Negacef is indicated for the treatment of the infections listed below in adults and children including neonates (from birth).

§ Nosocomial pneumonia

§ Broncho-pulmonary infections in cystic fibrosis

§ Bacterial meningitis

§ Chronic suppurative otitis media

§ Malignant otitis externa

§ Complicated urinary tract infections

§ Complicated skin and soft tissue infections

§ Complicated intra-abdominal infections

§ Bone and joint infections

§ Peritonitis associated with dialysis in patient on CAPD.

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Ceftazidime may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Ceftazidime may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing transurethral resection of the prostate (TURP).

The selection of ceftazidime should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram negative bacteria (see sections 4.4 and 5.1).

Ceftazidime should be co-administered with other antibacterial agents whenever the possible range of causive bacteria would not fall within its spectrum of activity.

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

Posology

Table 1: Adults and children ≥ 40 kg

Table 2: Children < 40 kg

Paediatric population

The safety and efficacy of ceftazidime administered as continuous infusion to neonates and infants ≤ 2 months has not been established.

Elderly

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

Hepatic impairment

Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment. There are no study data in patients with severe hepatic impairment (see also section 5.2). Close clinical monitoring for safety and efficacy is advised.

Renal impairment

Ceftazidime is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function, the dosage should be reduced (see also section 4.4).

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

Table 3: Recommended maintenance doses of ceftazidime in renal impairment – intermittent infusion

Adults and children ≥ 40 kg

In patients with severe infections the unit dose should be increased by 50% or the dosing frequency increased. In children the creatinine clearance should be adjusted for body surface area or lean body mass.

Children < 40 kg

Close clinical monitoring for safety and efficacy is advised.

Table 4: Recommended maintenance doses of ceftazidime in renal impairment – continuous infusion

Adults and children ≥ 40 kg

Caution is advised in dose selection. Close clinical monitoring for safety and efficacy is advised.

Children < 40 kg

The safety and effectiveness of ceftazidime administered as continuous infusion in renally impaired children < 40 kg has not been established, close clinical monitoring for safety and efficacy is advised.

If continuous infusion is used in children with renal impairment, 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 h.

Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the tables 5 & 6 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 250mg for 2 litres of dialysis solution).

For patients in renal failure on continuous arterio-venous 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 dose recommended under renal impairment.

For patients on veno-venous haemofiltration and veno-venous haemodialysis, follow the dosage recommendations in tables 5 & 6 below.

Table 5: Continuous veno-venous haemofiltration dose guidelines

Table 6: Continuous veno-venous haemodialysis dose guidelines

Method of administration

The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.

Negacef 1g should be administered by intravenous injection or infusion, or by deep intramuscular injection. Recommended intramuscular injection sites are the upper outer quadrant of the gluteus maximus or lateral part of the thigh. Negacef solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids. The standard recommended route of administration is by intravenous intermittent injection or intravenous continuous infusion. Intramuscular administration should only be considered when the intravenous route is not possible or less appropriate for the patient.

Hypersensitivity

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with ceftazidime must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftazidime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Spectrum of activity

Ceftazidime has a limited spectrum of antibacterial activity. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with ceftazidime. This particularly applies when considering the treatment of patients with bacteraemia and when treating bacterial meningitis, skin and soft tissue infections and bone and joint infections. In addition, ceftazidime is susceptible to hydrolysis by several of the extended spectrum beta lactamases (ESBLs). Therefore information on the prevalence of ESBL producing organisms should be taken into account when selecting ceftazidime for treatment.

Pseudomembranous colitis

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including ceftazidime, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftazidime (see section 4.8). Discontinuation of therapy with ceftazidime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Renal function

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.

Ceftazidime is eliminated via the kidneys; therefore the dose should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and efficacy. Neurological sequelae have occasionally been reported when the dose has not been reduced in patients with renal impairment (see section 4.2 and 4.8).

Overgrowth of non-susceptible organisms

Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. Enterococci, fungi) which may require interruption of treatment or other appropriate measures. Repeated evaluation of the patient's condition is essential.

Test and assay interactions

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

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.

Important information about the ingredients of Negacef:

Negacef 1g contains 121mg of sodium carbonate per vial.

This should be considered for patients who are on a controlled sodium diet.

Interaction studies have only been conducted with a probenecid and furosemide.

Concurrent use of high doses with nephrotoxic medicinal products may adversely affect renal function (see section 4.4).

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.

Pregnancy

There are limited amounts of data from the use of ceftazidime in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Ceftazidime should be prescribed to pregnant women only if the benefit outweighs the risk.

Breast-feeding

Ceftazidime is excreted in human milk in small quantities but at therapeutic doses of ceftazidime no effects on the breast-fed infant are anticipated. Ceftazidime can be used during breast-feeding.

