Levomycetin-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOMITSETIN-DARNITSA (LEVOMITSETIN-DARNITSA)

Composition:

Active substance: chloramphenicol;

One tablet contains chloramphenicol (levomycetin) 250 mg or 500 mg;

Excipients: potato starch, hydroxypropylcellulose, stearic acid.

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets are white or white with a slightly yellowish tint, flat cylindrical shape, with a score line and beveled edge. Slight greyish or yellowish specks may be present.

Pharmacotherapeutic group. Antibacterials for systemic use. Amphenicols. Chloramphenicol. ATC code J01BA01.

Pharmacological Properties

Pharmacodynamics

Chloramphenicol (levomycetin) is a broad-spectrum bacteriostatic antibiotic. Its action is associated with disruption of the protein synthesis process in microbial cells at the stage of transfer of amino acids from tRNA to ribosomes. It is 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 Streptococcus pneumoniae), Neisseria gonorrhoeae, Neisseria meningitidis, various strains of Proteus spp., and some strains of Pseudomonas aeruginosa; it is active against Rickettsia spp., Treponema spp., Chlamydia spp. (including Chlamydia trachomatis), and causative agents of purulent infections, typhoid fever, dysentery, meningococcal infection, brucellosis, rickettsiae, chlamydiae, and spirochetes. It has no effect on Mycobacterium tuberculosis, pathogenic protozoa, or fungi. It is active against bacterial strains resistant to penicillin, tetracyclines, and sulfonamides. Microbial resistance develops slowly. The drug is poorly active against acid-resistant bacteria, Pseudomonas aeruginosa, Clostridia, and protozoa.

The mechanism of action is due to inhibition of protein synthesis in microbial cells. At therapeutic concentrations, it exerts a bacteriostatic effect. Microbial resistance to the drug develops slowly, and cross-resistance to other chemotherapeutic agents usually does not occur. Due to its high toxicity, chloramphenicol is used to treat severe infections when less toxic antibacterial agents are ineffective or contraindicated.

Pharmacokinetics

Chloramphenicol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2–3 hours. Therapeutic blood concentrations are maintained for 4–5 hours. Oral bioavailability is approximately 80%. It penetrates well into organs, tissues, and body fluids, crosses the blood-brain barrier, placenta, and is excreted into breast milk. Approximately 50–60% of chloramphenicol is protein-bound in plasma. The highest concentrations of chloramphenicol are observed in the liver and kidneys. Up to 30% of the administered dose is excreted into bile. It penetrates well through the blood-brain barrier: maximum concentration in cerebrospinal fluid is observed 4–5 hours after a single oral dose. It undergoes hepatic biotransformation, with 90% being conjugated into inactive glucuronide. Chloramphenicol palmitate is hydrolyzed into its free form in the gastrointestinal tract prior to absorption. Chloramphenicol sodium succinate is hydrolyzed into its free form in plasma, liver, lungs, and kidneys. In fetuses and premature infants, the liver is insufficiently developed to conjugate chloramphenicol, leading to accumulation of toxic concentrations of the active form of the drug and potentially resulting in the development of "gray syndrome." In the intestine, under the influence of gut bacteria, chloramphenicol undergoes hydrolysis to form inactive metabolites.

Elimination is primarily via urine (mainly as inactive metabolites), partially via bile (up to 30% of the administered dose) and feces.

The elimination half-life in adults with normal renal and hepatic function is 1.5–3.5 hours; in cases of impaired renal function, it is 3–4 hours, and in cases of severe hepatic impairment, it is 4.6–11 hours.

Clinical characteristics.

Indications.

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug: typhoid fever, paratyphoid fever, yersiniosis, brucellosis, shigellosis, salmonellosis, tularemia, rickettsioses, chlamydiosis, purulent peritonitis, bacterial meningitis, infections of the biliary tract.

The drug is indicated in cases of ineffectiveness of other antimicrobial agents due to the possibility of developing severe adverse effects.

Contraindications.

