Fortaz (Ceftazidime Pentahydrate)

FORTAZ®

Glaxo Wellcome

Ceftazidime Pentahydrate

Antibiotic

Action And 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 E. coli and P. 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 S. aureus. However, the drug’s affinity for PBP-3 is very much less in this organism.

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). Doses of 250, 500 and 1 000 mg administered as a single bolus injection over 1minute resulted in peak serum concentrations within 20 minutes of about 20, 46 and 88 mg/L respectively. Mean urinary recovery of unchanged drug over 24 hours ranged from 77.4 to 85.5% with over 50% being excreted in the first 2 to 4 hours. Single i.v. infusions of 500, 1 000 and 2 000 mg administered over 20 to 30 minutes to normal adult volunteers resulted in peak serum concentrations within 30 minutes of about 41, 68 and 169 mg/L respectively. Mean urinary recovery of unchanged drug over 24 hours ranged from 83.7 to 87.1% with over 50% being excreted in the first 2 to 4 hours. In both routes, serum concentration-time curves follow a biexponential decay.

Peak serum concentrations following i.m. injections of 500 or 1 000 mg occurred at 1 hour and were about 17.4 and 38.8 mg/L respectively. Mean urinary recovery of ceftazidime over 24 hours ranged from 78.9 to 84.6%.

No accumulation of drug was noted during repeated i.m. doses of ceftazidime (1 g, t.i.d., 10 days).

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

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 to 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.

Indications And Clinical Uses: For the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:

Lower Respiratory Tract Infections: Pneumonia caused by P. aeruginosa; H. influenzae including ampicillin-resistant strains; Klebsiella species; Enterobacter species; P. mirabilis; E. coli; Serratia species; S. pneumoniae; and S. aureus including ampicillin-resistant (but not methicillin-resistant) strains.

Urinary Tract Infections: caused by P. aeruginosa; Enterobacter species; Proteus species (indole positive and negative); Klebsiella species, and E. coli.

Due to the nature of the underlying conditions which usually predispose patients to Pseudomonas infections of the lower respiratory and urinary tracts, a good clinical response accompanied by bacterial eradication may not be achieved despite evidence of in vitro sensitivity.

Skin Structure Infections: caused by P. aeruginosa; Klebsiella species; E. coli; P. mirabilis; Enterobacter species; S. aureus, including ampicillin-resistant (but not methicillin-resistant) strains; and S. pyogenes.

Bacteremia/Septicemia: caused by P. aeruginosa; Klebsiella species; E. coli; Serratia species; S. pneumoniae; S. aureus, including ampicillin-resistant (but not methicillin-resistant) strains; and S. epidermidis.

Bone Infections: caused by P. aeruginosa; P. mirabilis; Enterobacter species; and S. aureus, including ampicillin-resistant (but not methicillin-resistant) strains.

Peritonitis: caused by E. coli; Klebsiella species; and Peptostreptococcus species. Patients infected with Bacteroides species have also responded.

Meningitis: caused by H. influenzae and N. meningitidis. Ceftazidime has also been used successfully in a limited number of cases of meningitis due to P. aeruginosa.

Specimens for bacteriologic culture should be obtained prior to therapy in order to identify the causative organisms and to determine their susceptibilities to ceftazidime. Therapy may be instituted before results of susceptibility testing are known. However, modification of the treatment may be required once these results become available.

Contra-Indications: Patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibiotics.

Manufacturers’ Warnings In Clinical States: Before therapy with ceftazidime is instituted, careful enquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Ceftazidime should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. It should be given with caution to patients with Type 1 hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime 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 ceftazidime (and other broad-spectrum antibiotics). Therefore, it is important to consider its diagnosis in patients administered ceftazidime who develop diarrhea. Treatment with broad-spectrum antibiotics, including ceftazidime, alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by C. 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 ceftazidime administration or when it is severe, consideration should be given to the administration of vancomycin or other suitable therapy. Other possible causes of colitis should also be considered.

Precautions: Ceftazidime 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 50 mL/min/1.73 mor less) should be placed on the special dosage schedule for ceftazidime. (see Dosage). 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 ceftazidime, when administered alone, is significantly nephrotoxic. However, the effect of administering it 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 sequelae have occasionally been reported when the dose has not been reduced appropriately (see Dosage in Impaired Renal Function).

Prolonged treatment 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 ceftazidime has been observed for S. aureus, members of the Enterobacteriaceae family, Acinetobacter species, and Pseudomonas 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.

Pregnancy: Safety in pregnancy has not been established. The use of ceftazidime 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 ceftazidime doses of up to 25 times those usually administered to humans. These studies have revealed no evidence of impaired fertility or harm to the fetus caused by ceftazidime. Animal reproduction studies, however, are not always predictive of human response.

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

Geriatrics: 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 ferricynaide test, it is recommended that either glucose oxidase or hexokinase method be used to determine blood plasma glucose levels in patients receiving ceftazidime. 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.

