Ceftazidime
injection
Composition:
Each vial contains:
Ceftazidime Pentahydrate equivalent to Anhydrous Ceftazidime .................................................... 1 g
With Sodium Carbonate 118 mg per gram of Ceftazidime
Pharmacology:
Ceftazidime is a semysynthetic, broad-spectrum, betalactam antibiotic for parenteral administration. It is the pentahydrate of pyridinium, 1-[[7-[[(2-amino4-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, [6R-[6a, 7ß(Z)]]. THIDIM® (Ceftazidime for injection), is a sterile, dry, powdered 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.
THIDIM® in sterile crystalline form is supplied in vials equivalent to 1 g of anhydrous ceftazidime. Solutions of THIDIM® range in color from light yellow to amber, depending on the diluent and volume used. The pH of freshly constituted solutions usually ranges from 5-8. After i.v. administration of 500 mg and 1 g doses of ceftazidime over 5 minutes to normal adult male volunteers, mean peak serum concentrations of 45 and 90 µg/ml, respectively, were achieved.
After i.v. infusion of 500 mg, 1 g and 2 doses of Ceftazidime over 20-30 minutes to normal adult male volunteers mean peak serum concentrations of 42, 69 and 170 µg/ml, respectively, were achieved. The half-life following i.v. administration was approximately 1.9 hours. Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. There was no evidence of accumulation of ceftazidime in the serum in individuals with normal renal function following multiple i.v. doses of 1 and 2 g every 8 hours for 10 days. Following intramuscular (i.m.) administration of 500 mg and 1 g doses of ceftazidime to normal adult volunteers, the mean peak serum concentrations were 17 and 39 µg/ml, respectively, at approximately 1 hour. Serum concentrations remained above 4 µg/ml for 6 and 8 hours after the i.m. administration of 500 mg and 1 g doses, respectively. The half-life of ceftazidime in these volunteers was approximately 2 hours. The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime. Therefore, a dosage adjustment from the normal recommended dosage is not required for patients with hepatic dysfunction, provided renal function is not impaired. Approximately 80%-90% of an i.m. or i.v. dose of ceftazidime is excreted unchanged by the kidneys over a 24 - hour period. After the i.v. administration of single 500 mg or 1 g doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine.
Since ceftazidime is eliminated almost solely by the kidneys, its serum half-life is significantly prolonged in patients with impaired renal function. Consequently, dosage adjustments in such patients as described in the Dosage and administration section are suggested.
Ceftazidime is bactericidal in action, exerting its effect by inhibition of enzymes responsible for cell-wall synthesis. A wide range of gram-negative organisms is susceptible to ceftazidime in vitro, including strains resistant to gentamycin and other aminoglycosides.
Ceftazidime has been shown to be active against the following organisms both in vitro and in clinical infections.
Aerobes, Gram-negative: Citrobacter spp. including Citrobacter freundii and Citrobacter diversus, Enterobacter spp. including Enterobacter cloacae and Enterobacter aerogenes, Escherichia coli, Haemophilus influenzae including ampicillin-resistant strains, Klebsiella spp. including Klebsiella pneumoniae, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Pseudomonas spp. (including Pseudomonas aeruginosa) and Serratia spp.
Aerobes, Gram-positive: Staphylococcus aureus including penicillinase and non-penicillinase-producing strains, Streptococcus agalactiae (group B streptococci), Streptococcus pneumoniae and Streptococcus pyogenes (group A ß-hemolytic streptococci).
Anaerobes: Bacteroides spp. (NOTE: many strains of Bacteroides fragilis are resistant). Ceftazidime has been shown to be active in vitro against most strains of the following organisms; however, the clinical significance of these data is unknown: Acinetobacter spp.; Clostridium spp. (not including Clostridium difficile); Haemophilus parainfluenzae; Morganella morganii (formerly Proteus morganii); Neisseria gonorrhoeae; Peptococcus spp.; Peptostreptococcus spp.; Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri); Salmonella spp.; Shigella spp.; Staphylococcus epidermidis; and Yersinia enterocolitica. Ceftazidime and the aminoglycosides have been shown to be synergistic in vitro against Pseudomonas aeruginosa and the Enterobacteriaceae. Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against Pseudomonas aeruginosa. Ceftazidime is not active in vitro against methicillin-resistant staphylococci; Streptococcus faecalis and many other enterococci; Listeria monocytogenes; Campylobacter spp.; or Clostridium difficile.
