Sulmagraf

Description
White or almost white powder.

Pharmacotherapeutic Group
Antibiotic-cephalosporin + beta-lactamase inhibitor.

ATC Code: J01DD62

Pharmacological Properties
Pharmacodynamics
Antimicrobial constituent of Cefoperazone/Sulbactam is Cefoperazone-cephalosporin of the third generation which has an effect on sensitive bacteria during their active reproduction by means of biosynthesis inhibition of the 1 cell wall mucopeptide. Sulbactam is a irreversible inhibitor within the range of very common beta-lactamases which are yielded by bacteria that are resistant to beta-lactam antibiotics. It has no clinically significant antibacterial activity (with the exception of Neisseriaceae and Acinetobacter). The ability of Sulbactam to prevent the disrupting penicillins and cephalosporins by resistant bacteria was confirmed during studies with the use of bacteria resistant strains in respect of which Sulbactam had apparent synergism with penicillins and cephalosporins. In addition, Sulbactam interacts with some penicillin-binding proteins (PBPs); that’s why the combination of Cefoperazone/Sulbactam often has more marked specific effect on sensitive strains of bacteria in comparison with the use of Cefoperazone only. The combination of Cefoperazone/Sulbactam is active against all bacteria sensitive to Cefoperazone. In addition, this combination has synergism against various bacteria, first of all: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Cefoperazone/Sulbactam is active in vitro against broad-spectrum of clinically significant bacteria.

Gram Positive Bacteria:
Staphylococcus aureus (producing and not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (Group A beta-hemolytic streptococcus), Streptococcus agalactiae (Group B beta-hemolytic streptococcus,), most other beta-hemolytic streptococcus strains, many strains Streptococcus faecalis (enterococcus).

Gram Negative Bacteria:
Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp. (inc;uding Serratia marcescens), Salmonella spp. and Shigella spp., Pseudomonas aeruginosa and some other Pseudomonas spp., Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica. Anaerobic Micronychia:

Gram-negative rods (including Bacteroides fragilis, other Bacteroides spp. and Fusobacterium spp.).

Gram-positive and gram-negative cocci (including Peptococcus spp., Peptostreptococcus spp. and Veillonella spp.).

Gram-positive rods (including Clostridium spp., Eubacterium spp. and Lactobacillus spp.).

The following sensitivity levels were established for the combination of Cefoperazone/Sulbactam. The Minimal Inhibitory Concentration (MIC), in µg/mL, expressed in Cefoperazone concentration for sensitive bacteria is less or equal to 16; for bacteria with an intermediate sensitivity – varying from 17 to 63 and for resistant ones – more than 64. Sensitivity areas determined by the disk-diffusion method are as follows: for sensitive bacteria – ≥ 21 mm; for intermediate sensitivity -varying from 16 to 20 mm and for resistant ones – ≤ 15 mm.
The method of serial dilution of Cefoperazone/Sulbactam may be used to determine the MIC at t 1:1 ratio in broth and agar media.

To determine the MIC by the disk-diffusion method it is recommended to use a disk containing 30 µg of Sulbactam and 75 µg of Cefoperazone.

When using disks containing 30 µg of Sulbactam and 75 µg of Cefoperazone it is recommended to utilize the following rates of quality control. For reference strain Acinetobacter spp. (American typical culture collection, hereinafter АТСС 43498) area diameter is 26-32; for Pseudomonas aeruginosa (АТСС 27853) – 22-28; for Escherichia coli (АТСС 25922) – 27-33; for Staphylococcus aureus (АТСС 25923) – 23-30.

Pharmacokinetics
After intravenous injection of 2 g of Cefoperazone/Sulbactam (1 g Cefoperazone and 1 g of Sulbactam), maximum concentrations (Стах) of Sulbactam and Cefoperazone within 5 minutes were in average 130.2 and 236.8 µg/mL accordingly. This accounts for higher volume of Sulbactam distribution (Vd = 18.0-27.6 L) in comparison with that of Cefoperazone (Vd = 10.2-11.3 L).

After intramuscular injection of 1.5 g Cefoperazone/Sulbactam (1 g Cefoperazone and 0.5 g of Sulbactam), Стах of Sulbactam and Cefoperazone in serum were observed within 15 minutes to 2 hours after the injection. Стах in serum were 19.0 and 64.2 µg/mL of Sulbactam and Cefoperazone accordingly.

