Salbec

Cefoperazone, sulbactam.

Vials containing a mixture of (1:1) sterile Cefoperazone/Sulbactam 1g/1g.
Cefoperazone sodium contains 34 mg sodium (1.5mEq) per gram and sulbactam sodium contains 92 mg sodium (4mEq) per gram. SALBEC contains a total of 126 mg sodium.
Excipients/Inactive Ingredients: Not applicable, there are no excipients in SALBEC.

Pharmacotherapeutic Group: Third generation cephalosporins; cefoperazone, combinations. ATC Code: J01DD62.
Pharmacology: Pharmacodynamics: The antibacterial component of sulbactam/cefoperazone is cefoperazone, a third generation cephalosporin which acts against sensitive organisms during the state of active multiplication by inhibiting biosynthesis of cell wall mucopeptide. Sulbactam does not possess any useful antibacterial activity, except against Neisseriaceae spp and Acinetobacter spp. However, biochemical studies with cell-free bacterial systems have shown it to be an irreversible inhibitor of most important beta-lactamases (Richmond types II, III, IV, and V - plasmid or chromosomally mediated) produced by beta-lactam antibiotic-resistant organisms.
The potential for sulbactam preventing the destruction of penicillins and cephalosporins in resistant organisms is confirmed in whole organism studies using resistant strain in which sulbactam exhibits marked synergistic effects when given together with penicillins and cephalosporins. As sulbactam also binds with some penicillin binding proteins, sensitive strains are also often rendered more susceptible to the combination of sulbactam/cefoperazone than to cefoperazone alone.
Cefoperazone sodium is a broad-spectrum, bactericidal third generation cephalosporin antibiotic that acts by inhibition of cell wall synthesis.
The combination of sulbactam and cefoperazone is active against all organisms sensitive to cefoperazone but in addition demonstrates synergistic activity (up to fourfold reduction in minimum inhibitory concentration values with the combination versus those for each component) against 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.
Cefoperazone/sulbactam combination in-vitro is active against the following 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-haemolytic streptococci); Most other strains of beta-haemolytic 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, Fusobacterium species); Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella species); Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus species).
Susceptibility borders, established for sulbactam / cefoperazone, are shown as follows: See Tables 1 and 2.

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For MIC determination may be used serial dilution of sulbactam / cefoperazone in ratio 1:1 through culture in either broth or agar. It is recommended to be used disk diffusion method of susceptibility testing, containing 30 mcg sulbactam and 75 mcg cefoperazone for a disk.
A laboratory result of "susceptible" indicates that the infecting organism is likely to respond to sulbactam / cefoperazone therapy and a laboratory result of "resistant" indicates that the infecting organism is not likely to respond to therapy. A "moderately susceptible" laboratory result suggests that the infecting organism will be susceptible to sulbactam / cefoperazone if a higher than usual dosage of the medicinal product is used or if the infection is confined to tissues and fluids in which high antibiotic levels are attained.
It is recommended the following control stains to be used for quality control of disks for antibacterial susceptibility - 30 mcg / 75 mcg sulbactam / cefoperazone. (See Table 3.)

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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 - 21.61) compared to cefoperazone (Vd 10.2 - 11).
Following intramuscular administration of 1.5 g sulbactam/cefoperazone (0.5 g sulbactam, 1 g cefoperazone), the serum concentration peak of sulbactam and cefoperazone are reached within 15 minutes - 2 hours, after the administration. The mean peak concentrations of sulbactam and cefoperazone are 19.0 and 64.2 mcg/ml, respectively.
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.
Special populations: Administration in hepatic dysfunction: See Precautions.
Administration 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.
Administration in elderly: The pharmacokinetics of sulbactam/cefoperazone has 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.
Administration in children: Studies conducted in paediatrics 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: 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, and 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.

Monotherapy: Sulbactam/cefoperazone monotherapy 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; Septicaemia; Meningitis; Skin and soft tissue infections; Bone and joint infections; Pelvic inflammatory disease, endometritis, gonorrhoea, 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 SALBEC 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 Administration in renal impairment under Dosage & Administration).

Administration in adults: Daily dosage recommendations for sulbactam/cefoperazone in adults are as follows: See Table 4.

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Daily dose should be administered every 12 hours in equally divided doses.
In severe or refractory to the treatment infections, the daily dose of sulbactam/cefoperazone may be increased up to 8 g from the 1:1 ratio (i.e., cefoperazone activity - 4 g).
Patients receiving the 1:1 ratio may require additional cefoperazone, administered separately. Daily dose should be administered every 12 hours in equally divided doses. The recommended maximum daily dosage of sulbactam is 4 g.
Administration in hepatic impairment: See Precautions.
Administration in renal impairment: In patients with significantly impaired renal function (creatinine clearance < 30 ml/min), dosage regimen should be corrected in order to compensate the reduced sulbactam clearance. In patients with creatinine clearance between 15 and 30 ml/min, 1 g sulbactam should be administered, every 12 hours at the most (maximum daily dose sulbactam- 2 g), while in patients with creatinine clearance under 15 ml/min, 500 mg sulbactam should be administered, every 12 hours at the most (maximum daily dose sulbactam- 1 g). Additional administration of cefoperazone may be required in severe infections.
The pharmacokinetic profile of sulbactam is significantly altered by haemodialysis. The serum half-life of cefoperazone is reduced slightly during haemodialysis. Thus, dosing should be scheduled to follow a dialysis period.
Administration in elderly: See Pharmacology: Pharmacokinetics under Actions.
Administration in children: Daily dosage recommendations for sulbactam/cefoperazone in children are as follows: See Table 5.

