CEFOSULBIN

APPROVED

by Order of the Ministry of Health

of Ukraine

as of 25.06.09 No. 446

Registration Certificate

No. UA/9805/01/01

INSTRUCTION

For medical application of drug

CEFOSULBIN

 

 

Drug Formulation:

active substances: sodium sulbactam, sodium cefoperazone; 1 vial contains sodium sulbactam which is equivalent to  0.5 g or 1 g of sulbactam, and sodium cefoperazone which is equivalent to 0.5 g or 1 g of cefoperazone.

Dosage Form. Powder for preparation of injection solution.

Pharmacotherapeutic Group. Cephalosporins of III generation. Cefoperazone, combinations.

ATC Code J01D D62.

Clinical Characteristics.

Indications.

Treatment of infections caused by microorganisms susceptible to it:

-     infections of respiratory tracts (upper and lower segments);

-     infections of urinary tracts (upper and lower segments);

-     peritonitis, cholecystitis, cholangitis, and other abdominal infections;

-     septicaemia;

-     meningitis;

-     infections of skin and soft tissues;

-     inflammatory diseases of small pelvis organs, endometritis, gonorrhoea, and other genital infections.

 

Contraindications. Application of combined drug is contraindicated in patients with allergy to sulbactam, penicillins or cephalosporins in past history.

Method of Application and Dosage.

Drug solution may be introduced intravenously or intramuscularly.

Adults: average daily dose is 2-4 g per day (introduction every 12 hours). In case of severe course of infection the dose may be increased up to 8 g per day in 1:1 proportion (i.e. cefoperazone content 4 g). Patients that receive treatment in 1:1 proportion may require separate introduction of additional cefoperazone. In this case it is introduced every 12 hours in equal doses. The recommended maximum daily dose of sulbactam is 4g.

Application in patients with impaired renal function. In case of drug application in patients with seriously diminished renal function (creatinine clearance is under 30 ml/min), the dosage regime is subject to adjustment in order to compensate for the reduced clearance of sulbactam. Patients with creatinine clearance of 15-30 ml/min should take sulbactam in maximum dose of 1 g which is introduced every 12 hours (maximum daily dose is 2 g of sulbactam), and patients with creatinine clearance less than 15 ml/min should take sulbactam in maximum dose of 500 mg which is introduced every 12 hours (maximum daily dose is 1 g of sulbactam). In case of serious infections additional cefoperazone may be required.

Pharmacokinetic profile of sulbactam is significantly disturbed n case of haemodialysis. Period of cefoperazone half-life in plasma is slightly reduced in case of haemodialysis. Thus, the dosage regime is subject to adjustment in case of dialysis application.

Combined therapy. Due to the wide range of antibacterial activity of sulbactam/cefoperazone, the majority of infections are efficiently treated with the help of monotherapy with this drug. However, in some cases sulbactam/cefoperazone may be applied in combination with other antibiotics. In case of simultaneous application of aminoglycosides, it is necessary to control the function of liver and kidneys during the whole period of treatment.

Application in patients with impaired liver function. It may be necessary to adjust the dose in case of severe obstructive jaundice and serious liver diseases or in case when these two pathologies are accompanied by impaired renal function. Patients with impaired liver function and concurrent impairment of renal function require control of cefoperazone concentration in plasma, and if necessary – the relevant dose adjustment. In case the thorough control of drug concentration in plasma is absent, the cefoperazone dose should not exceed 2 g per day.

The drug dose for children is 40-80 mg/kg per day. The drug should be introduced every 6-12 hours in equal doses.

In case of serious infections these doses may be increased up to 160 mg/kg per day in 1:1 proportion. The dose should be introduced divided into 2-4 equal parts.

Application for treatment of babies. The drug should be introduced to 1st week babies every 12 hours. The maximum daily dose for babies should not exceed 80 mg/kg per day.

Intravenous introduction. For the purpose of drop infusion the content of each vial should be dissolved in the relevant amount of 5% dextrose water solution, 0.9% sodium chloride solution or sterile water for injections, then diluted to 20 ml with similar solution, and introduced drop-by-drop during 15-60 min.

 

General dose, g

Equivalent dose of sulbactam (g) + cefoperazone (g)

Solvent volume, ml

Maximum final concentration, mg/ml

1.0

0.5 + 0.5

3.4

125 + 125

2.0

1.0 + 1.0

6.7

125 + 125

 

The drug is compatible with water for injections, 5% dextrose solution in 0.225% sodium chloride solution, and 5% dextrose solution in sodium chloride isotonic solution in concentration starting from 10 mg of cefoperazone and 10 mg of sulbactam per 1 ml and up to 125 mg of cefoperazone and 125 mg of sulbactam per 1 ml.

