Macrocef

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Macrocef (Macrocef)

Composition:

Active substances: cefoperazone, sulbactam;

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

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or almost white powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use.
Beta-lactam antibiotics. Third-generation cephalosporins.
ATC code J01D D62.

Pharmacological properties.

Pharmacodynamics.

Cefoperazone sodium is a semi-synthetic third-generation cephalosporin antibiotic with a broad spectrum of activity, administered only by the parenteral route. Sulbactam sodium is a derivative of the basic penicillin nucleus. Cefoperazone acts by inhibiting the biosynthesis of the bacterial cell wall mucopeptide. Sulbactam acts as a beta-lactamase inhibitor, thereby restoring cefoperazone's activity against strains that produce beta-lactamase.

Mechanism of action.

The antibacterial component of the medicinal product Macrocef is cefoperazone—a third-generation cephalosporin that acts against susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the cell wall mucopeptide. Sulbactam has no significant intrinsic 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 key beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the degradation of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies using intact microorganisms and resistant strains, during which sulbactam demonstrated pronounced synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains often become more vulnerable to the action of the medicinal product Macrocef than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all microorganisms susceptible to cefoperazone. In addition, synergistic action is observed (reduction of minimum inhibitory concentrations of the combination against microorganisms by approximately four times compared to each component alone), with the most pronounced effect against the following microorganisms: Haemophilus influenzae, species of Bacteroides, species of Staphylococcus, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Macrocef demonstrates in vitro activity against a broad spectrum of clinically significant microorganisms.

Gram-positive microorganisms:

• Staphylococcus aureus (strains producing or not producing penicillinase);
• Staphylococcus epidermidis;
• Streptococcus pneumoniae (former name Diplococcus pneumoniae);
• Streptococcus pyogenes (beta-hemolytic streptococci group A);
• Streptococcus agalactiae (beta-hemolytic streptococci group B);
• most other strains of beta-hemolytic streptococci;
• many strains of Streptococcus faecalis (enterococci).

Gram-negative microorganisms:

• Escherichia coli;
• species of Klebsiella;
• species of Enterobacter;
• species of Citrobacter;
• Haemophilus influenzae;
• Proteus mirabilis;
• Proteus vulgaris;
• Morganella morganii (former name Proteus morganii);
• Providencia rettgeri (former name Proteus rettgeri);
• species of Providencia;
• species of Serratia (including S. marcescens);
• species of Salmonella and Shigella;
• Pseudomonas aeruginosa and some other species of Pseudomonas;
• Acinetobacter calcoaceticus;
• Neisseria gonorrhoeae;
• Neisseria meningitidis;
• Bordetella pertussis;
• Yersinia enterocolitica.

Anaerobic microorganisms:

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

The following range of susceptibility to the medicinal product Macrocef has been established.

Minimum inhibitory concentrations (MIC) (μg/mL, as cefoperazone concentrations):

Disk size of the sensitive zone (mm, Kirby-Bauer test):

To determine the MIC, serial dilutions of the drug Macrocef can be used by means of the agar or broth dilution method. It is recommended to use a disk susceptibility test containing 30 mcg of sulbactam and 75 mcg of cefoperazone. A laboratory report of "susceptible" indicates that therapy with the drug Macrocef is likely to be effective against the microorganism causing the infection, whereas a report of "resistant" indicates that such effective action is unlikely. A report of "intermediate" means that the microorganism may be susceptible to the drug Macrocef when administered at higher doses or if the infection has developed in those tissues or body fluids where high antibiotic concentrations are achieved.

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

Pharmacokinetics.

Distribution.

The mean peak concentrations of sulbactam and cefoperazone after 5-minute intravenous administration of a single 2 g dose (in a 1:1 ratio) of the drug (1 g sulbactam + 1 g cefoperazone) in healthy volunteers were 130 and 236.8 mcg/mL, respectively. This indicates a larger volume of distribution of sulbactam (Vd = 18.0–27.6 L) compared to that of cefoperazone (Vd = 10.2–11.3 L).

The mean peak concentrations of sulbactam and cefoperazone after 15-minute intravenous administration of a single 4.5 g dose (in a 1:2 ratio) of the drug (1.5 g sulbactam + 3 g cefoperazone) in healthy volunteers were 88.3 mcg/mL and 416.1 mcg/mL, respectively.

