Sulperazon

Sulperazon

cefoperazone + sulbactam

Manufacturer:

Pfizer

Distributor:

DKSH
Full Prescribing Info
Contents
Sulbactam sodium, cefoperazone sodium.
Description
Each vial contains sulbactam sodium/cefoperazone sodium combination in a 1:1 and 1:2 ratio in terms of free sulbactam and cefoperazone.
Sulbactam sodium is a derivative of the basic penicillin nucleus. It is an irreversible β-lactamase inhibitor for parenteral use only. Chemically, it is sodium penicillinate sulfone. It contains sodium 92 mg/g (sodium 4 mEq/g). Sulbactam is an off-white crystalline powder which is highly soluble in water. It has a molecular weight of 255.22.
Cefoperazone sodium is a semisynthetic broad-spectrum cephalosporin antibiotic for parenteral use only. It contains sodium 34 mg/g (sodium 1.5 mEq/g). Cefoperazone is a white crystalline powder which is freely soluble in water. It has a molecular weight of 667.65.
Action
Pharmacology: 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 sulbactam/cefoperazone 2 g (sulbactam 1 g, cefoperazone 1 g) 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 sulbactam/cefoperazone 1.5 g (sulbactam 0.5 g, cefoperazone 1 g) 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 fluids including bile, gallbladder, 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.
Use in Hepatic Dysfunction: See Precautions.
Use in Renal Dysfunction: In patients with different degrees of renal function administered with 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.
Use in the 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.
Use in Children: Studies conducted in pediatrics have shown no significant changes in the pharmacokinetics of the components of sulbactam/cefoperazone compared to adult values. The mean half-life in children has ranged from 0.91-1.42 hrs for sulbactam and 1.44-1.88 hrs for cefoperazone.
Toxicology: Preclinical Safety Data: Use in Children: Cefoperazone had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1000 mg/kg/day (approximately 16 times the average adult human dose) resulted in reduced testicular weight, arrested spermatogenesis, reduced germinal cell population and vacuolation of Sertoli cell cytoplasm. The severity of lesions was dose-dependent in the 100-1000 mg/kg/day range; the low dose caused a minor decrease in spermatocytes. This effect has not been observed in adult rats. Histologically, the lesions were reversible at all but the highest dosage levels. However, these studies did not evaluate subsequent development of reproductive function in the rats. The relationship of these findings to humans is unknown.
When sulbactam/cefoperazone (1:1) was given SC to neonatal rats for 1 month, reduced testicular weights and immature tubules were seen in groups given 300+300 mg/kg/day. Because there is a great individual variation in the degree of testicular maturation in rat pups, and because immature testes were found in controls, any relation to sulbactam/cefoperazone is uncertain. No such findings were seen in infant dogs at doses >10 times the average adult dose.
Microbiology: The antibacterial component of sulbactam/cefoperazone is cefoperazone, a 3rd 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 β-lactamases produced by β-lactam antibiotic-resistant organisms.
The potential for sulbactam's 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 and Staphylococcus spp, 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 β-hemolytic streptococci), Streptococcus agalactiae (group B β-hemolytic streptococci), most other strains of β-hemolytic streptococci, many strains of Streptococcus faecalis (enterococcus).
Gram-Negative Organisms: Escherichia coli, Klebsiella, Enterobacter and Citrobacter spp, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), Providencia sp, Serratia sp (including S. marcescens), Salmonella and Shigella spp, Pseudomonas aeruginosa and some other Pseudomonas sp, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.
Anaerobic Organisms: Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides and Fusobacterium spp).
Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella spp).
Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus spp).
Susceptibility Testing: The following susceptibility ranges have been established for sulbactam/cefoperazone: See Table 1.

Click on icon to see table/diagram/image

For minimum inhibitory concentration (MIC) determinations, serial dilutions of sulbactam/cefoperazone in a 1:1 or 1:2 sulbactam/cefoperazone ratio may be used with a broth or agar dilution method. Use of a susceptibility test disc containing sulbactam 30 mcg and cefoperazone 75 mcg 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 sulbactam/cefoperazone 30 mcg/75 mcg susceptibility discs. (See Table 2.)

Click on icon to see table/diagram/image
Indications/Uses
Monotherapy: Treatment of the following infections when caused by susceptible organisms: Upper and lower respiratory and urinary tract infections; peritonitis, cholecystitis, cholangitis and other intra-abdominal infections; septicemia; febrile neutropenia; 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 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 Incompatibilities under Interactions), renal function should be monitored during the course of therapy. (See Renal Dysfunction under Dosage & Administration.)
Dosage/Direction for Use
Adults: Daily Dosage Recommendations: See Table 3.