Both Sulbactam and Cefoperazone are adequately distributed in various tissues and body fluids, including bile, bile cyst, skin, cecal appendage,Fallopian tubes, ovaries, alvus, etc.
About 84 % of Sulbactam dose and 25 % of Cefoperazone dose injected in the form of combination of Cefoperazone/Sulbactam are eliminated out of the body by kidneys. The major part of the remaining dose of Cefoperazone is eliminated out of the body with bile. Cefoperazone doesn’t displace total bilirubin from a plasma protein linkage. Elimination half-life (Т1/2) of Sulbactam is in average about 1 hour and of Cefoperazone-1.7 hour. Serum concentration is proportional to the dose injected.

There is no data on any pharmacokinetic interactions between Cefoperazone and Sulbactam when injecting the combination of Cefoperazone/Sulbactam. During repeated administration of both Cefoperazone/Sulbactam constituents no significant pharmacokinetic changes were revealed. If the drug was injected every 8-12 hours no accumulation was observed.

Administration in Case of Compromised Liver Function
Since Cefoperazone is intensively eliminated out of the body with bile, then Т1/2 of Cefoperazone is usually lengthened while the drug excretion by kidneys increases for patients suffering from hepatic disorder and/or bile duct obstruction. Even in case of severely impaired liver function, the therapeutic concentration of Cefoperazone is achieved while Т1/2 is lengthened only 2-4 times.

Administration in Case of Compromised Kidney Function
Patients with renal compromises, who administered Cefoperazone/Sulbactam, showed high correlation between the total body clearance of Sulbactam and the calculated creatinine clearance. Patients with terminal renal insufficiency revealed Т1/2 significant lengthening of Sulbactam (in average varying from 6.9 to 9.7 hours in various studies). Haemodialysis caused significant changes in Т1/2, the total body clearance and volume of Sulbactam distribution.

Administration by Elderly People
Pharmacokinetics of Cefoperazone/Sulbactam was studied for elderly people with renal insufficiency and compromised kidney function. In comparison with healthy volunteers, Т1/2, was lengthened, the clearance decreased and volume of didistribution both of Sulbactam and Cefoperazone increased. Pharmacokinetics of Sulbactam correlated with the severity of kidney impairment, while pharmacokinetics of Cefoperazone – with the severity of liver impairment.

Administration by Children
During children’s study no significant changes in pharmacokinetics of Cefoperazone/Sulbactam were revealed in comparison with those found during adults’ study.
T1/2 of Sulbactam during pediatric studies varied from 0.91 to 1.42 hours, T1/2 of Cefoperazone -from 1.44 to 1.88 hours.

Indications for Use
Sulmagraf drug is intended for treatment of infectious inflammatory diseases caused by bacteria sensitive to this drug:
–    Upper and low respiratory infections
–    Urinary tract infections
–    Peritonitis, cholecystitis, cholangitis and other intra-abdominal infections
–    Sepsis
–    Meningitis
–    Skin and soft tissue infections
–    Bone and joint infections
–    Gonorrhea
–    Pelvic inflammatory diseases, endometritis and other reproductive tract infections.

Contraindications
Hypersensitivity to any drug constituent or to any other cephalosporins; severe hypersensitivity reactions to other beta-lactam antibiotics (see “Special Warnings” section).

With Caution
Severe liver and kidney disorders
Newborn infants, including immature ones.

Use During Pregnancy and Breastfeeding
Proper clinical studies of pregnant women were not conducted.

Cefoperazone/Sulbactam seeps through a placental barrier and inpours into breast milk. In case of pregnancy and breastfeeding, the drug should be administered only if the perceived benefit outweighs potential risks for a unborn child or a newborn infant.

Administration and Dosage
Intravenous (I.V.) or intramuscular (I.M.)

Administration by Adults
For adults it is recommended to administer Cefoperazone/Sulbactam in daily doses as follows:

Daily doses should be divided into equal parts and injected every 12 hours.

In case of severe or obstinate infections, daily doses of the drug may be increased to 8 g with 1:1 ratio of basic constituents (i.e. 4 g of Cefoperazone).

Those patients who administer Cefoperazone/Sulbactam in 1:1 ratio may require additional injection of Cefoperazone. Daily doses of the drug should be divided into equal parts and injected every 12 hours.

The recommended maximum daily dose of Sulbactam is 4 g.

Administration in Case of Compromised Kidney Function
Maximum daily dose of Sulbactam for patients with 15-30 mL/min creatinine clearance (CLCR) is 1 g every 12 hours (maximum daily dose of Sulbactam is 2 g); maximum daily dose of Sulbactam for patients with less than 15mL/min CLCR is 500 mg every 12 hours (maximum daily dose of Sulbactam is 1 g). In case of severe infections additional injection of

Cefoperazone may be required.

