Instructions for medical use Astaroxone -TZ 1125 Ceftriaxone and tazobactam, powder for preparation of solution for injection
Trade name of the drug: Astaroxone -TZ Active ingredients (INN): Sodium Ceftriaxone, sodium tazobactam Release form: 1 glass bottle with powder for the preparation of an injection solution. Composition Each bottle contains: Ceftriaxone sodium BP, in terms of anhydrous ceftriaxone 1000 mg Tazobactam sodium USP, in terms of tazobactam 125 mg Solvent: purified water for injection in an ampoule of 10 ml Pharmacotherapeutic group: Antibiotics (group of cephalosporins). Pharmacological properties Ceftriaxone is a third–generation cephalosporin. Ceftriaxone has a bactericidal effect, inhibits the synthesis of the bacterial cell wall of actively dividing cells by binding to one or more of the penicillin-binding proteins. These proteins are bound to the membrane of bacterial cells and may be involved in synthesis. The result of the formation of a defective cell wall is the instability of osmotic pressure in the cell. Bacterial cells have a unique set of penicillin-binding proteins. The affinity of ceftriaxone to penicillin-binding proteins for various bacterial species is associated with the antimicrobial activity spectrum of the drug. It is also suggested that cephalosporins, like penicillins, can increase the rate of decay of the bacterial cell wall by reducing the ability of the inhibitor of murein hydrolase, an enzyme involved in cell division. This enzyme can destroy the integrity of the bacterial cell wall. Tazobactam is penicillinate sulfone, structurally similar to sulbactam. Being a beta-lactamase inhibitor, it shows synergism with many drugs that are destroyed by the action of this enzyme, such as penicillins and cephalosporins. Tazobactam inhibits all beta-lactamases that clavulanic acid can inhibit and, in addition, it has a certain activity against the induced enzymes of the bacteria Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa. Tazobactam is a weak enzyme inducer, compared to other beta-lactamases. Combination of ceftriaxone and tazobactam The combination of tazobactam and ceftriaxone is active against all microorganisms sensitive to ceftriaxone. In addition, the combination shows synergism (reduction of minimum inhibitory concentrations) in comparison with individual components in relation to various microorganisms. Gram-negative aerobes: Acinetobacter calcoaceticus, Enterobacter aerogenes, Enterobactercloacae, Escherichia coli, Haemophilus influenzae (including ampicillin-resistant and beta-lactamase producing strains), Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumonia, Moraxella catarrhalis (beta-lactamase producing strains),Morganella morganii Neisseria gonorrhoeae (including strains producing and not producing penicillinase), Neisseria meningitides, Proteus mirabilis, Proteus vulgaris, Serratia marcescens. Ceftriaxone is also active against Pseudomonas aeruginosa. Gram-positive aerobes: Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pneumonia, Streptococcus pyogenes, Viridans group streptococci. Methicillin-resistant staphylococci are resistant to cephalosporins, including ceftriaxone. Anaerobes: Bacteroides fragilis, Clostridium species, Peptostreptococcus species. Many strains of Clostridium difficile are resistant. Aerobic gram-negative microorganisms: Citrobacter diversus, Citrobacter freundii, Providencia species (including Providencia rettgeri), Salmonella species (including Salmonella typhi), Shigella species. Aerobic gram-positive microorganisms: Streptococcus agalactiae, Prevotella (Bacteroides) bivius, Porphyromonas (Bacteroides) melaninogenicus. They are little active against Listeria monocytogenes and penicillin-resistant S. pneumoniae, which also cause meningitis. Pharmacokinetics The maximum concentration of ceftriaxone in plasma is reached within 30 minutes after administration. Ceftriaxone reaches a high concentration in the urine. In total, 33-67% of ceftriaxone is excreted unchanged, and the rest is excreted with bile and feces. After intravenous administration of 1 g of ceftriaxone, the average concentration in bile is 581 mcg / ml and 62.1 mcg / ml in plasma. The half-life is 8.7 hours. Ceftriaxone is 98% bound to plasma proteins. Ceftriaxone passes through the blood-brain barrier. It is not removed during peritoneal and hemodialysis. Tazobactam is metabolized to a single metabolite that does not have pharmacological and antibacterial activity. Tazobactam is excreted through the kidneys by glomerular filtration and tubular secretion. Tazobactam and its metabolite are excreted mainly by renal excretion, 80% of the administered dose is excreted unchanged, and the rest as the