NAME OF THE MEDICINE

Active ingredient: ceftazidime pentahydrate Chemical name: (6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-[(1-carboxy-1-methylethoxy)imino] acetyl] amino]8-oxo-3-[(1-pyridinio)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylate pentahydrate. Structural formula: Molecular formula: C22H22N6O7S2,5H2O Molecular weight: 637 CAS Registry no. : 78439-06-2

DESCRIPTION

Ceftazidime pentahydrate is a white or almost white, crystalline powder, slightly soluble in water and in methanol, practically insoluble in acetone and in alcohol. It dissolves in acid and alkali solutions. Ceftazidime Alphapharm is supplied in vials containing 1 g and 2 g of ceftazidime (as pentahydrate) with sodium carbonate anhydrous (116.4 mg per gram of ceftazidime). On the addition of water for injections, Ceftazidime Alphapharm dissolves with effervescence to produce a solution for injection. Ceftazidime Alphapharm contains approximately 54 mg (2.3 mEq) of sodium per gram of ceftazidime. 116.4 mg ceftazidime pentahydrate is equivalent to 100 mg ceftazidime free acid.

PHARMACOLOGY

Pharmacokinetics

Absorption of ceftazidime after oral administration is negligible; therefore, Ceftazidime Alphapharm is intended for parenteral use only. In man after a single intramuscular administration of 500 mg and 1 g, mean peak serum levels of 18 and 37 mg/L respectively are achieved at 1 hour falling to 8 and 2 mg/L and 20 and 5 mg/L at 4 and 8 hours respectively for the two doses. Five minutes after an intravenous bolus injection of 500 mg, 1 g and 2 g, mean serum levels are respectively 46, 87 and 170 mg/L falling to 17 and 6 mg/L, 32 and 10 mg/L and 85 and 15 mg/L at 1 and 4 hours respectively with the three doses. The serum half-life in adults with normal renal function is about 1.8 hours (1.2-2.9 hours). This may be prolonged to 20-35 hours in anuric patients. In neonates, the serum half-life of ceftazidime can be 3-4 times greater than that measured in adults. 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. In the presence of normal renal function approximately 80 to 90% of the dose is recovered in the urine within 24 hours. Less than 1% is excreted via the bile. The mean maximum concentrations of ceftazidime in bone, heart, bile, sputum, aqueous humour, synovial and pleural and peritoneal fluids were in excess of the in vitro minimum inhibitory levels for susceptible organisms (see Susceptibility Tests). Transplacental transfer of the antibiotic readily occurs. Ceftazidime penetrates the intact blood brain barrier poorly and low levels are achieved in the CSF. The pharmacokinetics of ceftazidime are similar whether it is administered by a single or by repeat dosage. Concurrent oral administration of probenecid did not affect the serum levels or urinary recoveries of ceftazidime. The pharmacokinetics of ceftazidime were not affected when administered intramuscularly with 0.5% lignocaine.

Microbiology

Ceftazidime is bactericidal in action, exerting its effect on target cell wall proteins and causing inhibition of cell wall synthesis. It is stable to most beta-lactamases produced by Gram-positive and Gram-negative organisms and consequently is active against many ampicillin- and cephalothin-resistant strains (but not methicillin-resistant strains). Ceftazidime has been shown to have in vitro activity against the following organisms:

Gram-negative: Pseudomonas aeruginosa Pseudomonas species (other) Klebsiella pneumoniae Klebsiella species (other) Proteus mirabilis

Proteus vulgaris

Morganella morganii (formerly Proteus morganii) Proteus rettgeri

Providencia species Escherichia coli Enterobacter species Citrobacter species Serratia species Acinetobacter species Neisseria gonorrhoeae Neisseria meningitidis

Haemophilus influenzae

(including ampicillin-resistant strains)

Gram-positive positive:

Staphylococcus aureus (methicillin-sensitive strains) Staphylococcus epidermidis (methicillin-sensitive strains) Micrococcus species

Streptococcus pyogenes Streptococcus Group B Streptococcus pneumoniae

Streptococcus species (excluding Streptococcus faecalis) Ceftazidime is not active in vitro against methicillin-resistant staphylococci, Streptococcus faecalis and many other Enterococci, Listeria monocytogenes, Campylobacter species or Clostridium difficile.

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.

Susceptibility Tests

Dilution or Diffusion Techniques

. Either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method [e.g. Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS)]. Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Note: The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

CONTRAINDICATIONS

Ceftazidime Alphapharm is contraindicated in persons who have shown hypersensitivity to cephalosporins or who have experienced a major allergy to penicillin (anaphylaxis, angioneurotic oedema, urticaria). Lignocaine should not be used as a diluent for intramuscular injection in patients who are hypersensitive to lignocaine.

PRECAUTIONS

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. Ceftazidime should be given only with special caution to patients with mild type I or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious hypersensitivity reactions may require adrenaline, hydrocortisone, antihistamine or other emergency measures. Ceftazidime should be prescribed with caution to individuals with a history of gastrointestinal disease, particularly colitis. Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including ceftazidime. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil), may prolong and/or worsen the condition and should not be used.