Pharmacokinetics of Sulbactam significantly changes in case of haemodialysis. Elimination half-life of Cefoperazone out of blood serum is somewhat lower during haemodialysis. Hence, the drug administration should be scheduled after dialysis.

Administration in Case of Compromised Liver Function
Changes in dosage may be required in case of severe bile duct obstruction, serious liver diseases as well as in case of compromised kidney function combined with any condition specified.

Cefoperazone concentration in serum of patients with compromised liver function and associated kidney disorder should be monitored and their dosage should be adjusted in case of need.

If a daily dose of Cefoperazone does not exceed 2 g, there is no need to exercise control over its concentration in serum (see “Special Warnings” section).

Administration by Children
For children it is recommended to administer Cefoperazone/Sulbactam in daily doses as follows:

Doses should be divided into equal parts and injected every 6-12 hours.

In case of severe or obstinate infections, daily doses of the drug may be increased to 160 g/day (with 1:1 ratio of basic constituents), such doses should be divided into 2-4 equal parts.

Administration by Newborn Infants
For newborn infants the drug should be injected every 12 hours within the first lifetime week. The maximum daily dose of Sulbactam for infants should not exceed 80 mg/kg/day.

Preparation of Solutions for Parenteral Use
Sulmagraf drug is compatible with injection grade water, 5% dextroglucose solution, 0.9 % sodium chloride solution, 5% dextroglucose solution in 0.225 % sodium chloride solution and 5% dextroglucose solution in 0.9 % sodium chloride solution in concentrations varying from 10 mg/mL of Cefoperazone and 5 mg/mL of Sulbactam to 250 mg/mL and 125 mg/mL accordingly.

Preparation of the Solution:

• Intramuscular (I.M.) injection

To prepare solution for I.M. injections, injection grade water or 2 % lidocaine hydrochloride solution should be used. It is prohibited to use 2 % lidocaine hydrochloride solution for the drug initial dilution taking into consideration their incompatibility. Compatibility can be achieved through two- stage preparation of the solution. Primarily the drug should be diluted in injection grade water and then -in 2 % lidocaine hydrochloride solution. The above Table specifies solvent cumulative volume.
The end solution should contain Cefoperazone/Sulbactam in the ratio 125 mg/125 mg in 1 mL of 0.5 % lidocaine (hydrochloride) solution.

•  Intravenous (I.V.) injection
To prepare solution for infusion injections, the vial content should be diluted as specified in the Table in one of the following infusion solutions: 5% dextroglucose solution, 5% dextroglucose solution in 0.225 % sodium chloride and 5% dextroglucose solution in 0.9 % sodium; 0.9 % sodium chloride solution The solution obtained should be diluted to 20-100 mL by the same solvent used for the initial dilution. Intravenous drip-feed should be provided for 15-60 minutes.

Preparation of Solutions with the Use of Lactated Ringer’s Solution
Lactated Ringer’s solution is unsuitable for the purpose of initial diluting the drug taking into consideration their incompatibility. Compatibility can be achieved through two- stage preparation of the solution: first of all, injection grade water should be used (see the Table above), then the solution obtained should be diluted by lactated Ringer’s solution to the 5 mg/mL concentration of Sulbactam (each 1 mL of the initial solution should be diluted in 25 mL of lactated Ringer’s solution).

For I.V. injections the vial content should be dissolved in adequate volume (the solvent volume is specified in the Table above) of one of solvents described in infusion solution preparation (see above) and should be injected for at least 3 minutes.

Adverse Effects
In general, the drug has good acceptability. Severity level of majority adverse effects was mild and medium.

All untoward reactions listed in the Instructions for medical use of the drug are presented in accordance with the MedDRA (Medical Dictionary for Regulatory Activities terminology) classification. Untoward reaction frequencies in each category are presented in accordance with the clinical priority.

Frequencies pursuant to CIOMS (Council For International Organizations Of Medical Sciences) III categories are as follows: very common ≥ 1/10 (≥ 10 %); common ≥ 1/100 & < 1/10 (≥ 1 % и < 10 %); uncommon 1/1,000 & < 1/100 (≥ 0.1 % & < 1 %);unknown: it is impossible to determine the frequency based on data available.

Untoward Reactions Table

§ – To calculate frequencies of adverse reactions in the form of deviations from target figures of laboratory analyses all data available on analyses results was taken into consideration including data on patients with deviations observed at the initial stage. Such prudent approach was utilized because the initial data did not allow to divide patients with analyses results deviations into subsets at the initial stage since there were changes in analyses results of some patients after initiation of treatment; and there were no significant changes in analyses results of other part of patients with analyses results deviations after initiation of the treatment.

