Oframax - instructions for use, dose, side effects, contraindications

Ceftriaxone is a third generation cephalosporin antibiotic for parenteral use, it has bactericidal action, inhibits the synthesis of the cell membrane, in vitro inhibits the growth of most gram-positive and gram-negative microorganisms. It is resistant to the action of β-lactamase enzymes (both penicillinase and cephalos porinase,produced by the majority of gram-positive and gram-negative bacteria). It is active against the following microorganisms:

- Gram-positive aerobes: Staphylococcus aureus (including strains forming penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus spp. groups of viridans;

- Gram-negative aerobes: Acinetobacter calcoaceticus, Borrelia burgdorferi, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including strains forming penicillinase), Haemophilus parainfluenzae, Klebsiella spp. (including Klebsiella pneumoniae), Moraxella catarrhalis, (including strains forming penicillinase), Morganella morganii, Neisseria gonorrhoeae (including strains forming penicillinase), Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris , Serratia spp. (including Serratia marcescens); individual strains of Pseudomonas aeruginosa are also sensitive;

- anaerobes: Bacteroides fragilis), Clostridium spp. (except Clostridium difficile), Peptostreptococcus spp.

Has in vitro activity against most strains of the following microorganisms, although the clinical significance of this is unknown: Citrobacter diversus, Citrobacter freundii, Providencia spp. (including Providencia rettgeri), Salmonella spp., including Salmonella typhi, Shigella spp .; Streptococcus agalactiae, Bacteroides bivius, Bacteroides melaninogenicus.

Methicillin-resistant staphylococci are resistant to cephalosporins, incl. to ceftriaxone, many Streptococcus strains of group D and enterococci, incl. Enterococcus faecalis, also resistant to ceftriaxone.

Pharmacokinetics:

With parenteral administration ceftriaxone well penetrates into tissues and body fluids.

The pharmacokinetics of ceftriaxone is non-linear. All major pharmacokinetic parameters based on total drug concentrations, except for the half-life, depend on the dose.

Suction

The maximum concentration (C max) in the blood plasma after a single intramuscular injection of 1 g of the drug is about 81 mg / l and is achieved within 2-3 hours after administration. The area under the concentration-time curve in the blood serum for intravenous and intramuscular injection coincide. This means that the bioavailability of ceftriaxone when administered intramuscularly is 100%.

Distribution

The volume of distribution of ceftriaxone is 7-12 liters. After a dose of 1-2 g ceftriaxone well penetrates into tissues and body fluids Time to reach the maximum concentration (TCmax) after intravenous infusion - at the end of the injection.

For more than 24 hours, its concentrations far exceed the minimum inhibitory concentrations for most pathogens in many tissues and fluids (including the lungs, heart, bile ducts, liver, tonsils, middle ear and nasal mucosa, bones, as well as cerebrospinal, pleural and synovial fluids and the secretion of the prostate).

With intravenous administration ceftriaxone quickly diffuses into the interstitial fluid, where it retains its bactericidal action against pathogens sensitive to it for 24 hours.

Binding to proteins

Ceftriaxone reversibly binds to albumin, and this binding is inversely proportional to concentration: for example, when the drug concentration in the serum is less than 100 mg / l, ceftriaxone binds to proteins with 95%, and at a concentration of 300 mg / l, only 85%. Due to the lower content of albumins in the interstitial fluid, the concentration of ceftriaxone in it is higher than in serum.

Penetration into the cerebrospinal fluid: in newborns and in children with inflammation of the meninges ceftriaxone penetrates into the cerebrospinal fluid, while in the case of bacterial meningitis, an average of 17% of the concentration of the drug in the blood serum diffuses into the cerebrospinal fluid, which is approximately 4 times greater than with aseptic meningitis. 24 hours after intravenous administration of ceftriaxone in a dose of 50-100 mg / kg body weight, the concentration in the cerebrospinal fluid exceeds 1.4 mg / L. The maximum concentration in the cerebrospinal fluid is reached approximately 4 hours after intravenous administration and is, on average, 18 mg / l. In adults with bacterial meningitis, 2 to 25 hours after the administration of ceftriaxone at a dose of 50 mg / kg body weight, the concentration of ceftriaxone was many times greater than the minimum suppressive dose that is required to suppress pathogens,most often causing bacterial meningitis. Ceftriaxone penetrates the placental barrier and in low concentrations into breast milk.

