Rocefin powder for the preparation of injectable solution for intramuscular injection
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Active ingredients
Ceftriaxone
Release form
Powder
Composition
Active ingredient: Ceftriaxone (Ceftriaxone) Active ingredient concentration (mg): 1 g
Pharmacological effect
Antibiotic group cephalosporins III generation for parenteral use. characterized by prolonged action. Ceftriaxone's bactericidal activity is due to inhibition of cell membrane synthesis. In vitro, ceftriaxone has a wide spectrum of action against gram-negative and gram-positive microorganisms. it is highly resistant to most β-lactamases (both penicillinases and cephalosporinases) produced by the gram and positive bacteria. groups a), streptococcus agalactiae (β-hemolytic, groups b), β-hemolytic streptococci (groups neither a, nor b), streptococcus viridans, streptococcus pneumoniae.methicillin-resistant staphylococcus spp. resistant to cephalosporins, including to ceftriaxone. as a rule, enterococcus faecalis, enterococcus faecium and listeria monocytogenes are also resistant. Executing companies: acinetobacter lwoffi, acinetobacter anitratus (mainly a. baumanii) *, aeromonas hydrophila, alcaligenes faecalis; , citrobacter diversus (incl., p. amalonaticus), citrobacter freundii *, escherichia coli, enterobacter spp. * (including enterobacter aerogenes *, enterobacter cloacae *), haemophilus ducreyi, haemophilus influenzae, haemophilus and non-refined, and hemophilus ducreyi, haemophilus influenzae, haemophilus, anthrafilus, and hemophilus ducreyi; alvei, klebsiella oxytoca, klebsiella pneumoniae **, moraxella spp. (Including moraxella catarrhalis, moraxella osloensis), morganella morganii, neisseria gonorrhoeae, neisseria meningitidis, pasteurella multocida, plesiomonas shigelloides, proteus mirabilis, proteus penneri *, proteus vulgaris *, pseudomonas spp. (including pseudomonas fluorescens *), providentia spp. (including providentia rettgeri *), salmonella spp. (including salmonella typhi), serratia spp. * (including serratia marcescens *), shigella spp., vibrio spp., yersinia spp. (including yersinia enterocolitica). * Some isolates of these species are resistant to ceftriaxone, mainly due to the formation of β-lactamases encoded by chromosomes. ** Some isolates of these species are stable due to the formation of a number of plasmid-mediated β-lactamases. Many strains of the above microorganisms that are multiresistant to other antibiotics, such as aminopenicillins and ureidopenicillins, first and second generation cephalosporins and aminoglycosides are sensitive to ceftriaxone. treponema pallidum is sensitive to ceftriaxone in vitro and in animal experiments. clinical trials show that ceftriaxone has good efficacy against primary and secondary syphilis. with very few exceptions, clinical isolates p. aeruginosa resistant to ceftriaxone. Aerobic bacteria: bacteroides spp. (bile sensitive) *, clostridium spp. (except c.difficile), fusobacterium spp. (including fusobacterium nucleatum), gaffkia anaerobica (formerly called peptococcus), peptostreptococcus spp. * Some isolates of these species are resistant to ceftriaxone due to the formation of β-lactamase. Many strains of β-lactamase forming bacteroides spp. (in particular, b. fragilis) resistant to cefriaxone. robust and clostridium difficile. Ceftriaxone sensitivity can be determined by disc diffusion method or serial dilution method on agar or broth, using a standard technique similar to that recommended by the national committee of clinical laboratory standards (nkklks). nkkls established the following criteria for evaluating the results of the sample for ceftriaxone: the test method is sensitive and moderately stable; the dilution method is overwhelming; mg / l = 8 16-32 = 64method of discs (disk with 30 μg ceftriaxone); growth delay zone diameter, mm = 21 20-41 = 13 To determine the need to take discs with ceftriaxone, because In vitro studies have shown that ceftriaxone is active against certain strains that are resistant when using disks designed for the whole group of cephalosporins. Instead of nkkls standards, other well-standardized standards, such as din and ics, can be used to determine the sensitivity of microorganisms. interpret the state of sensitivity.