• Hypersensitivity (allergy) to chloramphenicol, other phenicols, and/or other components of the drug;
• Blood disorders, including bone marrow suppression;
• Severe impairment of liver and/or kidney function;
• Glucose-6-phosphate dehydrogenase deficiency;
• Skin diseases (psoriasis, eczema, fungal infections);
• Porphyria.

Levomycetin should not be prescribed for acute respiratory diseases, tonsillitis, or for the prophylaxis of bacterial infection.

Interaction with other medicinal products and other types of interactions.

Prolonged use of levomycetin, which is a liver enzyme inhibitor, in the preoperative period or during surgery may reduce plasma clearance and prolong the duration of action of alfentanil.

Chloramphenicol inhibits the cytochrome P450 enzyme system; therefore, when used concomitantly with antiepileptic drugs (phenobarbital, phenytoin), indirect anticoagulants (dicoumarol, warfarin), and other medicinal products metabolized by this oxidase system, a reduced metabolism of these drugs, slowed elimination, increased plasma concentration, and increased toxicity are observed.

Oral hypoglycemic agents (chlorpropamide, tolbutamide) – when used concomitantly with chloramphenicol, an enhanced effect of oral hypoglycemic agents is observed (due to inhibition of hepatic metabolism and increased plasma concentration), requiring dose adjustment.

Phenobarbital, rifampicin, rifabutin – reduce the plasma concentration of chloramphenicol by accelerating its hepatic metabolism.

Paracetamol – when used concomitantly, a prolonged elimination half-life of chloramphenicol may be observed.

Phenytoin – when used concomitantly, both decreased and increased plasma concentrations of chloramphenicol may be observed.

Cyclosporine – when used concomitantly with chloramphenicol, an increased plasma level of cyclosporine may be observed. Monitoring of cyclosporine concentration is necessary when these drugs are used together.

Cyclophosphamide – concomitant use prolongs the elimination half-life of cyclophosphamide from 7.5 to 11.5 hours.

Tacrolimus – when used concomitantly with chloramphenicol, an increased plasma level of tacrolimus may be observed. The dose of tacrolimus should be adjusted when used concomitantly.

Levomycetin reduces the antibacterial effect of penicillins and cephalosporins.

Macrolides (erythromycin, oleandomycin), lincosamides (clindamycin, lincomycin), polyene antibiotics (nystatin, levorin) – when used concomitantly with chloramphenicol, mutual reduction in efficacy is observed because chloramphenicol may displace these drugs from their bound state or interfere with their binding to the 50S subunit of bacterial ribosomes. Therefore, their concomitant use should be avoided.

Cycloserine – concomitant use enhances the neurotoxicity of chloramphenicol.

MEDICINAL PRODUCTS THAT SUPPRESS HEMOPOIESIS (sulfonamides, carbamazepine, phenylbutazone, penicillamine, certain antipsychotics, including clozapine, procainamide, reverse transcriptase inhibitors, propylthiouracil, cytostatics, cimetidine, ristomycin), radiation therapy – concomitant use increases the risk of bone marrow suppression and severity of its manifestations. Therefore, their combined use should be avoided.

Estrogen-containing oral contraceptives – prolonged concomitant use may lead to reduced contraceptive reliability and increased frequency of breakthrough bleeding. Therefore, non-hormonal contraceptive methods are recommended during chloramphenicol treatment.

Iron preparations, folic acid, cyanocobalamin – chloramphenicol may reduce the effectiveness of these medicinal products.

Ethanol – concomitant use of ethanol may result in a disulfiram-like reaction (skin hyperemia, tachycardia, nausea, vomiting, reflex cough, seizures).

Special precautions for use

Due to the potential for severe hematopoietic organ damage resulting from the toxic effects of the drug, blood composition should be monitored during therapy, and liver and kidney function should be closely observed.