As for the data on white blood/neutrophil/platelet hemoglobin/counts & hematocrit level, study reports inform only about deviations from the rated values. There is no data on increase or decrease in blood values.

† – There is information on fatal cases.

Overdosage
Data on acute toxicity of Cefoperazone/Sulbactam for humans is limited. In case of overdosage, adverse effects (recorded during the use of the drug) could be expected. It should be kept in mind that high concentration of beta-lactam antibiotics in     cerebrospinal fluid may result in neurological disorders, including convulsions.

Treatment: to be symptomatic; haemodialysis is effective especially for the patients with compromised kidney function.

Interactions with Other Medicinal Products
Solutions of Sulmagraf drug and aminoglycosides should not be mixed taking into consideration their incompatibility. For the combination therapy with the use of Sulmagraf and aminoglycosides, two medicinal preparations should be introduced by means of successive infusions with the use of separate secondary catheters; and when one venous access is utilized a primary catheter should be washed thoroughly by a solution between dosing of preparations. Intervals between dosing of Sulmagraf drug and aminoglycoside during the day should be as long as possible.

Ethanol
When ethanol was administered during the treatment with Cefoperazone, disulfiram-like reactions were recorded for 5 days after its injection; such reactions were marked by “hot flushes”, hidrosis, headache and tachycardia. That’s why for the patients who needed artificial feeding (ingested or parenterally) the use of solutions containing ethanol should be avoided.

When using Benedict’s or Fehling’s solutions, a false-positive reaction to urinary glucose may be observed.

Special Instructions
There was information about hypersensitivity reactions including those resulting in fatalities during the treatment by beta- lactam antibiotics, including cephalosporins and Cefoperazone/Sulbactam. Risks of hypersensitivity reactions including those resulting in death are higher for the patients whose medical history revealed hypersensitivity reactions to many allergens. Prior to commencement of therapy with Cefoperazone/Sulbactam a thoroughgoing questioning should be provided for in order to find out if the patient had earlier hypersensitivity reactions to cephalosporins, penicillins and any other medicinal products (see “Contraindications” section). Antibiotics should be prescribed for any patient with care if such patient has any type of allergy especially to drugs. In case of allergic reaction occurrence, it is necessary to discontinue the drug and prescribe an adequate therapy. In case of severe anaphylactic reactions (see “Adverse Drug Reaction” section) urgent introduction of epinephrin, glucocorticosteroids is required; patency of airways, including intubation, should be ensured. Severe skin reactions, such as toxic epidermal necrolysis, Stevens- Johnson syndrome (SJS), exfoliative dermatitis, in some case with fatalities (see “Contradictions” section), were observed in patients treated with Cefoperazone/Sulbactam. If severe reactions develop, it is necessary to terminate the use of Cefoperazone/Sulbactam and prescribe a relevant treatment.

Patients should be warned about disulfiram-like reactions occurrence in case of consumption of alcoholic beverages if the patients are treated with Sulfagraf.

Severe bile duct obstruction, serious liver diseases as well as compromised kidney function combined with any condition specified may require change in dosing.

Cefoperazone concentration in serum of patients with compromised liver function and associated kidney disorder should be monitored and their dosage should be adjusted in case of need. If a daily dose of Cefoperazone does not exceed 2 g, there is no need to exercise control over its concentration in serum.

There were severe (major) bleeding rates, including fatalities, of patients treated with Cefoperazone/Sulbactam. Some patients treated with Cefoperazone suffered from vitamin K deficiency resulting in coagulopathy. It is very likely caused by down-regulation of gut indigenous flora which synthetizes this vitamin. Some groups of patients are considered at risk due to hypoalimentation, malabsorption syndrome (e.g.mucoviscidosis) or long term intravenous (I.V.) artificial feeding. In such cases, as well as for patients administering anticoagulants, it is necessary to exercise control over prothrombin time; and prescribe vitamin K when medically indicated. It is essential to terminate Cefoperazone/Sulbactam administration if there are persistent hemorrhages with no alternative causes for their occurrence.

In case of long term treatment with Sulmagraf, insensitive bacterial overgrowth may be observed as is the case with other antibiotics. During the treatment patients should be carefully monitored. In case of long term treatment it is recommended to exercise periodic control over indices of organ functions, including kidneys, liver and hematopoietic system. It is particularly important for newborn infants, first of all, for immature ones and young children.

It was informed about diarrhea cases connected with Clostridium difficile when practically all antimicrobial drugs were used, including Cefoperazone/Sulbactam. Diarrhea severity may vary from mild form to severe form. Treatment with antimicrobial drugs damages the gut indigenous flora resulting in overgrowth of Clostridium difficile.