Metabolism

Ceftriaxone does not undergo systemic metabolism, but turns into inactive metabolites under the influence of intestinal flora.

Excretion

The total plasma clearance of ceftriaxone is 10-22 ml / min. Kidney clearance is 5-12 ml / min. The half-life in healthy adults is about 8 hours. In newborns up to 8 days and in elderly people older than 75 years, the average half-life is approximately two to three times greater. In adults, 50-60% of ceftriaxone is excreted unchanged in the urine, and 40-50% is also unchanged with bile through the intestine where inactivation occurs. In neonates, approximately 70% of the administered dose is excreted by the kidneys. In renal failure or liver disease in adults pharmacokinetics ceftriaxone hardly changes, half-life period is lengthened slightly. If the kidney function is impaired, the excretion of bile increases, and if there is a pathology of the liver, then the excretion of ceftriaxone by the kidneys is enhanced.Half-life in patients on hemodialysis with creatinine clearance (CC) 0-5 ml / min - 14.7 hours, with KK 5-15 ml / min - 15.7 h, with KK 16-30 ml / min - 11 , 4 hours, with JS 31-60 ml / min - 12.4 hours.

Indications:Infections caused by susceptible to ceftriaxone pathogens: Bacterial septicemia, bacterial meningitis, disseminated Lyme disease (early and late stages of the disease); infection of the abdominal cavity (peritonitis, inflammatory diseases of the gastrointestinal tract, bile ducts), infections of bones, joints, connective tissue, skin, and wound infections; infection in patients with low immunity, infection of the kidneys and urinary tract, respiratory infections (especially pneumonia), as well as acute otitis media, urogenital infections (including uncomplicated gonorrhea). Prevention of infections in the postoperative period.

Contraindications:

Hypersensitivity to cephalosporins, penicillins, carbapenems. Hyperbilirubinemia in newborns and prematurity (in vivo studies have shown that ceftriaxone can displace bilirubin from association with serum albumin, increasing the risk of developing bilirubin encephalopathy in such patients). Newborns (< 28 days) who have already been prescribed or are expected to receive intravenous calcium-containing solutions, including long-term calcium-containing infusions, for example, with parenteral nutrition, due to the risk of calcium precipitate formation of ceftriaxone.

Some fatal cases of the formation of precipitates in the lungs and kidneys in newborns who have received ceftriaxone and calcium-containing solutions. In some cases, one venous access was used, and the formation of precipitates was observed directly in the system for intravenous administration, and at least one fatal case with different venous accesses and at different times of administration of ceftriaxone and calcium-containing solutions was also reported. Similar cases were observed only in newborns. The first trimester of pregnancy.

Carefully:

Lactation period, premature infants, renal and / or hepatic insufficiency, ulcerative colitis, enteritis or colitis associated with the use of antibacterial drugs.

Pregnancy and lactation:

Pregnancy

Ceftriaxone penetrates the placental barrier.Safety of use in pregnancy in women is not established. Preclinical reproductive studies not revealed embryotoxic, fetotoxic. teratogenic effect or other adverse effects of ceftriaxone on the fertility of males and females, the process of labor, perinatal and postnatal development of the fetus. In pregnancy (II, III trimesters), should be prescribed only according to strict indications, provided that the intended benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

In low concentrations ceftriaxone enters the breast milk. During the period of breastfeeding the drug is used with

Usually the course of treatment is 4-14 days. With complicated infections, a longer duration of administration may be required. The course of treatment for infections caused by Streptococcus pyogenes should be at least 10 days. Combination therapy Between the drug Oframax® and aminoglycosides against many gram-negative bacteria, synergy is observed. In spite of the fact that with care taking into account the ratio of the expected benefit to the possible risk of use or it is recommended to stop breastfeeding.

