Product Monograph

PrFORTAZ(r)

(ceftazidime for injection) USP

Antibiotic

GlaxoSmithKline Inc. 7333 Mississauga Rd Mississauga, Ontario L5N 6L4 Date of Preparation: June 17, 2002 Date of Revision: September 6, 2006 Control Number: 107378

(c)

GlaxoSmithKline Inc.

(r)

FORTAZ is a registered trademark, used under license by GlaxoSmithKline Inc

Product Monograph

PrFORTAZ(r) (ceftazidime for injection) USP

Antibiotic

Clinical Pharmacology

In vitro

studies indicate that the bactericidal action of ceftazidime, a semisynthetic cephalosporin antibiotic, results from inhibition of bacterial cell wall synthesis.

Ceftazidime has a high affinity for the Penicillin-Binding Protein-3 (PBP-3) and moderate affinity for the PBP-1a of certain Gram negative organisms such as Escherichia coli and Pseudomonas aeruginosa. The affinity for PBP-1b is much less than that for either PBP-3 or PBP-1a. PBP-3 is involved in the process of cross-wall formation (septation). Binding to this protein results in formation of filaments and eventual death of the bacterium. PBP-1a and PBP-1b are involved in longitudinal wall synthesis (elongation) prior to septation. Binding to these proteins results in spheroplast formation followed by rapid lysis. Ceftazidime has high affinity for PBP-1 and PBP-2 of Staphylococcus aureus. However, the drug's affinity for PBP-3 is very much less in this organism.

Contraindications

FORTAZ(r) (ceftazidime for injection) is contraindicated for patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibiotics.

Warnings

Before therapy with FORTAZ(r) (ceftazidime for injection) is instituted, careful enquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. FORTAZ(r) should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. Special care is indicated in patients who have experienced an allergic reaction to penicillins or other beta-lactams. If an allergic reaction to FORTAZ(r) occurs, treatment should be discontinued and standard agents (e.g. epinephrine, antihistamines, corticosteroids) administered as necessary. Pseudomembranous colitis has been reported to be associated with treatment with FORTAZ(r) (and other broad-spectrum antibiotics). Therefore, it is important to consider its diagnosis in patients administered FORTAZ(r) who develop diarrhea. Treatment with broad-spectrum antibiotics, including FORTAZ(r), alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis. Mild cases of colitis may respond to drug discontinuance alone. Moderate to severe cases should be managed with fluid, electrolyte, and protein supplementation as indicated. When the colitis is not relieved by discontinuance of FORTAZ(r) administration or when it is severe,

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 5 consideration should be given to the administration of vancomycin or other suitable therapy. Other possible causes of colitis should also be considered.

Precautions

FORTAZ(r) (ceftazidime for injection) should be administered with caution to individuals with a history of gastrointestinal disease, particularly colitis. Patients with impaired renal function (i.e. creatinine clearance of 50mL/min/1.73m2 or less) should be placed on the special dosage schedule for FORTAZ(r) recommended under DOSAGE AND ADMINISTRATION. Normal dosages in these individuals are likely to produce excessive serum concentrations of ceftazidime. Elevated levels of ceftazidime in these patients could lead to convulsions. The concomitant administration of aminoglycosides and some cephalosporins has caused nephrotoxicity. Although transient elevations of BUN and serum creatinine have been observed in clinical studies, there is no evidence that FORTAZ(r), when administered alone, is significantly nephrotoxic. However, the effect of administering FORTAZ(r) concomitantly with aminoglycosides is not known. Studies suggest that the concomitant use of potent diuretics, such as furosemide and ethacrynic acid, may increase the risk of renal toxicity with cephalosporins. Ceftazidime is eliminated via the kidneys, therefore the dosage should be reduced according to the degree of renal impairment. Neurological

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 6 sequelae have occasionally been reported when the dose has not been reduced appropriately (see Dosage in Impaired Renal Function and see ADVERSE REACTIONS) Prolonged treatment with FORTAZ(r) may result in the overgrowth of nonsusceptible organisms, including species originally sensitive to the drug. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Development of resistance during the administration of FORTAZ(r) has been observed for Staphylococcus aureus, members of the Enterobacteriaceae family, Acinetobacter species, Pseudomonas species, and Serratia species. 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. In common with other antibiotics, ceftazidime may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral contraceptives.

Pregnancy

The safety of FORTAZ(r) in pregnancy has not been established. The use of FORTAZ(r) in pregnant women requires that the likely benefit from the drug be weighed against the possible risk to the mother and fetus. Reproduction studies have been performed in mice and rats employing

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 7 ceftazidime doses of up to 25 times those usually administered to humans. These studies have revealed no evidence of impaired fertility or harm of the fetus caused by ceftazidime. Animal reproduction studies, however, are not always predictive of human response.

Nursing Mothers

Ceftazidime is excreted in human milk in low concentrations (3.8 - 5.2 mg/L). The clinical significance of this is unknown, therefore, caution should be exercised when FORTAZ(r) is administered to a nursing mother.

Elderly Patients

The elimination of ceftazidime may be reduced due to impairment of renal function.

Drug-Laboratory Test Interactions

Ceftazidime may cause a false-positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling's solution). As a false-negative result may occur in the ferricyanide test, it is recommended that either glucose oxidase or hexokinase method be used to determine blood plasma glucose levels in patients receiving FORTAZ(r). Ceftazidime does not interfere in the alkaline picrate assay for creatinine. A positive Coombs' test has been reported during treatment with cephalosporins. This phenomenon can interfere with cross matching of blood.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 8

Symptoms and Treatment of Overdosage

Overdosage of cephalosporins can lead to neurological sequelae including encephalopathy, convulsions and coma. Excessive serum levels of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Dosage and Administration

FORTAZ(r) (ceftazidime for injection) may be administered either intravenously or intramuscularly after reconstitution. Dosage and route of administration should be determined by severity of infection, susceptibility of the causative organism(s), and condition of the patient. The

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 10 intravenous route is preferable for patients with septicemia, peritonitis or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending. The usual duration of treatment is 7 to 14 days. For Streptococcal infections, therapy should be continued for at least 10 days.

Adults

The recommended daily dosage of FORTAZ(r) is 0.5 to 6 grams administered in equally divided doses every 8 to 12 hours (see Table 1).

For the treatment of infections caused by Staphylococcus species, a dosage of 1 or 2 g administered every 8 hours is recommended. For the treatment of infections (except those confined to the urinary tract) caused by Enterobacter species, a dosage of at least 1 g administered every 8 hours is recommended.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 11

Children Table 2

The maximum daily dose in children is 6g.

Neonates (aged 0-28 days)

In children aged one month or less the recommended dose is 25-50 mg/kg of FORTAZ(r) given twice daily. Data indicates that half-life of ceftazidime in neonates increases with decreasing gestational age and can be 3-4 times that in adults. An adjustment in dosing interval may be necessary with an increasing degree of prematurity. Additionally, clearance may increase rapidly in the first 2-3 weeks of life necessitating a readjustment of dose and/or dosing interval.

Use in Elderly

In acutely ill elderly patients with reduced renal clearance of ceftazidime, the daily dosage should not exceed 3 g.

Impaired Hepatic Function

No adjustment in dosage is required for patients with hepatic dysfunction provided renal function is not impaired (see PHARMACOLOGY).

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 12

Adults with Impaired Renal Function

Ceftazidime is excreted almost exclusively by glomerular filtration. In patients in whom the glomerular filtration rate (GFR) is less than or equal to 50 mL/min (0.83 mL/s), the dosage of FORTAZ(r) must be reduced to compensate for its slower excretion. After an initial loading dose of 1g of FORTAZ(r), a maintenance dosage schedule should be followed (see Table 3).

