INSTRUCTIONS FOR MEDICAL USE PARMACEF-With PARMACEF-S Trade name of the drug: PARMACEF-C Active substance (INN): cefoperazone, sulbactam Dosage form: powder for the preparation of an injectable solution for intramuscular and intravenous administration. Composition 1 bottle contains: cefoperazone sodium salt, in terms of cefoperazone – 1.0 g, and sulbactam sodium salt, in terms of sulbactam – 0.5 g. Description: white or almost white powder. Pharmacotherapeutic group: Antibacterial drugs for systemic use. Cephalosporins of the third generation. ATX Code: Ceftriaxone- J01DD04, Sulbactam- J01CG01 Pharmacological properties The antibacterial component of PARMACEF-C a is cefoperazone, a third–generation cephalosporin that acts bactericidal by inhibiting bacterial wall synthesis. Sulbactam has no real antibacterial activity, except for action against Neisseriaceae and Acinetobacter, however, it is an inhibitor of beta-lactamases – enzymes that are produced by microorganisms resistant to beta-lactam antibiotics. Sulbactam prevents the destruction of penicillins and cephalosporins by resistant microorganisms and demonstrates pronounced synergism with penicillins and cephalosporins. Since sulbactam also binds to some penicillin-binding proteins, sensitive microorganisms become more susceptible to the action of sulbactam/cefoperazone than to the action of cefoperazone alone. The combination of sulbactam and cefoperazone is active against such microorganisms: Haemophilus influenzae, Bacteroides species, Acinetabacter calcoaceticus, Enterobacter aerogens, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus. Sulbactam/cefoperazone exhibits in vitro activity against a wide range of clinically significant microorganisms. Gram-positive microorganisms: Staphylococcus aureus (including strains producing and not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae (mainly Diplococcus pneumoniae), Streptococcus pyogenes (beta-hemolytic streptococcus group A), Streptococcus agalactiae (beta- group B hemolytic streptococcus), most other types of beta-hemolytic streptococci, many types of Streptococcus faecalis. Gram-negative microorganisms: Escherichia coli, Klebsiella species, Enterobacter species, Citrobacter species, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii (important Proteus morganii), Providencia rettgeri (important Proteus rettgeri), Providencia species, Serratia species (including S. marcescens), species Salmonella and Shigella, Pseudomonas aeruginosa, some species of Pseudomonas, 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). Pharmacokinetics Approximately 84% of the dose of sulbactam and 25% of the dose of cefoperazone received with the administration of the drug PARMACEF-C is excreted by the kidneys. Most of the dose of cefoperazone is excreted with bile. After administration of sulbactam / cefoperazone, the average half–life of sulbactam is 1 hour, and cefoperazone is 1.7 hours. Plasma concentrations are proportional to the administered dose. The average values of the maximum concentrations of sulbactam and cefoperazone after administration of 1.5 g of sulbactam / cefoperazone intravenously for 5 minutes are 130.2 and 236.8 mcg/ml, respectively. This indicates a larger volume of sulbactam distribution (Va=18.0-27.6L) compared with the distribution of cefoperazone (Va = 10.2-11.3L). Both sulbactam and cefoperazone are subject to intensive distribution in tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus and others. In children, the average half–life of sulbactam ranges from 0.91 to 1.42 hours, and cefoperazone - from 1.44 to 1.88 hours. There are no data on any pharmacokinetic interaction between sulbactam and cefoperazone when they are used together in the form of a complex drug. After repeated administration, there were no significant changes in the pharmacokinetics of sulbactam / cefoperazone components and any accumulation of them when used every 8-12 hours. Indications for use In the form of monotherapy for the treatment of infections caused by sensitive microorganisms: • respiratory tract infections (upper and lower divisions); • intraabdominal infections (peritonitis, cholecystitis, cholangitis, etc.); • urinary tract infections (upper and lower divisions); • septicemia; • meningitis; • skin and soft tissue infections; • bone and joint infections; • pelvic inflammatory diseases, endometritis; • gonorrhea and other genital infections. With certain indications, PARMACEF-C can be used as part of combination therapy together with other antibiotics. Method of administration and dosage PARMACEF-C is intended for intravenous and intramuscular administration. Before starting therapy, it is necessary to exclude the presence of hypersensitivity in the patient by making a skin test. Use in adults. The recommended daily dose of PARMACEF-C is 2-4 g. The drug should be administered every 12 hours in an evenly distributed dose. In severe or refractory infections, the daily dose of PARMACEF-C can be increased to 8 g. In patients who receive PARMACEF-C, there may be a need for additional prescribing of cefoperazone drugs (it should be administered every 12 hours in an evenly distributed dose). The maximum daily dose of sulbactam is 4 g. Use in case of impaired liver function. Dose adjustment may be necessary in cases of severe obstructive jaundice and severe liver diseases or when both of these pathologies are accompanied by impaired renal function. In patients with impaired liver function and concomitant renal impairment, it is necessary to monitor the concentration of