Levomycetin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOMYCETIN (LAEVOMYCETIN)

Composition:

Active substance: chloramphenicol;

1 tablet contains chloramphenicol (levomycetin) equivalent to 100% substance 250 mg or 500 mg;

Excipients: potato starch, hydroxypropylcellulose, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: round-shaped tablets with a flat surface, white,
almost white, or white with a yellowish tint, with a score line and beveled edges.

Pharmacotherapeutic group.
Antibacterial agents for systemic use. Amphenicols. ATC code J01B A01.

Pharmacological Properties

Pharmacodynamics

Chloramphenicol is a broad-spectrum bacteriostatic antibiotic. Its action is associated with disruption of protein synthesis in microbial cells at the stage of amino acid transfer by 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 against Streptococcus spp. (including Streptococcus pneumoniae), Neisseria gonorrhoeae, Neisseria meningitidis, some strains of Proteus spp., and certain strains of Pseudomonas aeruginosa; it is active against Rickettsia spp., Treponema spp., Chlamydia spp. (including Chlamydia trachomatis), and pathogens of purulent infections, typhoid fever, dysentery, meningococcal infection, brucellosis, rickettsial diseases, chlamydial infections, 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 weakly active against acid-fast bacteria, Pseudomonas aeruginosa, Clostridia, and protozoa.

The mechanism of action is due to inhibition of protein synthesis in microbial cells. At therapeutic concentrations, it exhibits bacteriostatic activity. 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 for the treatment of severe infections when less toxic antibacterial agents are ineffective or contraindicated.

Pharmacokinetics

It is well and rapidly absorbed after oral administration: maximum blood concentration is reached within 2–3 hours; therapeutic blood concentration persists for 4–5 hours after administration. The drug penetrates into organs, tissues, and body fluids, crosses the blood-brain barrier, and penetrates well into cerebrospinal fluid (up to 50% of blood levels). The drug crosses the placenta and is detected in breast milk. Therapeutic concentrations of the drug are achieved in the vitreous body, cornea, iris, and aqueous humor of the eye following oral administration (it does not penetrate into the lens). The drug is primarily excreted in urine (mainly as inactive metabolites), partially in bile and feces. In the intestine, under the influence of intestinal bacteria, it is hydrolyzed to form inactive metabolites.

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 potential development of pronounced adverse effects.

Contraindications.

Hypersensitivity to chloramphenicol, other phenicol antibiotics, and/or to any component of the drug; bone marrow suppression, blood disorders; skin diseases (psoriasis, eczema, fungal infections); severe impairment of liver and/or kidney function; glucose-6-phosphate dehydrogenase deficiency; porphyria.

Chloramphenicol should not be prescribed for acute respiratory diseases, tonsillitis, or for the prevention of bacterial infections.

Interaction with other medicinal products and other forms of interactions.

Prolonged use of Chloramphenicol, which is an inhibitor of liver enzymes, in the preoperative period or during surgery, may reduce clearance and prolong the effect of alfadolone.

Chloramphenicol inhibits the cytochrome P450 enzyme system; therefore, when used concomitantly with antiepileptic drugs (phenobarbital, phenytoin) and indirect-acting anticoagulants (dicoumarol, warfarin), metabolism of these drugs is reduced, elimination is slowed, their plasma concentrations are increased, and their toxicity is enhanced.

When Chloramphenicol is used concomitantly with tolbutamide (butamide) and chlorpropamide, their hypoglycemic effect may be potentiated (due to inhibition of hepatic metabolism and increased plasma concentrations), requiring dose adjustment.

Phenobarbital, rifampicin, rifabutin reduce chloramphenicol plasma concentrations by accelerating its hepatic metabolism.

When used concomitantly with paracetamol, an extended elimination half-life of chloramphenicol may be observed.

Phenytoin. Concurrent use may result in either decreased or increased plasma concentrations of chloramphenicol.

Cyclosporine. When used concomitantly with chloramphenicol, an increased plasma concentration of cyclosporine may occur; monitoring of cyclosporine levels is required.

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

Tacrolimus. When used concomitantly with chloramphenicol, an increased plasma concentration of tacrolimus may occur. The dose of tacrolimus should be adjusted accordingly.

Chloramphenicol reduces the antibacterial effect of penicillins and cephalosporins.

Macrolides (erythromycin, oleandomycin, clindamycin), lincosamides (lincomycin), polyene antibiotics (nystatin, levorin). When used concomitantly with chloramphenicol, mutual antagonism of antimicrobial activity may occur because chloramphenicol may displace these agents from binding sites or interfere with their binding to the 50S subunit of bacterial ribosomes. Therefore, simultaneous use should be avoided.

Cycloserine. Concurrent use enhances the neurotoxicity of chloramphenicol.

Medicinal products that suppress hematopoiesis (sulfonamides, cytostatics, cimetidine, ristomycin) or radiation therapy may enhance the myelosuppressive effects of chloramphenicol when used concomitantly, increasing the severity of such effects.
When used concomitantly with vitamin B12, iron preparations, folic acid, Chloramphenicol may antagonize the hemopoietic stimulation induced by vitamin B12, thereby reducing the efficacy of these agents.

Prolonged concurrent use of Chloramphenicol and estrogen-containing oral contraceptives may lead to reduced contraceptive reliability and increased frequency of breakthrough bleeding.

Ethanol. When used concomitantly with ethanol, a disulfiram-like reaction (skin hyperemia, tachycardia, nausea, vomiting, reflex coughing, seizures) may develop.

Special precautions for use.

The drug should be used only under medical supervision.