TABLE 3: Recommended Maintenance doses of FORTAZ(r) in Renal Insufficency

* If the severity of the infection necessitates an increase in the dosing frequency, serum concentrations of ceftazidime should be used as guidelines.

When only serum creatinine levels are known, the following formulae may be used to estimate creatinine clearance. The serum creatinine must represent a steady state of renal function:

Males

Creatinine clearance (mL/s) = Weight (kg) X (140 - age) 49 x serum creatinine (umol/L) OR Creatinine clearance (mL/min) = Weight (kg) X (140 - age) 72 x serum creatinine (mg/dL)

Females

0.85 X above value.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 13 Mean serum half-life of ceftazidime in patients with no kidney function was reduced from a range of 24.0 - 35.4h between dialysis sessions to a range of 2.8 - 4.6h during hemodialysis. Therefore a loading dose of 1 g is recommended followed by 0.5 to 1.0 g after each hemodialysis period. Serum concentrations of ceftazidime should be carefully monitored and used as a basis to adjust the dosage. FORTAZ(r) can also be used in patients undergoing peritoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, a loading dose of FORTAZ(r) (1 g) is suggested, followed by 500 mg every 24 hours. Serum concentrations of ceftazidime should be carefully monitored and used as a basis to adjust the dosage.

ADMINISTRATION

Intramuscular

FORTAZ(r) may be administered by deep intramuscular injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus or vastus lateralis. The maximum dose of FORTAZ(r)should be one (1) gram for a single intramuscular injection.

Intermittent Intravenous Administration

The reconstituted solution may be slowly injected into the vein over a period of 3 to 5 minutes or given through the tubing of an administration set. During the infusion of the solution containing FORTAZ(r), the administration of other solutions should be discontinued temporarily.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 14

Continuous Intravenous Infusion

FORTAZ(r) may also be administered over a longer period of time. NOTE: If therapy with FORTAZ(r) is carried out in combination with an aminoglycoside antibiotic, each should be administered at different sites because of a physical incompatibility. An aminoglycoside should not be mixed with FORTAZ(r) in the same container.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 15

Pharmaceutical Information

CHEMISTRY

Proper Name

: ceftazidime for injection

Chemical Name:

Pyridinium, 1-[7-[[2-amino-4-thiazolyl) [1-carboxy-1-

methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5- thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, hydroxide, inner salt, pentahydrate, [6R- [6a, 7b(Z)]]-

Structural Formula:

S N

O

+ CH2N

C

N

5H2O

OC(CH3)2COOH Molecular Formula: C22H22N6O7S2 * 5H2O Molecular Weight: 636.6 (as pentahydrate)

Description:

Ceftazidime pentahydrate is a white to cream-

coloured powder. It is soluble in acid, alkali and dimethyl sulfoxide; slightly soluble in water, methanol and dimethylformamide; insoluble in 95% ethanol, ethyl acetate, acetone, 1, -4-dioxan, diethyl ether, toluene, petroleum spirit and chloroform.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 16

Composition

FORTAZ(r) vials contain a mixture of ceftazidime pentahydrate and sodium carbonate. The sodium carbonate at a concentration of 118 mg/g of ceftazidime activity has been admixed to facilitate dissolution. The total sodium content of the mixture is approximately 54 mg (2.3 mEq/g of ceftazidime activity). Solutions of FORTAZ(r) range in colour from light yellow to amber, depending upon the diluent and volume used. The pH of freshly reconstituted solutions usually ranges from 5.0 to 7.5.

RECONSTITUTION

CAUTION: Ensure adequate venting, addition of diluent generates a positive pressure.

For Intramuscular Use

Solutions for Reconstitution

Sterile Water for Injection or, if required Bacteriostatic Water for Injection with Benzyl Alcohol or Parabens (not for use in neonates) 0.5 w/v to 1.0% w/v Lignocaine Hydrochloride Injection.

Reconstitution Table

Shake well until dissolved.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 17

For Intravenous Use

Solution for Reconstitution

Sterile Water for Injection Reconstitute as follows:

Reconstitution Table

Shake well until dissolved. The prepared solution may be further diluted to the desired volume with any of the solutions listed under "Solutions for i.v. Infusion".

For Direct Intravenous Injection

Reconstitute as directed above.

For Intermittent Intravenous Infusion

Reconstitute as directed above for 1.0 g and 2.0 g vials of FORTAZ(r).

For Continuous Intravenous Infusion

Reconstitute 1.0 g and 2.0 g vials of FORTAZ(r) with 10 mL Sterile Water for Injection. The appropriate quantity of the reconstituted solution may be added to an intravenous bottle containing any of the solutions listed under "Solutions for i.v. Infusion".

g Pharmacy Bulk Vial

THE AVAILABILITY OF THE PHARMACY BULK VIAL IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 18 FORTAZ(r) FOR INJECTION does not contain any preservatives. The Pharmacy Bulk Vial is intended for multiple dispensing for intravenous use only, employing a single puncture. Reconstitute with 26 ml Sterile Water for Injection.

Reconstitution Table

Shake well until dissolved. Following reconstitution with Sterile Water for Injection, the solution should be dispensed and diluted for use within 8 hours at room temperature (not exceeding 25oC). Any unused reconstituted solution should be discarded after 8 hours. The appropriate quantity of the reconstituted solution may be added to an intravenous bottle containing any of the solutions listed below.

Solutions for i.v. Infusion

0.9% Sodium Chloride Injection M/6 Sodium Lactate Injection Ringers Injection USP Lactated Ringers Injection USP 5% Dextrose Injection 5% Dextrose and 0.225% Sodium Chloride Injection 5% Dextrose and 0.45% Sodium Chloride Injection 5% Dextrose and 0.9% Sodium Chloride Injection 10% Dextrose Injection

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 19 10% Invert Sugar in Water for Injection Normosol-M in 5% Dextrose Injection Sterile Water for Injection

Stability of Solutions

Storage

Reconstituted solutions should be administered within 12 hours when stored at room temperature (not exceeding 25degC), and within 48 hours when refrigerated, from the time of reconstitution, both when prepared as bolus injections, i.m. or i.v., and as infusion admixtures with the recommended i.v. diluents. Incompatibility FORTAZ(r) should not be added to blood products, protein a hydrolysates or amino acids. FORTAZ(r) should not be mixed together with an aminoglycoside. FORTAZ(r) is less stable in Sodium Bicarbonate Injection than in other intravenous fluids, therefore it is not recommended as a diluent. Precipitation has been reported when vancomycin has been added to FORTAZ(r) in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.

Availability of Dosage Forms

FORTAZ(r) for intramuscular or direct intravenous injection Vials containing the equivalent of 1 g ceftazidime are available in packs of ten.

FORTAZ(r) for intravenous injection or infusion Vials containing the equivalent of 1 g and 2 g ceftazidime are available in packs of ten. Vials containing the equivalent of 6 g ceftazidime are available in packs of 6.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 20

STORAGE

FORTAZ(r) in the dry state should be stored below 25degC and protected from light.

MICROBIOLOGY

The in vitro activity of ceftazidime against clinical isolates of various Gram positive and Gram negative aerobic and anaerobic micro-organisms is shown in Table 4. Susceptibility was determined by both agar and broth dilution methods, using an inoculum size of approximately 105 colony-forming units (CFU) per mL. Ceftazidime is not active in vitro against the following organisms: methicillin- resistant staphylococci, Streptococcus faecalis, Enterococcus species, Clostridium difficile, Listeria monocytogenes and Campylobacter sp. The MIC's of ceftazidime against aerobic bacteria are not significantly affected by changes in inoculum size in the range 102 to 105 CFU/mL. However, increasing the inoculum size to 107 CFU/mL has a pronounced effect on the MIC's for some organisms. In one study, when the inocula of various Enterobacteriaceae (10 Citrobacter species, 10 Enterobacter species, 20 indole-positive Proteus species) were increased in size from 105 to 107 CFU/mL, MIC values increased 8- to 128- fold.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 21

Legionnaires' Disease has been observed in patients treated with antimicrobial agents possessing demonstrated in vitro activity against Legionnaire's Disease bacterium.

