Vaxcel Cefobactam

Vaxcel Cefobactam

cefoperazone + sulbactam

Manufacturer:

Kotra

Distributor:

Fair Deal
Full Prescribing Info
Contents
Cefoperazone Sodium, Sulbactam Sodium.
Description
Each vial contains Cefoperazone Sodium/Sulbactam Sodium equivalent to Cefoperazone 500 mg and Sulbactam 500 mg.
Action
Pharmacology: Pharmacodynamics: The antibacterial component of sulbactam/cefoperazone is cefoperazone, a third generation cephalosporin, which acts against sensitive organisms during the stage of active multiplication by inhibiting biosynthesis of cell wall mucopeptide.
Sulbactam does not possess any useful antibacterial activity, except against Neisseriaceae and Acinetobacter. However, biochemical studies with cell-free bacterial systems have shown it to be an irreversible inhibitor of most important b-lactamases produced by b-lactam antibiotic-resistant organisms.
The potential for sulbactam preventing the destruction of penicillins and cephalosporins by resistant organisms was confirmed in whole-organism studies using resistant strains in which sulbactam exhibited marked synergy with penicillins and cephalosporins. As sulbactam also binds with some penicillin-binding proteins, sensitive strains are also often rendered more susceptible to sulbactam/cefoperazone than to cefoperazone alone. The combination of sulbactam and cefoperazone is active against all organisms sensitive to cefoperazone. In addition, it demonstrates synergistic activity (up to 4-fold reduction in minimum inhibitory concentrations for the combination versus those for each component) in a variety of organisms, most markedly the following: Haemophilus influenzae, Bacteroides sp, Staphylococcus sp, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.
Sulbactam/cefoperazone is active in vitro against a wide variety of clinically significant organisms: Gram-Positive Organisms: Staphylococcus aureus (penicillinase-and nonpenicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes (Group A b-hemolytic streptococci), Streptococcus agalactiae (Group B b-hemolytic streptococci), most other strains of b-hemolytic streptococci, many strains of Streptococcus faecalis (enterococcus).
Gram-Negative Organisms: Escherichia coli, Klebsiella sp, Enterobacter sp and Citrobacter sp, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), Providencia sp, Serratia sp (including S. marcescens), Salmonella sp, Shigella sp, Pseudomonas aeruginosa and some other Pseudomonas sp, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis and Yersinia enterocolitica.
Anaerobic Organisms: Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides sp, and Fusobacterium sp).
Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella sp ).
Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus sp).
Susceptibility Testing: The following susceptibility ranges have been established for sulbactam/cefoperazone: See Table 1.

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For MIC determinations, serial dilutions of sulbactam/cefoperazone may be used with a broth or agar dilution method. Use of a susceptibility test disc containing 30 mcg of sulbactam and 75 mcg of cefoperazone is recommended. A report from the laboratory of "susceptible" indicates that the infecting organism is likely to respond to sulbactam/cefoperazone therapy, and a report of "resistant" indicates that the organism is not likely to respond. A report of "intermediate" suggests that the organism would be susceptible to sulbactam/cefoperazone if a higher dosage is used or if the infection is confined to tissues or fluids where high antibiotic levels are attained.
The following quality control limits are recommended for 30 mcg/75 mcg sulbactam/cefoperazone susceptibility discs. (See Table 2.)