cefoperazone in plasma and, if necessary, appropriate dose adjustment. In the absence of careful monitoring of the concentration of the drug in plasma, the dose of cefoperazone should not exceed 2 g per day. Use in cases of impaired renal function. When applying PARMACEF-C in patients with creatinine clearance less than 30 ml / min, dose adjustment of the drug is necessary to compensate for the reduced clearance of sulbactam. With creatinine clearance of 15-30 ml / min, the maximum single dose of sulbactam is 1 g every 12 hours; with creatinine clearance of less than 15 ml / min, 500 mg every 12 hours. Therefore, in severe infections, additional prescribing of cefoperazone drugs may be necessary. When using dialysis, correction of the dose regimen of the drug PARMACEF-C is necessary (see Application features). Use in children. The recommended daily dose of PARMACEF-C is 40-80 mg / kg of body weight. The drug should be administered every 6-12 hours in evenly distributed doses. In severe or refractory infections, the daily dose of PARMACEF-C a can be increased to 160 mg / kg and distributed into 2-4 equal doses. Infants of the 1st week of life should be given the drug every 12 hours. The maximum daily dose for infants should not exceed 80 mg / kg. Intravenous use. For drip infusion, the contents of 1 vial (1.5 g) should be dissolved in 6.7 ml of 5% glucose solution in water, 0.9% sodium chloride solution or sterile water for injection, and then diluted to 20 ml before use with the same solvent. The drug is administered by infusion for 15-60 minutes. PARMACEF-C is compatible with water for injection, 5% glucose solution in 0.225% sodium chloride solution, 5% glucose solution in 0.9% sodium chloride solution in concentrations from 10 mg/ml of cefoperazone and 10 mg/ml of sulbactam to 250 mg/ml of cefoperazone and 250 mg/ml of sulbactam. Ringer lactate solution is suitable for dilution by intravenous infusion, but not for primary dilution. For intravenous injection, the contents of the vial should be dissolved as described above and administered for at least 3 minutes. Intramuscular use. Lidocaine solution is suitable for dilution with intramuscular use, but not for primary dissolution. Side effects From the digestive system: diarrhea, nausea, vomiting, pseudomembranous colitis. From the central nervous system and peripheral nervous system: headache, muscle twitching. Allergic reactions: maculopapular rash, urticaria, itching, fever, Stevens-Johnson syndrome, anaphylactic shock. From the hematopoietic system: reversible neutropenia, leukopenia, decreased hemoglobin and hematocrit levels, cases of eosinophilia, thrombocytopenia and hypoprothrombinemia. From the cardiovascular system: hypotension, vasculitis. From the urinary system: hematuria. Laboratory indicators: increased indicators of functional liver tests AST, ALT, the level of alkaline phosphatase and bilirubin. Local reactions: pain at the injection site, phlebitis at the infusion site (when administered through an intravenous catheter). Contraindications Hypersensitivity to any component of the drug and / or penicillins, cephalosporins. Drug interactions Simultaneous use of PARMACEF-C and alcohol-containing drugs or simultaneous use of alcohol on time or for 5 days after the end of treatment can lead to effects similar to the action of disulfiram (teturam): abdominal cramp, nausea, vomiting, headache, palpitations, shortness of breath, redness of the face. These effects are noted for 15-30 minutes after drinking alcohol and go away on their own after a few hours. This is due to the presence of the N-methylthiotetrazole side chain in the structure of the cefoperazone molecule, which inhibits the activity of the enzyme acetaldehyde dehydrogenase, which leads to the accumulation of acetaldehyde in the blood, which causes the described side effects. Concomitant use with anticoagulants (coumarin or indanedione derivatives), heparin or any thrombolytics increases the risk of bleeding. When using PARMACEF-C, pseudo-positive results are possible when determining the glucose content in urine by non-enzymatic methods and when setting the Coombs reaction. If PARMACEF-C a is used as part of combination therapy with aminoglycosides, it is necessary to monitor kidney function throughout the course of therapy (see Incompatibility). Special instructions In some patients, treatment with PARMACEF-C, as with other cephalosporins, can lead to the development of hypersensitivity reactions, including fatal anaphylactic reactions. The occurrence of such reactions is most likely in persons with a known hypersensitivity to many allergens in the anamnesis. With the development of allergic reactions, it is necessary to immediately cancel the drug and prescribe appropriate treatment. Severe anaphylactic reactions require immediate use of emergency therapy, in particular the introduction of adrenaline. According to the indications, it is possible to use oxygen therapy, intravenous administration of corticosteroids, ensuring the patency of the respiratory tract, including intubation. In some patients, treatment with cefoperazone, as well as other antibiotics, can lead to a deficiency of vitamin K in the body, which is probably due to the suppression of the intestinal microflora synthesizing this vitamin. Weakened patients, patients with limited nutrition, patients with cystic fibrosis, as well as patients who have been on parenteral nutrition for a long time are at such risk. In such cases, it is necessary to monitor the level of prothrombin and, if necessary, prescribe