Dosing and Administration:

Oramax ® is used intramuscularly and intravenously.

For adults and children over 12 years

The average daily dose of Oramax ® is 1-2 g once a day or 0.5-1 g every 12 hours.

In severe cases or in cases of infections caused by moderately sensitive microorganisms, the daily dose may be increased to 4 g.

Duration of treatment depends on the course of the disease. The drug should be continued to the patient for at least 48-72 hours after the temperature is normalized and the eradication of the pathogen is confirmed.

Usually the course of treatment is 4-14 days. With complicated infections, a longer duration of administration may be required. The course of treatment for infections caused by Streptococcus pyogenes, must be at least 10 days. Combination Therapy Between the drug Oframax ® and aminoglycosides against many gram-negative bacteria there is synergy. Despite the fact that the increased effectiveness of such combinations is not always predictable, it should be borne in mind in severe, life-threatening infections, for example conditional Pseudomonas aeruginosa. Because of the pharmaceutical incompatibility of ceftriaxone and aminoglycosides, they should be administered separately in the recommended doses for them.

Children

Newborns, infants and children under 12 years of age:

When prescribing Oramax ® once a day the following dosage regimens are recommended: newborns (up to 14 days) - 20-50 mg / kg of body weight once a day. The daily dose should not exceed 50 mg / kg of body weight. When determining the dose, there is no need to distinguish between full and premature babies. Oramax ® is contraindicated in newborns (< 28 days) who have already been prescribed or are expected to receive intravenous calcium-containing solutions, including long-term calcium-containing infusions, for example, with parenteral nutrition because of the risk of calcium precipitates formation of ceftriaxone.

Newborns, infants and young children (from 15 days to 12 years): 20-80 mg / kg body weight once a day. For the treatment of skin and soft tissue infections, the recommended daily intake in children is 50-75 mg / kg divided into 2 divided doses (every 12 hours). The total daily intake for children should not exceed 2 g.In the treatment of acute otitis media in children, a one-time

intramuscular injection at a dose of 50 mg / kg (but not more than 1 g).

Children with a body weight above 50 kg are prescribed doses for adults.

Intravenous doses of 50 mg / kg and above should be administered drip for at least 30 minutes.

Meningitis

In bacterial meningitis in newborns and in children, the initial dose is 100 mg / kg of body weight once a day (maximum 4 g). As soon as it was possible to isolate the pathogenic microorganism and determine its sensitivity, the dose should be reduced accordingly. The best results were achieved with a treatment duration of 4 days. With meningitis caused by Haemophilus influenzae 6 days. With meningitis caused by Streptococcus pneumoniae - 7 days.

Uncomplicated gonorrhea For the treatment of gonorrhea, caused by both generative and non-penicillinase-producing strains, the recommended dose is 250 mg once intramuscularly.

Prevention in the pre- and postoperative period

Before being infected or presumably infected surgical interventions to prevent postoperative of infections, depending on the danger of infection, a single administration of Oramax ® in a dose of 1-2 g is recommended 30-90 minutes prior to surgery.At operations on a thick and a rectum well has proved simultaneous but sequential administration of ceftriaxone and derivatives 5-nitroimidazoles, for example, ornidazole.

Lack of kidney and liver function

In patients with impaired renal function, under the condition of normal liver function, the dose of Oramax ® is not necessary to reduce. Only with renal insufficiency in the preterminal stage (CC below 10 ml / min) it is necessary that the daily dose of Oramax ® does not exceed 2 g.

In patients with impaired liver function, if the function of the kidneys is maintained, the dose of Oramax® should not be reduced.