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Pharmacokinetics: Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered with sulbactam/cefoperazone is excreted by the kidney. Most of the remaining dose of cefoperazone is excreted in the bile. After sulbactam/cefoperazone administration, the mean half-life for sulbactam is about 1 hr while that for cefoperazone is 1.7 hrs. Serum concentrations have been shown to be proportional to the dose administered. These values are consistent with previously published values for the agents when given alone.
Mean peak sulbactam and cefoperazone concentrations after the administration of 2 g of sulbactam/cefoperazone (1 g sulbactam, 1 g cefoperazone) IV over 5 min were 130.2 and 236.8 mcg/mL, respectively. This reflects the larger volume of distribution for sulbactam (Vd=18-27.6 L) compared to cefoperazone (Vd=10.2-11.3 L).
After IM administration of 1.5 g sulbactam/cefoperazone (0.5 g sulbactam, 1 g cefoperazone) peak serum concentrations of sulbactam and cefoperazone are seen from 15 min to 2 hrs after administration. Mean peak serum concentrations were 19 and 64.2 mcg/mL for sulbactam and cefoperazone, respectively. Both sulbactam and cefoperazone distribute well into a variety of tissues and fluid including bile, gall bladder, skin, appendix, fallopian tubes, ovary, uterus, and others.
There is no evidence of any pharmacokinetic drug interaction between sulbactam and cefoperazone when administered together in the form of sulbactam/cefoperazone.
After multiple dosing, no significant changes in the pharmacokinetics of either component of sulbactam/cefoperazone have been reported and no accumulation has been observed when administered every 8-12 hrs.
Hepatic Dysfunction: See Precautions.
Renal Dysfunction: In patients with different degrees of renal function administered sulbactam/cefoperazone, the total body clearance of sulbactam was highly correlated with estimated creatinine clearance. Patients who are functionally anephric, showed a significantly longer half-life of sulbactam (mean 6.9 and 9.7 hrs in separate studies). Hemodialysis significantly altered the half-life, total body clearance and volume of distribution of sulbactam. No significant differences have been observed in the pharmacokinetics of cefoperazone in renal failure patients.
Elderly: The pharmacokinetics of sulbactam/cefoperazone have been studied in elderly individuals with renal insufficiency and compromised hepatic function. Both sulbactam and cefoperazone exhibited longer half-life, lower clearance and larger volumes of distribution when compared to data from normal volunteers. The pharmacokinetics of sulbactam correlated well with the degree of renal dysfunction while for cefoperazone there was a good correlation with the degree of hepatic dysfunction.
Children: Studies conducted in pediatrics have shown no significant changes in the pharmacokinetics of the components of this product compared to adult values. The mean half-life in children has ranged from 0.91-1.42 hrs for sulbactam and from 1.44-1.88 hrs for cefoperazone.
Indications/Uses
Monotherapy: Sulbactam/cefoperazone is indicated for the treatment of the following infections when caused by susceptible organism: Respiratory tract infections (Upper and Lower).
Urinary Tract Infections (Upper and Lower).
Peritonitis, Cholecystitis, Cholangitis and other Intra-Abdominal Infections.
Septicemia.
Meningitis.
Skin and Soft Tissue Infections.
Bone and Joint Infections.
Pelvic Inflammatory Disease, Endometritis, Gonorrhea and other Infections of the Genital Tract.
Combination Therapy: Because of the broad spectrum of the activity of sulbactam/cefoperazone, most infections can be treated adequately with this antibiotic alone.
However, sulbactam/cefoperazone may be used concomitantly with other antibiotics if such combinations are indicated. If an aminoglycoside is used (see Interactions), renal function should be monitored during the course of therapy (see Dosage and Administration).
Dosage/Direction for Use
Use in Adults: Daily dosage recommendations for sulbactam/cefoperazone in adults are as follows: See Table 3.

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Doses should be administered every 12 hours in equally divided doses.
In severe or refractory infections the daily dosage of cefoperazone/sulbactam may be increased up to 8 g (i.e., 4 g cefoperazone activity). Patients may be required additional cefoperazone administered separately. Doses should be administered every 12 hours in equally divided doses.
The recommended maximum daily dosage of sulbactam is 4 g.
Use in Hepatic Dysfunction: See Precautions.
Use in Renal Dysfunction: Dosage regimens of cefoperazone/sulbactam should be adjusted in patients with marked decrease in renal function (creatinine clearance of less than 30 ml/min) to compensate for the reduced clearance of sulbactam. Patients with creatinine clearances between 15 and 30 ml/min should receive a maximum of 1 g of sulbactam administered every 12 hours (maximum daily dosage of 2 g sulbactam), while patients with creatinine clearance of less than 15 ml/min should receive a maximum of 500 mg of sulbactam every 12 hours (maximum daily dosage of 1 g sulbactam). In severe infections it may be necessary to administer additional cefoperazone. The pharmacokinetic profile of sulbactam is significantly altered by hemodialysis. The serum half-life of cefoperazone is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period.
Use in Elderly: See Pharmacology: Pharmacokinetics under Actions.
Use in Children: Daily dosage recommendations for cefoperazone/sulbactam in children are as follows: See Table 4.