Due to the possibility of developing severe hematopoietic organ damage as a result of the drug's toxic effects, peripheral blood counts should be monitored during treatment, and liver and kidney function should be closely observed.

If leukopenia, thrombocytopenia, anemia, or other pathological blood changes occur, Levomycetin must be discontinued immediately. Although regular monitoring of peripheral blood during chloramphenicol therapy may detect early hematological changes (such as 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 treatment has ended. Therefore, symptoms such as pallor, sore throat, fever, bleeding, and weakness (if they appear several weeks or months after discontinuation of the drug) require urgent medical attention.

In patients with impaired liver or kidney function, serum levels of Levomycetin may increase, and the risk of toxic reactions to the drug may be higher; therefore, dosage adjustments are necessary. It is advisable to periodically measure drug concentration in the blood and monitor liver and kidney function.

Clinical experience has not revealed differences in response to Levomycetin treatment among patients of different age groups. However, due to age-related differences in kidney and liver function, cardiovascular status, presence of comorbid conditions, and concomitant medication use, dosage selection in elderly patients should be cautious, usually starting at the lower end of the recommended dosage range.

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 treatment 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 who develop diarrhea following antibacterial therapy.

Without appropriate treatment, toxic megacolon, peritonitis, and shock may develop. The risk of colitis is particularly high in elderly patients with severe underlying diseases and in debilitated patients.

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

Blood count monitoring is required during treatment. Any evidence of harmful effects on blood components indicates the need for immediate discontinuation of the drug.

In patients previously treated with cytotoxic agents or who have undergone radiation therapy, the potential risks and expected benefits of Levomycetin therapy should be carefully evaluated, considering the possibility of severe adverse effects.

Chloramphenicol must not be used for the treatment of mild infections or for prophylactic purposes, nor for any infections for which less toxic antibiotics are available. Repeated courses and prolonged therapy should also be avoided.

Use with caution in patients with cardiovascular disorders or a predisposition to allergic reactions.

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

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

Treatment should not extend beyond the duration required to achieve therapeutic benefits without risk of complications or disease recurrence.

Use during pregnancy or breastfeeding.

The use of Levomycetin is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

The drug should be used with caution in individuals who drive vehicles or operate machinery due to the risk of possible adverse reactions affecting the nervous system.

Administration and Dosage

Chloramphenicol should be administered orally, 30 minutes before meals (in cases of nausea and vomiting – one hour after meals).

For adults: 250–500 mg 3–4 times daily; daily dose – 2 g. In particularly severe cases (e.g., typhoid fever, etc.), Chloramphenicol may be administered at a dose up to 4 g per day (maximum daily dose for adults) under strict monitoring of blood parameters and liver and kidney function; the daily dose should be divided into 3–4 administrations.

Single dose for children aged 3 to 8 years – 125 mg; for children aged 8 years and older – 250 mg; frequency – 3–4 times daily.

The treatment course with Chloramphenicol lasts 7–10 days. If indicated and provided good tolerability and absence of changes in peripheral blood, the treatment course may be extended up to 2 weeks.

Children. This pharmaceutical form of Chloramphenicol is not used in children under 3 years of age. Chloramphenicol should be prescribed to children aged 3 years and older with particular caution and only when no alternative therapy is available.

Overdose.

Severe complications affecting the hematopoietic system are generally associated with prolonged use of high doses (more than 3 g per day) – pale skin, sore throat and elevated body temperature, hemorrhages and bleeding, fatigue or weakness.

A symptom of overdose is the "gray syndrome" (cardiovascular syndrome in infants), which occurs in relative overdose (caused by accumulation of Chloramphenicol due to immaturity of liver enzymes and its direct toxic effect on the myocardium) – bluish-gray skin color, decreased body temperature, abdominal distension, vomiting, irregular respiration, diminished neurological responses, cardiovascular insufficiency, circulatory collapse, acidosis, myocardial conduction depression, coma, and fatal outcome. The "gray syndrome" may also occur in patients with impaired liver or kidney function and results from drug accumulation. The "gray syndrome" manifests at chloramphenicol plasma concentrations exceeding 50 mcg/mL.

Treatment. Gastric lavage, administration of saline laxatives, activated charcoal, high cleansing enema. In severe cases – symptomatic therapy, hemoadsorption.

Side effects.

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

Possible adverse reactions affecting the following organs and systems:

Neurological disorders: psychomotor disturbances, depression, delirium, confusion, peripheral neuritis, optic neuritis (including ophthalmoplegia), visual and auditory hallucinations, decreased visual and hearing acuity, taste disturbances, headache, encephalopathy.
Gastrointestinal tract: dyspepsia, abdominal distension, nausea, vomiting (the likelihood of which decreases when taken 1 hour after meals), diarrhea, irritation of the mucous membranes of the oral cavity and pharynx, dermatitis (including perianal dermatitis), suppression of intestinal microflora, dysbiosis, enterocolitis, stomatitis, glossitis.
Hepatobiliary system: liver function disorders.

Hematopoietic system: bone marrow suppression, reticulocytopenia, decreased hemoglobin levels, anemia, leukopenia, granulocytopenia, thrombocytopenia, erythrocytopenia, pancytopenia; rarely – aplastic anemia, hypoplastic anemia, agranulocytosis, cytoplasmic vacuolization of early erythrocyte forms.

Immune system: hypersensitivity reactions, including dermatoses, pruritus, skin rash, fever, angioneurotic edema, urticaria, anaphylaxis.

Other: possible development of superinfection, including fungal infections, hyperthermia, bacteriolysis reaction (Jarisch-Herxheimer reaction), collapse (in children).

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.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's location and address of business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.