Ringer’s lactated solution is acceptable for dilution in case of intravenous infusion, but not for the primary dilution. For the purpose of intravenous injection the content of vial is diluted as described above and introduced during 3 min at least. In case of direct intravenous injection the maximum single-time daily dose for adults is 2 g, for children – 50 mg/kg of body weight.

Intramuscular introduction. Lidocaine hydrochloride is acceptable for dilution in case of intramuscular introduction, but not for primary dilution.

 

Side effects. The drug is usually well-tolerated. The majority of side effects are weak or moderate, and do not require drug withdrawal.

The following side effects are possible in course of application:

On digestive system. Similarly to other antibiotics, the most frequent drug side effects are such symptoms as diarrhoea, nausea, and vomiting.

Skin reactions. Similarly to all penicillins and cephalosporins, the hypersensitivity may appear in the form of maculopapular rash and urticaria. The development of above-mentioned reactions is most likely in patients with allergy, to penicillin in particular, in the past history.

On blood system. There were cases of slight reduction in amount of neutrophils. Similarly to other beta-lactam antibiotics, the development of reversible neutropenia is possible in case of long-term application. Some patients may show positive result of direct Coombs test in course of treatment. Decrease in levels of haemoglobin or haematocrit, eosinophilia, thrombocytopenia, and hypothrombinemia may also be observed.

Other symptoms. Headache, fever, pain at injection point, and muscle twitching.

Changes in laboratory indices. There were cases of changeable increase in the results of functional liver tests for AsAT, AlAT, level of alkaline phosphatase in bilirubin.

Local reactions. The drug is well-tolerable when introduced intramuscularly. Pain at injection point may be rarely observed. Similarly to other cephalosporins and penicillins, if the drug is introduced via intravenous cannula, phlebitis at point of infusion is possible in some patients.

The following side effects were also observed. General: anaphylactic reaction (shock in particular); cardiovascular: hypotension, vasculitis; digestive tract: pseudomembranous colitis; blood system: leukopenia; skin: itching, Stevens-Johnson syndrome; urinary system: haematuria.

 

Overdosage. The signs of drug overdosage may appear in the form of intensified symptoms of its side effects. It is necessary to take into account that high concentrations of lactam antibiotics in cerebrospinal fluid may cause neurological reactions, cramps in particular. Since cefoperazone and sulbactam are excreted from circulation system by means of haemodialysis, this procedure may intensify the elimination of the drug from the body in case of overdosage in patients with impaired renal function.

Application during Pregnancy and Breast-Feeding Periods. The drug penetrates through placental barrier. Pregnant are treated with the drug only in cases when the possible benefit for mother exceeds the potential risk for foetus.

Peculiarities of Application.

Hypersensitivity. There have been reports of severe, and sometimes fatal anaphylactic reactions in patients that received treatment with beta-lactams or cephalosporins. Such reactions are more likely in patients with known hypersensitivity to numerous allergens in the history. In case of allergic reaction the drug must be immediately withdrawn, and the relevant treatment shall be applied. Severe anaphylactic reactions require immediate application of emergency therapy, adrenaline introduction in particular. Also possible are: oxygen therapy, intravenous introduction of corticosteroids, ensuring of airways patency, including intubation.

General safety measures. Similarly to other antibiotics, treatment with cefoperazone may lead to development of vitamin K deficiency in some patients. The mechanism of this phenomenon is probably connected with inhibition of intestinal microflora which under normal conditions synthesizes this vitamin. Thus, the risk group includes patients with malnutrition, disturbed absorption (e.g., in case of gallbladder fibrosis), and patients that have been on parenteral (intravenous) nutrition for a long time. It is necessary to control prothrombin time in such patients. The similar control is required in case of patients that receive anticoagulant treatment. Exogenous vitamin K intake is required in above-mentioned cases.

Similarly to other antibiotics application, the long-term treatment with the drug may cause intensification of resistant microflora growth. The patients should stay under thorough control in course of treatment. One should be ready for periodic signs of disturbed activity of kidneys, liver and blood system – same as in case of application of other systemic drugs. This is especially important concerning newly-born, premature babies in particular.

Application in case of impaired renal function. In case of drug application in patients with impaired renal function the general clearance of sulbactam is closely correlated with established creatinine clearance. In patients with severely impaired renal function the period of sulbactam half-life is significantly increased. Haemodialysis significantly influences the half-life term, general clearance, and distribution volume of sulbactam. Any changes in cefoperazone pharmacokinetics in patients with impaired renal function have not been observed.