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Doses should be administered every 6 to 12 hours in equally divided doses.
In serious or refractory infections, these dosages may be increased up to 160 mg/kg/day. Doses should be administered in two to four equally divided doses (see Precautions).
Use in Neonates: For neonates in the first week of life, the drug should be given every 12 hours. The maximum daily dosage of sulbactam in pediatrics should not exceed 80 mg/kg/day. For doses of sulbactam/cefoperazone requiring more than 80 mg/kg/day cefoperazone activity, additional cefoperazone should be administered.
Administration: For intramuscular and intravenous administration only.
Intravenous Administration: For intermittent infusion, each vial of sulbactam/cefoperazone should be reconstituted with the appropriate amount (see Instructions for Use/Handling under Cautions for Usage) of 5% Dextrose in Water, 0.9% Sodium Chloride Injection or Sterile Water for Injection and then diluted to 20 ml with the same solution followed by administration over 15-60 min.
Lactated Ringer's Solution is a suitable vehicle for intravenous infusion, however, not for initial reconstitution (see Interactions).
For intravenous injection, each vial should be reconstituted as described previously and administered over a minimum of 3 minutes.
Intramuscular Administration: Lidocaine HCl 2% is a suitable vehicle for IM administration, however, not for initial reconstitution (see Interactions and Instructions for Use/Handling under Cautions for Usage).
Overdosage
Limited information is available on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans.
Overdosage of the drug would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. The fact that high CSF concentrations of β-lactam antibiotics may cause neurologic effects, including seizures, should be considered. Because cefoperazone and sulbactam are both removed from the circulation by hemodialysis, these procedures may enhance the elimination of the drug from the body if overdosage occurs in patients with impaired renal function
Contraindications
Sulbactam/cefoperazone is contraindicated in patients with known allergy to penicillins, sulbactam, cefoperazone or any of the cephalosporins.
Special Precautions
Hypersensitivity: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam or cephalosporin therapy. These reactions are more apt to occur in individuals with a history of hypersensitivity reactions to multiple allergens. If an allergic reactions occurs, the drug should be discontinued and the appropriate therapy instituted.
Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroid and airway management, including intubation, should be administered as indicated.
Use In Hepatic Dysfunction: Cefoperazone is extensively excreted in bile. The serum half-life of cefoperazone is usually prolonged and urinary excretion of the drug increased in patients with hepatic diseases and/or biliary obstruction.
Even with severe hepatic dysfunction, therapeutic concentrations of cefoperazone are obtained in bile and only a 2- to 4-fold increase in half-life is seen.
Dose modification may be necessary in case of severe biliary obstruction, severe hepatic disease or in cases of renal dysfunction coexistent with either of those conditions.
In patients with hepatic dysfunction and concomitant renal impairment, cefoperazone serum concentrations should be monitored and dosage adjusted as necessary. In these cases, dosage should not exceed 2 g/day of cefoperazone without close monitoring of serum concentrations.
General: As with other antibiotics, vitamin K deficiency has occurred in a few patients treated with cefoperazone. The mechanism is most probably related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with poor diet, malabsorption states (e.g., cystic fibrosis) and patients on prolonged intravenous alimentation regimens. Prothrombin time should be monitored in these patients receiving anticoagulant therapy and exogenous vitamin K administered as indicated.
As with other antibiotics, overgrowth of nonsusceptible organisms may occur during prolonged use of sulbactam/cefoperazone.
Patients should be observed carefully during treatment. As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy; this includes renal, hepatic and hematopoietic systems. This is particularly important in neonates, especially when premature and other infants.
Use In Infancy: Sulbactam/cefoperazone has been effectively used in infants. It has not been extensively studied in premature infants or neonates.
Therefore, in treating premature infants and neonates potential benefits and possible risks involved should be considered before instituting therapy.
Cefoperazone does not displace bilirubin from plasma protein binding sites.
Use During Pregnancy: Reproduction studies have been performed in rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility and no teratological findings. Sulbactam and cefoperazone cross the placental barrier.
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.
Use In Nursing Mother: Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly into breast milk of nursing mothers, caution should be exercised when sulbactam/cefoperazone is administered to a nursing mother.
Use In Children: Infants: Sulbactam/cefoperazone has been effectively used in infants. It has not been extensively studied in premature infants or neonates. Therefore, in treating premature infants and neonates potential benefits and possible risks involved should be considered before instituting therapy.
Use In Pregnancy & Lactation
Use During Pregnancy: Reproduction studies have been performed in rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility and no teratological findings. Sulbactam and cefoperazone cross the placental barrier.
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.
Use In Nursing Mother: Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly into breast milk of nursing mothers, caution should be exercised when sulbactam/cefoperazone is administered to a nursing mother.
Side Effects
Sulbactam/cefoperazone is generally well tolerated. The majority of adverse events are of mild or moderate severity and are tolerated with continued treatment.
Gastrointestinal: As with other antibiotics, the most frequent side effects observed with sulbactam/cefoperazone have been gastrointestinal. Diarrhea/loose stools have been reported most frequently followed by nausea and vomiting.
Dermatologic Reactions: As with all penicillins and cephalosporins, hypersensitivity manifested by maculopapular rash, urticaria has been reported. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.
Hematology: Slight decreases in neutrophils have been reported.
As with other β-lactam antibiotics, reversible neutropenia may occur with prolonged administration. Some individuals have developed a positive direct Coombs' test during treatment. Decreased hemoglobin or hematocrit have been reported, which is consistent with published literature on cephalosporins. Transient eosinophilia and thrombocytopenia have occurred and hypoprothrombinemia has been reported.
Miscellaneous: Headache, fever, injection pain and chills occurred in patients.
Laboratory Abnormalities: Transient elevations of liver function tests, SGOT, SGPT, alkaline phosphatase and bilirubin levels have been noted.
Local Reactions: Sulbactam/cefoperazone is well tolerated following IM administration. Occasionally, transient pain may follow administration by this route. As with other cephalosporins and penicillins, when sulbactam/cefoperazone is administered by an IV catheter some patients may develop phlebitis at the infusion site.
In post-marketing experience, the following additional undesirable effects have been reported: General: Anaphylactoid reaction (including shock).
Cardiovascular: Hypotension.
Gastrointestinal: Pseudomembranous colitis.
Skin/Appendages: Pruritus, Stevens-Johnson syndrome.
Hematopoietic: Leucopenia.
Urinary: Hematuria.
Drug Interactions
Alcohol: A reaction characterized by flushing, sweating, headache and tachycardia has been reported when alcohol was ingested during and as late as the fifth day after cefoperazone administration. A similar reaction has been reported with certain other cephalosporins and patients should be cautioned concerning ingestion of alcoholic beverages in conjunction with administration of sulbactam/cefoperazone. For patients requiring artificial feeding orally or parenterally, solutions containing ethanol should be avoided.
Drug Laboratory Test Interactions: A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution.
Caution For Usage
Instructions for Use/Handling: Reconstitution: See Table 5.