only metabolite. Tazobactam is also secreted into the bile. Tazobactam binds to plasma proteins by about 30%. Binding to proteins of tazobactam metabolites is insignificant. Tazobactam is widely distributed in tissues and body fluids, including the intestinal mucosa, gallbladder, lungs, female reproductive organs (uterus, ovaries and fallopian tubes), intercellular fluid and bile. Indications for use To reduce the development of drug-resistant bacteria and support the effectiveness of ceftriaxone sodium and tazobactam, the drug should be used only for the treatment of infections caused by sensitive microorganisms. The combination of ceftriaxone sodium and tazobactam for injection is indicated for the following conditions: Infectious and inflammatory diseases of the upper and lower respiratory tract and ENT organs (including acute and chronic bronchitis, pneumonia, community-acquired pneumonia, lung abscess, pleural empyema, acute bacterial otitis media of the middle ear); Infectious and inflammatory diseases of the skin and soft tissues; Infectious and inflammatory diseases of the genitourinary organs (pyelitis, acute and chronic pyelonephritis, cystitis, prostatitis, epididymitis, etc.); Infectious and inflammatory diseases of bones and joints, maxillofacial region; Infectious and inflammatory diseases of the abdominal cavity (peritonitis, cholecystitis, pancreatitis, etc.); Uncomplicated gonorrhea, including caused by microorganisms that secrete penicillinase; Sepsis and bacterial septicemia; Bacterial meningitis and endocarditis; Mild chancre and syphilis; Lyme disease (spirochetosis); Salmonellosis and salmonella-bearing; Infections in immunocompromised patients; Prevention of postoperative infectious complications. Method of administration and dosage: Children: For the treatment of serious infections, the recommended dose is 50-75 mg / kg (in terms of ceftriaxone), divided into 2 injections every 12 hours. The total daily dose should not exceed 2 g (in terms of ceftriaxone). For newborns up to 2 weeks, the daily dose is 20-50 mg / kg. For the treatment of acute bacterial otitis media, a single I / m dose of 50 mg / kg is recommended (but not more than 1 g in terms of ceftriaxone). Adults: The usual dose for adults is 1000/125 mg of ceftriaxone / tazobactam 1-2 times a day, depending on the severity of the infection. The total daily dose should not exceed 4 g (in terms of ceftriaxone). For use before surgery (prevention of surgical infectious complications), a single intravenous dose of 1 g of ceftriaxone is recommended 30 minutes – 2 hours before surgery. Treatment with Astaroxone-TZ should continue for at least 2 days after the symptoms of infection disappear. The usual duration of therapy is 4-14 days; depending on the severity of the infection, it may be necessary to extend the duration of therapy. In the treatment of infections caused by Streptococci pyogenes, therapy should be continued for at least 10 days. Ceftriaxone can be administered by intramuscular injection or slow intravenous injection / infusion after solution recovery, according to the instructions given below. Instructions for use For intravenous bolus administration, the drug is dissolved in sterile water for injection, sodium chloride solution or dextrose solution in a ratio of 1:10, for intramuscular administration in 1% lidocaine solution. The dilution of Astaroxone-TZ with the appropriate solvent (water for injection, sodium chloride solution, glucose) is shown in the table. Intravenous injection should be administered for at least 2-4 minutes. Intravenous infusion should be administered for at least 30 minutes. After dilution of the drug in a 1% lidocaine solution, the finished solution is injected deeply intramuscularly. Doses over 1 g (in terms of ceftriaxone) should be divided into 2 injections with an interval of 12 hours. The prepared solution of the drug should be used immediately. Do not use solvents containing calcium (for example, Ringer's solution or Hartmann's solution) to restore Astaroxone-TZ or further dilute the reduced solution for intravenous administration. This can lead to the formation of sediment! Side effects The combination of ceftriaxone and tazobactam is usually well tolerated. When using the drug , the following side reactions may develop: From the nervous system: headache, dizziness, drowsiness, convulsions (with renal insufficiency), hearing impairment; From the digestive tract: nausea, vomiting, constipation, flatulence, anorexia, cramps and abdominal pain, taste disorders, stomatitis, ulceration of the oral mucosa, oral candidiasis, glossitis, pseudomembranous colitis, dysbiosis; From the liver: transient increase in the activity of