If leukopenia, thrombocytopenia, anemia, or other pathological blood changes occur, the drug should be discontinued immediately. Although regular monitoring of peripheral blood during chloramphenicol therapy may detect early hematological changes (leukopenia, reticulocytopenia, or granulocytopenia) before they become irreversible, it does not eliminate the risk of aplastic anemia due to bone marrow suppression. Aplastic anemia, thrombocytopenia, and granulocytopenia typically manifest after completion of treatment. Therefore, symptoms such as skin pallor, sore throat, elevated body temperature, unusual bleeding, or weakness (if they appear several weeks or months after discontinuation of the drug) require urgent medical attention.

In patients previously treated with cytostatic agents or radiation therapy, the potential risks and expected benefits of treatment with this drug should be carefully weighed due to the possibility of severe adverse effects. Concomitant use of chloramphenicol with other medicinal products that may cause bone marrow suppression should be avoided. To enhance treatment safety, therapeutic drug monitoring of plasma chloramphenicol concentration should be performed whenever possible. The therapeutic range is 5–15 μg/mL.

Antibacterial therapy may disrupt the normal flora of the large intestine and promote overgrowth of Clostridium difficile, whose toxins are the primary cause of pseudomembranous colitis. Pseudomembranous colitis may occur both during drug administration and up to 2 months after completion of antibacterial therapy. Cases of pseudomembranous colitis, ranging from mild to life-threatening forms, have been reported with nearly all antibacterial agents, including chloramphenicol. Therefore, it is essential to confirm the diagnosis in patients presenting with diarrhea following antibacterial therapy. Without appropriate treatment, toxic megacolon, peritonitis, and shock may develop. It should be noted that colitis development is most likely in severely ill elderly patients and in debilitated patients.

Antibacterial agents may lead to overgrowth of non-susceptible microorganisms, including fungi. If infections caused by non-susceptible organisms develop during treatment, appropriate measures should be taken.

In patients with impaired liver or kidney function, serum levels of chloramphenicol may increase, and the risk of toxic reactions to the drug may be higher; therefore, dosage adjustment is necessary. Periodic measurement of drug concentration in blood, along with monitoring of liver and kidney function, is recommended.

Clinical experience has not revealed differences in response to chloramphenicol treatment among patients of different age groups. However, due to age-related differences in kidney and liver function, cardiovascular function, presence of comorbidities, and concomitant medication use, dosage selection for elderly patients should be done cautiously, typically starting at the lower end of the dosing range.

Chloramphenicol should be prescribed with caution in patients predisposed to allergic reactions.

Concomitant use of ethanol may lead to a disulfiram-like reaction (skin hyperemia, tachycardia, nausea, vomiting, reflex cough, seizures).

Uncontrolled prescription of Levomycetin-Darnytsia and its use for mild infections, acute respiratory diseases, or as a prophylactic agent to prevent bacterial infections, especially in pediatric practice, is unacceptable.

Administration of chloramphenicol may provoke acute attacks of porphyria. The drug is hazardous for patients with porphyria.

Chloramphenicol may affect the development of immune response; therefore, it should not be administered during active immunization.

Repeated courses of chloramphenicol therapy should be avoided. Treatment should last no longer than necessary to achieve positive results without risking complications or disease recurrence.

Use with caution in patients with cardiovascular diseases.

Use during pregnancy or breastfeeding

Chloramphenicol is contraindicated during pregnancy. Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery

Until the individual patient's response to the drug is known, patients should refrain from driving or operating machinery, considering that nervous system disturbances may occur during chloramphenicol therapy.

Method of Administration and Dosage

Administer orally, 30 minutes before meals; in cases of nausea or vomiting – 1 hour after food intake.

The dosage regimen should be individually determined based on the severity of the disease and the patient's condition.

Adults: Administer 250–500 mg three to four times daily. The daily dose is 2000 mg. In particularly severe cases, the medicinal product may be administered orally at a dose of up to 4000 mg per day (maximum daily dose for adults) under strict monitoring of blood status and liver and kidney function. The daily dose should be divided into 3–4 administrations.

Children: For children aged 3 to 8 years, the single dose is 125 mg; for children aged 8 years and older – 250 mg. Frequency of administration: 3–4 times daily.