The ratios of MBC to MIC in 50% human serum (inoculum of 105 CFU/mL) are shown in Table 5.

In general, the inhibitory activity of ceftazidime is not influenced by changes in pH between 6.5 and 7.5 but MIC values for more acidic media (i.e. pH 5.5 to 6.0) were marginally higher (i.e. 2-fold or less) than at neutral pH. The presence of 50% human serum did not significantly affect the inhibitory activity of ceftazidime. The rates of hydrolysis of ceftazidime relative to those of cephaloridine by various beta-lactamases are shown in Table 6.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 23

A unit of beta-lactamase activity was defined as the amount of enzyme which hydrolyzed 1 mmol of cephaloridine per minute at pH7.

* * Relative to a value of 100 for cephaloridine.

Development of Resistance

Resistance to ceftazidime was induced in 8 bacterial isolates by daily passage in serial broth dilutions of the drug. In general, there was a progressive increase in the MIC of ceftazidime during 12 successive daily subcultures. Two strains (Enterobacter cloacae and Citrobacter freundii), however, showed a rapid increase in resistance to ceftazidime within 6 days. Subsequent culturing in antibiotic-free media for 6 days resulted in restoration of sensitivity to a varying degree as shown in Table 7.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 24

TABLE 7: Comparative ceftazidime MIC's of parent and derivative strains Ceftazidime MIC's * (mg/L)

Agar dilution method

R = Strain after 12 subcultures in ceftazidime

R3 = Strain R after 3 subcultures in antibiotic-free broth R6 = Strain R after 6 subcultures in antibiotic-free broth NG = No Growth

Induced resistance to ceftazidime was associated with cross-resistance to other antibiotics. MIC's were increased 2- to 8-fold for first generation cephalosporins (cephalothin, cephradine, cefazolin), up to 16-fold for second generation cephalosporins (cefamandole, cefoxitin, cefuroxime) and up to 1033-fold for cefotaxime. Pseudomonas aeruginosa rendered ceftazidime-resistant exhibited cross-resistance to azlocillin and carbenicillin, but sensitivities to gentamicin and amikacin were unaffected.

Susceptibility Testing

The standard single-disc susceptibility test (using the 30 mcg FORTAZ(r) disc) and dilution susceptibility should be interpreted according to the criteria in Table 8.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 25

Organisms should be tested with FORTAZ(r) discs, since ceftazidime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam discs are used.

Pharmacology

Animals

The secondary pharmacological actions of ceftazidime have been studied in four species - mouse, rat, cat and dog. The possible effects of ceftazidime on the central nervous system, cardiovascular, respiratory and autonomic nervous systems, gastrointestinal tract and in smooth muscle contractions have been determined. The following effects were observed:

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 26

Human

Ceftazidime is poorly absorbed when given orally (e.g. following a 250 mg dose the average urinary recovery was less than 1% of the dose).

Intravenous Administration

Bolus Injections

Ceftazidime was administered as single bolus injections (over 1 min) to 22 healthy male volunteers in three doses: 250 mg (6 subjects, mean age 34 years), 500 mg (8 subjects, mean age 33 years) and 1000 mg (8 subjects, mean age 35 years). Serum concentration-time curves follow a biexponential decay (see Figure 1).

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 27

FIGURE 1: Serum concentrations of ceftazidime administered intravenously over 1 min

Serum Concentration mg/L

0 1 2 3 4 5 6 7 8

Time after Injection (Hours)

250 mg 500 mg 1 g

Mean urinary recovery of unchanged drug over 24 hours ranged from 77.4 to 85.5% (Table 10) with over 50% being excreted in the first two to four hours. Figure 2 shows urinary concentrations of ceftazidime for various collection intervals following injection. Derived pharmacokinetic indices (based on a two- compartment model) are summarized in Table 10.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 28

FIGURE 2: Urinary concentrations of ceftazidime after single bolus intravenous injections

No accumulation of drug occurred during repeated administrations of ceftazidime (2 g t.i.d., 10 days). Trough serum level did not increase after dose 2 and urinary recoveries over the first eight hours averaged 81.2% after dose 1 and 76.3% after dose 28. Pharmacokinetic parameters remained unchanged (see Table 10).

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 29

TABLE 10: Average pharmacokinetic parameters of ceftazidime after i.v. bolus administration

* 8h collection only

Intravenous Infusion

Single intravenous infusions of 500 mg (6 subjects, mean age 35 years), 1000 mg (7 subjects, mean age 33 years) and 2000 mg (7 subjects, mean age 30 years) of ceftazidime were administered over 20 to 30 minutes to normal adult male volunteers. Serum concentration-time curves (Figure 3) follow a biexponential decay.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 30

FIGURE 3: Serum concentrations of ceftazidime infused intravenously over 20-30 minutes

Mean urinary recovery of unchanged drug over 24 hours ranged from 83.7 to 87.1% (Table 11) with over 50% being excreted in the first two to four hours. Figure 4 shows urinary concentrations of ceftazidime for various collection intervals following infusion. Derived pharmacokinetic indices (based on a two- compartment model) are summarized in Table 11.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 31

FIGURE 4: Urinary concentrations of ceftazidime after single intravenous infusions over 20-30 minutes

TABLE 11: Average pharmacokinetic parameters of ceftazidime after i.v. infusion

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 32

Intramuscular Injection: Serum concentration-time curves following intramuscular injection of 500 mg (8 subjects, mean age 32 years) or 1000 mg (8 subjects, mean age 34 years) of ceftazidime is shown in Figure 5.

FIGURE 5: Serum concentrations of ceftazidime

administered intramuscularly

Mean urinary recovery of ceftazidime over 24 hours ranged from 78.9 to 84.6% (Table 12). Figure 6 shows urinary concentrations of ceftazidime for various collection intervals following injection. Derived pharmacokinetic indices (based on a one-compartment model) are summarized in Table 12.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 33

FIGURE 6: Urinary concentrations of ceftazidime after single intramuscular injections

Table 12: Average pharmacokinetic parameters of ceftazidime after i.m. administration

No accumulation of drug was noted during repeated intramuscular doses of ceftazidime (1 g, t.i.d., 10 days). Pharmacokinetic parameters remained unchanged (Table 12).

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 34 The pharmacokinetic parameters of 1 g of ceftazidime in 1% lidocaine (6 healthy male volunteers, mean age 37 years) did not differ significantly from those obtained without the use of lidocaine. When ceftazidime was administered to two subjects (750 mg im) in the recumbent position, average peak serum levels were lower (20.8 mg/L) and serum half-life was longer (2.6 hours) when compared to the two mobile volunteers (36.4 mg/L and 1.8 hours, respectively). The area-under-the-curve was not significantly affected by physical activity.

Excretion and Metabolism

Ceftazidime is not metabolized. Metabolites were not detected either in the serum by HPLC or in the urine by chromatography or bioautography. Hepatic clearance (i.e. biliary excretion) accounts for less than 1% of the total clearance of ceftazidime in the presence of normally functioning kidneys. The mean renal clearance of ceftazidime was 97.6 mL/min (range 76 to 110 mL/min). The calculated plasma clearance of 116.4 mL/min (range 97 - 139 mL/min) indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid prior to dosing had no effect on the elimination kinetics of ceftazidime. This suggested that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms.

Protein Binding

In vitro

In vitro

studies with human serum revealed that 5-23% of ceftazidime is protein bound and is independent of drug concentration.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 35

Tissue and Body Fluid Concentrations

Therapeutic concentrations of ceftazidime in tissues and body fluids other than serum are presented in Table 13.