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Daily dose should be administered every 6 to 12 hours, in equally divided doses.
In serious or refractory to the treatment infections, these doses may be increased up to 160 mg/kg/day from the ratio 1:1 (i.e., cefoperazone activity - 160 mg/kg/day). Daily dose should be administered in two to four equally divided doses (see Use in Children under Precautions and Pharmacology: Pharmacokinetics: Administration in children under Actions).
Administration 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 children should not exceed 80 mg/kg/day (see Use in Children under Precautions).
Intravenous Administration: For intermittent intravenous 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 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 Instructions for Use/Handling: Lactated Ringer's Solution under Cautions for Usage).
For intravenous injection, each vial should be reconstituted as previously described and to be 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 Instructions for Use/Handling: Lidocaine under Cautions for Usage).

There is insufficient experience of acute toxicity with cefoperazone sodium and sulbactam sodium in humans. Overdose with medicinal product is supposed to result in reactions which are adverse drug reactions, reported for the product, with higher intensity. It must be taken note of the fact, that high concentrations in central nervous system of beta-lactam antibiotics may provoke neurological effects, including seizures. As both cefoperazone and sulbactam are removed from circulation through dialysis, these procedures may quicken medicinal product elimination from the organism, if overdose occurs in patients with impaired renal function.

Sulbactam/cefoperazone is contraindicated in patients with established hypersensitivity to penicillins, sulbactam, cefoperazone, or to other antibiotic from the cephalosporin-class.

Hypersensitivity: Serious, rarely fatal hypersensitivity (anaphylactic) reactions are seen in patients which were administered therapies with beta-lactams or cephalosporins. Such reactions are most likely to appear in patients with history for hypersensitivity to great number of allergens. If hypersensitivity reaction occurs, the medicinal product should be stopped and appropriate treatment should be commenced.
Severe anaphylactic reactions require immediately adrenaline administration. If needed oxygen, corticoids intravenously should be administered and an adequate airway, including intubations should be assured.
Administration in hepatic impairment: Cefoperazone is extensively excreted in bile. The serum half-life of active substance is usually prolonged in patients with hepatic disease and/or biliary obstruction and its urine excretion is increased. Even in severe hepatic impairment, cefoperazone reaches therapeutic bile concentrations, and only 2-4 fold half life prolongations is seen.
Doses modification is required only in cases of severe biliary obstruction, severe hepatic disease or in cases of concomitant renal impairment and some of the previously mentioned conditions.
In patients with hepatic insufficiency and concomitant renal impairment, cefoperazone serum concentrations should be monitored and, if need, doses should be adapted, accordingly. In case careful serum concentrations monitoring is not carried out, cefoperazone dose should not be higher than 2 g.
General principles: As with other antibiotics, vitamin K deficiency had occurred in small number of patients treated with cefoperazone. The mechanism is most probably related to the suppression of gut flora which normally synthesize this vitamin. Those at higher risk include patients with a poor nutritional status, malabsorption states (e.g., cystic fibrosis), and patients on prolonged intravenously nutrition. Prothrombin time should be monitored in these patients and in patient on anticoagulant treatment and exogenous vitamin K should be administered, as indicated.
As with other antibiotics, prolonged use of sulbactam / cefoperazone may result in the overgrowth of nonsusceptible organisms. Careful observation of the patients during treatment is essential. As with all potent, systemic antibiotics, it is recommended during prolonged treatment patients to be monitored for organ and systemic disorders, these include renal, hepatic and haemopoetic systems. It is especially important in new-borns, particularly pre-term, and for breast-fed children.
Effects on Ability to Drive and Use Machines: Cefoperazone is not known to affect the ability to drive or operate machinery. No studies on the effects on the ability to drive and use machines have been performed.
Use in Children: Administration in breast-fed children: Sulbactam/cefoperazone was successfully administered in breast-fed children. Administration in pre-terms and newborns was not studied in detail. Though, before prescribing therapy to pre-terms and newborns, the ratio benefits / risks should be assessed (see Pharmacology: Pharmacokinetics: Administration in children and Toxicology: Preclinical Safety Data under Actions). Cefoperazone does not displace bilirubin from its sites for plasma proteins binding.

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 or harm to the fetus. Sulbactam and cefoperazone pass 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 medicinal product should be used during pregnancy only if clearly needed.
Lactation: Only low quantities of sulbactam and cefoperazone are excreted in human milk. Although sulbactam and cefoperazone passes poorly into breast milk of nursing mothers, caution should be exercised when sulbactam/cefoperazone is administered to a nursing woman.