Pharmacokinetics
Ceftriaxone pharmacokinetics is non-linear. All major pharmacokinetic parameters, based on total concentrations of the drug, except for the half-life, depend on the dose. Absorption of Cmax in the plasma after a single intramuscular injection of 1 g of the drug is about 81 mg / l and is reached within 2-3 hours after administration. AUC after i / v and i / m administration are the same. This means that the bioavailability of ceftriaxone after i / m administration is 100%. The distribution of Vd of ceftriaxone is 7-12 liters. After administration in a dose of 1-2 g, ceftriaxone penetrates well into tissues and body fluids. For more than 24 hours, its concentrations far exceed the minimum inhibitory concentrations for most pathogens in more than 60 tissues and fluids (including the lungs, heart, biliary tract, liver, tonsils, middle ear and nasal mucosa, bones, as well as spinal, pleural, and synovial fluids and secretions of the prostate gland).After iv administration, ceftriaxone rapidly penetrates into the cerebrospinal fluid, where bactericidal concentrations against sensitive microorganisms persist for 24 hours. Ceftriaxone reversibly binds to albumin, and the degree of binding decreases with increasing concentration, decreasing, for example, from 95% at plasma concentrations less than 100 mg / l to 85% at a concentration of 300 mg / l. Due to the lower concentration of albumin in the tissue fluid, the proportion of free ceftriaxone in it is higher than in plasma. Ceftriaxone penetrates through the inflamed brain membranes in children, including newborns. 24 hours after i / v administration of Rocefin in doses of 50–100 mg / kg of body weight (to newborns and infants, respectively), the concentrations of ceftriaxone in the cerebrospinal fluid exceed 1.4 mg / l. Cmax in the cerebrospinal fluid is reached approximately 4 hours after the intravenous route and is, on average, 18 mg / l. With bacterial meningitis, the average concentration of ceftriaxone in the cerebrospinal fluid is 17% of the concentration in plasma, with aseptic meningitis - 4%. In adult patients with meningitis 2–24 hours after a dose of 50 mg / kg body weight, the concentration of ceftriaxone in the cerebrospinal fluid many times exceeds the minimum inhibitory concentrations for the most common causative agents of meningitis. Ceftriaxone penetrates the placental barrier and in low concentrations is excreted in breast milk . Metabolism Ceftriaxone is not subjected to systemic metabolism, but is converted into inactive metabolites by the action of intestinal flora. Withdrawal The total plasma clearance of ceftriaxone is 10-22 ml / min. Renal clearance is 5-12 ml / min. 50-60% of ceftriaxone is excreted unchanged with urine, and 40-50% is excreted unchanged with bile. In adults, T1 / 2 is about 8 hours. Pharmacokinetics in special clinical situations In newborns, about 70% of the dose is excreted in the urine. In infants during the first 8 days of life, as well as in persons over 75 years old, T1 / 2 is 2 or 3 times more than in adults. In case of impaired renal or liver function, the pharmacokinetics of ceftriaxone changes slightly, only a slight increase in T1 / 2 is noted. If only kidney function is impaired, bile excretion increases, if only liver function is impaired, excretion through urine increases.
Indications
Infections caused by pathogens susceptible to Rocefin: sepsis; meningitis; disseminated Lyme disease (early and late stages of the disease); infections of the abdominal organs (peritonitis, infections of the biliary tract and the gastrointestinal tract); infections of bones, joints, soft tissues, skin, and wound infections; infections in immunocompromised patients; infections of the kidneys and urinary tract; infections of the respiratory tract, especially pneumonia, and infections of the upper respiratory tract; infections of the genital organs, including gonorrhea. Perioperative prophylaxis of infections.
Contraindications
Hypersensitivity to cephalosporins and penicillins. Hyperbilirubinemia in newborns and premature infants (in vivo studies have shown that ceftriaxone can displace bilirubin from its association with serum albumin, increasing the risk of bilirubin encephalopathy in these patients). Newborns (? 28 days),? Intravenous treatment with calcium-containing solutions, including prolonged calcium-containing infusions, for example, with parenteral nutrition, is assumed due to the risk of formation of calcium precipitates The other salts of ceftriaxone (see the sections “Route of Administration and Doses” and “Interaction with Other Drugs”). Fatal cases of precipitate formation in lungs and kidneys in newborns who received Rocefin and calcium-containing solutions are described. In some cases, one venous access was used, and the formation of precipitates was observed directly in the system for intravenous administration, at least one case was described with a fatal outcome at various venous approaches and at different times of administration of the drug Rocefin and calcium-containing solutions. Similar cases were observed only in newborns (see the section “Post-marketing surveillance”).
Precautionary measures
The drug should be stored out of the reach of children at a temperature not higher than 30 ° C.
Use during pregnancy and lactation
The safety of using Rocefin in pregnant women has not been established. Ceftriaxone penetrates the placental barrier. During pregnancy, especially in the first trimester, the drug should be prescribed only according to strict indications. Pre-clinical experimental reproduction studies did not reveal embryotoxic, fetotoxic, teratogenic effects or other adverse effects of the drug on fertility of males and females, the process of labor,perinatal and postnatal fetal development. In low concentrations, ceftriaxone is excreted in breast milk. When prescribing it during lactation (breastfeeding) care should be taken.
Dosage and administration
Standard dosing regimen. Adults and children over 12 years: 1-2 g once a day (every 24 hours). In severe cases or with infections whose pathogens have only moderate sensitivity to ceftriaxone, the daily dose can be increased to 4 g. The duration of treatment depends on the course of the disease. As is always the case with antibiotic therapy, administration of the drug Rocefin should be continued in patients for at least 48-72 hours after normalization of temperature and confirmation of eradication of the pathogen.