TABLE 13: Ceftazidime Concentration in Body Tissues and Fluids

* Cystic fibrosis patients

* * Sputum collected for 8h period

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 36 Concentrations of ceftazidime in the breast milk of 11 puerperal women following intravenous administration of 2 g doses every 8 hours for 5 days were determined by bioassay. Mean +- S.D. concentrations of ceftazidime averaged 3.8 +- 2.0 ug/mL (before the next dose), 5.2 +- 3.0 ug/mL (1 hour after dosing) and 4.5 +- 1.7 ug/mL (3 hours after dosing). Excretion of ceftazidime into breast milk remained constant between days 2 and 4 of therapy.

Factors Influencing Pharmacokinetics

Sex

The peripheral comparative volume of distribution was smaller in females (mean 3.5 +- 0.5 L) than in males (6.7 +- 0.6 L) following intravenous administration (1 g, bolus injection). Following intramuscular administration (1 g), the time to peak concentration occurred earlier in the men (1.0 +- 0.1h - vastus lateralis and 1.1 +- 0.1h - gluteus maximus) than in women (1.3 +- 0.03h and 1.5 +- 0.2h, respectively). Peak serum concentrations were greater in women (37.2 +- 0.2 mg/L - vastus lateralis and 34.0 +- 2.3 mg/L - gluteus maximus) than in men (29.4 +- 1.6 mg/L and 27.6 +- 2.3 mg/L, respectively).

Pregnancy

Intramuscular injections of at least three doses of ceftazidime (1 g t.i.d.) were administered to 9 pregnant women (mean age 25.6 yr; mean gestational age 20.2 weeks) scheduled for abortion following diagnosis of fetal Cooley's anemia. Amniotic fluid levels of 1.0 - 5.5 ug/mL were observed between 2 and 6 hours after dosing. Serum levels of ceftazidime were approximately 50% lower in pregnant than non-pregnant females.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 37

Age

Neonates and Infants

Two studies were conducted in neonates (aged 0-29 days) which indicated that the serum half-life of ceftazidime in neonates could be 3-4 times that of an adult. In the first study, 56 neonates (aged less than 29 days) were administered ceftazidime at a dose of 25 mg/kg every 12 hours. The mean serum half-life was 7.57 hours. In the second study 29 neonates (aged less than 12 days) were dosed with 30- 50 mg/kg of ceftazidime every 12 hours had an overall elimination half-life of 4.28 hours. The 30 mg/kg bid dose gave sustained serum levels of ceftazidime throughout the dosing interval and was found to be appropriate for the neonate population. In another study, conducted in both neonates and infants (1 day to 12 months of age) 53 patients were administered ceftazidime as a single intravenous bolus injection at a mean dose of 31 mg/kg (25.0 - 35.7 mg/kg) in addition to other antimicrobial therapy. Serum levels are presented in Table 14. The mean serum half-life for babies aged 2 months or younger was prolonged (4.2 +- 1.6h). Those aged greater than 2 months had a half-life of 2.0 +- 0.6h.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 38

TABLE 14

In another study pediatric patients (mean age, 3.5 years) with Gram-negative infections received a single intravenous infusion over 15 minutes of either 15 mg/kg (8 patients) or 50 mg/kg (5 patients) of ceftazidime. Serum levels were measured by bioassay. Pharmacokinetic data are presented in Table 15.

Elderly

Ceftazidime, at a dose of 2 g b.i.d., was administered as a bolus intravenous injection to 13 elderly patients with a mean age of 77 years (63 - 83 years) and to 6 younger volunteers (24 - 32 years). A mean serum half-life of 2.9 hours was observed for the elderly patients and 1.75 hours in the young volunteers. The elderly patients were continued on treatment and no accumulation was noted on day 7.

Impaired Renal Function

The relationship between serum elimination half-life and glomerular filtration rate (GFR) is curvilinear. The half-life increases steeply at GFR's less-than 50 mL/min/1.73m2 (see Figure 7).

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 39

FIGURE 7: The relationship between serum elimination half-life and glomerular filtration rate

The pharmacokinetic parameters obtained following intravenous administration of a 1g bolus dose of ceftazidime to 14 patients (mean age 49 years) with severely impaired renal function and those from 8 healthy volunteers (mean age 35 years) are given in Table 16.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 40

TABLE 16: Mean Pharmacokinetic Parameter after 1 g Ceftazidime i.v.

Co = Fictive serum concentration at time zero

AUCT = Area under the serum concentration/time curve to infinity

b = Serum elimination rate constant t1/2b = Serum half-life

Vdb = Volume of distribution during the post-distributive phase UR = Urinary recovery over 24h

Mean maximum urine levels ranged between 0.2 g/L in patients with a GFR of <5 mL/min to 0.8 g/L with a GFR of 88 mL/min. In another study, six normal volunteers and four end-stage renal disease (ESRD) patients on hemodialysis were administered a single 1 g i.v. dose of ceftazidime. The apparent volumes of distribution were similar in both groups. The terminal half-life in the normal subjects ranged from 1.3 to 1.7 hours, while in the ESRD patients it ranged from 25.5 to 35.4 hours. Dialysis clearance ranged from 27 to 50 mL/min, while the total body clearance in the normals ranged from 98 to 184 mL/min. In another study single bolus doses of ceftazidime (15 mg/kg iv) were administered to 5 normal volunteers and 19 uremic patients (See Table 17). Four of the latter patients received an additional dose during hemodialysis.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 41

TABLE 17: Pharmacokinetic parameters of ceftazidime in healthy volunteers and in patients with impaired renal function

C1cr = creatinine clearance Vd = volume of distribution The pharmacokinetics of ceftazidime were studied in 12 patients with end-stage chronic renal failure during peritoneal dialysis. Mean serum levels (mg/L) following the i.v. administration of ceftazidime (1 g) to 5 patients at 0.25, 2 and 12 hours after starting peritoneal dialysis were 50.6 +- 11.2, 35.6 +- 3.7 and 22.7 +- 7.9 respectively. The mean serum half-life during and after peritoneal dialysis was 8.7 +- 3.1 hours and 26.9 +- 11 hours respectively. Four patients were administered ceftazidime (1 g) via an intraperitoneal catheter. The mean serum levels (mg/L) at 0.25, 2 and 8 hours were 14.2 +- 3.1, 40 +- 3.1 and 32.5 +- 6.4 respectively. Five male and one female patient undergoing continuous ambulatory peritoneal dialysis (CAPD) were administered 1 g ceftazidime. Two litres of dialysis fluid were used every six hours. The mean concentrations of ceftazidime in plasma and dialysate are shown in Figure 8. Using a dwell time of 4 to 6 hours,

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 42 approximately 10% of a dose of ceftazidime is removed. The data indicate that the half-life of ceftazidime is reduced to approximately 12 hours.

FIGURE 8: Mean ceftazidime levels in plasma and dialysate of CAPD patients

Cystic Fibrosis

The pharmacokinetics of an intravenous infusion (20 min) of 50 mg/kg ceftazidime were studied in 10 patients (20.8 +- 4.8 yr, 4 female, 6 males) with cystic fibrosis and 10 normal volunteers (21.6 +- 1.9 yr, 3 females, 7 males). Serum elimination half-lives were 1.76 +- 0.21h in controls and 1.50 +- 0.19h in cystic fibrotics. Total body clearance was 41.9% greater in the cystic fibrosis group (142.4 +- 16.9 mL/min/1.73m2) compared to controls (100.5 +- 10.3

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 43 mL/min/1.73m2). Although the fraction of the dose recovered in urine was the same in each group, renal clearance was 40.9% greater in patients with cystic fibrosis (130.1 +- 11.4 and 92.7 +- 11.6 mL/min/1.73m2 respectively). The mechanisms responsible for the altered renal clearance of ceftazidime in cystic fibrotic patients is not known.

