Sulperazon

Sulperazon

cefoperazone + sulbactam

Manufacturer:

Pfizer
Full Prescribing Info
Contents
Sulbactam sodium, cefoperazone sodium.
Description
Each vial contains the equivalent of sulbactam 500 mg and cefoperazone 500 mg.
Sulperazon is sulbactam sodium/cefoperazone sodium combination available as a dry powder for reconstitution in a 1:1 ratio in terms of free SBT/CPZ.
Sulbactam sodium is a derivative of the basic penicillin nucleus. It is an irreversible β-lactamase inhibitor for parenteral use only. Sulbactam sodium is sodium penicillinate sulfone. It contains sodium 92 mg (4 mEq) per gram. Sulbactam is an off-white crystalline powder which is highly soluble in water. Molecular Weight: 255.22.
Cefoperazone sodium is a semisynthetic broad-spectrum cephalosporin antibiotic for parenteral use only. It contains sodium 34 mg (1.5 mEq) per gram. Cefoperazone is a white crystalline powder which is freely soluble in water. Molecular Weight: 667.65.
Action
Pharmacology: The antibacterial component of Sulperazon 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 spp. 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 Sulperazon than to cefoperazone alone.
Microbiology: 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.
Sulperazon is active in vitro against a wide variety of clinically significant organisms:
Gram-Positive: 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 and many strains of Streptococcus faecalis (enterococcus).
Gram-Negative: Escherichia coli, Klebsiella, Enterobacter and Citrobacter spp, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), Providencia spp, Serratia spp (including S. marcescens), Salmonella and Shigella spp, Pseudomonas aeruginosa and some other Pseudomonas spp, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis and Yersinia enterocolitica.
Anaerobic: Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides and Fusobacterium spp), gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella spp) and gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus spp).
Susceptibility Testing: The following susceptibility ranges have been established for Sulperazon: See Table 1.


Click on icon to see table/diagram/image


For MIC determinations, serial dilutions of Sulperazon 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 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 Sulperazon 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 Sulperazon 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.


Click on icon to see table/diagram/image


Pharmacokinetics: Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered with Sulperazon is excreted by the kidney. Most of the remaining dose of cefoperazone is excreted in the bile. After Sulperazon 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 a single dose of 2 g Sulperazon (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).
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 Sulperazon 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 Sulperazon, 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.
Children: Studies conducted in pediatrics have shown no significant changes in the pharmacokinetics of the components of Sulperazon 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.
Elderly: The pharmacokinetics of Sulperazon 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.
Toxicology: Preclinical Safety Data: Children: Cefoperazone had adverse effects on the testes of prepubertal rats at all doses tested. SC 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- to 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 Sulperazon (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 study drug is uncertain. No such findings were seen in infant dogs at doses >10 times the average adult dose.
Indications/Uses
Monotherapy: For the treatment of the following infections when caused by susceptible organisms: Respiratory tract infections (upper and lower); urinary tract infections (upper and lower); peritonitis, cholecystitis, cholangitis and other intra-abdominal infections; skin and soft tissue infections.
Combination Therapy: Because of the broad spectrum of activity of Sulperazon, most infections can be treated adequately with this antibiotic alone. However, Sulperazon may be used concomitantly with other antibiotics if such combinations are indicated. If an aminoglycoside is used (see Incompatibilities: Aminoglycosides), renal function should be monitored during the course of therapy (see Use in Renal Dysfunction under Dosage & Administration).
Dosage/Direction for Use
Adults: Daily dosage recommendation for Sulperazon in adults are as follows: 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 Sulperazon may be increased up to 8 g of the 1:1 (ie, 4 g of cefoperazone 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 dosage of sulbactam is 4 g.
Children: Daily dosage recommendations for Sulperazon in children are as follows: 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. Doses should be administered in 2-4 equally divided doses (see Use in children under Precautions and Toxicology under Actions).
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 Sulperazon requiring >80 mg/kg/day cefoperazone activity, additional cefoperazone should be administered separately (see Use in children under Precautions).
Elderly: See Pharmacokinetics under Actions.
Use in Hepatic Dysfunction: See Precautions.
Use in Renal Dysfunction: Dosage regimens of Sulperazon should be adjusted in patients with marked decrease in renal function (creatinine clearance of <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 hrs (maximum daily dosage of 2 g sulbactam), while patients with creatinine clearances of <15 mL/min should receive a maximum of 500 mg of sulbactam every 12 hrs (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.
Administration: IV: For intermittent infusion, each vial of Sulperazon should be reconstituted with the appropriate amount (see Instructions for Use/Handling: Reconstitution as follows) 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 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 Instructions for Use/Handling: Lactated Ringer's Solution as follows).
For IV injection, each vial should be reconstituted as mentioned previously administered over a minimum of 3 min.
IM: Lidocaine HCl 2% is a suitable vehicle for IM administration, however, not for initial reconstitutions (see Incompatibilities: Lidocaine under Interactions, and Instructions for Use/Handling: Lidocaine as follows).
Instructions for Use/Handling: Reconstitution: See Table 5.