Indications:
THIDIM® (Ceftazidime for injection/ceftazidime sodium injection) is indicated for the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:
- Lower respiratory tract infections, including pneumonia, caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin- resistant strains; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli; Serratia spp.; Citrobacter spp.; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin-susceptible strains).
- Skin and skin structure infections caused by Pseudomonas aeruginosa; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A ß-hemolytic streptococci).
- Urinary tract infections, both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp.; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Klebsiella spp.; and Escherichia coli.
- Bacterial septicemia caused by Pseudomonas aeruginosa; Klebsiella spp.; Haemophilus influenzae; Escherichia coli; Serratia spp.; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin susceptible strains).
- Bone and joint Infections caused by Pseudomonas aeruginosa; Klebsiella spp.; Enterobacter spp.; and Staphylococcus aureus (methicillin-susceptible strains).
- Intra-abdominal infections, including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp. (many strains of Bacteroides fragilis are resistant).
- Central Nervous System Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis. THIDIM® has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae.
Contra indications:
THIDIM® (Ceftazidime) is contraindicated in patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibiotics.
Warnings and precautions:
Before therapy with THIDIM® (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.
If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to THIDIM® occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, i.v. fluids, i.v. antihistamines, corticosteroids, presor amines. and airway management, as clinically indicated. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftazidime. The total daily dosage should be reduced when ceftazidime is administered to patients with renal insufficiency (see Dosage and Administration).
Drug/Laboratory test interactions: The administration of Ceftazidime may result in a false - positive reaction for glucose in the urine using Clinitest® tablets, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or Tes-Tape®) be used.
Pregnancy: Teratogenic effects: Reproduction studies have revealed no evidence of impaired fertility or harm to the fetus due to THIDIM®.
There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing mothers: Ceftazidime is excreted in human milk in low concentrations. Caution should be exercised when THIDIM® is administered to a nursing woman.
Adverse reactions:
Ceftazidime is generally well tolerated. The incidence of adverse reactions associated with the administration of ceftazidime was low in clinical trials. The most common were local reactions following i.v. injection and allergic and gastrointestinal reactions. Other adverse reactions were encountered infrequently. No disulfiram like reactions were reported. The following adverse effects from clinical trials were considered to be either related to ceftazidime therapy or were of uncertain etiology:
Local effects, reported in fewer than 2% of patients, were phlebitis and inflammation at the site of injection.
Hypersensitivity reactions, reported in 2.7% of patients, were pruritus, rash, and fever. Immediate reactions, generally manifested by rash and/or pruritus. Angioedema and anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely. Gastrointestinal Symptoms, reported in fewer than 2.4% of patients, were diarrhea, nausea, vomiting, and abdominal pain. Central Nervous System Reactions (fewer than 1%) included headache, dizziness and paresthesia. Seizures have been reported with several cephalosporins including ceftazidime. In addition, encephalopathy, asterixis and neuromuscular excitability have been reported in renally impaired patients treated with unadjusted dosage regimens of ceftazidime.
Less frequent adverse events (fewer than 1 %) were candidiasis (including oral thrush) and vaginitis. Hematologic: Exceedingly rare cases of hemolytic anemia have been reported.
Laboratory Test Changes were transient and included eosinophilia (1.6-3.7%), positive Coombs' test without hemolysis 4.7%, thrombocytosis 0.4% and slight elevations in one or more of the hepatic enzymes, aspartate aminotransferase (AST, SGOT) 2.8%, alanine aminotransferase (ALT, SGPT) 3.2%, and alkaline phosphatase 0.8%. As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen, and/or serum creatinine were observed occasionally. Transient leucopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis were seen very rarely. In addition to adverse reaction listed above that have been observed in patients treated with ceftazidime, the following adverse reactions and altered laboratory test have been reported for cephalosporin class antibiotics:
Adverse reactions: Urticaria, Stevens Johnson Syndrome, Erythema multiforme, Toxic nephropathy, Hepatic dysfunction including cholestasis, Aplastic anemia hemorrhage.
Altered laboratory tests: Prolonged prothrombine time, false positive test for urinary glucose, elevated bilirubin, pancytopenia.
