Macrocef powder for solution for injection 1000 mg + 1000 mg vial No. 5

Instructions for Macrocef powder for solution for injection 1000 mg + 1000 mg vial No. 5

Composition

active ingredients: cefoperazone, sulbactam;

1 vial contains: cefoperazone sodium equivalent to cefoperazone 1000 mg, sulbactam sodium equivalent to sulbactam 1000 mg.

Dosage form

Powder for solution for injection.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group

Antibacterial agents for systemic use.

Beta-lactam antibiotics. Third generation cephalosporins.

ATX code J01D D62.

Pharmacological properties

Pharmacodynamics

Cefoperazone sodium is a semisynthetic cephalosporin antibiotic of the third generation with a broad spectrum of action, used only parenterally. Sulbactam sodium is a derivative of the basic penicillin nucleus. Cefoperazone acts by inhibiting the biosynthesis of the mucopeptide of the bacterial cell wall. Sulbactam acts as a beta-lactamase inhibitor, thereby restoring the activity of cefoperazone against strains that produce beta-lactamase.

Mechanism of action.

The antibacterial component of the drug Macrocef is cefoperazone - a 3rd generation cephalosporin that acts against sensitive microorganisms in the stage of active multiplication by inhibiting the biosynthesis of cell wall mucopeptide. Sulbactam does not have pronounced antibacterial activity, except for activity against Neisseriaceae and Acinetobacter. However, biochemical studies on cell-free bacterial systems have shown that sulbactam is an irreversible inhibitor of the most important beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the degradation of penicillins and cephalosporins by resistant organisms has been demonstrated in whole-organism studies using resistant strains, in which sulbactam demonstrated marked synergism with penicillins and cephalosporins. Since sulbactam also binds to some penicillin-binding proteins, susceptible strains are often more susceptible to Macrocef than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, synergism of action is observed (a decrease in the minimum concentrations of the combination that inhibit microorganisms by approximately 4 times compared to such concentrations of each component separately) with the most pronounced effect against the following microorganisms: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Macrocef exhibits in vitro activity against a wide range of clinically significant microorganisms.

Gram-positive microorganisms:

- Staphylococcus aureus (strains that produce or do not produce penicillinase);

- Staphylococcus epidermidis;

- Streptococcus pneumoniae (previous name 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 microorganisms:

- Escherichia coli;

- Klebsiella species;

- Enterobacter species;

- Citrobacter species;

- Haemophilus influenzae;

- Proteus mirabilis;

- Proteus vulgaris;

- Morganella morganii (previous name Proteus morganii);

- Providencia rettgeri (previous name 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 microorganisms:

- 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 range of sensitivity to the drug Macrocef has been established.

Minimum inhibitory concentrations (MICs) (µg/ml as cefoperazone concentrations):

Dimensions of the sensitive zone disk (mm, Kirby-Bauer test):

Serial dilutions of Macrocef can be used to determine the MIC using the agar or broth dilution method. The use of a disk susceptibility test containing 30 μg of sulbactam and 75 μg of cefoperazone is recommended. A laboratory response of “susceptible” means that therapy with Macrocef is likely to be effective against the infecting organism, and a response of “resistant” means that such an effective effect is unlikely. An “intermediate” response means that the organism may be susceptible to Macrocef when used at higher doses or if the infection has developed in tissues or body fluids where high concentrations of the antibiotic are reached.

Recommended quality control limits for sulbactam/cefoperazone 30 µg/75 µg susceptibility disks:

Pharmacokinetics

Distribution.

The mean peak concentrations of sulbactam and cefoperazone following a single 2 g dose (1:1 ratio) of sulbactam and cefoperazone (1 g sulbactam + 1 g cefoperazone) administered intravenously over 5 minutes to healthy volunteers were 130 and 236.8 μg/mL, respectively. This indicates a larger volume of distribution for sulbactam (Vd = 18.0–27.6 L) compared to cefoperazone (Vd = 10.2–11.3 L).