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

Elimination.

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 via bile. After administration of the drug, the mean elimination 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 correspond to previously published results of pharmacokinetic studies of these components when administered separately.

After intramuscular administration of 1.5 g of the drug (0.5 g sulbactam and 1 g cefoperazone), peak plasma concentrations of sulbactam and cefoperazone were achieved between 15 minutes and 2 hours after administration. Mean peak plasma concentrations were 19 and 64.2 mcg/mL for sulbactam and cefoperazone, respectively.

With repeated administration of the drug, no significant changes in the pharmacokinetics of the components of the drug Macrocef have been reported, and no accumulation was observed when administered every 8–12 hours.

Patients with hepatic impairment.
See section "Special precautions".

Patients with renal impairment.

In patients with varying degrees of renal impairment receiving the drug, total systemic clearance of sulbactam strongly correlated with creatinine clearance. In patients with non-functioning kidneys, the elimination half-life of sulbactam was significantly prolonged (averaging 6.9 and 9.7 hours according to different studies). Hemodialysis significantly alters the elimination half-life, total systemic 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 were studied in elderly patients with impaired renal and hepatic function. Both components of the drug, sulbactam and cefoperazone, had a longer elimination half-life, lower clearance, and larger volume of distribution compared to those in healthy volunteers. Pharmacokinetic data for sulbactam correlate well with the degree of renal impairment, whereas data for cefoperazone correlate well with the degree of hepatic impairment.

Children.

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

Sulbactam and cefoperazone are well distributed into various tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, and others.

There is no evidence of pharmacokinetic interaction between sulbactam and cefoperazone when co-administered in the form of the drug Macrocef.

Cefoperazone does not displace bilirubin from binding sites on plasma proteins.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of infections caused by susceptible strains of microorganisms:

• respiratory tract infections (upper and lower respiratory tract);
• cholecystitis, cholangitis, peritonitis, and other intra-abdominal infections;
• urinary tract infections (upper and lower urinary tract);
• septicemia;
• meningitis;
• skin and soft tissue infections;
• bone and joint infections;
• pelvic inflammatory diseases, endometritis, gonorrhea, and other genital infections.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

Combination therapy. Due to 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 may be used in combination with other antibiotics. When aminoglycosides are used concomitantly (see section “Administration and dosage”), renal function must be monitored throughout the course of therapy (see section “Incompatibilities”).

Alcohol. Reactions such as facial flushing, sweating, headache, and tachycardia have been reported when alcohol is consumed during treatment with cefoperazone and for 5 days after its administration. Similar reactions have also been observed with some other cephalosporins. Patients should be warned about possible adverse reactions that may occur when consuming alcoholic beverages during treatment with Macrocef. Solutions containing ethanol should not be used during enteral or parenteral nutrition.

Interaction with substances used in laboratory tests. False-positive urine glucose reactions may occur when using Benedict's or Fehling's solution.

Special precautions for use.

Hypersensitivity. Severe, and sometimes fatal, hypersensitivity reactions (anaphylactic reactions) have been reported in patients receiving beta-lactam or cephalosporin antibiotics, including sulbactam/cefoperazone. The likelihood of such reactions is higher in individuals with a history of hypersensitivity to multiple allergens.

Before initiating therapy with sulbactam/cefoperazone, carefully investigate the patient’s history of hypersensitivity reactions to cephalosporins, penicillins, or other drugs (see section "Contraindications"). Antibiotics should be administered with caution in patients with any type of allergy, particularly to drugs.

If allergic reactions occur, discontinue the drug and initiate appropriate treatment. Severe anaphylactic reactions require immediate administration of epinephrine. Oxygen therapy, intravenous corticosteroids, and measures to ensure airway patency, including intubation, may be necessary (see section "Adverse reactions").

Cases of severe skin reactions, sometimes fatal, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis, have been reported in patients treated with sulbactam/cefoperazone. If a severe skin reaction occurs, discontinue sulbactam/cefoperazone therapy and initiate appropriate treatment (see section "Adverse reactions").

