INSTRUCTION
for medical use of the medicinal product
LEVOMYCETIN - DONATION
(LEVOMICETIN-DARNITSA)
Storage:
active substance: chloramphenicol;
1 tablet contains chloramphenicol (levomycetin) 250 mg or 500 mg;
excipients: potato starch, hydroxypropyl cellulose, stearic acid.
Medicinal form. Tablets.
The main physicochemical properties: tablets are white or white with a slightly yellowish tint, flat-cylindrical, with a line and a chamfer. The presence of grayish or yellowish specks is allowed.
Pharmacotherapeutic group. Antibacterial agents for systemic use. Amphenicol. Chloramphenicol. ATX code J01B A01.
Pharmacological properties.
Pharmacodynamics.
Levomycetin (chloramphenicol) is a broad-spectrum bacteriostatic antibiotic. The action is associated with the disruption of the process of protein synthesis in the microbial cell at the stage of transfer of tRNA amino acids to ribosomes. Effective against many gram-positive and gram-negative bacteria: Escherichia coli, Shigella flexneri spp., Shigella boydii spp., Shigella sonnei spp., Salmonella spp. (including Salmonella typhi), acts on Streptococcus spp. (including on Streptococcus pneumoniae), Neisseria gonorrhoeae, Neisseria meningitidis, a number of strains of Proteus spp., on some strains of Pseudomonas aeruginosa; active against Ricketsia spp., Treponema spp., Chlamydia spp. (including Chlamydia trachomatis), causative agents of purulent infections, typhoid, dysentery, meningococcal infection, brucella, rickettsia, chlamydia, spirochetes. Does not work on Mycobacterium tuberculosis, pathogenic protozoa and fungi. Active against strains of bacteria resistant to penicillin, tetracyclines, and sulfonamides. Resistance of microorganisms develops slowly. The drug is weakly active against acid-resistant bacteria, Pseudomonas aeruginosa, clostridia and protozoa.
The mechanism of action is due to inhibition of protein synthesis in the cells of microorganisms. In therapeutic concentrations, it has a bacteriostatic effect. Resistance of microorganisms to the drug develops slowly and, as a rule, cross-resistance to other chemotherapeutic agents does not occur. Due to its high toxicity, Levomycetin is used to treat severe infections in which less toxic antibacterial agents are ineffective or contraindicated.
Pharmacokinetics.
It is quickly and almost completely absorbed from the digestive system. The maximum concentration in blood plasma is reached after 2–3 hours. The therapeutic concentration in the blood is maintained for 4–5 hours. Bioavailability after oral administration is 80%. It penetrates well into organs, tissues and body fluids, penetrates through the blood-brain barrier, the placenta, and into breast milk. 50–60% of chloramphenicol binds to blood plasma proteins. The highest concentrations of chloramphenicol are observed in the liver and kidneys. Up to 30% of the administered dose of chloramphenicol is observed in the bile. Penetrates well through the blood-brain barrier: the maximum concentration in the cerebrospinal fluid is observed 4-5 hours after a single internal use. It is biotransformed in the liver, 90% binds to inactive glucuronide. Chloramphenicol palmitate is hydrolyzed to the free state in the digestive system before absorption. Chloramphenicol sodium succinate is hydrolyzed to a free state in blood plasma, liver, lungs and kidneys. In fetuses and premature babies, the liver is not sufficiently developed to bind chloramphenicol, which leads to the accumulation of toxic concentrations of the active form of the drug and can lead to the development of "gray syndrome". In the intestines, under the action of intestinal bacteria, chloramphenicol is hydrolyzed with the formation of inactive metabolites.
It is excreted mainly with urine (mainly in the form of inactive metabolites), partly with bile (up to 30% of the applied dose) and feces.
The elimination half-life in adults with normal kidney and liver function is 1.5–3.5 hours, in case of impaired kidney function – 3–4 hours, in case of severe impaired liver function – 4.6–11 hours.
Clinical characteristics.
Indication.
Infectious-inflammatory diseases caused by microorganisms sensitive to the drug: typhoid, paratyphoid, yersiniosis, brucellosis, shigellosis, salmonellosis, tularemia, rickettsiosis, chlamydia, purulent peritonitis, bacterial meningitis, biliary tract infections.