Clostridium difficile produces A and B toxins which cause progress of diarrhea connected with Clostridium difficile. Abundant number of toxins generated by Clostridium difficile strains may cause increase in case fatality rates of patients since such infections may be resistant to the antimicrobial therapy; in this case colectomy may be required. The use of drugs that inhibit intestinal motility is contraindicated.

Possible progress of diarrhea connected with Clostridium difficile should be taken into consideration for all patients suffering from diarrhea followed by the use of antibiotics. Extensive medical monitoring should be provided for 2 months for the patients recovered from diarrhea connected with Clostridium difficile after introduction of antimicrobial drugs. Administration by Newborn Infants

Cefoperazone/Sulbactam is effective for newborn infants. But the use of this drug for newborn infants, including immature ones, has not been thoroughly studied. Thus, prior to treating immature and newborn infants with Sulmagraf drug, it is necessary to assess the benefit level for a patient and risk for developing severe adverse reactions.

Cefoperazone doesn’t displace bilirubin from albuminous compounds in blood plasma.

Effects on the Ability to Drive and Use Machines
Based on clinical practice of Sulmagraf use there is little likelihood of its effect on the ability to drive and use mechanisms.

Dispensing Form
Powder to prepare solutions for intravenous (I.V.) and intramuscular (I.M.) injections, 0.25 g + 0.25 g; 0.5 g + 0.5 g; 0.75 g + 0.75 g; 1.5 g + 1.5 g; 2,0 g + 2.0 g.

If the drug is produced at Suzhou Dawnrays Pharmaceutical Co. Ltd. China:
0.25 g + 0.25 g; 0.5 g + 0.5 g; 0.75 g + 0.75 g; 1.5 g + 1.5 g; 2,0 g + 2.0 g of active substances should be placed in vials made of colorless glass of the 1st type with a halobutyl rubber stopper and a combined aluminum-plastic cap.

1 vial with the drug and instructions for medical use should be placed in an outer carton.
For in-patient facilities: 10 vials with the drug in outer cartons should be placed in a carton box. A vial should be placed into an outer carton together with the instructions for medical use.

If the drug is produced at Ruzpharma LLC, Russia:
0.25 g + 0.25 g; 0.5 g + 0.5 g or 0.75 g + 0.75 g of active substances should be placed in vials made of colorless glass of the 1st hydrolytic class with a volume of 10 or 20 mL. 1.5 g + 1.5 g or 2,0 g + 2.0 g of active substances should be placed in vials made of colorless glass of the 1st hydrolytic class with a volume of 20 mL.  Vials should be hermetically closed by medical rubber stoppers, crimped with aluminum caps or combined caps (aluminum caps with protective plastic covers).

1 a vial with the drug and instructions for medical use should be placed in an outer carton.

For in-patient facilities: 10-50 vials with the drug and equal quantity of instructions for medical use should be placed in a carton box.

Storage Conditions
In places protected from the light at a temperature not exceeding 25 °C.
Keep out of the reach of children.

Expiry Date
2 years
Do not use after expiry date.

Drug Dispensing Terms
Dispensed as medical prescription.

Name and Address of the Legal Entity in Which Name
the Marketing Authorization Was Issued
Suzhou Dawnrays Pharmaceutical Co. Ltd., China/
Suzhou Dawnrays Pharmaceutical Со. Ltd., China.
215128, People’s Republic of China, Suzhou, “Wuzhong” Economic Growth District, Tyanling street, 22.

Manufacturer
Suzhou Dawnrays Pharmaceutical Co. Ltd., China/
Suzhou Dawnrays Pharmaceutical Со. Ltd., China.

Production site address:
215128, People’s Republic of China, Suzhou, “Wuzhong” Economic Growth District, Tyanling street, 22.
Tel.: +86-(512)-6562-6868; Fax +86-(512)-6562-8688
Web-site: www.dawnrays.com
OR
Ruzpharma, LLC, Russia
Production site address:
143132, Moscow Oblast Ruzsky District, Tuchkovo work settlement, ul. Komsomolskya, d.12, str.1.

Representative Office in the RF
Phamnovatsii LLC, Russia
127055, Moscow, ul. Sushchevskaya, d.27, str.2, etazh 3, pom. III, kom. 3, office 39

Company Receiving Consumers’ Complaints
PHARMCOMPLIANCE PHARMACOVIGILANCE AGENCY, Limited Lability Company
117186, Moscow, ul. Nagornaya, d.15-8, pom. I, office 61.
Tel: +7 495 142 24 87
Cell No.: 7 901 369 45 95
e-mail: pv@farmakonadzor.com

Director General
Phamnovatsii LLC

D.O. Prokopenko