Sulperazon

Sulperazon

cefoperazone + sulbactam

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Sulbactam sodium, cefoperazone sodium.
Description
Vials of the 1:1 product contain the equivalent of 500 mg + 500 mg and 1000 mg + 1000 mg of sulbactam and cefoperazone, respectively.
Sulbactam sodium/cefoperazone sodium combination is 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 beta-lactamase inhibitor for parenteral use only. Chemically it is sodium penicillinate sulfone. It contains 92 mg sodium (4 mEq) per gram. Sulbactam is an off-white crystalline powder which is highly soluble in water. The molecular weight is 255.22.
Cefoperazone sodium is a semisynthetic broad-spectrum cephalosporin antibiotic for parenteral use only. It contains 34 mg sodium (1.5 mEq) per gram. Cefoperazone is a white crystalline powder which is freely soluble in water. The molecular weight is 667.65.
Excipients/Inactive Ingredients: None.
Action
Pharmacology: Pharmacodynamics: The anti-bacterial 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 beta-lactamases produced by beta-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 four-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 species, Staphylococcus species, 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 non-penicillinase-producing strains; Staphylococcus epidermidis, Streptococcus pneumoniae (formerly Diplococcus pneumoniae); Streptococcus pyogenes (Group A beta-hemolytic streptococci); Streptococcus agalactiae (Group B beta-hemolytic streptococci); Most other strains of beta-hemolytic streptococci; Many strains of Streptococcus faecalis (enterococcus).
Gram-Negative Organisms: Escherichia coli, Klebsiella species, Enterobacter species, Citrobacter species, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Providencia rettgeri (formerly Proteus rettgeri), Providencia species, Serratia species (including S. marcescens), Salmonella and Shigella species, Pseudomonas aeruginosa and some other Pseudomonas species, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.
Anaerobic Organisms: Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides species, and Fusobacterium species); Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella species); Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus species).
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 in a 1:1 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 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 hour while that for cefoperazone is 1.7 hours. 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 grams of sulbactam/cefoperazone (1 g sulbactam, 1 g of cefoperazone) intravenously over 5 minutes were 130.2 and 236.8 mcg/ml, respectively. This reflects the larger volume of distribution for sulbactam (Vd = 18.0-27.6 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, 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 to 12 hours.
Use in Hepatic Dysfunction: See Precautions.
Use in 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 hours in separate studies). Haemodialysis 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 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 to 1.42 hours for sulbactam and from 1.44 to 1.88 hours for cefoperazone.
Toxicology: Preclinical Safety Data: Use in Pediatrics: Cefoperazone had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1,000 mg/kg per 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 1,000 mg/kg per 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 subcutaneously 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 over 10 times the average adult dose.
Indications/Uses
Monotherapy: Sulbactam/cefoperazone is indicated 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, 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 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 - Aminoglycosides under Cautions for Usage), renal function should be monitored during the course of therapy (see Use in Renal Dysfunction under Dosage & 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.
8 g of the 1:1 ratio (i.e., 4 g cefoperazone activity). Patients receiving the 1:1 ratio may require 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 sulbactam/cefoperazone 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 clearances 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 haemodialysis. 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 sulbactam/cefoperazone 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 of the 1:1 ratio. Doses should be administered in two to four equally divided doses (see Use in Infancy under Precautions and Pharmacology: Toxicology: Preclinical Safety Data - Use in Pediatrics under Actions).
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 (see Use in Infancy under Precautions).
Intravenous Administration: For intermittent infusion, each vial of sulbactam/cefoperazone should be reconstituted with the appropriate amount (see Special Precautions for Disposal and Other Handling - Reconstitution 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 to 60 minutes.
Lactated Ringer's Solution is a suitable vehicle for intravenous infusion, however, not for initial reconstitution (see Incompatibilities - Lactated Ringer's Solution and Special Precautions for Disposal and Other Handling - Lactated Ringer's Solution under Cautions for Usage).
For intravenous injection, each vial should be reconstituted as previously mentioned and administered over a minimum of 3 minutes.
Intramuscular Administration: Lidocaine HCl 2% is a suitable vehicle for intramuscular administration, however, not for initial reconstitution (see Incompatibilities - Lidocaine and Special Precautions for Disposal and Other Handling - Lidocaine 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 haemodialysis, these procedures may enhance 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 hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated severe hypersensitivity to beta-lactms (see Precautions).
Special Precautions
Hypersensitivity: Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with sulbactam/cefoperazone, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, carbapenems or other beta-lactam agents. If an allergic reaction occurs, sulbactam/cefoperazone must be discontinued immediately and appropriate alternative therapy instituted.
General: Serious haemorrhage cases, including fatalities, have been reported with sulbactam/cefoperazone. As with other antibiotics, Vitamin K deficiency resulting in coagulopathy has occurred in patients treated with sulbactam/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, and patients receiving anticoagulant therapy, and exogenous vitamin K administered as indicated. Discontinue sulbactam/cefoperazone if there is persistent bleeding and no alternative explanations are identified.
As with other antibiotics, overgrowth of non-susceptible 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 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. 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 two months after the administration of antibacterial agents.
Effects on Ability to Drive and Use Machines: Clinical experience with sulbactam/cefoperazone indicates that it is unlikely to impair a patient's ability to drive or use machinery.
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 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.
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 (see Pharmacology: Toxicology: Preclinical Safety Data - Use in Pediatrics under Actions).
Cefoperazone does not displace bilirubin from plasma protein binding sites.
Use In Pregnancy & Lactation
Usage 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.
Usage in Nursing Mothers: 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.
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 ADRs were observed in clinical trials (comparative and non-comparative studies) and in the post-marketing.
All ADRs listed in the label are presented by MedDRA SOC and are presented in the order of clinical importance. (See Table 5).

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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
Special Precautions for Disposal and Other Handling: Reconstitution: (See Table 6).

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Sulbactam/cefoperazone has been shown to be compatible with these diluents: water for injection, 5% dextrose, normal saline, 5% dextrose in 0.225% saline, and 5% dextrose in normal saline. Cefoperazone is compatible at concentrations ranging from 10-250 mg/ml of diluent. Sulbactam is compatible at concentrations ranging from 5-125 mg/ml of diluent.
Lactated Ringer's Solution: Sterile Water for Injection should be used for reconstitution (see Incompatibilities - Lactated Ringer's Solution under Cautions for Usage). A two-step dilution is required using Sterile Water for Injection (shown in table as previously mentioned) 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 section 6.2 Incompatibilities - Lidocaine). For a concentration of cefoperazone of 250 mg/ml or larger, a two-step dilution is required using Sterile Water for Injection (shown in table above) further diluted with 2% lidocaine to yield solutions containing up to 125 mg cefoperazone and 125 mg sulbactam per 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 Combination Therapy under 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 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 these mixture has been shown to be incompatible. However, a two 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 Special Precautions for Disposal and Other Handling - Lactated Ringer's Solution under Cautions for Usage).
Lidocaine: Initial reconstitution with 2% lidocaine HCl solution should be avoided since this mixture has been shown to be incompatible. However, a two 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 Special Precautions for Disposal and Other Handling - Lidocaine under Cautions for Usage).
Storage
Store below 30°C and protected from light.
Shelf-Life: 24 months (dry powder); 1 day (reconstituted suspension at room temperature).
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. 2 g x 1's.
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