Sulbactam/cefoperazone is usually well tolerated. The most of adverse drug reactions are mild to moderate in intensity and they are generally transient in the course of treatment. In summarized data from comparative and non­-comparative clinical studies, inclusive nearly 2500 patients, the following adverse drug reactions are observed: Gastrointestinal: As with most of the antibiotics, the most common adverse drug reactions are gastrointestinal. The most common were observed: diarrhea/loose stools - 3.9%, followed by nausea and vomiting - 0.6%.
Dermatological reactions: As with all penicillins and cephalosporins, hypersensitivity is seen, manifested by maculopapular rash - 0.6%, and urticaria - 0.08%. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.
Haematological: Slight decreases in neutrophil count 0.4% (5/1131) have been seen. As with other beta-lactam antibiotics, reversible neutropenia may occur with prolonged administration - 0.5% (9/1696). In some patients, positive direct Coombs' test was observed - 5.5% (15/296) during treatment. Decreased hemoglobins - 0.9% (13/1416) or hematocrits 0.9% (13/1409) have been reported, which is consistent with published literature on other cephalosporins. Transient eosinophilia - 3.5% (40/1130) and thrombocytopenia - 0.8% (11/1414) were observed, as well as hypoprothrombinemia - 3.8% (10/262).
Others: Headache - 0.04%, temperature - 0.5%, pain at the injection site - 0.08%, fever - 0.04%.
Laboratory tests: Transient elevations of liver function enzymes values were observed: ASAT - 5.7% (94/1638), ALAT - 6.2% (95/1529), alkaline phosphatase - 2.4% (37/1518) and bilirubin levels - 1.2% (12/1040).
Local reactions: Sulbactam/cefoperazone is well tolerated after intramuscular administration. Occasionally, transient pain may follow administration by this route. As with others penicillins and cephalosporins, when sulbactam / cefoperazone is administered by intravenous infusion some patients may develop phlebitis (0.1%) at the infusion site.
The following additional adverse drug reactions were observed: General: anaphylactic reaction (including shock).
Cardio-vascular: hypotonia.
Gastrointestinal: pseudomembranous colitis.
Hematology: leucopenia.
Skin/skin appendices: pruritus, Stevens-Johnson syndrome.
Urinary: haematuria.
Vascular: vasculitis.

Ethanol (Alcohol): Adverse reactions, like flushing, sweating, headache and tachycardia where reported after concomitant alcohol ingestion during cefoperazone treatment or alcohol intake up to five days after therapy cessation. Similar reactions were observed also during the administration of other cephalosporins, and the patients should be warned to avoid alcohol during sulbactam / cefoperazone therapy. In patients, who need artificial oral or parenteral nutrition, solutions containing ethanol should be avoided.
Laboratory Test Interactions: A false-positive reaction for glucose in urine may occur with Benedict's or Fehling's solutions.

Instructions for Use/Handling: SALBEC (cefoperazone/ sulbactam) is available in 2.0g vials. (See Table 6.)

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For use, a 6.7 ml volume of diluent should be added, yielding a maximum final concentration of 125 mg/ml cefoperazone and 125 mg/ml sulbactam.
Cefoperazone/sulbactam has been shown to be compatible with water for injection, 5% dextrose, 0.9% normal saline, 5% dextrose in 0.225% saline, and 5% dextrose in normal saline at concentrations up to 125 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 as follows). A two step dilution is required using Sterile Water for Injection (previously shown in table) further diluted with Lactated Ringer's Solution to a sulbactam concentration of 5mg/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 as follows).
For a concentration of cefoperazone of 250 mg/ml or larger, a two step dilution is required using Sterile Water for Injection 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.
Reconstitution and administration of the contents should be performed under suitable aseptic conditions.
The reconstituted solution must be clear, not coloured with no visible particulate matter. SALBEC vials are intended for single administration, any unused solution should be discarded.
Incompatibilities: Aminoglycosides: Sulbactam/cefoperazone solutions and aminoglycosides shall not be mixed, due to physical incompatibility. If combined therapy with sulbactam/cefoperazone and aminoglycosides is intended (see Combined therapy under Indications/Uses), this can be carried out via divided intermittent intravenous infusion, using separate intravenous catheter; the starting intravenous catheter shall be washed with appropriate solvent very well between the doses. It is also recommended, sulbactam/cefoperazone doses to be administered in the course of the day, as far as possible in time from the aminoglycosides' time of administration.
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 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 Instructions for Use/Handling: Lactated Ringer's Solution as previously mentioned).
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 Instructions for Use/Handling: Lidocaine as previously mentioned).
Furthermore, sulbactam/cefoperazone is not compatible with nicardipine, ondansetron, perfenzazin, promethazine, protamine, vinorelbine, filgrastim, amifostine.

SALBEC is stored below 25°C in the original package.
Shelf Life: Two (2) years.

Cephalosporins

J01DD62 - cefoperazone and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

POM

Powd for soln for inj/infusion (vial) 2 g x 10's.