1. Name Of The Medicinal Product
'Kefadim'.
2. Qualitative And Quantitative Composition
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Vial Size
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500mg
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1g
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2g
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Active constituent
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Ceftazidime pentahydrate
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580mg
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1.16g
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2.33g
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equivalent to ceftazidime
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500mg
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1.0g
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2.0g
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Other constituents
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Sodium carbonate
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59mg
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118mg
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236mg
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3. Pharmaceutical Form
Powder for solution for injection
4. Clinical Particulars
4.1 Therapeutic Indications
Kefadim is indicated in the treatment of the following infections when due to susceptible micro- organisms:
Lower respiratory tract infections
Skin and soft tissue infections
Bone and joint infections
Urinary tract infections
Gynaecological infections
Intra-abdominal infections, including peritonitis
Septicaemia
Central nervous system infections, including meningitis. In meningitis, it is recommended that the results of a sensitivity test are known before treatment with ceftazidime as a single agent.
Kefadim may be used alone in cases of confirmed or suspected sepsis. It may also be used concomitantly with other antibiotics, such as aminoglycosides, in severe and life-threatening infections and in the immunocompromised patient.
4.2 Posology And Method Of Administration
Ceftazidime may be given intravenously or by deep intramuscular injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus, or lateral part of the thigh).
The guidelines for dosage of Kefadim are listed in Table 1.
Table 1: Recommended Dosage Schedule for Kefadim
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DOSE
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FREQUENCY
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Adults
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Usual recommended dose
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1g IV or im
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q 8 or 12 h
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Uncomplicated urinary tract infections
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250mg IV or im
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q 12 h
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Bone and joint infections
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2g IV
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q 12 h
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Complicated urinary tract infections
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500mg IV or im
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q 8 or 12 h
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Uncomplicated pneumonia; mild skin and skin-structure infections
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500mg-1g IV or im
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q 8 h
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Serious gynaecological and intra-abdominal infections
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2g IV
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q 8 h
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Meningitis
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2g IV
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q 8 h
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Very severe life-threatening infections, especially in immunocompromised patients
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2g IV
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q 8 h
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Pseudomonal lung infections in patients with cystic fibrosis with normal renal function*
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30-50mg/kg IV to a maximum of 6g/day
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q 8 h
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Neonates and children up to 2 months
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12.5-30mg/kg IV
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q 12 h
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Infants and children (2 months to 12 years of age)
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17-50mg/kg IV to a maximum of 6g/day**
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q 8 h
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*Although clinical improvement has been shown, complete eradication of infecting organisms cannot be expected in patients with chronic respiratory disease and cystic fibrosis.
**The higher dose should be reserved for immunocompromised children or children with cystic fibrosis or meningitis.
Adults and the elderly: The usual dosage range for ceftazidime is 500mg to 2g every eight to twelve hours. The dosage and route of administration should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.
In view of the reduced clearance of ceftazidime in acutely ill elderly patients, the daily dosage should not normally exceed 2g, especially in those over 80 years of age (Table 2).
Infants and children over 2 months of age: The dosage range is 50-150mg/kg/day IV, in three divided doses, with a maximum of 6g/day. The higher dose should be reserved for immunocompromised children, or children with cystic fibrosis or meningitis.
Neonates and children up to 2 months of age: The dosage range is 25 to 60mg/kg/day, given as two divided doses. In the neonate, the serum half-life of ceftazidime can be three to four times that in adults.
Dosage in impaired renal function: Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (GFR <50ml/min), it is recommended that the dose of ceftazidime should be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1g may be given. An estimate of GFR should be made to determine the appropriate maintenance dose. The recommended dosage is shown in Table 2.