Clostridium difficile

infection rarely manifests as diarrhoea in neonates.

Peak concentrations of ceftazidime in the CSF are considerably lower than those in the plasma. Its use in the treatment of infections of the CNS, e.g. meningitis, brain abscess, etc. is not advised at present. Resistance to initially susceptible Enterobacter species can develop during treatment with ceftazidime. As with other broad spectrum antibiotics, prolonged use of ceftazidime may result in the overgrowth of non- susceptible organisms (e.g. Candida, Enterococci) which may require interruption of treatment or adoption of appropriate measures. Repeated evaluation of the patient's condition is essential. Prescribing ceftazidime in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug- resistant bacteria. Inducible type I beta-lactamase resistance has been noted with some organisms (e.g., Enterobacter spp., Pseudomonas spp. and Serratia spp. ). As with other extended-spectrum beta-lactam antibiotics, resistance can develop during therapy, leading to clinical failure in some cases. When treating infections caused by these organisms, periodic susceptibility testing should be performed when clinically appropriate. If patients fail to respond to monotherapy, an aminoglycoside or similar agent should be considered. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal and hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Distal necrosis can occur after inadvertent intra-arterial administration of ceftazidime. Vials of Ceftazidime Alphapharm as supplied are under reduced pressure; a positive pressure is produced on reconstitution due to the release of carbon dioxide. See Dosage and Administration for recommended techniques of reconstitution.

Patients with Impaired Renal Function

Ceftazidime has shown some evidence of renal toxicity in animals. Clinical studies have shown only transient elevations in serum urea and serum creatinine. It is excreted almost entirely by glomerular filtration and its half-life is prolonged in patients with impaired renal function. In such patients dosage adjustment may be required in order to avoid the clinical consequences of elevated antibiotic levels. Neurological sequelae have occasionally been reported when the dose has not been reduced appropriately (see Dosage and Administration).

Use in Patients with Impaired Liver Function

Transient rises in hepatic enzymes have been noted in some patients given ceftazidime, so careful monitoring of hepatic function is advised when any dysfunction exists. Repeated use of lignocaine hydrochloride as a diluent for I.M. use should be avoided in patients with severe liver disease or decreased hepatic blood flow due to the possibility of lignocaine toxicity resulting from decreased metabolism and consequent accumulation.

Use in Pregnancy (Risk Category B1)

The safety of ceftazidime in pregnancy has not been established, although animal studies have not produced evidence of embryopathic or teratogenic effects attributable to ceftazidime. Therefore, it may be administered during known or suspected pregnancy only if in the opinion of the treating physician the expected benefits outweigh the possible risks.

Category B1:

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

Use in Lactation

Ceftazidime is excreted in human breast milk in low concentrations; therefore, it is not recommended for nursing mothers unless the expected benefits to the mother greatly outweigh any potential risk to the infant.

Use in Children

Ceftazidime is effective in the treatment of neonatal infections caused by susceptible organisms.

INTERACTIONS WITH OTHER MEDICINES

Oral contraceptives

In common with other antibiotics, ceftazidime may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Chloramphenicol

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. There is some evidence in the literature that concurrent use of two beta-lactam antibiotics may exhibit antagonism.

Effect on 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, Fehlings, Clinitest) may be observed. Ceftazidime does not interfere in the alkaline picrate assay for creatinine.

DOSAGE AND ADMINISTRATION

Note:

Vials of Ceftazidime Alphapharm as supplied are under reduced pressure; a positive pressure is produced on reconstitution due to the release of carbon dioxide.

General dosage recommendations

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 6 g per day: for instance, 500 mg, 1 g or 2 g given 12 or 8 hourly by I.V. or I.M. injection. In urinary tract infections and in many less serious infections, 500 mg or 1 g 12 hourly is usually adequate. In the majority of infections, 1 g 8 hourly or 2 g 12 hourly should be given. In very severe infections, 2 g 8 or 12 hourly should be administered. Individual doses exceeding 1 g should be administered intravenously.

Children:

The usual dosage range for children aged over 12 months is 25 to 100 mg/kg/day (up to a maximum of 6 g/day) given as two or three divided doses. The maximum daily dosage (6 g) may be given to children with very serious infections e.g. those who are immunocompromised or who suffer from cystic fibrosis. Neonates and infants up to 12 months: 25-100 mg/kg/day in two divided doses. In neonates the serum half- life of ceftazidime can be 3-4 times greater than that measured in adults.

Use in the elderly:

In view of the reduced clearance of ceftazidime in elderly patients, the daily dosage should be adjusted according to renal function.

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, ie glomerular filtration rate (GFR) greater than 50 mL/min. In patients with suspected renal insufficiency, an initial loading dose of 1 g of ceftazidime may be given. An estimate of GFR should be made to determine the appropriate maintenance dose. 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 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 ceftazidime serum levels should be monitored and trough levels 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. The serum creatinine should represent a steady state of renal function:

Males:

Creatinine clearance (mL/min) =

Weight (kg) x (140 - age in years) x 88.4

72 x serum creatinine (micromol/L)

Females:

0.85 x above value. 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 is approximately 3 hours. The appropriate maintenance dose of ceftazidime should be repeated following each haemodialysis period. Continuous ambulatory peritoneal dialysis (CAPD) removed approximately 10% of the antibiotic when the dwell time was 4-6 hours.