Toxicology

Acute Toxicity TABLE 18

All deaths in mice occurred within 24 hours after an intravenous dose or within 6 hours following an intraperitoneal dose. Toxic signs consisted of purplish colouration of the skin, immobility and bradypnea alternating with jumping and convulsions. Survivors exhibited no abnormal signs or symptoms at 24 hours following the test dose. Post-mortem examinations revealed meningorrhagia, especially in the cerebellum, and pulmonary congestion. Death in rats occurred within 24 hours following subcutaneous injection and 6 hours following intraperitoneal dosing. Purplish colouration and reduction in elasticity of the skin, bradypnea, corneal opacity, piloerection, and immobility

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 44 followed by jumping and convulsions were observed. All survivors appeared normal by 48 hours post-dose. Post-mortem examinations revealed meningorrhagia, pulmonary congestion, splenic cysts and spots, and, in rats who received ip dosing, dilation of the caecum with large amount of contents. Groups of 6 rats of each sex were given a single intravenous or subcutaneous dose of ceftazidime (5 g/kg). One female died immediately after i.v. injection while the remaining animals survived in good condition. All animals were sacrificed 7 days post-dose. Post-mortem examinations revealed mild renal damage in the form of paling and slight dilation of some renal tubules containing cellular debris. A single i.v. dose of ceftazidime (5 g/kg) was administered to 6-month-old Beagle dogs (2/sex), which survived in good condition except for intermittent emesis and transient tachycardia. The animals were sacrificed 7 days post-dose for extensive histological examinations, but no pathological findings were noted.

Subchronic and Chronic Toxicity

TABLE 19

* Ages at commencement of treatment.

* * Each dosage group was composed of equal numbers of males and females.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 45

Rat

: 30-day study, intravenous and subcutaneous

All rats given 8.1 g/kg i.v. and 2 of 12 given 2.7 g/kg died within 10 minutes in convulsive shock and were found to have dilation of proximal and distal convoluted renal tubules. The 8.1 g/kg dose given sc was tolerated by females for the entire 30-day treatment period; males, however, had to be sacrificed after their third dose, and were found to have coagulative necrosis of 50 to 85% of the proximal convoluted tubules, but no other organ pathology. Toxicity in survivors was similar by either route of administration. The following biochemical and morphological changes were observed in survivors during or immediately following the treatment period: decreases in serum transaminases, protein (8.1 g/kg/day dose), alkaline phosphatase, calcium, and triglycerides; increases in serum sodium, potassium, inorganic phosphorus, protein (<8.1 g/kg/day doses), and cholesterol; increased weights of liver, kidney, spleen, ovaries, and adrenals; thymus involution; neutrophilia, lymphocytosis, and normocytic normochromic anemia; and increased urinary volume and output of epithelial cells, protein, and electrolytes. All of these abnormalities regressed during the recovery period. Post-mortem examination of both treatment mortalities and sacrificed survivors of the 8.1 g/kg/day regimen revealed pulmonary edema, subpleural hemorrhages, fatty change in liver cells, and dilation and fluid content of renal tubules.

Rat:

12-week study, intramuscular

All animals survived treatment and no abnormal physical or behavioural symptoms were observed. The injections were well tolerated at the i.m. sites.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 46 The following statistically significant changes in laboratory parameters which, nevertheless, still fell within the normal range occurred in the 0.9 g/kg/day group: erythrocyte counts increased in females and decreased in males; decreases in serum alkaline phosphatase, SGPT, hematocrit, and hemoglobin; increases in serum creatinine, bilirubin, potassium, BUN, and SGOT; and inconsistent changes in lymphocyte and neutrophil counts. The following laboratory abnormalities were observed in the 0.3 and 0.9 g/kg/day groups: increases in serum cholesterol; inconsistent changes in serum proteins; and increases in urinary volume and pH and decreases in specific gravity.

Rat:

28-week study, subcutaneous

One male from the 2.7 g/kg/day group was killed on Day 95 for investigation of suspected hepatotoxicity. Post-mortem examination revealed splenomegaly and hepatic fibroplasia. A female from the 0.9 g/kg/day group died on Day 183 and was found to have congestion of the lung, thymus, liver and kidney. All other rats survived the entire treatment period. Adverse effects noted in the 2.7 g/kg/day group were local irritation, loose feces, lethargy, decreased weight gain, and a general loss of condition characterized by a rough sticky coat, dirty tail, irregular thickening of the skin, and increased aggressiveness. Observed laboratory abnormalities in the 0.9 and 2.7 g/kg/day groups were decreases in serum hemoglobin, packed cell volume, and erythrocyte counts; increases in neutrophil, lymphocyte, and platelet counts; increases in prothrombin time; decreases in serum albumin, triglycerides, SGOT, SGPT, and alkaline phosphatase; increases in serum cholesterol and bilirubin; hematuria, bacteriuria, and increases in urinary volume and protein output. Post-mortem

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 47 examinations revealed increased weights of liver, kidneys, spleen, and adrenals (in females), fibrosis around the central veins of the liver, hemorrhage and fibroplasia at the injection site, and salivary gland edema. Abnormalities which did not regress during the recovery period were increased weights of liver, spleen, adrenals (in females), and kidneys (in males).

Rat

: 27-week study, subcutaneous

Environmental control failure resulted in the normal temperatures of 18 - 22degC being exceeded, and rats being exposed to temperatures as high as 29degC. The toxicity of ceftazidime in heat-stressed animals was much higher in females than in males. All females in the 2.5 g/kg/day group died or had to be sacrificed after 8 to 12 weeks of treatment and were found to have extensive centrilobular liver necrosis, and in some, subendocardial fibrosis of the left ventricle. Although males survived the 2.5 g/kg/day dosage regimen, they also showed hepatic changes including fibrosis. Animals of both sexes in the high dose group were found to have dilation of renal tubules with casts and debris. Changes in laboratory parameters in both sexes were decreased plasma enzyme activities and hypercholesterolemia at 0.1 g/kg/day or more, increased urinary protein at 0.5 g/kg/day or more, and increased BUN, hyperkalemia, hypoglycemia, hypochromic macrocytic anemia, leukocytosis, thrombocytosis, and increased diuresis at 2.5 g/kg/day. Dog: 30- to 32- days study, intravenous and subcutaneous/intramuscular All beagles survived the treatment in good general condition apart from an erythematous skin condition which developed in six dogs, including one control. The i.m. and sc injections produced dose-related transient pain and irritation

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 48 which varied from mild to severe. The i.v. injections caused no apparent local effects but were associated with a dose-related incidence of emesis. Observed abnormalities consisted of increased total iron binding capacity in males at 0.18 g/kg/day, and increases in relative liver weight, hypoglycemia (in females), and hypertriglyceridemia at 0.54 g/kg/day. Post-mortem examinations revealed no abnormal pathology.

Infant Dog

: 35-day study, intravenous

All beagles survived the treatment in good condition. Observed abnormalities consisted of salivation, emesis, and loose feces in the 0.3 and 1.0 g/kg/day groups. These symptoms regressed during the recovery period. A tendency toward decreased SGOT levels was noted in the 1.0 kg/day group, but the mean change was not statistically significant. No other laboratory abnormalities were observed. Post-mortem findings were also negative.