transaminases, alkaline phosphatase, LDH or bilirubin, liver dysfunction, cholestasis; From the blood system: decrease in hemoglobin and hematocrit, transient eosonophilia, neutropenia, leukopenia, aplastic and hemolytic anemia, thrombocytopenia, agranulocytosis, hypoprothrombinemia, prolongation of prothrombin time, decrease in plasma coagulation factors (II, VII, IX, X); From the genitourinary system: impaired renal function, interstitial nephritis, dysuria, vaginitis, urolithiasis, nephrolithiasis, itching in the perineum, increased creatinine and/ or urea nitrogen in the blood serum; Allergic reactions: hypersensitivity reactions, skin rashes, itching, allergic pneumonitis, allergic dermatitis, urticaria, exanthema, Quincke's edema, rarely – drug fever or chills, serum sickness, anaphylactic shock, bronchospasm. As with the use of other drugs, in some cases there may be adverse reactions from the skin, such as erythema multiforme, Stevens-Johnson syndrome, Lyell syndrome. Local reactions: pain or infiltration at the injection site, thrombophlebitis after intravenous administration Contraindications Hypersensitivity to cephalosporins and beta-lactamase inhibitors (including penicillins, carbapenems). Pregnancy (I trimester). With caution: hyperbilirubinemia in newborns, premature infants, renal and / or hepatic insufficiency, ulcerative colitis, enteritis or colitis associated with the use of antibacterial agents, pregnancy, breast-feeding. Drug interactions When used concomitantly with NSAIDs and other platelet aggregation inhibitors, the likelihood of bleeding increases. Diuretics and aminoglycosides potentiate the nephrotoxic effect of ceftriaxone. The pharmaceutical preparation is incompatible with aminoglycosides, fluconazole, labetalol, vancomycin, pentamidine, calcium-containing solutions. Special instructions The appointment of Astaroxone-TZ in the absence of confirmation of bacterial infection, as well as for preventive purposes, is undesirable, since in this case the risk of developing bacteria resistant to the drug increases. Before starting treatment with Astaroxone-TZ, it should be clarified whether the patient had allergic reactions to cephalosporins, penicillins and other drugs. Diarrhea caused by Clostridium difficile is observed in almost all patients using antibacterial drugs, including Astaroxone-TZ, and can be from mild to severe severity. When the drug was administered, even at the recommended doses, a temporary increase in the level of urea nitrogen and plasma creatinine was observed. An increase in prothrombin time was observed in some patients. If the prothrombin time increases during treatment or before treatment, this indicator was higher, then vitamin K (10 mg daily) should be administered. Prolonged use of Astaroxone-TZ can lead to the growth of resistant microorganisms. As with the use of other cephalosporins, the development of anaphylactic shock cannot be excluded. With a combination of renal and hepatic insufficiency and in patients on hemodialysis, dose adjustment and monitoring of plasma concentrations are required (blood levels are recommended to be monitored periodically and with isolated liver and kidney dysfunction). Newborns (</= 28 days) Newborns with hyperbilirubinemia, especially premature infants, should not receive ceftriaxone. In newborns, ceftriaxone should not be combined with calcium-containing intravenous solutions, such as parenteral nutrition, due to the risk of precipitation of ceftriaxone salt with calcium. Pregnancy and lactation Pregnancy The drug Astaroxone-TZ should not be used in the first trimester of pregnancy. Lactation The drug penetrates into breast milk in a small amount. Therefore, breastfeeding should be stopped for the duration of treatment. The drug should be stored out of the reach of children and do not use the drug after the expiration date. Overdose Symptoms: neuroreflective excitability syndrome, encephalopathy, seizures in patients with renal insufficiency, nausea, vomiting, diarrhea. Treatment: hemodialysis and supportive therapy. Product form: Powder 1125 mg in a bottle of colorless glass, together with instructions for medical use in a cardboard box. Expiration date: 3 years. Do not use after the expiration date. Storage conditions: Store in a dry place protected from light, at a temperature not higher than 25 ° C. Keep out of reach of children! Conditions of release from pharmacies: It is available on a doctor's prescription. Manufacturer: HARASHA PHARMA PVT. LTD., (HARASHA PHARMA PVT. LTD.) Plot No. 125, EPIP Road, Mauja Jharmajri, Baddi, Dist. Solan (HP), India Implemented by: M.R. HEALTHCARE PVT. LTD. Tanda Mallu, Kashipur Road, Ramnagar, Distt. Nainital, Uttarakhand-244715