In patients with renal-hepatic insufficiency, the daily dose should not exceed 2 g without determining the concentration of the drug in the blood plasma. In cases of simultaneous presence of severe pathology of the liver and kidneys, the concentration of ceftriaxone in serum should be monitored regularly and, if necessary, adjusted to its dose. Patients on dialysis, additional administration of the drug after dialysis is not required. However, the concentration of ceftriaxone in the serum should be monitored for possible dose adjustment, since the rate of excretion in these patients may be reduced.

Patients of elderly and senile age Usual doses for adults, without adjustments for age.

Lyme disease

50 mg / kg (maximum daily dose - 2 g) adults and children once a day for 14 days.

Instructions for preparation and introduction of the solution

Intramuscular injection

For intramuscular injection, the drug should be diluted in a 1% solution of lidocaine and inserted deep into the gluteus muscle. It is recommended to inject no more than 1 g of the drug into one buttock. A solution of lidocaine can never be administered intravenously!

Dosage	Volume of solvent
250 mg	2 ml
1000 mg	3.5 ml

Intravenous administration

For intravenous injection, the drug is diluted in water for injection and administered intravenously slowly for 2-4 minutes.

Dosage	Volume of solvent
250 mg	5 ml
1000 mg	10 ml

Intravenous infusion

The duration of intravenous infusion, for at least 30 minutes. For intravenous infusion, 2 g of Oramax® powder should be diluted in approximately 40 ml of a solution that does not contain calcium, for example: 0.9% sodium chloride solution, 0.45% sodium chloride solution and 2.5% dextrose solution, 5% dextrose solution, 10% dextrose solution, 5% fructose solution, 6-10% hydroxyethyl starch solution, in water for injection.Oramax® solutions should not be mixed or added to solutions containing other antimicrobial agents or other solvents, other than those listed above, because of possible incompatibility. Solvents containing calcium, such as Ringer's solution or Hartmann's solution, can not be used to prepare Oramax® solutions for intravenous administration and subsequent dilution, due to the possible formation of precipitates. The formation of precipitates of calcium salts of ceftriaxone can also occur with the mixing of Oramax ® and calcium-containing solutions using one venous access. Do not use Oramax ® simultaneously with calcium-containing solutions for intravenous administration, including prolonged infusions of calcium-containing solutions, for example, with parenteral nutrition using Yconnector. For all groups of patients, except for newborns, it is possible to consistently administer Oramax ® and calcium-containing solutions with thorough washing of infusion systems between infusions of a compatible liquid.

No reports of ceftriaxone interaction and oral calcium-containing drugs or the interaction of ceftriaxone for intramuscular administration and calcium-containing drugs for intravenous or oral administration.

Side effects:The side effects observed with the drug disappear either on their own or after the drug is discontinued.

Allergic reactions: allergic pneumonitis, bronchiosis, anaphylactic or anaphylactoid reactions, allergic dermatitis.

Nervous system: headache and dizziness, convulsive seizure.

Gastrointestinal tract: unformed stool or diarrhea, abdominal pain, bloating, nausea, vomiting, stomatitis, glossitis, taste disorder, colitis, pseudomembranous colitis, bloody stool, precipitation of calcium ceftriaxone salts in the gallbladder with the corresponding symptomatology, pancreatitis, increased activity of hepatic enzymes (alanine aminotransferase ( ALT) and aspartate aminotransferase (ACT)), alkaline phosphatase, jaundice, cholelithiasis, "sluggish phenomenon" of the gallbladder, hyperbilirubinemia.

Genitourinary system: oliguria, mycoses of genital organs, vaginitis, hematuria, the formation of precipitates in the kidneys, the formation of calculi in the kidneys, renal failure, glucosuria, hypercreatininaemia, the presence of sediment in the urine. Hematologic changes: eosinophilia, leukopenia, granulocytopenia, anemia, hemolytic anemia, thrombocytosis, thrombocytopenia, lymphopenia, neutropenia, increased thromboplastin and prothrombin time, decreased prothrombin time, basophilia, agranulocytosis, bleeding disorders, epistaxis, leukocytosis, lymphocytosis, monocytosis.