The drug is indicated in cases of ineffectiveness of other antimicrobial agents due to the possibility of developing severe side effects.
Contraindication.
• Increased individual sensitivity (allergy) to chloramphenicol, other amphenicols and/or other components of the medicinal product;
• blood diseases, including hematopoiesis suppression;
• pronounced liver and/or kidney function disorders;
• glucose-6-phosphate dehydrogenase enzyme deficiency;
• skin diseases (psoriasis, eczema, fungal diseases);
• porphyria.
Levomycetin should not be prescribed for acute respiratory diseases, angina, and
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also to prevent bacterial infection.
Interaction with other medicinal products and other types of interactions.
Long-term use of chloramphenicol, which is an inhibitor of liver enzymes, in the preoperative period or during surgery may reduce plasma clearance and prolong the duration of action of alfentanil.
Chloramphenicol suppresses the enzyme system of cytochrome P450, therefore, when it is used simultaneously with antiepileptic drugs (phenobarbital, phenytoin), indirect anticoagulants (dicumarin, warfarin) and other drugs metabolized by this oxidase system, the metabolism of these drugs is weakened, the excretion slows down, and the increase in their concentration in the blood plasma and increase in their toxicity.
Oral hypoglycemic drugs (chlorpropamide, tolbutamide) - when used with chloramphenicol, there is an increase in the effect of oral hypoglycemic drugs (due to suppression of metabolism in the liver and an increase in their concentration in the blood plasma), which requires dose correction.
Phenobarbital, rifampicin, rifabutin - reduce the concentration of chloramphenicol in the blood plasma by accelerating its metabolism in the liver.
Paracetamol - with simultaneous use, a prolongation of the half-life of chloramphenicol may be observed.
Phenytoin - with simultaneous use, both a decrease and an increase in the concentration of chloramphenicol in the blood plasma can be observed.
Cyclosporin - with simultaneous use with chloramphenicol, an increase in the level of cyclosporin in the blood plasma may be observed. With the simultaneous use of these drugs, it is necessary to monitor the concentration of cyclosporine.
Cyclophosphamide - simultaneous use prolongs the half-life of cyclophosphamide from 7.5 to 11.5 hours.
Tacrolimus - with simultaneous use with chloramphenicol, an increase in the level of tacrolimus in the blood plasma may be observed. With simultaneous use, the dose of tacrolimus must be adjusted.
Levomycetin reduces the antibacterial effect of penicillins and cephalosporins.
Macrolides (erythromycin, oleandomycin), lincosamides (clindamycin, lincomycin), polyene antibiotics (nystatin, levorin) - when chloramphenicol is used simultaneously with these drugs, a mutual weakening of the effect is noted due to the fact that chloramphenicol can displace these drugs from the bound state or prevent their binding to the 50S subunit of bacterial ribosomes. Therefore, their simultaneous use should be avoided.
Cycloserine - simultaneous use increases the neurotoxicity of chloramphenicol.
Medicines that suppress hematopoiesis (sulfanamides, carbamazepine, phenylbutazone, penicillamine, some antipsychotics, including clozapine, procainamide, reverse transcriptase inhibitors, propylthiouracil, cytostatics, cimetidine, ristomycin), radiation therapy - simultaneous use increases the risk of suppression of bone of the brain and the severity of its manifestations. Therefore, their simultaneous use should be avoided.
Estrogen-containing oral contraceptives - long-term simultaneous use can lead to a decrease in the reliability of contraception and an increase in the frequency of breakthrough bleeding. In this regard, it is recommended to use non-hormonal methods of contraception during treatment with chloramphenicol.
Preparations of iron, folic acid, cyanocobalamin - chloramphenicol can reduce the effectiveness of these medicines.
Ethanol - with the simultaneous use of ethanol, the development of a disulfiram-like reaction is possible (hyperemia of the skin, tachycardia, nausea, vomiting, reflex cough, convulsions).
Features of application.
In view of the possibility of the development of severe damage to hematopoietic organs as a result of the toxic effect of the drug, the composition of peripheral blood should be monitored during therapy, and the condition of the liver and kidneys should be monitored.