Dog:

13-week study, intramuscular

All beagles survived the treatment in good condition. The injections were well tolerated at the i.m. site. No physical or behavioral abnormalities were observed. The following hematological changes were noted in the 0.25 and 0.50 g/kg/day groups: decreased serum hemoglobin, hematocrit, lymphocytes, and platelets, and prolonged prothrombin time. These changes were statistically significant but the values remained within the normal range. Other laboratory findings were increases in total serum cholesterol and BUN. Post-mortem examinations revealed protein casts in the lumen of renal tubules in 6 males, including 2 out of the 3 male controls.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 49

Dog:

28-week study, intravenous

Two beagles were sacrificed during the study and found to have, respectively, a cerebellar lesion and polyarteritis. All other dogs survived the study in satisfactory condition. Adverse effects of treatment were discomfort during injection, and a dose-related incidence of salivation and vomiting. Laboratory abnormalities were generally confined to the 0.595 and 0.850 g/kg/day groups and consisted of decreases in serum gamma-globulin and SGPT, and increases in cholesterol, albumin, and total protein. Post-mortem examinations revealed hepatomegaly, injection phlebitis, proteinaceous droplets in proximal convoluted tubular cells, and infiltration of the prostate.

Nephrotoxicity Studies

TABLE 20

In female mice, a single sc dose of ceftazidime 6 g/kg resulted in no evidence of nephrotoxicity. Doses of 8 and 10 g/kg produced coagulative necrosis of inner cortical tubules. Cephaloridine (1.1 g/kg) was associated with more severe tubular necrosis than was ceftazidime (10 g/kg), the exerted its toxicity primarily on tubules of the outer cortex. The concurrent administration of furosemide 50 mg/kg potentiated the nephrotoxicity of cephaloridine but not that of ceftazidime.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 50 Pre-treatment with probenecid (100 mg/kg) prevented the nephrotoxicity of cephaloridine but not that of ceftazidime. In male rats, single sc doses of ceftazidime, 4 g/kg or more, produced acute tubular necrosis (inner cortex) and elevations in serum urea nitrogen. This effect was not potentiated by concurrent administration of either gentamicin (35 mg/kg) or furosemide (100 mg/kg), nor was it prevented by pre-treatment with probenecid (100 mg/kg). In both mice and rats (single dose studies), prolonged observation indicated that the tubular necrosis caused by a single dose of ceftazidime was maximal in severity 48 hours post-dose. Significant improvement was noted after 3 days, with nearly complete regeneration after 7 days. Male rats given sc injections of ceftazidime 4 g/kg/day for 10 days exhibited increased urinary excretion of enzymes, protein and epithelial cells, which were maximal on day 2 but gradually returned to normal with continued treatment. Ten-day treatment with either gentamicin (35 mg/kg/day), amikacin (250 mg/kg/day), or tobramycin (60 mg/kg/day) produced necrosis, mainly of outer cortical tubules. Combination of an aminoglycoside regimen with ceftazidime 4 g/kg/day produced inner cortical tubular necrosis similar to that observed for ceftazidime alone, but with less outer cortical tubular necrosis than that caused by the aminoglycoside alone. In the rabbit, single ceftazidime doses of 500 mg/kg im, and 400 or 800 mg/kg sc were not nephrotoxic. Cephaloridine (140 mg/kg i.m. or 200 mg/kg sc), and cefazolin (800 mg/kg sc) caused marked abnormalities of plasma urea and creatinine, and of tubular ion transport, gluconeogenesis, and histology.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 51

Mutagenicity Studies

Ceftazidime was evaluated in vivo and in vitro in a series of standard mutagenicity assays.

In Vitro Assays

The mutagenic potential of ceftazidime was assessed using a modified Ames test, a modified fluctuation test (Harefield) and a yeast gene conversion test (Davis). The results of the Ames plate incorporation assay, in which six concentrations of antibiotic were tested in the presence and absence of microsomes, showed a significantly positive result with Salmonella typhimurium strain TA 1537 at 0.9 mcg of ceftazidime/plate but this was believed to have occurred by chance. Ceftazidime was negative in the modified Ames test in which it was pre-incubated with liver microsomes. In the modified pre-incubation fluctuation test, no mutagenic effects were observed at ceftazidime concentrations up to 430 ug/mL. Similarly, ceftazidime did not induce detectable gene conversion in

Saccharomyces cerevisiae

JD1 cells at concentrations up to 860 ug/mL.

In-vivo Micronucleus Test

In a micronucleus test, mice received single intraperitoneal injections of 0.56, 1.67 or 5.02 g/kg ceftazidime. No evidence of a clastogenic effect was noted.

In-vivo Cytogenicity Study

A micronucleus test was used to compare the clastogenic properties of freshly prepared solutions of ceftazidime with samples of ceftazidime stored for up to 24 hours at 25degC. Mice were injected with single ip doses of 1.0

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 52 or 2.5 g/kg. Neither fresh nor stored (which contains pyridine as a degradation product of the antibiotic during storage) solutions of ceftazidime induced a significant increase in detectable chromosomal damage. However, a significant (p<0.05) reduction in the ratio of immature to mature erythrocytes occurred in mice given 2.5 g/kg of ceftazidime (stored solution) 24 hours previously.

Tolerance Studies

An aqueous solution of ceftazidime 25% w/v was tested for intramuscular irritancy in both adult (1.0 mL) and infant (0.2 mL) rabbits. Lesions consisting of hemorrhage, inflammation, and necrosis were produced which regressed and had almost completely healed by 14 days post-dose. Intra-arterial injection of 0.5 mL ceftazidime 25% w/v into rabbit ears produced minimal local damage, being morphologically and histologically similar to that caused by intra-arterial injection of 0.5 mL normal saline. The intracisternal injection of ceftazidime, ampicillin sodium, and gentamicin sulphate caused convulsions of dose-related severity in male rabbits. The minimum dosage levels at which convulsions were observed were 5 mg/kg for ceftazidime, 12 mg/kg for ampicillin sodium, 4.5 mg/kg for gentamicin sulphate.

Immunological Studies

Ceftazidime (25 mg/kg, im) was administered as an aqueous solution to 10 rabbits (5M, 5F) once weekly for 6 weeks. Sera taken 7 days after the last dose were negative for ceftazidime antibody by both enzyme-linked. immunosorbent assay (ELISA) and passive cutaneous anaphylaxis (PCA) test. Four doses of ceftazidime (25 mg/kg) in an aqueous emulsion with Freund's adjuvant were given to 6 rabbits (3M, 3F) as a single inoculation followed by

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 53 boosters on days 21, 56 and 95. Sera taken on day 102 were all negative for drug antibody by ELISA, but 1 out of 6 (female subject) was positive by PCA test. This antibody was skin fixing and heat labile. Antisera prepared with cephaloridine, cephalexin, cephalothin, and cefotaxime showed cross-reactivity with a ceftazidime-cytochrome C antiserum, but did not cross-react with an antiserum prepared with a ceftazidime-human gamma globulin conjugate. The effects of storage of ceftazidime (either as a dry powder at 37degC for 4 months or as a 25% w/v solution at 25degC for 72 hours) on its immunogenicity and elicitogenicity (i.e. the ability to produce anaphylaxis in an immunized subject) were studied in rabbits and guinea pigs. Immunogenicity was unaffected but elicitogenicity was found to increase with storage. Solutions of ceftazidime and its degradation products, formed on both wet and dry storage as above, did not cause the release of allergic mediators from human peripheral blood basophils or from fragments of human lung parenchyma in vitro.