Application in case of impaired liver function. Cefoperazone is excreted with bile to a large degree. In patients with liver diseases and/or biliary tracts obstruction the period of cefoperazone half-life in plasma is usually increased, and output with urine is greater. Even in case of severely impaired liver function, the therapeutic concentrations of cefoperazone are detected in bile, and its period of half-life in plasma is increased by 2-4 times.

In case of severe obstruction of biliary passages, serious liver diseases or concurrent impairment of renal function, the dose adjustment may be needed.

Application in elderly and old age. In course of application of both sulbactam and cefoperazone the prolongation of half-life period, decrease in general clearance and increase in distribution volume as compared to data received in young volunteers were observed. The sulbactam pharmacokinetics was directly correlated with the level of renal function, and cefoperazone pharmacokinetics was well correlated with impairment of liver function.

Application for treatment of children. Study of children population has not detected any changes in pharmacokinetics of drug components as compared to adults.

Application for treatment of babies. The drug is efficiently applied in babies. However, there has been no comprehensive research of its application in premature babies and newly-born. Therefore, before starting the treatment of premature or newly-born babies it is necessary to estimate the potential benefit and possible risk of such treatment. Cefoperazone does not force bilirubin out of places of binding with plasma proteins.

Ability to Affect Rate of Reactions when Driving or Operating Other
Mechanisms.
Influence is unlikely.

Interaction with Other Drugs and Other Types of Interaction.

Aminoglycosides. Mixing the drug with aminoglycosides in one syringe leads to mutual inactivation; if these groups of antibacterial agents must be applied simultaneously, introduce them at different points with 1 hour interval. The drug increases the risk of development of nephrotoxicity of aminoglycosides, and furosemide.

Bacteriostatic drugs (chloramphenicol, erythromycin, sulfanilamides, and tetracyclines) reduce the drug activity.

Probenecid reduces tubular secretion of sulbactam; this results in increase of plasmatic concentration and period of half-excretion of the drugs, and increase in risk of intoxication. Increases the risk of bleeding in course of application with non-steroid anti-inflammatory drugs.

Alcohol.  In case of alcohol taking in course of treatment and within 5 days after the treatment with cefoperazone such reactions as redness of face, sweating, headache, and tachycardia were observed. Similar reactions were observed in case of application of other cephalosporins as well. Patients should be careful when drinking alcohol beverages in course of treatment with the drug. In case of artificial nutrition (oral or parental), solutions containing ethanol should not be used.

 

Pharmacological Properties.

Pharmacodynamics. The drug contains cefoperazone (3rd generation cephalosporin antibiotic) and sulbactam (irreversible inhibitor of the majority of β-lactamases produced by penicillin-resistant microorganisms). The antibacterial component of the drug is cefoperazone which influences the susceptible microorganisms at the stage of active reproduction by inhibiting the biosynthesis of mucopeptide of cell membrane. Sulbactam possesses no real antibacterial action, except for action against Neisseriaceae and Acinetobacter. However, the biochemical studies on cell-free bacterial systems have detected the sulbactam ability to irreversibly inhibit the most important β-lactamases produced by penicillin-resistant microorganisms. The sulbactam potential in respect of prevention of destruction of penicillins and cephalosporins by resistant microorganisms has been proved in course of studies on resistant microorganism strains during which sulbactam has demonstrated strong synergy with penicillins and cephalosporins. Since sulbactam also binds with some penicillin-binding proteins, the susceptible microorganisms become more susceptible to sulbactam/cefoperazone action than to action of cefoperazone action only.

Combination of sulbactam and cefoperazone is active in respect of all the microorganisms susceptible to cefoperazone. Moreover, when the above-mentioned combination is applied, its components demonstrate synergy in respect of such microorganisms: Haemophilus influenzae, Bacteroides spp., Acinetobacter calcoaceticus, Enterobacter aerogens, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Sulbactam/cefoperazone is in vitro active in respect of the wide range of clinically significant microorganisms.

Gram-positive microorganisms: Staphylococcus aureus (strains that produce or do not produce penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (mainly Diplococcus pneumoniae), Streptococcus pyogenes (A group β-haemolytic streptococcus), Streptococcus agalactiae (B group β-haemolytic streptococcus), most of other β-haemolytic streptococci; most of Streptococcus faecalis strains (enterococci).

Gram-negative microorganisms: Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (mainly Proteus morganii), Providencia rettgeri (mainly Proteus rettgeri), Providencia spp., Serratia spp. (including S. marcescens), Salmonella spp. and Shigella spp., Pseudomonas aeruginosa and some species of Pseudomonas, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitides, Bordetella pertussis, Yersinia enterocolitica.

