Ceftazidime Injection contains 250 mg, 500 mg, 1 g or 2 g of ceftazidime (as pentahydrate)

Qualitative and quantitative composition

Ceftazidime Alphapharm Powder for Injection is supplied as a white or almost white, crystalline powder, containing 116.4 mg sodium carbonate per gram of ceftazidime. On addition of Water for injection, Ceftazidime Alphapharm Powder for Injection dissolves with effervescence to produce a clear solution for injection or infusion.

Pharmaceutical form

Powder for Injection/Infusion.

Clinical particulars

Posology and Method of Administration

Posology

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

Adults

1-6 g/day in 2 or 3 divided doses by IV or IM injection. Urinary tract and less severe infections.

• 500 mg or 1g 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 8 or 12 hours, or 3 g every 12 hours. Fibrocystic adults with pseudomonal lung infections. 100-150 mg/kg/day in 3 divided doses. In adults with normal renal function 9 g/day has been used without ill effect.

Infants and children (> 2 months)

30 - 100 mg/kg/day in 2 or 3 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 - 2 months)

25-60 mg/kg/day in 2 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.

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 GFR:- Recommended maintenance doses of ceftazidime 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 ceftazidime recommended in the above table should be repeated.

Peritoneal dialysis

Ceftazidime may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD). In addition to intravenous use, ceftazidime 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 the tables below: Continuous venovenous haemofiltration dosage guidelines for ceftazidime

a

Maintenance dose to be administered every 12 h.

Ceftazidime dosage guidelines during continuous venovenous haemodialysis

a

Maintenance dose to be administered every 12 h.

Method of Administration

Use Ceftazidime Alphapharm Powder for Injection intravenously or by deep intramuscular injection. Recommended IM injection sites are the upper outer quadrant of the gluteus maximus or lateral part of the thigh. Ceftazidime solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids.

Contraindications

Patients with known hypersensitivity to cephalosporin antibiotics. Hypersensitivity to ceftazidime pentahydrate or to any of the excipients.

Special Warnings and Special Precautions for Use

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. 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. Ceftazidime should be prescribed with caution to individuals with a history of gastrointestinal disease, particularly colitis.

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). Elevated levels of ceftazidime in patients with renal insufficiency can lead to seizures, encephalopathy, asterixis, neuromuscular excitability and myoclonia. Continued dosage should be determined by degree of renal impairment, severity of infection and susceptibility of the causative organism.

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 IM 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Use in Pregnancy (Category B11)

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.

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.

Paediatric Use

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

Interaction with Other Medicinal Products and Other Forms of Interaction

Concurrent use of high doses with nephrotoxic medicines may adversely affect renal function (see Special Warnings and Special Precautions for Use). Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of Ceftazidime Alphapharm Powder for Injection 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.

Effects on Ability to Drive and Use Machines

None reported.

Overdose

Overdosage can lead to neurological sequelae including encephalopathy, convulsions and coma. Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.

Pharmacological properties

Pharmacodynamic Properties

Bacteriology

Ceftazidime is bactericidal in action. It acts by inhibiting bacterial cell wall synthesis. A wide range of pathogenic strains and isolates are susceptible in vitro including strains resistant to gentamicin and other aminoglycosides. Ceftazidime is highly stable to most clinically important b-lactamases produced by both Gram-positive and Gram-negative organisms, therefore it is active against many ampicillin- and cephalothin- resistant strains. Ceftazidime has high intrinsic activity in vitro and acts within a narrow MIC range for most genera with minimal changes in MIC at varied inoculum levels. In vitro the activities of ceftazidime and aminoglycosides in combination are additive. There is evidence of synergy in some strains. Ceftazidime is active in vitro against the following organisms:

Gram-negative

Pseudomonas aeruginosa. Pseudomonas spp (including Ps. pseudomallei). Escherichia coli. Klebsiella spp (including Klebsiella pneumoniae). Proteus mirabilis. Proteus vulgaris. Morganella morganii (formerly Proteus morganii). Proteus rettgeri. Providencia spp. Enterobacter spp. Citrobacter spp. Serratia spp. Salmonella spp. Shigella spp. Yersinia enterocolitica. Pasteurella multocida. Acinetobacter spp. Neisseria gonorrhoeae. Neisseria meningitidis. Haemophilus influenzae (including ampicillin resistant strains) Haemophilus parainfluenzae (including ampicillin resistant strains).