Reproduction and Teratology Studies

Teratology

Mouse

Four groups of pregnant female mice were administered sc injections of either saline (28 mice) or ceftazidime (1.5 g/kg/day - 21 mice, 3.25 g/kg/day - 20 mice, 6.5 g/kg/day - 29 mice) from day 6 to day 15 of pregnancy inclusive (period of organogenesis). Eight mice from the control group and eight from the group given 6.5 g/kg/day were allowed to give birth and rear their young to weaning. The remaining animals were sacrificed on day 18 of pregnancy and an

examination made of their uterine contents.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 54 The following external or soft tissue defects were found, each occurring in a single fetus only: control - left testis absent (1 mouse); 1.5 g/kg - small depression in palate (2 mice), right testis not found (1 mouse); cleft palate (1 mouse); 3.25 g/kg - small swelling at base of tail (1 mouse); 6.5 g/kg - enlarged space in thoracic cavity (1 mouse); cleft palate (1 mouse), enlarged thin walled bladder (1 mouse), small depression in palate (1 mouse). The high incidence of skeletal variants seen in all groups (control: 39.51%, 1.5 g/kg: 53.98%, 3.25 g/kg: 50.70%, and 6.5 g/kg: 63.55%) was due to the large number of fetuses with supernumerary ribs. The incidence of rib variants was significantly higher (p<0.05) in the high-dose group (6.5 g/kg) than in the control group. The overall incidence of skeletal abnormalities was 15% (controls), 20% (3.25 g/kg ceftazidime) and 24% (6.5 g/kg ceftazidime). These consisted mainly of obliquely fused sternebrae. In the group treated with the high dose (6.5 g/kg), one fetus had extra ribs on cervical vertebrae 6 and 7 and one fetus had a bifid hyoid bone. The number of live pups/litter born to mice treated with the high-dose (6.5 g/kg) was significantly (p<0.05) lower (10) when compared to controls (13). Similarly the litter weights for the treated group were consistently and significantly (p<0.05) lower than those in the control group throughout lactation.

Rabbit

Female Dutch rabbits were given intramuscular injections of 0 (18 rabbits), 25 mg/kg (27), 50 mg/kg (18), 100 mg/kg (18) or 200 mg/kg (9) ceftazidime daily from day 6 to day 18 of pregnancy (organogenesis). On day 29, the rabbits were sacrificed and the uterine contents examined.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 55 Twenty-nine rabbits dosed with ceftazidime were either found dead (18) or had to be destroyed (11) due to ill-health (diarrhea and emaciation) or because they had aborted their fetuses. One rabbit in the control group was found dead on day 10 of pregnancy. The incidence of death was not dose-related (highest incidence occurred in the group given 25 mg/kg/day). A decrease in body weight was noted during the first week of dosing and continued for the duration of the study in those rabbits receiving doses greater than 25 mg/kg of ceftazidime per day. Results of the examination of the uterine contents are presented in the Table 21.

TABLE 21

Two dead fetuses were reported - one in the control group (flexed forepaws) and one in 25 mg/kg/day group. Three fetuses (25 mg/kg group) from a litter of 5 had one or more of the following gross external abnormalities: anencephaly, gastroschisis, 1st and 3rd toes absent from both forepaws, 4th toe on right hind paw absent, tail twisted, craniorachischisis, lower jaw absent, eyes open, fore and hind limb buds present, tail and anogenital papilla present, thoracic and abdominal organs exposed.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 56

Peri- and Postnatal Study

Groups of 20 female AHA rats (approximately 10 wk of age, 200 g body weight) received a daily sc injection of either 0, 0.1, 0.5 or 2.5 g/kg ceftazidime. Animals were dosed from day 17 of pregnancy to the day of parturition and subsequently on days 1-21 inclusive postpartum. No significant adverse reactions were seen during pregnancy with the exception of the high dose (2.5 g/kg) group which produced large quantities of soft wet feces. During the second and third week of the lactation period the dams treated with ceftazidime gained weight more rapidly than the control group and this effect was dose-related. At termination (day 21 postpartum), pups in the high-dose group (2.5 g/kg) had gained significantly (p<0.05) less weight (47.95 g) than controls (52.23 g). This was observed throughout lactation. Two of the dams in the high-dose (2.5 g/kg) group were killed due to the death of their litters. Both animals had gastrointestinal disorders due to heavy growth of Gram-positive Streptococcus. One dam in the 0.5 g/kg group was killed due to ill health (diarrhea due to bacterial typhlitis).

Fertility and Reproduction

Groups of 20 male and 40 female mice received sc injections of either saline or 1.5, 3.25 or 6.5 g/kg of ceftazidime daily throughout gametogenesis and mating and in the case of females through pregnancy. Males were treated for 60 days prior to mating and females for 14 days. One half of the pregnant mice were sacrificed on day 18 of pregnancy while the remainder were allowed to litter and rear their young for 21 days. Two pups from each litter were retained to study any effects on fertility of the F1 generation.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 57 Treatment with ceftazidime had no adverse effect on the fertility of either male or female mice. A high incidence of skeletal variants seen in all of the groups (control: 45.48%, 1.5 g/kg/day: 55.04%, 3.25 g/kg/day: 64.40%, 6.5 g/kg/day: 73.97%) was due to the large number of fetuses with supernumerary ribs. The incidence of bone variants was significantly higher (p<0.05) in the high-dose group (6.5 g/kg/day) as compared to the controls. Throughout lactation, the mean pup weights (F1 generation) for the mid - (3.25 g/kg/day) and high - (6.5 g/kg/day) dose groups were lower than the corresponding control values but the differences did not achieve statistical significance. There were no significant differences in pregnancy rates for any of the F1 generation groups. The mean pup weights (F2 generation) during lactation in the high-dose group were consistently less than those of controls but the differences were not statistically significant and this was attributed to the lighter weights of the dams.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 58

GlaxoSmithKline

References or Selected Bibliography

1. Acred P, Ryan DM, Sowa MA, Watts CM: The in-vivo antibacterial activity of ceftazidime (GR20263) - a comparison with other new b- lactam antibiotics and gentamicin. J Antimicrob Chemother 1981; 8(Suppl.B):247-255.

2. Bauernfeind A: An evaluation of the activity of cephalosporins against Pseudomonas aeruginosa. J Antimicrob Chemother 1981; 8(Suppl. B):111-117.

3. Bint AJ, Yeoman P, Kilburn P, Anderson R, Stansfield E: The in- vitro activity of ceftazidime compared with that of other cephalosporins. J Antimicrob Chemother 1981; 8(Suppl. B):47-51.

4. Brumfitt W, Hamilton-Miller JMT: The susceptibility of nosocomial pathogens to ceftazidime. J Antimicrob Chemother 1981; 8(Suppl. B):15-21.

5. Chow AW, Bartlett KH: Comparative in-vitro activity of ceftazidime (GR 20263) and other b-lactamase stable cephalosporins against anaerobic bacteria. J Antimicrob Chemother 1981; 8(Suppl. B):91- 95.

6. Chow AW, Bartlet KH: Comparative in-vitro activity of ceftazidime (GR20263) and other b-lactamase stable cephalosporins against Pseudomonas. J Antimicrob Chemother 1981; 8(Suppl. B):345-348.

7. Harper PB: The in-vitro properties of ceftazidime. J Antimicrob Chemother 1981; 8(Suppl. B):5-13.

8. Jones RN, Barry AL, Thornsberry C, Gerlach EH, Fuchs PC, Gavan TL, Sommers HM: Ceftazidime, a pseudomonas-active cephalosporin: in-vitro antimicrobial activity evaluation including recommendations for disc diffusion susceptibility tests. J Antimicrob Chemother 1981; 8(Suppl. B):187-211.

9. Shah PM: Bactericidal activity of ceftazidime against Pseudomonas aeruginosa under conditions simulating serum pharmacokinetic. J Antimicrob Chemother 1981; 8(Suppl. B):135-140.

10. Thabaut A, Durosoir J-L, Saliou P: Comparison of the in-vitro activities of ceftazidime and new cephalosporins against 107 strains of Pseudomonas aeruginosa and 249 strains of cefazolin-resistant Enterobacteriaceae. J Antimicrob Chemother 1981; 8(Suppl. B):123-125.