The mean maximum concentrations of sulbactam and cefoperazone after intravenous administration over 15 minutes of a single dose of 4.5 g (in a ratio of 1:2) of the drug (1.5 g sulbactam + 3 g cefoperazone) in healthy volunteers were 88.3 μg/ml and 416.1 μg/ml, respectively.

The maximum serum concentrations of sulbactam and cefoperazone after the first intramuscular injection of 1.5 g of the drug (0.5 g of sulbactam + 1 g of cefoperazone) in healthy volunteers were 11 μg/ml and 45.3 μg/ml and 29.9 μg/ml and 58.4 μg/ml, respectively, after the seventh dose when the drug was administered every 12 hours.

Breeding.

When the drug is used, approximately 84% of the sulbactam dose and 25% of the cefoperazone dose are excreted by the kidneys. Most of the remaining cefoperazone dose is excreted in the bile. After administration, the mean half-life of sulbactam is approximately 1 hour and that of cefoperazone is 1.7 hours. Plasma concentrations are proportional to the administered dose. These data are consistent with previously published pharmacokinetic studies of these components when administered separately.

After intramuscular administration of 1.5 g of the drug (0.5 g of sulbactam and 1 g of cefoperazone), maximum plasma concentrations of sulbactam and cefoperazone were reached within 15 minutes to 2 hours after administration. The mean maximum plasma concentrations were 19 and 64.2 μg/ml for sulbactam and cefoperazone, respectively.

After multiple administration of the drug, no significant changes in the pharmacokinetics of the components of the drug Macrocef were reported, and their cumulation was not observed when administered every 8–12 hours.

Patients with liver dysfunction.

See the section "Application features".

Patients with renal impairment.

In patients with varying degrees of renal impairment, the total body clearance of sulbactam was significantly correlated with the determined creatinine clearance. In patients with renal insufficiency, the half-life of sulbactam was significantly longer (mean 6.9 and 9.7 hours, respectively, in different studies). The use of hemodialysis significantly changes the half-life, total body clearance, and volume of distribution of sulbactam. No significant differences in the pharmacokinetics of cefoperazone were observed in patients with renal insufficiency.

Elderly patients.

The pharmacokinetics of the drug have been studied in elderly patients with renal and hepatic impairment. Both components of the drug, sulbactam and cefoperazone, had a longer half-life, lower clearance, and larger volume of distribution compared with the corresponding values in healthy volunteers. The pharmacokinetic data for sulbactam correlate well with the degree of renal impairment, while the data for cefoperazone correlate well with the degree of hepatic impairment.

Children.

Studies in children have shown no significant changes in the pharmacokinetics of the components of the drug compared to adult patients. In children, the mean half-life of sulbactam ranged from 0.91 to 1.42 hours and that of cefoperazone from 1.44 to 1.88 hours.

Sulbactam and cefoperazone are well distributed in various tissues and fluids of the body, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, etc.

There is no evidence of a pharmacokinetic interaction between sulbactam and cefoperazone when they are used together in the form of the drug Macrocef.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Indication

The drug is used to treat infections caused by sensitive strains of microorganisms:

– respiratory tract infections (upper and lower);

– cholecystitis, cholangitis, peritonitis and other abdominal infections;

– urinary tract infections (upper and lower);

– septicemia;

– meningitis;

– skin and soft tissue infections;

– bone and joint infections;

– pelvic inflammatory disease, endometritis, gonorrhea and other genital infections.

Contraindication

Contraindicated in patients with hypersensitivity to the active substances (sulbactam, cefoperazone), to beta-lactams or any excipients.

Interaction with other medicinal products and other types of interactions

Combination therapy. Given the broad spectrum of activity of the drug, Macrocef can be used as monotherapy for adequate treatment of most infections. However, under certain indications, the drug can be used together with other antibiotics. When using aminoglycosides simultaneously (see the section "Method of administration and dosage"), it is necessary to monitor renal function throughout the course of therapy (see the section "Incompatibility").