Fertility

No data are available.

No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8).

The most common adverse reactions are eosinphilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or uticarcial rash, pain and/or inflammation following intramuscular injection and positive Coomb's test.

Data from sponsored and unsponsored clinical trials have been used to determine the frequency of common and 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. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following convention has been used for the classification of frequency:

§ Very common ≥1/10

§ Common ≥1/100 and <1/10

§ Uncommon ≥1/1,000 and <1/100

§ Rare ≥1/10,000 and <1/1000

§ Very rare <1/10,000

§ Unknown (cannot be estimated from the available data)

¹There have been reports of neurological sequelae including tremor, myoclonia, convulsions, encephalopathy and coma in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.

²Diarrhoea and colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.

³ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase.

⁴There have been rare reports where DRESS has been associated with ceftazidime.

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

To report any side effect(s):

The National Pharmacovigilance and Drug Safety Center (NPC)

Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

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

Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment (see sections 4.2 and 4.4)

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

Pharmacotherapeutic group: Anti-bacterials for systemic use.

Third-generation cephalosporins ATC code: J01DD02

Mechanism of action

Ceftazidime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

PK/PD relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftazidime for individual target species (i.e. %T>MIC).

Mechanism 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 extended-spectrum beta-lactamases (ESBLs), including the SHV family of ESBLs and 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

§ bacterial efflux pumps.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

S=Susceptible, I=Intermediate, R=Resistant

¹The breakpoints relate to high dose therapy (2 g x 3).

²Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes.

Microbiological 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 ceftazidime in at least some types of infections is questionable.

Absorption

After intramuscular administration of 500 mg and 1 g of ceftazidime, peak plasma levels of 18 and 37 mg/l respectively are achieved rapidly. Five minutes after intravenous bolus injection of 500 mg, 1 g or 2 g, plasma levels are 46, 87 and 170mg/l, respectively. The kinetics of ceftazidime are linear within the single dose range of 0.5 to 2 g following intravenous or intramuscular dosing.

Distribution

The serum protein binding of ceftazidime is low at 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, concentrations of 4 to 20 mg/l or more are achieved in the CSF when the meninges are inflamed.

Biotransformation

Ceftazidime is not metabolised.

Elimination

After parenteral administration plasma levels decrease with a half-life of about 2 h. Ceftazidime is excreted unchanged into the urine by glomerular filtration; approximately 80 to 90 % of the dose is recovered in the urine within 24 h. Less than 1 % is excreted via the bile.

Special patient populations

Renal impairment

Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced (see section 4.2).

Hepatic impairment

The presence of mild to moderate hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days provided renal function was not impaired (see section 4.2).

Elderly

The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination half-life ranged from 3.5 to 4 hours following single or 7 days repeat BID dosing of 2 g IV bolus injections in elderly patients 80 years or older.

Paediatric population

The half-life of ceftazidime is prolonged in preterm and term neonates by 4.5 to 7.5 hours after doses of 25 to 30 mg/kg. However, by the age of 2 months the half-life is within the range for adults.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeat dose toxicity, genotoxicity, toxicity to reproduction. Carcinogenicity studies have not been performed with ceftazidime.

Inactive Ingredients:

1. Sodium Carbonate

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 with vancomycin added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.

Before reconstitution, store below 30°C. Protect from light and heat.

After reconstitution, see “Stability after reconstitution” in section 6.6.

Clear glass vial with a printed label, one vial packed in a printed box along with a leaflet.

Clear glass vial with a printed label, 10 vials packed in a printed box along with a leaflet.

Instructions for Use/Handling

All sizes of vials of Negacef 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.

See the following table for different volumes and solution concentrations, which may be useful when fractional doses are required.

*NOTE: Addition should be in two stages

Solutions range from light yellow to yellow 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 1mg/ml and 40mg/ml is compatible with:

-    Sodium Chloride 9mg/ml (0.9%) solution for 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 0.05mg/ml and 0.25mg/ml is compatible with Intra-peritoneal Dialysis Fluid (Lactate).

§ Ceftazidime may be constituted for i.m. use with 0.5% or 1% Lidocaine Hydrochloride Injection. Solutions in lidocaine must never be administered intravenously.

Preparation of solution for 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.

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. Ceftazidime is compatible with the most commonly used intravenous fluids.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Stability after reconstitution

In keeping with good pharmaceutical practice, it is preferable to use freshly constituted solutions of Negacef for injection. If this is not practicable, satisfactory potency is retained for 24 hours in the refrigerator (2 - 8°C) when prepared in Water for Injection BP or any of the injections listed above.