Use in hepatic impairment. Cefoperazone is predominantly excreted via bile. In patients with hepatic disease and/or biliary obstruction, the serum half-life of cefoperazone is usually prolonged, and renal excretion increases. Even in cases of severe hepatic dysfunction, therapeutic concentrations of cefoperazone are achieved in bile, with only a 2- to 4-fold prolongation of the elimination half-life.

Dosage adjustment may be necessary in cases of severe biliary obstruction, severe hepatic disease, or renal impairment associated with any of these conditions.

In patients with both hepatic and concomitant renal impairment, serum cefoperazone concentrations should be monitored, and dosage adjusted as needed. If serum concentration monitoring is not feasible, the cefoperazone dose should not exceed 2 g/day.

General warnings. Hemorrhagic events, sometimes fatal, have been reported during treatment with sulbactam/cefoperazone. As with other antibiotics, vitamin K deficiency leading to coagulopathy has been observed in patients receiving sulbactam/cefoperazone. The mechanism is likely related to suppression of intestinal bacterial flora normally responsible for vitamin K synthesis. High-risk patients include those with restricted nutrition, malabsorption, and those receiving long-term parenteral (intravenous) nutrition. In such patients and in patients receiving oral anticoagulants, prothrombin time (or international normalized ratio) should be monitored to detect potential bleeding or thrombocytopenia, and vitamin K supplementation should be administered if indicated. If prolonged bleeding occurs without other identifiable cause, discontinue sulbactam/cefoperazone.

Prolonged use of antibiotics, including the medicinal product Macrocef, may lead to overgrowth of non-susceptible microorganisms. Patients should be closely monitored during treatment. As with other potent systemic agents, periodic monitoring for signs of organ system dysfunction—including renal, hepatic, and hematopoietic function—is recommended during prolonged use of Macrocef, particularly in premature infants and neonates.

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

C. difficile produces toxins A and B, which contribute to the development of diarrhea. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as such infections may be resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in all patients who develop diarrhea following antibacterial therapy. A careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after discontinuation of antibacterial therapy.

Children. Macrocef has been effectively used in infants; however, comprehensive studies on its use in premature or full-term neonates have not been conducted. Therefore, the potential benefits and risks of using the drug should be carefully evaluated before initiating treatment in premature or full-term neonates.

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

This medicinal product contains sodium — caution is advised when administering the drug to patients with impaired renal function or to those on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Studies in rats using doses 10 times higher than the human dose showed no evidence of impaired fertility or teratogenic effects. Sulbactam and cefoperazone cross the placental barrier, but comprehensive and well-controlled studies in pregnant women have not been conducted. Since animal reproductive study results may not always be extrapolated to humans, the drug should be used during pregnancy only if clearly indicated.

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

Ability to affect reaction speed when driving or operating machinery.

The effect of the medicinal product on the ability to drive or operate machinery is unlikely.

Administration and dosage.

Macrocef (sulbactam sodium / cefoperazone sodium combination) is supplied in vials and is administered only by the parenteral route.

Adults. The usual dose of the medicinal product for adults is 2–4 g per day (i.e. 1–2 g of cefoperazone per day) administered intravenously or intramuscularly in evenly divided doses every 12 hours.

In severe or refractory infections, the daily dose of the drug may be increased up to 8 g (i.e., cefoperazone dose — 4 g), administered intravenously in evenly 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 precautions".

Use in renal impairment. The dosing regimen should be adjusted in patients with significantly impaired renal function (creatinine clearance less than 30 mL/min) to compensate for reduced sulbactam clearance. In patients with creatinine clearance of 15–30 mL/min, sulbactam should be administered at a maximum dose of 1 g given every 12 hours (maximum daily sulbactam dose — 2 g). In patients with creatinine clearance less than 15 mL/min, sulbactam should be administered at a maximum dose of 500 mg every 12 hours (maximum daily sulbactam dose — 1 g). In severe infections, additional separate administration of cefoperazone may be required.

The pharmacokinetic profile of sulbactam is significantly altered during hemodialysis.

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

Use in elderly patients. See section "Pharmacokinetics".

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

For severe or refractory infections, the daily dose may be increased up to 160 mg/kg body weight (80 mg of cefoperazone/kg body weight), divided evenly into 2–4 doses (see section "Special Instructions").

Use for treatment of newborns. Newborns during the first week of life should receive 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 administer a dose of cefoperazone exceeding 80 mg/kg body weight/day, the additional dose of cefoperazone should be given separately (see section "Special Instructions").