The treatment course with the drug is 7–10 days. If indicated, and provided there is good tolerability and no changes in peripheral blood composition, the treatment course may be extended up to 2 weeks.

Children

The drug is indicated for children aged 3 years and older.

Treatment with this drug in children aged 3 years and older should be initiated with particular caution and only when no alternative therapy is available.

Overdose

Symptoms. Severe hematopoietic system complications are usually associated with prolonged administration of high doses (over 3 g per day) – pale skin, sore throat, elevated body temperature, bleeding and hemorrhages, fatigue or weakness. Chloramphenicol blood levels exceeding 25 mcg/mL are considered toxic.

Other adverse reactions typical for chloramphenicol may also occur (see section "Adverse Reactions").

Particularly dangerous is the "gray syndrome," which primarily occurs in newborns (whose mothers received chloramphenicol during childbirth or who received chloramphenicol therapy within the first 48 hours of life), but may also occur in older children or especially sensitive individuals in cases of overdose (abdominal distension, vomiting, respiratory distress with severe metabolic acidosis, bluish-gray skin color, hypothermia, irregular respiration, decreased neurological responsiveness, myocardial conduction depression, cardiovascular insufficiency, circulatory collapse, coma, and fatal outcome).

The "gray syndrome" may also occur due to drug accumulation in cases of relative overdose (accumulation of chloramphenicol caused by immaturity of liver enzymes and its direct toxic effect on the myocardium) in patients with impaired liver or kidney function. The "gray syndrome" manifests at chloramphenicol plasma concentrations exceeding 50 mcg/mL.

Treatment. Discontinue the drug and initiate symptomatic therapy; perform gastric lavage, administer enterosorbents (including activated charcoal), saline laxatives, and high cleansing enema. In severe cases – hemoadsorption.

Adverse Reactions

The most severe adverse reactions include: aplastic anemia, bone marrow suppression, and gray baby syndrome.

Other adverse reactions affecting the following organs and systems may also occur:

Gastrointestinal tract: dyspepsia, abdominal distension, nausea, vomiting (the likelihood of occurrence is reduced when administered 1 hour after meals), diarrhea, irritation of the oral and pharyngeal mucosa, dry mouth, intestinal flora suppression, dysbiosis, enterocolitis, stomatitis, glossitis.

Liver and biliary system: liver function disturbances.

Nervous system: psychomotor disturbances, mild depression, confusion, headache, encephalopathy, delirium. Prolonged use of high doses may lead to taste disturbances, decreased hearing and visual acuity, development of visual and auditory hallucinations, optic and peripheral neuritis (including paralysis of the eyeballs). If any of these symptoms occur, the drug must be discontinued immediately.

Blood and lymphatic system: toxic effects on the hematopoietic system, bone marrow suppression, reticulocytopenia, decreased hemoglobin levels, anemia, leukopenia, granulocytopenia, thrombocytopenia, erythrocytopenia, pancytopenia; rarely – aplastic anemia, thrombocytopenic purpura, hypoplastic anemia, agranulocytosis, cytoplasmic vacuolization of early erythroid forms.

Skin and subcutaneous tissue: allergic reactions, including fever, skin rashes (including macular and vesicular), dermatoses; anaphylactic reactions, including urticaria, angioneurotic edema, facial swelling, Quincke's edema, skin itching, hyperemia.

General disorders: risk of superinfection, including fungal infections, dermatitis (including perianal dermatitis), hyperthermia, collapse (in children).

Cases of Jarisch-Herxheimer reaction (bacteriolysis reaction) have been reported during treatment of typhoid fever (more commonly associated with parenteral forms of chloramphenicol).

Cases of paroxysmal nocturnal hemoglobinuria have also been reported.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is an important procedure. It enables ongoing monitoring of the benefit-risk balance for the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 2 blisters per carton; tablets in blister packs.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity.

13 Boryspylska Street, Kyiv, 02093, Ukraine.