Side effects
Gastrointestinal tract (about 2%): unformed stools or diarrhea, nausea, vomiting, stomatitis, glossitis, taste disorder (less than 1%). Hematological changes (about 2%): eosinophilia, leukopenia; less often (<1%): granulocytopenia, hemolytic anemia, thrombocytosis, thrombocytopenia, an increase in thromboplastin and prothrombin time. Individual cases of agranulocytosis (<500 cells / μl) have been described, most of which developed after 10 days of treatment and applying a cumulative dose of 20 g or more. Skin reactions (about 1%): rash, allergic dermatitis, pruritus, urticaria, edema. Selected cases of severe adverse reactions (exudative erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome)). Others (rarely observed): headache and dizziness, precipitation of the calcium salts of ceftriaxone in the gallbladder with appropriate symptoms, pancreatitis with appropriate symptoms, pancreatitis activity of liver enzymes (ALT, AST), ALP, hyperbilirubinemia, oliguria, increased serum creatinine concentration, mycosis of the genital organs, vaginitis, fever, chills, increased sweat separation, flushing, allergic pneumonitis, bronchospasm, nosebleeds, hematuria, jaundice, reduction in prothrombin time, convulsive seizure, palpitations, serum sickness, as well as anaphylactic or anaphylactoid reactions. Separate fatal cases of formation of precipitates in the lungs and kidneys are reported. necropsy in neonates receiving Rocefin and calcium-containing solutions. However, in some cases, one venous access was used, and the formation of precipitates was observed directly in the system for intravenous administration.Also, at least one case has been described with a fatal outcome, with various venous approaches and at different times of administration of the drug Rocefin and calcium-containing solutions. At the same time, according to the autopsy results, no precipitates were detected in this newborn. Similar cases were observed only in newborns (see the section "Special Instructions"). Very rare cases of pseudomembranous colitis (<0.01%) and bleeding disorders, as well as kidney calculi were described, mainly in children over 3 years old who received either large daily doses of the drug (? 80 mg / kg per day), or cumulative doses of more than 10 g, as well as having additional risk factors (limiting fluid intake, bed rest, etc.). The formation of stones in the kidney can be asymptomatic or manifest clinically, and can lead to renal failure. This adverse event is reversible and disappears after cessation of therapy with Rocefin. Local reactions (very rare): phlebitis after intravenous administration. It can be avoided by injecting the drug slowly over 2-4 minutes. Intramuscular injection without the use of lidocaine is painful.
Overdose
Treatment: conduct symptomatic therapy. There is no specific antidote. Hemodialysis and peritoneal dialysis are not effective.
Interaction with other drugs
With the simultaneous use of high doses of Rocefin and potent diuretics (for example, furosemide, no renal dysfunction was observed. There is no indication that Rocefin increases the nephrotoxicity of aminoglycosides, not. which could cause ethanol intolerance and bleeding, which is inherent in some other cephalosporins. Probenecid does not affect Rocefin excretion. Bacterios tATybeans do not reduce the bactericidal effect of ceftriaxone. In vitro, antagonism between chloramphenicol and ceftriaxone has been detected. .
special instructions
When using Rocefin, as well as other cephalosporins, even with careful history taking, the possibility of anaphylactic shock cannot be ruled out.Patients with hypersensitivity to penicillin should be aware of the possibility of cross-allergic reactions. When Rocefin is used, as with other antibiotics, superinfection may develop. Patients with renal insufficiency usually do not need dose adjustment due to the fact that ceftriaxone is eliminated through urine and bile. It is recommended to periodically determine the concentration of the drug in the blood. In patients with impaired renal function and liver, the daily dose of Rocefin should not exceed 2 g without monitoring the concentration of the drug in the blood. In patients who received Rocefin, rare cases of changes in prothrombin time are described. Patients with vitamin K deficiency (impaired synthesis, malnutrition) may require monitoring the prothrombin time during therapy and prescribing vitamin K (10 mg / week) with an increase in the prothrombin time before or during therapy. After ceftriaxone, usually in doses exceeding standard recommended, with ultrasound of the gallbladder revealed shadows, which were mistaken for stones. They are precipitates of the ceftriaxone calcium salt, which disappear after the completion or cessation of therapy with Rocefin. Such changes rarely produce any symptoms, but even in such cases only conservative treatment is recommended. If these phenomena are accompanied by clinical symptoms, then the decision to cancel the drug is made by the attending physician. Patients receiving Rocefin have described rare cases of pancreatitis, which has developed, possibly due to obstruction of the biliary tract. Most of these patients already had risk factors for stagnation in the biliary tract, for example, previous therapy, severe illness, and full parenteral nutrition. At the same time, it is impossible to exclude the triggering role, formed under the influence of Rocefin, precipitates in the biliary tract in the development of pancreatitis. Care should be taken in appointing Rocefin to newborns with hyperbilirubinemia. Rocefin should not be used in newborns, especially premature babies, who are at risk for developing bilirubin encephalopathy. With long-term treatment, a blood picture should be regularly monitored. In rare cases, false positive results of the Coombs test may occur in patients treated with Rocefin. Like other antibiotics, Rocefin may give a false positive result for galactosemia.False positive results can also be obtained when determining glucose in the urine, therefore, during therapy with Rocefin, glucosuria, if necessary, should be determined only by the enzymatic method.