0.9% Sodium Chloride 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, M/6 Sodium Lactate Injection BP, Compound Sodium Lactate Injection BP (Hartmann's Solution), 5% 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.

At Ceftazidime concentration 0.05 mg/ml - 0.25 mg/ml: Intraperitoneal Dialysis Fluid (Lactate) BPC 1973

When admixed at 4 mg/m, either components will retain satisfactory potency: 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 10 IU/ml in 0.9% Sodium Chloride Injection BP, Heparin 50 IU/ml in 0.9% Sodium Chloride Injection BP, Hydrocortisone (hydrocortisone sodium succinate) 1mg/ml in 0.9% Sodium Chloride Injection BP, Hydrocortisone (hydrocortisone sodium succinate) 1mg/ml in 5% Dextrose Injection BP, Potassium Chloride 10 mEq/L in 0.9% Sodium Chloride Injection BP, Potassium Chloride 40 mEq/L in 0.9% Sodium Chloride Injection BP.

7. MARKETING AUTHORISATION HOLDER

Noridem Enterprises Ltd., (trading as Demo), Evagorou & Makariou, Mitsi Building 3, Suit. 115, 1065 Nicosia, Cyprus.

8. MARKETING AUTHORISATION NUMBERS

1g - PL 24598/0004 2g - PL 24598/0005

9. DATE OF FIRST AUTHORISATION/ RENEWAL OF AUTHORISATION

2/9/2008

10. DATE OF REVISION OF TEXT

09/2015