Anaerobic microorganisms: gram-negative bacilli (including Bacteroides fragilis, other species of Bacteroides and Fusobacterium spp.); gram-positive and gram-negative cocci (including Peptococcus spp., Peptostreptococcus spp. and Veillonella spp.); gram-positive bacilli (including Clostridium spp., Eubacterium spp. and Lactobacillus spp.).

The established ranges of drug effective concentrations (MIC, mcg/ml according to cefoperazone concentration) are as follows: susceptible – less than 14, intermediary – 17-36, resistant – more than 64.

Pharmacokinetics. About 84% of sulbactam and 25% of cefoperazone are excreted by kidneys. The major part of cefoperazone is excreted with bile. After introduction of sulbactam/cefoperazone the average half-excretion period is 1 hour for sulbactam, and 1.7 hour for cefoperazone. The concentrations in blood plasma are proportional to the dose introduced. This data corresponds to pharmacokinetic parameters of components when they are taken separately.

Average values of maximum concentrations of sulbactam and cefoperazone after 2 g of the drug (1 g of sulbactam, and 1 g of cefoperazone) being introduced intravenously during 5 minutes are 130.2 and 236.8 mcg/ml, respectively. This indicates the larger distribution volume of sulbactam (Vα = 18.0-27.6 l) as compared to cefoperazone distribution (Vα = 10.2-11.3 l). Both components of the drug are intensively distributed in body tissues and organs, including bile, gallbladder, skin, appendix, oviducts, ovaries, uterus, etc. In children the period of half-excretion for sulbactam is between 0.91 and 1.42 hours, and for cefoperazone – between 1.44 and 1.88 hours. Data of pharmacokinetic interaction between sulbactam and cefoperazone when simultaneously applied in combination is absent. Repeated introduction has not revealed any significant changes in pharmacokinetics of sulbactam/cefoperazone components and their cumulation when taken every 8-12 hours. Cefoperazone is excreted with bile to a large degree. The period of cefoperazone half-excretion from blood serum is increased, and the degree of excretion with urine is usually increased in patients with liver diseases and obstruction of biliary tracts. Even in cases of severely impaired liver function the drug amount in bile reaches the therapeutic concentration while the period of drug half-excretion from blood plasma is increased by 2-4 times.

 

Pharmaceutical Characteristics.

Main Physicochemical Properties. Sterile powder of white colour, water-soluble (followed by formation of solution of yellowish or yellow colour).

 

Incompatibility. The drug should not be directly mixed with aminoglycosides due to physical incompatibility between them. If there is a need in combined therapy with the drug and aminoglycosides, they should be applied one by one by means of separate drop infusion using separate secondary intravenous tubes system; meanwhile the primary intravenous tubes system should be thoroughly rinsed with the relevant solution during the break between infusions of the above-mentioned drugs. It is also recommended that intervals between the introduction of the drug and introduction of glycosides within 24 hours were as long as possible.

Primary dilution with Ringer’s lactated solution is not recommended due to incompatibility. However, the application of double-stage dilution process where the primary solvent is water for injections gives the possibility to avoid incompatibility in case of further dilution with Ringer’s lactated solution. For the purpose of dilution the sterile water for injections should be used. For the purpose of further dilution it is necessary to use the double-stage method where the sterile water for injections (Section “Method of Application and Dosage”) is then diluted with Ringer’s lactated solution up to the sulbactam concentration of 5 mg/ml (2 ml of primary solution are diluted in 50 ml or 4 ml of primary solution are diluted in 100 ml of Ringer’s lactated solution).

Primary dilution with 2% lidocaine solution is not recommended due to incompatibility. However, the application of double-stage dilution method where the primary solvent is water for injections gives the possibility to avoid incompatibility in case of further dilution with 2% lidocaine hydrochloride solution. For the purpose of dilution the sterile water for injections should be used. In order to achieve the cefoperazone concentrations of 250 mg/ml or above, it is necessary to apply the double-stage method when the sterile water for injections is diluted with 2% lidocaine solution until the solution containing up to 250 mg of cefoperazone and 125 mg of sulbactam per 1 ml in approximately 0.5% solution of lidocaine hydrochloride is obtained.

Effective Period. 2 years.

Storage Conditions.

Store in original packaging under the temperature below 25°C in place out of reach of children.

Packaging. 1 vial in carton box.

Category of Selling. On prescription.

Manufacturer. Bioveeta Laboratories Ltd.

Location. B705, Vardhaman vatika, G.B. Road, Manpada, Thane (W), India.

Date of Last Revision.