Click on icon to see table/diagram/image

Doses should be administered every 12 hrs in equally divided doses.
In severe or refractory infections, the daily dosage of sulbactam/cefoperazone may be increased up to 8 g of the 1:1 ratio (ie, cefoperazone 4 g activity) or 12 g of the 1:2 ratio (ie, cefoperazone 8 g activity). Patients receiving the 1:1 ratio may require additional cefoperazone administered separately. Doses should be administered every 12 hrs in equally divided doses.
The recommended maximum daily dose of sulbactam is 4 g.
In febrile neutropenia, total daily dose can be administered 2-3 times a day in equally divided doses.
Elderly: See Pharmacology: Pharmacokinetics under Actions.
Children: Daily Dosage Recommendations: See Table 4.

Click on icon to see table/diagram/image

Doses should be administered every 6-12 hrs in equally divided doses.
In serious or refractory infections, these dosages may be increased up to 160 mg/kg/day of the 1:1 ratio or 240 mg/kg/day of the 1:2 ratio (160 mg/kg/day cefoperazone activity). Doses should be administered in 2-4 equally divided doses (see Pharmacology: Toxicology: Preclinical Safety Data: Use in Children under Actions and Use in children under Precautions).
Neonates: For neonates in the 1st week of life, Sulperazon should be given every 12 hrs. The maximum daily dosage of sulbactam in pediatrics should not exceed 80 mg/kg/day. For doses of sulbactam/cefoperazone requiring >80 mg/kg/day cefoperazone activity, the 1:2 ratio must be used (see Use in children under Precautions).
Hepatic Dysfunction: See Precautions.
Renal Dysfunction: Dosage regimens of sulbactam/cefoperazone should be adjusted in patients with marked decrease in renal function [creatinine clearance (CrCl) of <30 mL/min] to compensate for the reduced renal clearance of sulbactam. Patients with creatinine clearance between 15 and 30 mL/min should receive a maximum of 1 g of sulbactam administered every 12 hrs (maximum daily dosage of sulbactam 2 g), while patients with CrCl of <15 mL/min should receive a maximum of sulbactam 500 mg every 12 hrs (maximum daily dosage of sulbactam 1 g). In severe infections, it may be necessary to administer additional cefoperazone separately.
The pharmacokinetic profile of sulbactam is significantly altered by hemodialysis. The serum half-life of cefoperazone is slightly reduced during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period.
Administration: IV: For intermittent infusion, each vial of sulbactam/cefoperazone should be reconstituted with the appropriate amount (see 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 IV infusion, however, not for initial reconstitution (see Incompatibilities: Lactated Ringer's Solution under Interactions and Cautions for Usage).
For IV injection, each vial should be reconstituted as mentioned previously and administered over a minimum of 3 min.
IM: Lidocaine HCl 2% is a suitable vehicle for IM administration, however, not for initial reconstitution (see Incompatibilities under Interactions and Cautions for Usage).
Overdosage
Limited information is available on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans. Overdosage of Sulperazon would be expected to produce manifestations that are principally extensions of the adverse reactions reported with Sulperazon. The fact that high cerebrospinal fluid 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 elimination of the drug from the body if overdosage occurs in patients with impaired renal function.
Contraindications
Patients with known allergy to penicillins, sulbactam, cefoperazone or any of the cephalosporins.
Warnings
Based on the Ministry of Public Health Announcement: Do not use in hypersensitive patients. Sulperazon may cause allergic reaction and could be fatal. Penicillin-sensitive patients may be allergic to Sulperazon.
If skin rash, irritation or edema occurs, Sulperazon should be discontinued and consult the physician.
Special Precautions
Hypersensitivity: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-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 reaction occurs, Sulperazon should be discontinued and the appropriate therapy instituted.
Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, IV steroids 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 cases of severe biliary obstruction, severe hepatic disease or in cases of renal dysfunction coexistent with 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 cefoperazone 2 g/day 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 synthesizes this vitamin. Those at risk include patients with poor diet, malabsorption states (eg, cystic fibrosis) and patients on prolonged IV alimentation regimens. Prothrombin time should be monitored in these patients, and 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.
Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including sulbactam sodium/cefoperazone sodium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. Clostridium difficile associated diarrhea must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
Effects on the Ability to Drive or Operate Machinery: Clinical experience with sulbactam/cefoperazone indicates that it is unlikely to impair a patient's ability to drive or use machinery.
Use in 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/cefoperazone crosses 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, Sulperazon should be used during pregnancy only if clearly needed.
Use in Lactation: Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly into the breast milk of nursing mothers, caution should be exercised when sulbactam/cefoperazone is administered to a nursing mother.