In the event of leukopenia, thrombocytopenia, anemia or other pathological changes in the blood, the drug should be discontinued immediately. Although continuous monitoring of the composition of peripheral blood during treatment with chloramphenicol can detect early changes from the side of the blood system (leukopenia, reticulocytopenia or granulocytopenia) before they become irreversible, this does not exclude the possibility of aplastic anemia due to the development of bone marrow depression. Aplastic anemia, thrombocytopenia, and granulocytopenia usually occur after the end of treatment. Therefore, such symptoms as pale skin, sore throat and elevated body temperature, unusual bleeding, weakness (if they appear several weeks or months after the withdrawal of the drug) require urgent help.
In patients who have previously used cytostatic drugs or radiation therapy, the potential risks and expected benefits of treatment with the drug should be compared in view of the possibility of the development of severe side effects. The use of chloramphenicol with other drugs that can cause suppression of bone marrow function should be avoided. To increase the safety of treatment, monitoring should be carried out if possible
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plasma concentration of chloramphenicol. The therapeutic range is 5–15 μg/ml.
Treatment with antibacterial drugs leads to disruption of the normal flora of the large intestine and can cause an overgrowth of Clostridium difficile, whose toxins are the main cause of pseudomembranous colitis. Pseudomembranous colitis occurs both during the use of the drug and within 2 months after the end of antibacterial therapy. Mild to life-threatening pseudomembranous colitis has been reported with almost all antibacterial drugs, including chloramphenicol. Therefore, it is important to clarify the diagnosis in patients with diarrhea after the use of antibacterial drugs. In the absence of the necessary treatment, toxic megacolon, peritonitis, and shock may develop. It should be taken into account that the development of colitis is most likely in severe diseases in elderly patients, as well as in weakened patients.
The use of antibacterial drugs can lead to the overgrowth of non-susceptible microorganisms, in particular fungi. If infections caused by non-susceptible microorganisms develop during treatment, appropriate measures should be taken.
In patients with impaired liver or kidney function, an increase in the level of chloramphenicol in blood serum is possible and the risk of developing toxic reactions to this drug may be higher, so the dosage should be adjusted accordingly. It is advisable to periodically determine the concentration of the drug in the blood, checking the functions of the liver and kidneys.
Clinical experience has not revealed differences in responses to treatment with chloramphenicol between patients of different age groups. However, taking into account the age-related features of kidney, liver, and cardiovascular system functions, the presence of concomitant diseases, and the use of other medications, it is necessary to determine the dose of the drug for elderly patients carefully, starting, as a rule, from the lower limit of the dosage range.
Levomycetin should be prescribed with caution to patients with a tendency to allergic reactions.
Simultaneous use of ethanol leads to the development of a disulfiram-like reaction (skin hyperemia, tachycardia, nausea, vomiting, reflex cough, convulsions).
Uncontrolled prescription of Levomycetin-Darnytsia and its use in mild forms of infectious processes, in acute respiratory diseases or as a prophylactic agent to prevent bacterial infections, especially in pediatric practice, is unacceptable.
The appointment of chloramphenicol can provoke acute attacks of porphyria. The drug is dangerous for use in patients with porphyria.
Chloramphenicol can affect the development of the immune response, it cannot be prescribed during active immunization.
Repeated courses of treatment with chloramphenicol should be avoided, therapy should last no longer than is necessary to obtain positive results without the risk of developing complications or disease recurrence.
Use with caution in cardiovascular diseases.
Use during pregnancy or breastfeeding.
The use of chloramphenicol is contraindicated during pregnancy. Breastfeeding should be stopped during drug treatment.
The ability to influence the speed of reaction when driving vehicles or other mechanisms.
Until the patient's individual reaction to the drug is clarified, one should refrain from driving vehicles or other mechanisms, given that during therapy with chloramphenicol, disturbances from the nervous system may be observed.
Method of application and dosage.
Apply inside 30 minutes before eating; in case of nausea, vomiting - 1 hour after eating.
The dosage regimen should be set individually depending on the severity of the disease and the patient's condition.
Adults use 250–500 mg 3–4 times a day. The daily dose is 2000 mg. In particularly severe cases, the drug can be used orally in a dose of up to 4000 mg (maximum daily dose for adults) per day under strict control of the blood and liver and kidney functions. Divide the daily dose into 3–4 doses.
Children aged 3 to 8 years should be prescribed a single dose of 125 mg, children aged 8 years and older - 250 mg. Frequency of reception - 3-4 times a day.