Click on icon to see table/diagram/image


Sulperazon 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 per mL and up to 250 mg cefoperazone and 125 mg sulbactam per 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 (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: Lidocaine under Interactions). For a concentration of cefoperazone of ≥250 mg/mL, a 2-step dilution is required using Sterile Water for Injection (shown in Table 5) further diluted with 2% lidocaine to yield solutions containing up to 250 mg cefoperazone and 125 mg sulbactam per mL in approximately 0.5% lidocaine HCl solution.
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 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 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.
Special Precautions
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 (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 Sulperazon. 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 children.
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 the 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 co-existent 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.
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulbactam sodium/cefoperazon 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. CDAD 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 machines.
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 teratogenic 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, 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 breast milk of nursing mothers, caution should be exercised when Sulperazon is administered to a nursing mother.
Use in children: Sulperazon has been effectively used in children. It has not been extensively studied in premature infants or neonates. Therefore, in treating premature children 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 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 teratogenic 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, 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 breast milk of nursing mothers, caution should be exercised when Sulperazon is administered to a nursing mother.
Adverse Reactions
Sulperazon is generally well tolerated. The majority of adverse events are of mild or moderate severity and are tolerated with continued treatment. In pooled clinical trial data from comparative and noncomparative studies in approximately 2500 patients the following was observed:
Gastrointestinal: As with other antibiotics, the most frequent side effects observed with Sulperazon have been gastrointestinal. Diarrhea/loose stools 3.9% have been reported most frequently followed by nausea and vomiting 0.6%.
Dermatologic Reactions: As with all penicillins and cephalosporins, hypersensitivity manifested by maculopapular rash 0.6% and urticarial 0.8%, 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 0.4% (5/1131) have been reported. As with other β-lactam antibiotics, reversible neutropenia 0.5% (9/1696) may occur with prolonged administration. Some individuals have developed a positive direct Coombs' test 5.5% (15/269) during treatment. Decreased hemoglobin 0.9% (13/1416) or hematocrit 0.9% (13/1409) have been reported, which is consistent with published literature on cephalosporins. Transient eosinophilia 3.5% (40/1130) and thrombocytopenia 0.8% (11/1414) have occurred, and hypoprothrombinemia 3.8% (10/262) has been reported. Some cases of hemolytic anemia have been reported following treatment with cephalosporins.
Miscellaneous: Headache 0.04%, fever 0.5%, injection pain 0.08%, chills 0.04%.
Laboratory Abnormalities: Transient elevations of liver function test, SGOT 5.7% (94/1638), SGPT 6.2% (95/1529), alkaline phosphatase 2.4% (37/1518) and bilirubin 1.2% (12/1040) levels have been noted.
Local Reactions: Sulperazon is well tolerated following IM administration. Occasionally, transient pain at the infusion site may follow administration by this route. As with other cephalosporins and penicillins, when Sulperazon is administered by an IV catheter, some patients 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.
Hematopoietic: Leucopenia.
Skin/Appendages: Pruritus, Stevens-Johnson syndrome.
Urinary: Hematuria.
Vascular: Vasculitis.
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.
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 certain other cephalosporins and patients should be cautioned as to the possible adverse events following the ingestion of alcoholic beverages in conjunction with administration of Sulperazon. For patients requiring artificial feeding orally or parenterally, solutions containing ethanol should be avoided.
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 certain other cephalosporins and patients should be cautioned concerning ingestion of alcoholic beverages in conjunction with administration of Sulperazon. 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 Sulperazon and aminoglycosides should not be directly mixed, since there is a physical incompatibility between them. If combination therapy with Sulperazon 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 Sulperazon 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: Lactated Ringer's Solution under Dosage & Administration).
Lidocaine: Initial reconstitution with 2% lidocaine HCl solution should be avoided since these mixtures were 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 solution (see Instructions for Use/Handling: Lidocaine under Dosage & Administration).
Storage
Store below 25°C in a dry place.
Shelf-Life: 24 months.
MIMS Class
ATC Classification
J01RA01 - penicillins, combinations with other antibacterials ; Belongs to the class of combinations of antibacterials. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj & solvent (vial) 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