Table 2: Recommended Maintenance Dosage of Kefadim in Patients with Renal Insufficiency
CREATININE CLEARANCE (ML/MIN)
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RECOMMENDED DOSE OF KEFADIM
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FREQUENCY
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50-31
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1g
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q 12 h
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30-16
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1g
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q 24 h
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15-6
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500mg
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q 24 h
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<5
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500mg
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q 48 h
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When only serum creatinine is available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:
Males:
Females:
0.85 x above value
In patients with severe infections who would normally receive 6g of Kefadim daily, were it not for renal insufficiency, the dose in Table 2 may be increased by 50% or the dosing frequency increased appropriately. Continued dosage should be determined by further monitoring of creatinine clearance, severity of the infection, and susceptibility of the causative organism. In such patients, it is recommended that ceftazidime serum levels should be monitored and trough levels should not exceed 40mg/litre.
In children, as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass and the dosing frequency reduced in cases of renal insufficiency.
The serum half-life of ceftazidime during haemodialysis ranges from 3 to 5 hours.
In patients undergoing haemodialysis, a loading dose of 1g of Kefadim is recommended, followed by 1g after each haemodialysis period. Kefadim can also be used in patients undergoing intraperitoneal and continuous ambulatory peritoneal dialysis (CAPD). In such patients, a loading dose of 1g of Kefadim may be given, followed by 500mg every 24 hours. In addition to intravenous use, Kefadim can be incorporated in the dialysis fluid at a concentration of 250mg for 2 litres of dialysis fluid.
NOTE: Kefadim should generally be continued for 2 days after the signs and symptoms of infection have disappeared, however, in complicated infections, longer therapy may be required.
Intramuscular administration: Kefadim should be reconstituted with Water for Injections PhEur or 0.5% or 1% Lignocaine Hydrochloride Injection BP. Refer to Table 3
Table 3:Preparation of Solutions of Kefadim
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AMOUNT OF DILUENT TO BE ADDED (ML)
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APPROXIMATE AVAILABLE VOLUME (ML)
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APPROXIMATE CEFTAZIDIME CONCENTRATION (MG/ML)
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Intramuscular
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500mg
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1.5
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1.925
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260
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1g
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3.0
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3.85
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260
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Intravenous
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500mg
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5
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5.425
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92
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1g
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10
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10.85
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92
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2g
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10
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11.7
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170
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Infusion (100ml)
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2g
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100*
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101.7
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20
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*Note: Addition should be in 2 stages (see 'Instructions for reconstitution' below).
Intravenous administration: For direct intermittent intravenous administration, reconstitute Kefadim with Water for Injections PhEur (see Table 3). Slowly inject the solution directly into the vein over a period of 3 to 5 minutes or give through the tubing of a giving set. Ceftazidime is compatible with the most commonly used intravenous fluids (see section 6.6).
For intravenous infusion, reconstitute the 2g infusion (100ml) vial with 100ml Water for Injections PhEur or one of the compatible intravenous fluids. Alternatively, reconstitute the 500mg, 1g or 2g vial and add an appropriate quantity of the resulting solution to an IV container with one of the compatible intravenous fluids.
Intermittent intravenous infusion with a Y-type giving set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.
When Kefadim is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, please follow the recommended techniques of reconstitution described below.
Instructions for reconstitution:
For 500mg im/IV, 1g im/IV and 2g IV vials
1. Inject the diluent and shake well to dissolve. The vials may contain a vacuum to assist injection of the diluent.
2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.
3. Invert the vial and completely depress the syringe plunger prior to insertion.
4. Insert the needle through the vial stopper. Be sure the needle remains within the solution and withdraw contents of the vial in the usual manner. Pressure in the vial may aid withdrawal.
5. The withdrawn solution may contain carbon dioxide bubbles, which should be expelled from the syringe before injection.
For 2g infusion vials
1. Inject 10ml of the diluent and shake to dissolve. The vials may contain a vacuum to assist injection of the diluent.
2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.
3. Insert a vent needle to release pressure before adding additional diluent to the vial. Add diluent and then remove the vent needle.
4. Additional pressure that may develop in the vial, especially after storage, should be relieved prior to administration to the patient.