11. Wittmann DH, Schassan H-H, Kohler F, Seibert W: Pharmacokinetic studies of ceftazidime in serum, bone, bile, tissue fluid and peritoneal fluid. J Antimicrob Chemother 1981; 8(Suppl. B):293- 297.

12. Neu HC, Labthavikul P: Antibacterial activity and b-lactamase stability of ceftazidime, an aminothiazolyl cephalosporin potentially active against Pseudomonas aeruginosa. J Antimicrob Ag Chemother 1982; 21(1):11-18.

13. Norrby SR, Burman LA, Linderholm H, Trollfors B: Ceftazidime: pharmacokinetics in patients and effects on the renal function. J Antimicrob Chemother 1982; 10:199-206.

14. Simpson IN, Plested SJ, Harper PB: Investigation of the ss- lactamase stability of ceftazidime and eight other new cephalosporin antibiotics. J Antimicrob Chemother 1982; 9:357-360.

15. Walstad RA, Thurmann-Nielsen E, Dale LG, Brunn JN: Blister- and lymphatic fluid studies of ceftazidime, a new cephalosporin with antipseudomonal activity. Br J Clin Pharmacol 1982; 14(4):626P.

16. Adam D, Reichart B, Williams KJ: Penetration of ceftazidime into human tissue in patients undergoing cardiac surgery. J Antimicrob Chemother 1983; 12(Suppl. A):269-273.

17. Assael BM, Boccazzi A, Caccamo ML, Giunta A, Marini A, Padoan R, Rusconi F, Sereni F: Clinical pharmacology of ceftazidime in paediatrics. J Antimicrob Chemother 1983; 12(Suppl. A):341-346.

18. Clumeck N, Gordts B, Dab I, Jaspar N, Van Laethem Y, Butzler J-P: Ceftazidime as a single agent in the treatment of severe Pseudomonas aeruginosa infections. J Antimicrob Chemother 1983; 12(Suppl. A):207-211.

19. Clumeck N, Van Laethem Y, Gordts B, Jaspar N, Butzler J-P: Use of ceftazidime in the therapy of serious infections, including those due to multiresistant organisms. Antimicrob Ag Chemother 1983; 24(2):176-180.

20. Cox CE: A comparison of ceftazidime and tobramycin in the treatment of complicated urinary tract infections. J Antimicrob Chemother 1983; 12(Suppl. A):47-52

21. Daschner FD, Petersen EE, Just H-M, Hillemanns HG: Penetration of ceftazidime into serum, myometrium, endometrium, salpinges and subcutaneous tissue. J Antimicrob Chemother 1983; 12(Suppl. A):247-249.

22. Davies BI, Maesen FPV, van Noord JA: Treatment of chronic and recurrent respiratory infections with intramuscular ceftazidime. J Antimicrob Chemother 1983; 12(Suppl. A):1-8.

23. Dutoy JP, Wauters G: The treatment of bone infections with ceftazidime. J Antimicrob Chemother 1983; 12(Suppl. A):229-233.

24. Harding SM, Harper PB: The pharmacokinetic behaviour of ceftazidime in man and the relationship between serum levels and the in vitro susceptibility of clinical isolates. Infection 1983; 11(Suppl. 1):S49-S53.

25. Hayes MV, Orr DC: Mode of action of ceftazidime: affinity for the penicillin-binding proteins of Escherichia coli K12, Pseudomonas aeruginosa and Staphylococcus aureus. J Antimicrob Chemother 1983; 12:119-126.

26. Kemmerich B, Warns H, Lode H, Borner K, Koeppe P, Knothe H: Multiple-dose pharmacokinetics of ceftazidime and its influence on fecal flora. Antimicrob Ag Chemother 1983; 24(3):333-338.

27. Lundbergh P, Jarstrand C, Morfeldt-Manson L, Weiland O: Ceftazidime in septicaemia. J Antimicrob Chemother 1983; 12(Suppl. A):199-205.

28. Mandell LA, Nicolle LE, Ronald AR, Duperval R, Robson HG, Feld R, Vincelette J, Fong I: A multicentre prospective randomized trial comparing ceftazidime with cefazolin/tobramycin in the treatment of hospitalized patients with non-pneumococcal pneumonia. J Antimicrob Chemother 1983; 12(Suppl. A):9-20.

29. Modai J, Vittecoq D, Decazes JM, Wolff M, Meulemans A: Penetration of ceftazidime into cerebrospinal fluid of patients with bacterial meningitis. Antimicrob Ag Chemother 1983; 24(1):126- 128.

30. Naber KG, Kees F, Grobecker H: Ceftazidime: pharmacokinetics in young volunteers versus elderly patients and therapeutic efficacy with complicated urinary tract infections. J Antimicrob Chemother 1983; 12(Suppl. A):41-45.

31. Piot P, Van Dyck E, Colaert J: In vitro activity of ceftazidime (GR20263) and other b-lactam antibiotics against Haemophilus influenzae. Infection 1983; 11(Suppl. 1):S32-S34.

32. Sommers D, Walters L, Van Wyk M, Harding SM, Paton AM, Ayrton J: Pharmacokinetics of ceftazidime in male and female volunteers. Antimicrob Ag Chemother 1983; 23(6):892-896.

33. Tourkantonis A, Nicolaidis P: Pharmacokinetics of ceftazidime in patients undergoing peritoneal dialysis. J Antimicrob Chemother 1983; 12(Suppl. A):263-267.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 61 Walstad RA, Hellum KB, Blika S, Dale LG, Fredriksen T, Myhre KI, Spencer GR: Pharmacokinetics and tissue penetration of ceftazidime: studies on lymph, aqueous humour, skin blister, cerebrospinal and pleural fluid. J Antimicrob Chemother 1983; 12(Suppl. A):275-282. Wittman DH, Schassan H-H: Penetration of eight b-lactam antibiotics into the peritoneal fluid - A pharmacokinetic investigation. Arch Surg 1983; 118:205-213. Ackerman BH, Rose J, Tofte RW, Rotschafer JC: Effect of decreased renal function on the pharmacokinetics of ceftazidime. Antimicrob Ag Chemother 1984; 25(6):785-786. Leeder JS, Spino M, Isles AF, Tesoro AM, Gold R, MacLeod SM: Ceftazidime disposition in acute and stable cystic fibrosis. Clin Pharmacol Ther 1984; 36(3):355-362. Reed MD, O'Brien CA, Aronoff SC, Klinger JD, Blumer JL: Ceftazidime as initial therapy for suspected bacterial infections in hospitalized pediatric patients. Antimicrob Ag Chemother 1984; 26(3):318-321. Turner A, Pedler SJ, Carswell F, Spencer GR, Speller DCE: Serum and sputum concentrations of ceftazidime in patients with cystic fibrosis. J Antimicrob Chemother 1984; 14(5):521-527. Welage LS, Schultz RW, Schentag JJ: Pharmacokinetics of ceftazidime in patients with renal insufficiency. Antimicrob Ag Chemother 1984; 25(2):201-204. Gooch WM III, Swenson E: Use of ceftazidime in the management of bacterial cellulitis in infants and children. Curr Ther Res 1985; 37(1):3-8. Mulhall A, de Louvois J: The pharmacokinetics and safety of ceftazidime in the neonate. J Antimicrob Chemother 1985; 15(1):97- 103. Richards DM, Brogden RN: Ceftazidime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1985; 29(2):105-161. Low DC, Bissenden JG, Wise R: Ceftazidime in neonatal infections. Archives of Disease in Childhood 1985; 60: 360- 364. Pollock I, Mulhall A, deLouvois J: Ceftazidime in the treatment of neonatal infection. Journal of Hospital Infection 1985; 6: 158-165.

DCTM/044/550/2006-08-28/131-pm-pristine-fortaz.doc 62