Alcohol. When drinking alcohol during the course of treatment and within 5 days after the use of cefoperazone, reactions such as facial flushing, sweating, headache, tachycardia were noted. Similar reactions were observed with the use of some other cephalosporins. Patients should be warned about possible adverse reactions that occur when drinking alcoholic beverages while using the drug Macrocef. When using artificial nutrition (oral or parenteral), solutions containing ethanol should not be used.

Interaction with substances used in laboratory tests. The reaction to glucose in the urine may be falsely positive when using Benedict's or Fehling's solution.

Application features

Hypersensitivity: Severe and sometimes fatal hypersensitivity reactions (anaphylactic reactions) have been reported in patients receiving beta-lactam or cephalosporin antibiotics, including sulbactam/cefoperazone. These reactions are more likely to occur in individuals with a history of hypersensitivity reactions to multiple allergens.

Before initiating therapy with sulbactam/cefoperazone, careful inquiry should be made regarding the patient's history of hypersensitivity reactions to cephalosporins, penicillins, or other drugs (see Contraindications). Antibiotics should be administered with caution to patients with known allergies, especially to drugs.

If allergic reactions develop, the drug should be discontinued and appropriate treatment should be initiated. Severe anaphylactic reactions require immediate administration of epinephrine. If necessary, oxygen therapy, intravenous steroids, and airway management, including intubation, should be considered (see Adverse Reactions).

Severe skin reactions, sometimes fatal, such as toxic epidermal necrolysis, Stevens-Johnson syndrome and exfoliative dermatitis, have been reported in patients receiving sulbactam/cefoperazone. If a severe skin reaction occurs, sulbactam/cefoperazone should be discontinued and appropriate treatment initiated (see section 4.8).

Use in hepatic impairment. Cefoperazone is largely excreted in the bile. In patients with liver disease and/or biliary obstruction, the serum half-life of cefoperazone is generally prolonged and urinary excretion is increased. Even in severe hepatic impairment, therapeutic concentrations of cefoperazone are observed in the bile and only a 2- to 4-fold prolongation of the half-life is observed.

Dose adjustment may be necessary in cases of severe biliary obstruction, severe liver disease, or renal dysfunction associated with any of these conditions.

In patients with impaired liver function and concomitant renal dysfunction, serum cefoperazone concentrations should be monitored and the dosage adjusted if necessary. Unless careful monitoring of serum concentrations is performed, the dose of cefoperazone should not exceed 2 g/day.

General Precautions: Bleeding, sometimes fatal, has been reported with sulbactam/cefoperazone. As with other antibiotics, vitamin K deficiency, resulting in coagulopathy, has been reported in patients receiving sulbactam/cefoperazone. The mechanism of this phenomenon is likely to be due to suppression of the intestinal bacterial flora that normally synthesizes vitamin K. Patients at risk include those with restricted nutrition, malabsorption, and those receiving prolonged parenteral (intravenous) nutrition. In such patients and in patients taking oral anticoagulants, prothrombin time (or international normalized ratio) should be monitored for possible bleeding, thrombocytopenia, and vitamin K should be administered if indicated. In the event of prolonged bleeding, if there is no other cause for this phenomenon, sulbactam/cefoperazone should be discontinued.

Clostridium difficile-associated diarrhea. Clostridium difficile-associated diarrhea has been reported with nearly all antibacterial agents, including sulbactam sodium/cefoperazone sodium. The severity of the symptoms may range from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal intestinal flora and leads to overgrowth of C. difficile.

C. difficile produces toxins A and B, which in turn contribute to diarrhea. Hypertoxin-producing strains of C. difficile increase morbidity and mortality because such infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in all patients with diarrhea associated with antibacterial therapy. A careful history is necessary, as diarrhea associated with C. difficile has been reported to develop 2 months after completion of antibacterial therapy.

Children: Macrocef has been used effectively in infants, but comprehensive studies of the drug in premature or full-term newborns have not been conducted. Therefore, before starting treatment in premature or full-term newborns, the potential benefits and risks of using the drug should be carefully evaluated.