NOTE: To preserve product sterility, it is important that a gas relief needle is not inserted through the vial closure before the product has dissolved.
4.3 Contraindications
Ceftazidime is contra-indicated in patients with known hypersensitivity to ceftazidime or cephalosporin antibiotics.
4.4 Special Warnings And Precautions For Use
Warnings
Before therapy with ceftazidime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Ceftazidime should be given only with special caution to patients with type 1 or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious acute hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine, or other emergency measures.
Pseudomembranous colitis has been reported with the use of ceftazidime, other cephalosporins and virtually all broad-spectrum antibiotics, therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with antibiotic use. Such colitis may range in severity from mild to life-threatening. Symptoms can appear during or after treatment.
Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken.
Precautions
Kefadim has not been shown to be nephrotoxic, however, because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when ceftazidime is administered to such patients to avoid the clinical consequences, eg, seizures due to elevated levels of antibiotics (see section 4.2). Continued dosage should be determined by degree of renal impairment, severity of infection and susceptibility of causative organisms.
As with other antibiotics, prolonged use of Kefadim may result in the overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Kefadim should be used with caution in individuals with a history of gastro-intestinal disease, particularly colitis.
Ceftazidime does not interfere with enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics or potent diuretics, such as furosemide (frusemide). Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity and ototoxicity were not noted when Kefadim was given alone in clinical trials.
4.6 Pregnancy And Lactation
Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Kefadim. There are, however, no controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Ceftazidime is excreted in human milk in low concentrations and consequently caution should be exercised when ceftazidime is administered to a nursing woman.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
The most common side-effects were local reactions following intravenous injection and allergic and gastro-intestinal reactions.
Local effects: Phlebitis or thrombophlebitis, and inflammation at the site of injection.
Hypersensitivity: Pruritus, urticarial rash, fever and very rarely angioedema and anaphylaxis (bronchospasm and/or hypotension).
Skin and subcutaneous tissue disorders: As with other cephalosporins, there have been rare reports of toxic epidermal necrolysis reported in association with ceftazidime.
Gastro-intestinal: Diarrhoea, nausea, vomiting and abdominal pain, pseudomembranous colitis (see section 4.4 - 'Warnings'). Very rarely, oral thrush.
Central nervous system: Headache, dizziness, paraesthesias and bad taste. There have been reports of neurological sequelae, including tremor, myoclonica, convulsions and encephalopathy, in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.
Reproductive system disorder: Candidiasis and vaginitis.
Laboratory test changes (usually transient): Eosinophilia, positive Coombs' test without haemolysis, thrombocytosis and slight elevations in one or more hepatic enzymes: AST (SGOT), ALT (SGPT), LDH, GGT and alkaline phosphatase. Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine have been observed occasionally. Transient leucopenia, neutropenia, agranulocytosis, thrombocytopenia and lymphocytosis have been seen very rarely.
4.9 Overdose
Signs and symptoms: Toxic signs and symptoms following an overdose of ceftazidime may include pain, inflammation and phlebitis at the injection site. Overdosage can lead to neurological sequelae, including encephalopathy, convulsions and coma.
The administration of inappropriately large doses of parenteral cephalosporins may cause dizziness, paraesthesias and headaches. Seizures may occur following overdosage with some cephalosporins, particularly in patients with renal impairment in whom accumulation is likely to occur.
Laboratory abnormalities that may occur after an overdose include elevations in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leucopenia and prolongation of the prothrombin time.
The subcutaneous median lethal dose in rats and mice ranged from 5.8 to 20g/kg and the intravenous median lethal dose in rabbits was >2g/kg.
Treatment: If seizures occur, the drug should be discontinued promptly; anti-convulsant therapy may be administered if clinically indicated. An airway should be established. Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures.
In cases of severe overdosage, especially in a patient with renal failure, combined haemodialysis and haemoperfusion may be considered if response to more conservative therapy fails.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Ceftazidime is a semi-synthetic, beta-lactam antibiotic, for parenteral administration.