Administration method.

Intravenous administration.

For intravenous infusion, the contents of each vial of the drug Macrocef should be reconstituted with an appropriate volume of 5% dextrose solution, 0.9% sodium chloride injection solution, or water for injections, then diluted to 20 ml with the same solution and administered over 15–60 minutes.

Reconstitution.

Ringer's lactate solution is an acceptable diluent for intravenous infusion, but not for primary 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 administration.

The medicinal product is compatible with the following diluents: water for injections, 5% glucose solution, 0.9% sodium chloride solution, 5% glucose in 0.225% sodium chloride solution, and 5% dextrose in 0.9% sodium chloride solution. Cefoperazone is compatible at concentrations ranging from 0.5 to 250 mg per 1 mL of diluent. Sulbactam is compatible at concentrations ranging from 5 to 125 mg per 1 mL of diluent.

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

Lidocaine. 2% lidocaine hydrochloride solution is an acceptable diluent for preparing a solution for intramuscular administration, but not for primary reconstitution. Sterile water for injections should be used for reconstitution (see section "Incompatibilities").

Unused medicinal product or waste material must be disposed of in accordance with local requirements.

Children. The medicinal product is used in children (see section "Dosage and administration").

Overdose.

There is limited information on acute toxicity of sodium cefoperazone and sodium sulbactam in humans. Overdose of the medicinal product is expected to produce manifestations that are mainly an extension of its known adverse effects reported during normal use. It should be noted that high concentrations of beta-lactam antibiotics in cerebrospinal fluid may cause neurological reactions, including seizures. Since cefoperazone and sulbactam are removed from circulation by hemodialysis, this procedure may enhance drug elimination in cases of overdose in patients with impaired renal function.

Adverse reactions.

The medicinal product is generally well tolerated. Most adverse reactions are of mild or moderate severity and have a favorable course during long-term treatment.

The adverse reactions listed below were observed during the use of the medicinal product Macrocef. The frequency of adverse reactions is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

Adverse reactions are listed by system organ classes according to MedDRA [Medical Dictionary for Regulatory Activities] in order of clinical importance.

* Adverse reactions reported during the post-marketing period.

† The frequency calculations for laboratory test abnormalities included all available laboratory values, including those from patients with abnormal baseline values. This conservative approach was adopted because baseline data did not allow differentiation between patient subgroups with baseline abnormalities who experienced treatment-related significant changes in laboratory parameters and those who did not.

Abnormalities in leukocyte, neutrophil, platelet, hemoglobin, and hematocrit levels were observed only during clinical trials. Increases and decreases in levels were not differentiated.

§ Reports of fatal outcomes have been received.

Reporting of adverse reactions after drug registration is of significant importance. It enables ongoing monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

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

Storage conditions.

Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Incompatibilities.

Aminoglycosides. Solutions of the medicinal product Macrocef and aminoglycosides should not be mixed directly due to physical incompatibility. If combination therapy with Macrocef and aminoglycosides is necessary, sequential separate infusion should be administered using a separate secondary intravenous infusion system, with the primary intravenous infusion line thoroughly flushed with an approved solution between infusions of the specified drugs. It is also advisable to maximize the time intervals between administrations of Macrocef and aminoglycosides within a 24-hour period.

Lactated Ringer’s solution. Primary dilution with lactated Ringer’s solution is not recommended, as these substances have been found to be incompatible. However, a two-step dilution process, in which the initial diluent is water for injections, can avoid incompatibility when further dilution with lactated Ringer’s solution is performed (see section “Instructions for use and dosage”).

Lidocaine. Primary dilution with 2% lidocaine solution is not recommended due to incompatibility. However, a two-step dilution process, in which the initial diluent is water for injections, can avoid incompatibility when further dilution with 2% lidocaine hydrochloride solution is performed (see section “Instructions for use and dosage”).

Packaging.

1 or 5 vials with powder in a cardboard box.

Prescription status.

By prescription only.

Manufacturer.

LLC "ISTFARM", Ukraine (packaging from in bulk form by Hebei Huamin Pharmaceutical Company Limited, China).

Manufacturer’s address and location of business operations.

13, Remontna Street, Kyiv, 02099, Ukraine