In newborns with bilirubin encephalopathy, cefoperazone does not displace bilirubin from plasma protein binding sites.

This medicine contains sodium - caution should be exercised when using the drug in patients with impaired renal function or patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Pregnancy. Studies of the effect of the drug on reproductive function, which were conducted in rats at doses 10 times higher than the human dose, did not reveal evidence of impaired fertility or teratogenic effects. Sulbactam and cefoperazone penetrate the placental barrier, but there are no comprehensive and well-controlled studies in pregnant women. Given that the results of studies on the effect of the drug on reproductive function in animals cannot always be extrapolated to humans, the drug should be used during pregnancy only if there are clear indications.

Breastfeeding. Only a small portion of the administered dose of sulbactam and cefoperazone passes into breast milk. Macrocef should be administered with caution to nursing mothers, despite the fact that both components of the drug pass into breast milk in small amounts.

Ability to influence reaction speed when driving vehicles or other mechanisms

The effect of the drug on the ability to drive or operate other mechanisms is unlikely.

Method of administration and doses

Macrocef (sulbactam sodium/cefoperazone sodium combination) is available in vials and is for parenteral use only.

Adults: The usual adult dose is 2–4 g/day (i.e. 1 to 2 g cefoperazone/day) administered intravenously or intramuscularly in equally divided doses every 12 hours.

In severe or refractory infections, the daily dose of the drug may be increased to 8 g (i.e., the dose of cefoperazone is 4 g), administered intravenously in equally divided doses every 12 hours. The recommended maximum daily dose of sulbactam is 4 g (8 g of the drug).

Hepatic impairment. See section "Special warnings and precautions for use".

Use in renal impairment. The dosage regimen for the drug should be adjusted for patients with significantly reduced renal function (creatinine clearance less than 30 ml/min) to compensate for the reduced clearance of sulbactam. Patients with creatinine clearance 15-30 ml/min should be prescribed sulbactam at a maximum dose of 1 g administered every 12 hours (maximum daily dose of sulbactam - 2 g), and patients with creatinine clearance less than 15 ml/min should be prescribed sulbactam at a maximum dose of 500 mg administered every 12 hours (maximum daily dose of sulbactam - 1 g). In severe infections, additional separate administration of cefoperazone may be necessary.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

The serum half-life of cefoperazone is slightly reduced during hemodialysis. Therefore, the dosage regimen should be adjusted according to the dialysis period.

Use in the elderly. See section "Pharmacokinetics".

Use in the treatment of children. The usual daily dose of the drug for children is 40 to 80 mg / kg body weight (i.e. 20–40 mg cefoperazone / kg body weight), evenly divided into 2–4 doses.

In severe or refractory infections, the daily dose may be increased to 160 mg/kg body weight (80 mg cefoperazone/kg body weight), divided into 2-4 doses (see section "Special instructions").

Use for the treatment of newborns. Newborns of the 1st week of life should be given the drug every 12 hours. The maximum daily dose of sulbactam for children should not exceed 80 mg / kg body weight (160 mg / kg body weight of the drug Macrocef). If it is necessary to use a dose of cefoperazone exceeding 80 mg / kg body weight / day, an additional dose of cefoperazone should be prescribed separately (see the section "Features of use").

Method of administration and doses

Intravenous administration.

For drip infusion, the contents of each vial of Macrocef should be reconstituted in an appropriate amount of 5% aqueous dextrose solution, 0.9% sodium chloride solution for injection, or water for injection, and then made up to 20 ml with the same solution, followed by administration over 15–60 minutes.

Restoration.

Lactated Ringer's solution is an acceptable solvent for intravenous infusion, but not for initial reconstitution (see section "Incompatibilities").

For intravenous injection, the contents of each vial should be diluted as described above and administered over at least 3 minutes.

Intramuscular injection.

The drug is compatible with the following solvents: water for injection, 5% glucose solution, 0.9% sodium chloride solution, 5% glucose solution in 0.225% sodium chloride solution and 5% dextrose solution in 0.9% sodium chloride solution. Cefoperazone is compatible at concentrations ranging from 10 to 250 mg per 1 ml of solvent. Sulbactam is compatible at concentrations ranging from 5 to 125 mg per 1 ml of solvent.