In vitro tests demonstrate that ceftazidime is bactericidal. It acts against a wide range of Gram-negative organisms, including strains resistant to gentamicin and other aminoglycosides. It is also active against Gram-positive organisms, and is highly stable to most clinically important beta-lactamases, whether plasmid or chromosomally mediated.
Ceftazidime has been shown to have in vitro activity against the following organisms:
Pseudomonas spp. (including Pseudomonas aeruginosa); Klebsiella spp. (including Klebsiella pneumoniae); Proteus mirabilis and Proteus vulgaris; Morganella morganii (formerly Proteus morganii); Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri); Escherichia coli; Enterobacter spp.; Citrobacter spp.; Serratia spp.; Salmonella spp.; Shigella spp.; Yersinia enterocolitica; Pasteurella multocida; Acinetobacter spp.; Neisseria gonorrhoeae; Neisseria meningitidis; Haemophilus influenzae (including ampicillin-resistant strains); Haemophilus parainfluenzae (including ampicillin-resistant strains); Staphylococcus aureus (methicillin-sensitive strains); Staphylococcus epidermidis (methicillin-sensitive strains); Streptococcus pyogenes; Streptococcus Group B; Streptococcus pneumoniae; Streptococcus spp.; Peptococcus spp.; Peptostreptococcus spp.; Clostridium spp.; (but not C. difficile); Bacteroides spp. (but most strains of B. fragilis are resistant).
Using the ICS agar dilution method (or its equivalent) for susceptibility testing, the criteria for dilution methods are:
MIC <16mg/litre:
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Susceptible
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MIC>16 but <64mg/litre:
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Moderately susceptible (ie, susceptible to high dosage or if infection confined to tissues or fluids [eg, urine] in which high antibiotic levels are attained)
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MIC
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Resistant
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and for the standard disc test using a 30 microgram ceftazidime disc, are (zone diameters):
Zone
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Susceptible
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Zone 15-17mm:
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Moderately susceptible
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Zone
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Resistant
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Ceftazidime is not active in vitro against methicillin-resistant staphylococci; Streptococcus faecalis and many other enterococci; Listeria monocytogenes; Campylobacter spp. or C. difficile.
Ceftazidime and the aminoglycosides have been shown to be synergistic in vitro against some strains of P. aeruginosa and the Enterobacteriaceae. Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against P. aeruginosa
5.2 Pharmacokinetic Properties
After intravenous administration of 500mg or 1g of ceftazidime, over 5 minutes, to normal adults, mean peak serum concentrations were 45mg/litre and 90mg/litre, respectively. Following intravenous infusion of 500mg, 1g and 2g of ceftazidime, over 20 to 30 minutes, to normal adults, mean peak serum concentrations of 42, 69 and 170mg/litre, respectively, were achieved. The average serum concentrations in these adults, over an 8 hour period, are given in Table 4.
Table 4:Ceftazidime Concentrations in Serum
CEFTAZIDIME DOSAGE (IV)
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SERUM CONCENTRATIONS (MG/LITRE)
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0.5h
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1h
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2h
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4h
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8h
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500mg
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42
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25
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12
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6
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2
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1g
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60
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39
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23
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11
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3
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2g
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129
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75
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42
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13
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5
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Following intramuscular administration of 500mg and 1g ceftazidime to normal adults, mean peak serum concentrations at approximately 1 hour were 17mg/litre and 39mg/litre, respectively. Serum concentrations remained above 4mg/litre for 6 and 8 hours after the intramuscular administration of 500mg and 1g doses, respectively.
The half-life of ceftazidime was approximately 1.9 hours after intravenous administration and 2 hours after intramuscular administration.
Less than 10% of ceftazidime was protein bound and the degree of protein binding was independent of concentration.
Following multiple intravenous doses of 1g and 2g every 8 hours for 10 days, there was no evidence of accumulation of ceftazidime in the serum of individuals with normal renal function.