Use in Children: Infancy: Sulbactam/cefoperazone has been effectively used in infants. It has not been extensively studied in premature infants and neonates. Therefore, in treating premature infants and neonates, potential benefits and possible risks involved should be considered before instituting therapy (see Pharmacology: Toxicology: Preclinical Safety Data: Use in Children under Actions).
Cefoperazone does not displace bilirubin from plasma protein-binding sites.
Use In Pregnancy & Lactation
Use in 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/cefoperazone crosses 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, Sulperazon should be used during pregnancy only if clearly needed.
Use in Lactation: Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly into the breast milk of nursing mothers, caution should be exercised when sulbactam/cefoperazone is administered to a nursing mother.
Adverse Reactions
Sulbactam/cefoperazone is generally well tolerated. The majority of adverse events are of mild or moderate severity and are tolerated with continued treatment.
The following adverse drug reactions (ADRs) were observed in clinical trials (comparative and non-comparative studies) and in the post-marketing.
All ADRs listed as follows are presented by MedDRA SOC. Within each frequency category, the ADRs are presented in the order of clinical importance.
CIOMS III Categories: Very Common: ≥1/10 (≥10%); common: ≥1/100 to <1/10 (≥1% and <10%); uncommon: ≥1/1000 to <1/100 (≥0.1% and <1%); not known: Frequency cannot be estimated from available data.
Blood and Lymphatic System Disorders: Very Common: Leucopenia*, neutropenia*, positive Coomb's direct test*, decreased haemoglobin and haematocrit*, thrombocytopenia*, eosinophilia*. Not Known: Hypoprothrombinaemia.
Immune System Disorders: Not Known: Anaphylactoid reaction including shock.
Nervous System Disorders: Uncommon: Headache.
Vascular Disorders: Not Known: Vasculitis, hypotension.
Gastrointestinal Disorders: Common: Diarrhoea, nausea, vomiting. Not Known: Pseudomembranous colitis.
Hepatobiliary Disorders: Very Common: Increased alanine aminotransferase, aspartate aminotransferase and blood alkaline phosphatase*. Common: Increased blood bilirubin*.
Skin and Subcutaneous Tissue Disorders: Uncommon: Pruritus, urticaria. Not Known: Stevens-Johnson syndrome, maculopapular rash.
Renal and Urinary Disorders: Not Known: Haematuria.
General Disorders and Administration Site Conditions: Uncommon: Infusion site phlebitis, injection site pain, pyrexia, chills.
*In the calculation for laboratory abnormality ADR frequencies, all available laboratory values, including those of subjects with baseline abnormalities, were included. This conservative approach was taken because the raw data did not allow distinction between the subset of subjects with baseline abnormalities who had treatment-emergent significant laboratory changes from those subjects with baseline abnormalities who did not have treatment-emergent significant laboratory changes. For leucocytes, neutrophils, platelets, haemoglobin and haematocrit, only abnormalities are reported in studies. Increases and decreases are not differentiated.
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 5th day after cefoperazone administration. A similar reaction has been reported with other certain 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.
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 Combination Therapy under Indications), this can be accomplished by sequential intermittent IV infusion provided that separate secondary IV tubing is used and that the primary IV tubing is adequately irrigated with an approved diluent 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 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 lactated Ringer's solution (see Instructions for Use and Handling under Cautions for Usage).
Lidocaine: Initial reconstitution with 2% lidocaine HCl should be avoided since these mixtures have been shown to be incompatible. However, a 2-step dilution process involving initial reconstitution with water for injection will result in a compatible mixture when further diluted with 2% lidocaine HCl solution (see Instructions for Use and Handling under Cautions for Usage).
Caution For Usage
Instructions for Use and Handling: Reconstitution: Sulbactam/cefoperazone is available in 1 g and 1.5 g strength vials. (See Table 5.)

Click on icon to see table/diagram/image

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 cefoperazone 10 mg/mL and sulbactam 5 mg/mL and up to cefoperazone 250 mg/mL and sulbactam 125 mg/mL.
Lactated Ringer's Solution: Sterile water for injection should be used for reconstitution (see Incompatibilities: Lactated Ringer's Solution under Interactions). A 2-step dilution is required using sterile water for injection (see Table 5) further diluted with Lactated Ringer's solution to a sulbactam concentration of 5 mg/mL (use 2 mL initial dilution in 50 or 4 mL initial dilution in 100 mL of Lactated Ringer's solution).
Lidocaine: Sterile water for injection should be used for reconstitution (see Incompatibilities: Lidocaine under Interactions). For a concentration of cefoperazone of ≥250 mg/mL, a 2-step dilution is required using sterile water for injection (see Table 5) further diluted with 2% lidocaine to yield solutions containing up to cefoperazone 250 mg/mL and sulbactam 125 mg/mL in approximately a 0.5% lidocaine HCl solution.
Storage
Store 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 (vial) 1 g x 1's. 1.5 g x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in