Adverse Reactions: The most common adverse effects have been local reactions following i.v. injection, allergic reactions, and gastrointestinal reactions. Other adverse effects have been encountered less frequently.

Local (2.8% of patients): thrombophlebitis or phlebitis and pain with i.v. administration. Pain after i.m. injection.

Hypersensitivity (2.7% of patients): pruritus, urticaria, allergic exanthema, and fever. There have been rare reports of toxic epidermal necrolysis. Angioderma and anaphylaxis (including bronchospasm and/or hypotension) have been reported very rarely.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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: Ceftazidime may be administered either i.v. or i.m. 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 i.v. 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: 0.5 to 6 g daily administered in equally divided doses every 8 to 12 hours.

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.

Children: The maximum daily dose in children is 6 g.

Neonates (aged 0 to 28 days): In children aged 1 month or less the recommended dose is 25 to 50 mg/kg given twice daily.

Data indicate that half-life of ceftazidime in neonates increases with decreasing gestational age and can be 3 to 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 to 3 weeks of life necessitating a readjustment of dose and/or dosing interval.

Geriatrics: 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.

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 must be reduced to compensate for its slower excretion. After an initial loading dose of 1 g, a maintenance dosage schedule should be followed.

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

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/100 mL)

Females: 0.85 X above value.

Mean serum half-life of ceftazidime in patients with no kidney function was reduced from a range of 24.0 to 35.4 hours between dialysis sessions to a range of 2.8 to 4.6 hours 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.

Ceftazidime can also be used in patients undergoing peritoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, a loading dose of 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.

I.M.: Ceftazidime may be administered by deep i.m. injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus or vastus lateralis. The maximum dose should be 1 g for a single i.m. injection.

I.V.: Intermittent i.v. 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 ceftazidime, the administration of other solutions should be discontinued temporarily.

Continuous i.v. infusion: Ceftazidime may also be administered over a longer period of time.

Note: If therapy 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 this product in the same container.

Reconstitution: Caution: Ensure adequate venting. Addition of diluent generates a positive pressure.

I.M.: Solutions for reconstitution are sterile water for injection or, if required bacteriostatic water for injection with benzyl alcohol or parabens (not for use in neonates) and 0.5 to 1.0% lignocaine hydrochloride injection.

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.

Direct i.v. injection: Reconstitute as directed above.

Intermittent i.v. infusion: Reconstitute as directed above for 1 g or 2 g vials.

Continuous i.v. infusion: Vials: Reconstitute 1 g or 2 g vials with 10 mL Sterile Water for Injection. The appropriate quantity of the reconstituted solution may be added to any of the solutions listed under Solutions for I.V. Infusion.

Pharmacy Bulk Vial 6 g: The availability of the pharmacy bulk vial is restricted to hospitals with a recognized i.v. admixture program.

This product does not contain any preservatives. The Pharmacy Bulk Vial is intended for multiple dispensing for i.v. use only, employing a single puncture. Reconstitute with 26 mL Sterile Water for Injection.

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 25°C). Any unused reconstituted solution should be discarded after 8 hours. The appropriate quantity of the reconstituted solution may be added to an i.v. bottle containing any of the solutions listed below.

Solutions for I.V. Infusion and Infusion Bottles: 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, 10% invert sugar in water for injection and Normosol-M in 5% dextrose injection.

Stability: Reconstituted solutions should be administered within 12 hours when stored at room temperature (not exceeding 25°C), 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: Ceftazidime should not be added to blood products, protein hydrolysates or amino acids. It should not be mixed together with an aminoglycoside. Ceftazidime is less stable in Sodium Bicarbonate Injection than in other i.v. fluids; therefore it is not recommended as a diluent.

Precipitation has been reported when vancomycin has been added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and the i.v. lines between administration of these two agents.

Availability And Storage: I.M. or direct i.v. injection: Each vial contains: the equivalent of 500 mg and 1 g ceftazidime. Nonmedicinal ingredients: sodium carbonate. Packs of 10. I.V. injection or infusion: Each vial contains: the equivalent of 1 g and 2 g ceftazidime. Packs of 10. Vials contain: the equivalent of 6 g ceftazidime. Packs of 6. Vials contain a mixture of ceftazidime pentahydrate and sodium carbonate. Sodium carbonate at a concentration of 118 mg/g of ceftazidime activity has been admixed to facilitate dissolution. Total sodium content of the mixture is approximately 2.3 mEq/g (54 mg of ceftazidime activity). Gluten- and tartrazine-free.

Ceftazidime pentahydrate is a white to cream-colored powder. Solutions range in color from light yellow to amber, depending upon the diluent and volume used. The pH of freshly reconstituted solutions ranges from 5.0 to 7.5.

Store the dry powder between 15 and 30°C. Protect from light.

FORTAZ® Glaxo Wellcome Ceftazidime Pentahydrate Antibiotic

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