Gram-positive

Staphylococcus aureus (methicillin-sensitive strains) Staphylococcus epidermidis (methicillin-sensitive strains) Micrococcus spp. Streptococcus pyogenes (Group A b-haemolytic streptococci) Streptococcus Group B (Strept agalactiae). Streptococcus pneumoniae. Streptococcus mitis. Streptococcus spp (excluding Enterococcus (Streptococcus) faecalis).

Anaerobic strains

Peptococcus spp. Peptostreptococcus spp. Streptococcus spp. Propionibacterium spp. Clostridium perfringens. Fusobacterium spp. Bacteroides spp (many strains of Bacteroides fragilis resistant) Ceftazidime is not active in vitro against the following organisms:- Methicillin-resistant staphylococci. Enterococcus (Streptococcus) faecalis and many other Enterococci. Clostridium difficile. Listeria monocytogenes. Campylobacter spp.

Pharmacokinetic Properties

Absorption

After IM administration of 500 mg and 1 g, peak levels of 18 and 37 mg/L respectively are rapidly achieved and 5 minutes after IV bolus injection of 500 mg, 1 g or 2 g, serum levels are respectively 46, 87 and 170 mg/L.

Distribution

Therapeutically effective concentrations are still present in the serum 8-12 hours after either IV or IM 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 CSF in the absence of inflammation. However, therapeutic levels of 4-20 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 80-90% of the dose is recovered in the urine within 24 hours. Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced. (See section on renal impairment). Less than 1% is excreted via the bile, which limits the amount entering the bowel.

Pharmaceutical particulars

List of Excipients

Sodium carbonate (anhydrous).

Incompatibilities

Ceftazidime is less stable in Sodium Bicarbonate Injection than in 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. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.

Special Precautions for Storage

Store vials prior to reconstitution at or below 25C. Store in outer packaging. Protect from light. Shelf life is 2 years. If storage is necessary once reconstituted, store at 2 to 8degC for not more than 24 hours.

Nature and Contents of Container

Individually cartoned vials of Ceftazidime Alphapharm Powder for Injection containing 250 mg, 500 mg or 1 g ceftazidime (as pentahydrate) for intramuscular or intravenous use. Individually cartoned vials of Ceftazidime Alphapharm Powder for Injection containing 2 g ceftazidime (as pentahydrate) for intravenous use. Not all pack sizes and strengths may be marketed.

Instructions for Use/Handling

Ceftazidime is compatible with most commonly used intravenous fluids. All sizes of vials of Ceftazidime Alphapharm Powder for 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.

ate ation

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

Ceftazidime is compatible with most commonly used intravenous fluids. However, Sodium Bicarbonate Injection is not recommended as a diluent (see incompatibilities). 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). Ceftazidime may be constituted for intramuscular use with 0.5% or 1% Lignocaine Hydrochloride Injection. Both components retain satisfactory potency when ceftazidime at 4 mg/mL is admixed 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 Ceftazidime Alphapharm Powder 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 IM or IV 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 IV infusion from Ceftazidime Alphapharm Powder for Injection (mini-bag or burette-type set):-

Prepare using a total of 50 ml of compatible diluent, added in TWO stages as below:- 1 g and 2 g vials for IV 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 15-30 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.

Medicines classification

Prescription Only Medicine

Name and address

Mylan New Zealand Limited PO Box 11-183 Ellerslie AUCKLAND Telephone: 09-579-2792

Date of preparation

23 August 2013