The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals who received 2g intravenously every 8 hours for 5 days. Therefore, dosage adjustment is not required for patients with hepatic dysfunction, unless renal function is also impaired.
Approximately 80% to 90% of a dose of ceftazidime is excreted unchanged by the kidneys over a 24 hour period. The elimination of ceftazidime by the kidneys resulted in high urinary concentrations.
Concentrations of ceftazidime in excess of the minimum inhibitory levels of common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids.
Transplacental transfer of the antibiotic readily occurs.
Ceftazidime penetrates the intact blood-brain barrier poorly and low levels are achieved in the CSF in the absence of inflammation. Therapeutic levels of 4 to 20mg/litre or more are achieved in the CSF when the meninges are inflamed.
5.3 Preclinical Safety Data
Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse micronucleus test and an Ames test were both negative for mutagenic effects.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium carbonate.
6.2 Incompatibilities
Solutions of Kefadim, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction. However, if concurrent therapy with Kefadim and an aminoglycoside is indicated, each of these antibiotics should be administered in different sites.
Precipitation has been reported when vancomycin has been added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.
Kefadim is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. Sodium Bicarbonate Injection is not recommended as a diluent. Solutions of Kefadim in 5% Dextrose or 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers and volume control devices of common intravenous infusion sets
6.3 Shelf Life
Unreconstituted vials: 2 years.
Reconstituted vials: It is good practice to reconstitute immediately prior to use. If this is not feasible, Kefadim should be stored in a refrigerator and used within 24 hours. After reconstitution, protection from light is not necessary. The pH of freshly reconstituted solutions ranges from 5.0 to 7.5.
6.4 Special Precautions For Storage
Unreconstituted vials: Protect from light. Do not store above 25°C.
6.5 Nature And Contents Of Container
Kefadim is supplied as a sterile dry powder in single-dose flint Type I or III glass vial with a rubber closure and aluminium seal containing 500mg, 1g and 2g ceftazidime (as pentahydrate) with sodium carbonate (118mg per gram of ceftazidime).
The total sodium content of the mixture is approximately 54mg (2.3mEq) per gram of ceftazidime
6.6 Special Precautions For Disposal And Other Handling
Solutions of Kefadim range from light yellow to amber, depending on the diluent and concentration.
Kefadim is compatible with the more commonly used intravenous infusion fluids. Solutions at concentrations between 1mg/ml and 40mg/ml in the following infusion fluids may be stored for up to 24 hours at room temperature: 0.9% Sodium Chloride Injection BP; M/6 Sodium Lactate Injection BP; Ringer's Injection USP; Lactated Ringer's Injection USP; 5% Dextrose Injection BP; 0.225% Sodium Chloride and 5% Dextrose Injection BP; 0.45% Sodium Chloride and 5% Dextrose Injection BP; 0.9% Sodium Chloride and 5% Dextrose Injection BP; 10% Dextrose Injection BP; and 10% Invert Sugar in Water for Injection.
At a concentration of 4mg/ml, Kefadim has been found compatible for 24 hours at room temperature in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with cefuroxime sodium, 3mg/ml; heparin, 10u/ml or 50u/ml; or potassium chloride, 10mEq/l or 40mEq/l.
Parenteral drug products should be inspected visually and cloudy solutions should be discarded.
Kefadim powder and solutions will darken, depending on storage conditions. However, product potency is not adversely affected if storage conditions and storage periods are observed.
7. Marketing Authorisation Holder
Flynn Pharma Ltd
Alton House
4 Herbert Street
Dublin 2
Ireland
8. Marketing Authorisation Number(S)
Vials 500mg:
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PL 13621/0014
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Vials 1g:
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PL 13621/0015
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Vials 2g:
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PL 13621/0016
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9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation:
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1st June 2005
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10. Date Of Revision Of The Text
1st June 2005