vitamin K preparations. Similar control should be carried out in patients receiving anticoagulant therapy. Prolonged use of PARMACEF-C a can lead to increased growth of resistant microorganisms, therefore careful monitoring of the patient's condition is necessary. You should be prepared for periodic manifestations of disorders of the kidneys, liver and hematopoietic system. This is especially important for newborns, in particular premature babies, as well as other infants. Use in cases of impaired renal function. In patients with impaired renal function of varying degrees when using PARMACEF-C, the total clearance of sulbactam is closely correlated with a certain creatinine clearance. In patients with severe renal impairment, there is a significant increase in the half-life of sulbactam. Hemodialysis significantly affects the half-life, total clearance and volume of sulbactam distribution. There were no changes in the pharmacokinetics of cefoperazone in patients with renal insufficiency. Use in case of impaired liver function. Cefoperazone is largely excreted with bile. In patients with liver diseases and / or biliary tract obstruction, the half-life of cefoperazone in plasma is prolonged, and urinary excretion increases. Even with severe liver function disorders, therapeutic concentrations of cefoperazone are determined in the bile, and the half-life in plasma increases 2-4 times. In cases of severe biliary tract obstruction, severe liver disease, or in the presence of concomitant renal dysfunction, dose adjustment may be necessary (see Method of administration and dose). Use in the elderly and senile age. When using both sulbactam and cefoperazone, there is an elongation of the half-life, a decrease in total clearance and an increase in the volume of distribution. The pharmacokinetics of sulbactam directly correlates with the level of renal function, and the pharmacokinetics of cefoperazone correlates with impaired liver function. Application for the treatment of children. The pharmacokinetics of the components of the drug PARMACEF-C in the pediatric population has no significant differences compared to adults. PARMACEF-C is effectively used in infants. However, comprehensive studies of the use of the combination of cefoperazone / sulbactam in premature infants or newborns have not been conducted. Therefore, before starting treatment of premature infants or newborns, the potential benefits and possible risks of therapy should be carefully evaluated. Sulbactam and cefoperazone penetrate the placental barrier. Therefore, during pregnancy, PARMACEF-C should be taken only when the expected benefit to the woman exceeds the potential risk to the fetus. Sulbactam and cefoperazone are excreted in small amounts with breast milk, therefore, when using PARMACEF-C a during lactation, the issue of stopping breastfeeding should be resolved. PARMACEF-C should be used with extreme caution in children under 2 years of age. About the effect on the reaction speed when driving vehicles or working with other mechanisms. There are no messages at the moment. Incompatibility Solutions of PARMACEF-C and aminoglycosides should not be mixed directly, since there is a physical incompatibility between them. If combination therapy with PARMACEF-With om and aminoglycosides is necessary, their sequential separate drip infusion should be applied using a separate secondary intravenous tube system; in this case, the primary intravenous tube system should be thoroughly rinsed with an appropriate solution in the interval between infusions of these drugs. It is also advisable that during the day the intervals between the administration of PARMACEF-C a and aminoglycosides should be as long as possible. Primary dilution with Ringer lactate solution is not recommended, since this mixture is incompatible. However, the use of a two-stage dilution process avoids incompatibility: first, sterile water is used for injection, then the resulting solution is diluted with a Ringer lactate solution to a sulbactam concentration of 5 mg / ml (2 ml of the primary solution is diluted in 50 ml of Ringer lactate solution or 4 ml of the primary solution in 100 ml of Ringer lactate solution). Primary dilution with a 2% lidocaine solution is not recommended, since this mixture is incompatible. However, the use of a two-stage dilution process avoids incompatibility: first, sterile water is used for injection, then the resulting solution is diluted with a 2% lidocaine solution (to obtain a solution that contains up to 250 mg / ml of cefoperazone and 250 mg / ml of sulbactam in approximately 0.5% lidocaine hydrochloride solution). Overdose In case of overdose, it is possible to increase the manifestations of adverse reactions of PARMACEF-S. High concentrations of the drug in the cerebrospinal fluid can cause neurological reactions, in particular seizures, which is typical for beta-lactam antibiotics. Cefoperazone and sulbactam are excreted by hemodialysis, so this procedure can enhance the elimination of the drug from the body. Release form 1.5 g in vials; 1 bottle in a pack. Storage conditions Store in a dry place protected from light at a temperature not higher than 25 C. The drug should be kept out of the reach of children Expiration date 2 years. Do not use after the expiration date. Conditions of release from pharmacies By prescription. Produced for PARMAN HEALTHCARE LLP NETAJI SHIV MANDIR ROAD, ULHASNAGAR THANE, INDIA - 421004 Manufacturer MAXMED LIFE SCIENCES PVT LTD PLOT NO. 54, SECTOR IIDC, PANTNAGAR, RUDRAPUR, UTTARAKHAND, INDIA 263153.