Skin reactions: rash, itching, urticaria, edema, exudative erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), maculopapular rash.

Other: fever, chills, increased sweating, "hot flashes" of blood, a feeling of palpitations, serum sickness, the formation of precipitates in the lungs.

Local reactions: with intravenous injection - phlebitis, soreness, tightening along the veins; intramuscular injection - soreness, sensation of warmth, tightness or condensation at the injection site.Phlebitis can be avoided by injecting the drug slowly for 2-4 minutes.

Effect on the results of laboratory tests

False positive results of Coombs test, false positive result of the test for galactosemia, false positive results in the determination of glucose in urine by non-enzyme methods.

Overdose:Excessively high concentrations of ceftriaxone in plasma can not be reduced by hemodialysis or peritoneal dialysis. Symptomatic measures are recommended for the treatment of overdose cases.

Interaction:Ceftriaxone and aminoglycosides have a synergistic effect on many gram-negative bacteria. Indications that ceftriaxone increases the nephrotoxicity of aminoglycosides, no. The use of alcohol after administration of ceftriaxone was not accompanied by a disulfiram-like reaction. Nonsteroidal anti-inflammatory drugs and other inhibitors of platelet aggregation increase the likelihood of bleeding.

With simultaneous use with "loop" diuretics and other nephrotoxic drugs, there were no violations of kidney function.

Probenecid does not affect the excretion of ceftriaxone.

Bacteriostatic antibiotics reduce the bactericidal effect of ceftriaxone. In vitro, antagonism between chloramphenicol and ceftriaxone was detected. Do not use solvents containing calcium, such as Ringer's solution or Hartmann's solution, in the preparation of ceftriaxone solutions for intravenous administration and their subsequent dilution due to the possible formation of precipitates. The formation of precipitates of calcium salts of ceftriaxone can also occur when mixing ceftriaxone and calcium-containing solutions using a single venous access. Can not use ceftriaxone simultaneously with calcium-containing solutions for intravenous administration, including long infusions of calcium-containing solutions, for example, with parenteral nutrition using the Y-connector. For all groups of patients, except for newborns, sequential administration of ceftriaxone and calcium-containing solutions is possible with thorough washing of infusion systems between infusions of a compatible liquid.

Ceftriaxone is pharmaceutically incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Special instructions:

With simultaneous severe renal and hepatic insufficiency, the concentration of the drug in the plasma should be regularly determined.

In patients on hemodialysis, it is necessary to monitor the concentration of ceftriaxone in the plasma, because they can decrease the rate of its removal. With long-term treatment, it is necessary to regularly monitor the picture of peripheral blood, indicators of the functional state of the liver and kidneys. After applying ceftriaxone, usually at doses exceeding the standard recommended, ultrasound examination of the gallbladder revealed shadows that were mistaken for stones. They are precipitates of the calcium salt of ceftriaxone, which disappear after completion or discontinuation of ceftriaxone therapy. Such changes rarely give any symptomatology, but in such cases only conservative treatment is recommended. If these phenomena are accompanied by clinical symptoms, then the decision to cancel the drug is left to the discretion of the attending physician. Ceftriaxone does not contain an N-methylthiotetrazol group, which could cause ethanol to be intolerant, so when it does not interact with ethanol to development of disulfiram-like reactions inherent in some cephalosporins. Despite the detailed collection of anamnesis, which is the rule for other cephalosporin antibiotics, it is impossible to exclude the possibility of developing an anaphylactic reaction (anaphylactic reactions were fatal), which requires immediate therapy - first intravenously injected epinephrine, then glucocorticosteroids. With the use of other cephalosporins in the treatment of ceftriaxone, autoimmune hemolytic anemia may develop. Cases of severe hemolytic anemia in adults and children, including fatal cases, have been reported. With the development of anemia in a patient treated with ceftriaxone, it is impossible to exclude the diagnosis of cephalosporin-associated anemia and it is necessary to cancel the treatment until the cause is clarified. As with most other antibacterial drugs, cases of the development of diarrhea caused by Clostridium difficile (C. difficile) have been documented in the treatment of ceftriaxone, varying in severity: from mild diarrhea to colitis with fatalities. Treatment with antibacterial drugs suppresses the normal microflora of the colon and provokes the growth of C. difficile. In turn, S.difficile forms toxins A and B, which are factors in the pathogenesis of diarrhea caused by C. difficile. C. difficile strains, hyper-producing toxins, are the causative agents of infections with a high risk of complications and mortality, due to their possible resistance to antimicrobial therapy, treatment may require colectomy. It is necessary to remember the possibility of developing diarrhea caused by C. difficile in all patients with diarrhea after antibiotic therapy. It is necessary to carefully collect the anamnesis, tk. cases of diarrhea caused by C. difficile have been reported, more than 2 months after antibiotic therapy. If the diarrhea caused by C. difficile is suspected or confirmed, it may be necessary to cancel the current diarrhea not directed to S. difficile antibiotic therapy. In accordance with clinical indications, appropriate treatment should be prescribed with the introduction of fluid and electrolytes, proteins, antibiotic therapy for C. difficile, surgical treatment.