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Sulbactam/cefoperazone has been shown to be compatible with water for injection, 5% dextrose, normal saline, 5% dextrose in 0.225% saline and 5% dextrose in normal saline at concentrations of 10 mg cefoperazone and 5 mg sulbactam/ml and up to 250 mg cefoperazone and 125 mg sulbactam/ml.
Lactated Ringer's Solution: Sterile Water for Injection should be used for reconstitution (see Incompatibilities as follows). A 2-step dilution is required using Sterile Water for Injection (shown in Table 5) further diluted with Lactated Ringer's Solution to a sulbactam concentration of 5 mg/ml (use 2 ml initial dilution in 50 ml or 4 ml initial dilution in 100 ml Lactated Ringer's Solution).
Lidocaine: Sterile Water for Injection should be used for reconstitution (see Incompatibilities as follows). For a concentration of cefoperazone of 250 mg/ml or larger, a 2-step dilution is required using Sterile Water for lnjection (shown in Table 5) further diluted with 2% lidocaine to yield solutions containing up to 250 mg cefoperazone and 125 mg sulbactam/ml in approximately a 0.5% lidocaine HCl solution.
Incompatibilities: Aminoglycosides: Solutions of sulbactam/cefoperazone and aminoglycosides should not be directly mixed, since there is a physical incompatibility between them. If combination therapy with sulbactam/cefoperazone and an aminoglycoside is contemplated (see Indications) this can be accomplished by sequential intermittent intravenous infusion provided that separate secondary intravenous tubing is used, and that the primary intravenous tubing is adequately irrigated with approved diluents between doses. It is also suggested that doses of sulbactam/cefoperazone be administered throughout the day at times as far removed from administration of the aminoglycoside as possible.
Lactated Ringer's Solution: Initial reconstitution with Lactated Ringer's Solution should be avoided since these mixtures have been shown to be incompatible. However, a 2-step dilution process involving initial reconstitution in water for injection will result in a compatible mixture when further diluted with Lactated Ringer's Solution (see Instructions for Use/Handling).
Lidocaine: Initial reconstitution with 2% lidocaine HCl solution should be avoided since this mixture has been shown to be incompatible. However, a 2-step dilution process involving initial reconstitution in water for injection will result in a compatible mixture when further diluted with 2% lidocaine HCl (see Instructions for Use/Handling).
Storage
Store below 30°C. Protect from light.
Reconstituted solution stable for 1 day at storage below 25°C.
MIMS Class
ATC Classification
J01DD62 - cefoperazone and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj (white or off-white powder which gives clear solution after reconstitution) (vial) 1 g x 1's, 10's.
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