Lactated Ringer's solution. Sterile water for injections should be used for reconstitution (see section "Incompatibilities"). A two-step dilution using sterile water for injections is required (see table above); the resulting solution should then be diluted with lactated Ringer's solution to obtain a sulbactam concentration of 5 mg/ml (50 ml or 100 ml of lactated Ringer's solution should be added to 2 ml or 4 ml of the initially diluted solution, respectively).

Lidocaine. Lidocaine hydrochloride 2% solution is an acceptable solvent for the preparation of a solution for intramuscular administration, but not for initial dilution. Sterile water for injections should be used for reconstitution (see section "Incompatibilities").

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children. The drug is used in children (see section "Method of administration and dosage").

Overdose

Information on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans is limited. Overdosage of the drug is expected to produce effects that are primarily an increase in the adverse effects reported with the drug. It should be noted that high concentrations of beta-lactam antibiotics in the cerebrospinal fluid may cause neurological reactions, including convulsions. Since cefoperazone and sulbactam are removed from the circulation by hemodialysis, this procedure may enhance the elimination of the drug in case of overdose in patients with impaired renal function.

Adverse reactions

The drug is generally well tolerated. Most adverse reactions are mild or moderate in severity and have a favorable course with long-term treatment.

The following are the adverse reactions observed during the administration of the drug Macrocef. The frequency of adverse reactions is indicated as: very common (≥ 1/10), common (≥ 1/100 - frequency unknown (cannot be estimated from the available information).

Adverse reactions are listed by MedRA [Medical Dictionary for Regulatory Activities] system organ class in order of clinical importance.

* Adverse reactions reported in the post-marketing period.

† All available laboratory values, including those from patients with baseline abnormalities, were included in the calculation of the incidence of laboratory abnormalities. This conservative approach was taken because the baseline information does not allow us to differentiate between subgroups of patients with baseline abnormalities who had significant treatment-related changes in laboratory values and those who did not.

Abnormalities in leukocyte, neutrophil, platelet, hemoglobin, and hematocrit levels were observed only during the studies. Elevations and decreases in levels were not differentiated.

§ Fatalities have been reported.

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the link: https://aisf.dec.gov.ua/.

Expiration date

2 years (from the date of manufacture of the bulk form).

Storage conditions

Store in the original packaging out of the reach of children at a temperature not exceeding 25 °C.

Incompatibility

Aminoglycosides. Solutions of the drug Macrocef and aminoglycosides should not be directly mixed, since there is a physical incompatibility between them. If there is a need for combined therapy with the drug Macrocef and aminoglycosides, their sequential separate drip infusion should be used, using a separate secondary intravenous infusion system, while the primary intravenous infusion system should be thoroughly flushed with an approved solution between infusions of the specified drugs. It is also advisable that the intervals between the administration of the drug Macrocef and aminoglycosides during the day should be as long as possible.

Lactated Ringer's Solution: Initial dilution with lactated Ringer's Solution is not recommended as these substances have been shown to be incompatible. However, the use of a two-step dilution process, in which the primary solvent is water for injections, allows the avoidance of incompatibility upon further dilution with lactated Ringer's Solution (see section 4.2).

Lidocaine: Initial dilution with 2% lidocaine solution is not recommended as these substances are incompatible. However, the use of a two-step dilution process, in which the primary solvent is water for injections, allows to avoid incompatibility upon further dilution with 2% lidocaine chloride solution (see section "Method of administration and dosage").

Packaging

1 or 5 vials of powder in a cardboard box.

Vacation category

According to the recipe.

Producer

LLC "ISTPHARM", Ukraine (packaging from the form in bulk NSPS Hebei Huamin Pharmaceutical Company Limited, China).

Location of the manufacturer and address of its place of business

Ukraine, 02099, Kyiv, Remontna St., 13