The course of treatment with the drug is 7–10 days. According to indications, subject to good tolerability and absence of changes in the composition of peripheral blood, it is possible to extend the course of treatment up to 2 weeks.
Children.
Apply to children over 3 years old.
For the treatment of children aged 3 years and older, the drug should be prescribed with extreme caution and only in the absence of alternative therapy.
Overdose.
Symptoms Serious complications from the hematopoietic system are usually associated with long-term use of large doses of the drug (more than 3 g per day) - pale skin, sore throat and elevated body temperature, bleeding and hemorrhages, fatigue or weakness. Chloramphenicol levels
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nicol in the blood, exceeding 25 μg/ml, are considered toxic.
It is also possible to develop other side reactions characteristic of chloramphenicol (see the section "Side reactions").
Particularly dangerous is the "gray syndrome", which is observed mainly in newborns (whose mothers used chloramphenicol during childbirth or in whom chloramphenicol therapy was started in the first 48 hours of life), but in case of overdose, it is also possible in older children or especially sensitive people (abdominal bloating )
"Gray syndrome" can also be observed due to the accumulation of the drug in case of relative overdose (accumulation of chloramphenicol due to the immaturity of liver enzymes and its direct toxic effect on the myocardium) in patients with impaired liver and kidney function. "Gray syndrome" is manifested when the concentration of chloramphenicol in the blood plasma exceeds 50 μg/ml.
Treatment. Cancellation of the drug and appointment of symptomatic therapy, gastric lavage, appointment of enterosorbents (including activated carbon), saline laxative, high cleansing enema. In severe cases - hemosorption.
Adverse reactions.
The most severe side reactions are: aplastic anemia, inhibition of bone marrow activity and "gray syndrome".
The development of adverse reactions on the part of the following organs and systems is also observed:
On the part of the gastrointestinal tract: dyspepsia, flatulence, nausea, vomiting (the probability of development decreases when used 1 hour after a meal), diarrhea, irritation of the mucous membrane of the oral cavity and throat, dry mouth, inhibition of intestinal microflora, dysbacteriosis, enterocolitis, stomatitis, glossitis.
From the side of the liver and biliary tract: impaired liver function.
From the nervous system: psychomotor disorders, moderate depression, confusion, headache, encephalopathy, delirium. Long-term use of large doses of the drug can lead to impaired sense of taste, reduced hearing and vision, development of visual and auditory hallucinations, optic and peripheral neuritis (including paralysis of the eyeballs). If these symptoms occur, it is necessary to immediately stop using the drug.
From the blood and lymphatic system: toxic effect on the hematopoietic system, suppression of the bone marrow, reticulocytopenia, decrease in the level of hemoglobin in the blood, anemia, leukopenia, granulocytopenia, thrombocytopenia, erythrocytopenia, pancytopenia; rarely – aplastic anemia, thrombocytopenic purpura, hypoplastic anemia, agranulocytosis, cytoplasmic vacuolization of early erythrocyte forms.
From the side of the skin and subcutaneous tissue: allergic reactions, including in the form of fever, skin rashes (including macular and vesicular), dermatoses; anaphylaxis reactions, including urticaria, angioneurotic edema, facial edema, Quincke's edema, skin itching, hyperemia.
General disorders: possible development of superinfection, including fungal, dermatitis (including perianal dermatitis), hyperthermia, collapse (in children).
There were reports of the development of Yarish-Herxheimer reactions (bacteriolysis reaction) in the course of typhoid therapy (more relevant to parenteral forms of chloramphenicol).
Cases of paroxysmal nocturnal hemoglobinuria have been reported.
Reporting of suspected adverse reactions.
The reporting of suspected adverse reactions after the registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.
Expiration date. 5 years.
Storage conditions.
Store in the original packaging at a temperature not higher than 25 °C.
Keep out of the reach of children.
Packaging.
10 tablets in a contour blister pack, 2 contour blister packs in a pack; 10 tablets each in contour blister packs.
Leave category. By prescription.
Producer. PrJSC "Pharmaceutical firm "Darnytsia".
The location of the manufacturer and the address of the place of its activity.
Ukraine, 02093, Kyiv, st. Boryspilska, 13.