Overdosage:
Ceftazidime overdosage has occurred in patients with renal failure. In the presence of renal insufficiency, hemodialysis or peritoneal dialysis may aid in the removal of ceftazidime from the body.
Dosage and administration:
The usual adult dosage is 1 gram administered intravenously or intramuscularly every 8 -12 hours. The dosage and route should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient
Table 1 : Recommended dosage schedule
Dose
|
Frequency in dosing hourly
| |
| Adults | ||
| Usual recommended dosage | 1 gram i.v. or i.m |
8 - 12
|
| Uncomplicated urinary tract infections | 250 mg i.v. or i.m. |
12
|
| Bone and joint infections | 2 grams i.v. |
12
|
| Complicated urinary tract infections | 500 mg i.v. or i.m. |
8 - 12
|
| Uncomplicated pneumonia; mild skin and skin structure infections | 500 mg - 1 gram i.v. or i.m. |
8
|
| Serious gynecologic and intra-abdominal infections | 2 grams i.v. |
8
|
| Meningitis | 2 grams i.v. |
8
|
| Very severe life-threatening infections, especially in immunocompromised patients | 2 grams i.v. |
8
|
| Lung infections caused by Pseudomonas spp. in patients with cystic fibrosis with normal renal function | 30 - 50 mg/kg i.v. maximum 6 grams/day |
8
|
| Neonates (0-4 weeks) | 30 mg/kg i.v. |
12
|
| Infants and children (1month-12 years) | 30 - 50 mg/kg i.v. maximum 6 grams/day |
8
|
Impaired hepatic function: No adjustment in dosage is required for patients with hepatic dysfunction.
Impaired renal function: Ceftazidime, is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate [GFR] ‹ 50 ml per minute), it is recommended that the dosage of Ceftazidime be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of THIDIM® may be given. An estimate of GFR should be made to determine the appropriate maintenance dose. The recommended dosage is presented in the below table.
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:
| Creatinine clearance (ml/min) = |
Weight (kg) x (140-age)
|
| ______________________________ | |
72 x serum creatinine (mg/dl)
|
Females: 0.85 x male value
Table 2 : RECOMMENDED MAINTENANCE DOSES OF CEFTAZIDIME IN RENAL INSUFFICIENCY
Creatinine clearance ml/min
|
Approx serum creatinine umol/L (mg/dl)
|
Recommended unit dose of ceftazidime g
|
Frequency of dosing hourly
|
50 - 31
|
150 - 200
(1.7 - 2.3)
|
1.0
|
12
|
30 - 16
|
200 - 350
(2.3 - 4.0)
|
1.0
|
24
|
15 - 6
|
350 - 500
(4.0 - 5.6)
|
0.5
|
24
|
‹ 5
|
› 500
(› 5.6)
|
0.5
|
48
|
Pharmaceutical precautions:
Vials of THIDIM® for injection should be stored at a temperature below 25°C. Occasional storage at temperatures not higher than 30°C for up to 2 months is not detrimental to the product. Protect unconstituted vials from light.
Solutions of THIDIM® for injection retain satisfactory potency for 18 hours if kept below 25°C and for 7 days if refrigerated. Some increase in the colour of prepared solutions of THIDIM® for injection may occur on storage. THIDIM® for injection may be reconstituted for intramuscular administration using 0.5% or 1.0% Lignocaine Hydrochloride Injection BP the resultant solutions may be stored for 18 hours below 25°C or 7 days under refrigeration. Ceftazidime and aminoglycosides should not be mixed in the same giving set or syringe.
Instruction for reconstitution
VOLUMES OF DILUENT
Vial size
|
Volume of diluent +
to be added (ml)
|
Approximate concentrations
(mg/ml)
|
| 1 g intramuscular 1 g intravenous |
3.0 ml
10.0 ml
|
250
90
|
NOTE:
Addition should be in two stages (see text)+ usually water for injections | ||
For 500 mg i.m. or i.v., 1 g i.m, or i.v. Bolus vials
THIDIM® (Ceftazidime) 1 g
Box of 1 vial Reg. No. DKL9511622744B1
ON MEDICAL PRESCRIPTION ONLY.
HARUS DENGAN RESEP DOKTER.
Store below 25°C.
Protect from light.
Manufactured by .
PT DANKOS FARMA
Jakarta - Indonesia
For:
PT KALBE FARMA Tbk.
Bekasi - Indonesia
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