As with other antibacterial drugs, superinfections can develop. In patients who received ceftriaxone, rare cases of prothrombin time change are described.Patients with vitamin K deficiency (impaired synthesis, eating disorder) may need to monitor prothrombin time during therapy and prescribe vitamin K (10 mg / week) with an increase in prothrombin time before or during therapy.

Despite the availability of data on the formation of intravascular precipitates only in newborns at the use of ceftriaxone and calcium-containing infusion solutions or any other calcium-containing drugs, ceftriaxone Do not mix or prescribe to children and adults patients concomitantly with calcium-containing infusion solutions, even using different venous accesses. In patients who received ceftriaxone, rare cases of pancreatitis, which developed, possibly, as a result of obstruction of the biliary tract, are described. Most of these patients already had risk factors for congestion in the biliary tract, for example, previous therapy, severe diseases and completely parenteral nutrition. At the same time, it is impossible to exclude the starting role of precipitates formed in the biliary tract under the influence of ceftriaxone in the development of pancreatitis.The safety and efficacy of Oramax ® in newborns, infants and young children have been determined for the doses described in the "Dosage and Administration" section. In vitro studies

showed that similar to other cephalosporin antibiotics, ceftriaxone is able to displace bilirubin, associated with serum albumin. Therefore, in newborns with hyperbilirubinemia and especially in preterm neonates ceftriaxone can not be applied.

During the period of breastfeeding the drug is used with caution, taking into account the ratio of the expected benefit to the possible risk of use or it is recommended to stop breastfeeding.

Elderly and debilitated patients may require the appointment of vitamin K. For long-term treatment should be a regular full blood test.

Effect on the ability to drive transp. cf. and fur:

There is no evidence of the effect of the drug on driving vehicles and working with machines and mechanisms. However, one should remember about the possible occurrence of dizziness during therapy with Oramax®.

Form release / dosage:

Powder for the preparation of solution for intravenous and intramuscular injection of 250 mg and 1000 mg.

Packaging:

In a vial of 5 ml (for 250 mg) or 15 ml (for 1000 mg) of a transparent colorless glass of type I, closed with a rubber stopper, rigidly covered with an aluminum cap closing with a tearing plastic lid; one bottle with instructions for use in a cardboard bundle.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Do not freeze. Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N012523 / 01

Date of registration:15.07.2011

The owner of the registration certificate:Ranbaxy Laboratories LimitedRanbaxy Laboratories Limited India

Manufacturer: & nbsp

RANBAXY LABORATORIES, Ltd. India

Representation: & nbspRABBAYS LABORATORY LIMITEDRABBAYS LABORATORY LIMITED

Information update date: & nbsp17.11.2015

Illustrated instructions

Instructions

Oframax® (Oframax®)