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.

Instructions for reconstitution:

Ceftazidime Alphapharm may be reconstituted with Water for Injections or, for intramuscular injection, with 1.0% or 0.5% Lignocaine. See table for addition volumes and solution concentrations. To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, hold at 2 to 8degC for not more than 24 hours. Protect from light. Following reconstitution, use in one patient on one occasion only and discard any residue. Preparation of Solution

#

Note: Addition should be in two stages (see text).

+

Use sodium chloride solution 0.9%, glucose solution 10% or other approved diluent (see below)

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.

g I.M./I.V. and 2 g 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 obtained in about 1-2 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 headspace. The withdrawn solution may contain small bubbles of carbon dioxide; they may be disregarded.

g I.V. infusion vial:

This vial may be reconstituted for short intravenous infusion (e.g. up to 30 minutes) as follows:

1. Insert the syringe needle through the vial closure and inject 10 mL 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 obtained in about 1-2 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 40 mL 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.

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. Solutions of Ceftazidime Alphapharm Injection reconstituted in Water for Injections retain satisfactory potency for 12 hours if kept below 25degC or for 7 days if refrigerated (2-8degC). When reconstituted in 0.5% Lignocaine Hydrochloride Injection BP the corresponding times are 6 hours at below 25degC or 4 days under refrigeration (2-8degC). Some increase in the colour of prepared solutions of Ceftazidime Alphapharm for injection may occur on storage. It is, however, advisable to use the reconstituted product as soon as possible. Ceftazidime is compatible with the intravenous fluids shown below. Solutions at concentrations between 1 mg/mL and 40 mg/mL in these infusion fluids may be stored for up to 12 hours below 25degC or 7 days if refrigerated (2-8degC). 0.9% Sodium Chloride Injection BP M/6 Sodium Lactate Injection BP M/6 Compound Sodium Lactate Injection BP (Hartmann's Solution) 5% 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 Sodium Bicarbonate Injection is not recommended as a diluent. Ceftazidime Alphapharm Injection may be stored for up to 12 hours below 25degC or 7 days under refrigeration (2-8degC) at concentrations of between 0.05 mg/mL and 0.25 mg/mL in Intraperitoneal Dialysis Fluid (Lactate) BPC 1973. Ceftazidime Alphapharm Injection has been found compatible for 12 hours below 25degC or 7 days under refrigeration (2- 8degC) when admixed at 4 mg/mL with: Potassium Chloride 10 mEq/L or 40 mEq/L in 0.9% Sodium Chloride Injection BP. Heparin (10 and 50 units/mL) in 0.9% Sodium Chloride. Ceftazidime Alphapharm Injection (4 mg/mL) has been found compatible for 24 hours when stored below 25degC or 7 days when refrigerated (2-8degC do not freeze) when admixed with Cloxacillin. Ceftazidime Alphapharm Injection (5 mg/mL) is compatible for 12 hours when stored below 25degC or 7 days when refrigerated (2-8degC do not freeze) when admixed with metronidazole. 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.

Therefore, it would be prudent to flush giving sets and intravenous lines between the administration of these two agents. Protect from light. Ceftazidime Alphapharm Injection may be reconstituted for intramuscular administration using 0.5% Lignocaine Hydrochloride Injection BP; the resultant solutions may be stored for 6 hours below 25degC or 4 days under refrigeration (2-8degC). 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.

Sodium bicarbonate injection is not recommended as a diluent.

Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.

OVERDOSAGE

Overdosage can lead to neurological sequelae including encephalopathy, convulsions and coma. Ceftazidime can be removed by haemodialysis. Contact the Poisons Information Centre on 131126 (Australia) for advice on the management of overdosage.

PRESENTATION AND STORAGE CONDITIONS

Ceftazidime Alphapharm is available in individually cartoned vials containing 1 g of ceftazidime (as pentahydrate) for intramuscular or intravenous use, in packs of 1 and 5 *; or 2 g ceftazidime (as pentahydrate) for intravenous use in packs of 1. *Not marketed in Australia. Vials of unreconstituted Ceftazidime Alphapharm should be stored in the original package at a temperature below 25degC and have a shelf-life of 2 years if stored under these conditions. Protect from light. For storage conditions of the reconstituted solution, see DOSAGE AND ADMINISTRATION - Administration.

NAME AND ADDRESS OF THE SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond 30 - 34 Hickson Road Millers Point NSW 2000 ABN 93 002 359 739 www.alphapharm.com.au

POISON SCHEDULE OF THE MEDICINE

S4 - Prescription Only Medicine

DATE OF FIRST INCLUSION ON THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG)

21/05/2010

DATE OF MOST RECENT AMENDMENT

07/03/2013