Levomycetin

I N S T R U C T I O N for medical use of the medicinal product LEVOMYCETIN (LAEVOMYCETINUM)

Composition:

Active substance: levomycetin (chloramphenicol);

1 tablet contains levomycetin (chloramphenicol) 500 mg (0.5 g);

Excipients: potato starch; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or white with a slightly yellowish tint, with a flat surface, bevelled edges and a score line.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Amphenicols. Chloramphenicol.

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 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, some strains of Proteus spp., and certain strains of Pseudomonas aeruginosa; it is active against Rickettsia spp., Treponema spp., Chlamydia spp. (including Chlamydia trachomatis), causative agents of purulent infections, typhoid fever, dysentery, meningococcal infection, brucellosis, rickettsiae, chlamydia, 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-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 generally does not occur. Due to its high toxicity, chloramphenicol should be used only for the treatment of 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 (BBB), placenta, and is excreted into breast milk. Plasma protein binding ranges from 50% to 60%. The highest concentrations of chloramphenicol are observed in the liver and kidneys. Up to 30% of the administered dose is excreted in bile. Maximum concentration in cerebrospinal fluid (CSF) is observed 4–5 hours after a single oral dose.

Chloramphenicol is metabolized in the liver, where 90% is conjugated to inactive glucuronide. Chloramphenicol palmitate is hydrolyzed to its free form in the gastrointestinal tract prior to absorption. Chloramphenicol sodium succinate is hydrolyzed to 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 baby syndrome." In the intestine, under the action of intestinal bacteria, chloramphenicol undergoes hydrolysis to form inactive metabolites.

The drug is primarily excreted in urine (mainly as inactive metabolites), partially in 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 extends to 3–4 hours; in severe hepatic impairment, it ranges from 4.6 to 11 hours.

Clinical characteristics.

Indications.

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug: typhoid fever, paratyphoid fevers, 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 pronounced adverse effects.

Contraindications.

• Hypersensitivity (allergy) to chloramphenicol (levomycetin), thiamphenicol, azidamphenicol, or to 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.

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

Interaction with other medicinal products and other types of interactions.

Alfentanil: prolonged use of chloramphenicol, which is a liver enzyme inhibitor, in the preoperative period or during surgery may reduce the plasma clearance of alfentanil and prolong its duration of action.

Medicinal products that suppress hematopoiesis (cytostatics, carbamazepine, phenylbutazone, penicillamine, certain antipsychotics, including clozapine, procainamide, reverse transcriptase inhibitors, propylthiouracil, sulfonamides, cimetidine, ristomycin), radiation therapy: possible enhancement of their myelosuppressive effects on the bone marrow. Therefore, such combinations should be avoided.

Hypoglycemic agents (e.g., tolbutamide (butamide), chlorpropamide): possible potentiation of their hypoglycemic effect (due to inhibition of metabolism of these agents in the liver and increased concentration), requiring dose adjustment.

Phenobarbital, rifampicin, rifabutin: decreased plasma concentration of chloramphenicol due to accelerated hepatic metabolism.

Phenytoin: possible decrease or increase in plasma concentration of chloramphenicol.

Chloramphenicol-induced inhibition of the cytochrome P450 enzyme system may reduce hepatic metabolism of phenobarbital, phenytoin, dicoumarol, warfarin, and other drugs metabolized by this oxidase system, leading to delayed elimination, increased blood concentration, and enhanced toxicity of these drugs.

Paracetamol (acetaminophen): possible increase in chloramphenicol toxicity due to prolonged elimination half-life and increased plasma concentration.

Calcineurin inhibitors (cyclosporine, tacrolimus): possible increase in their plasma levels. Monitoring of plasma concentrations of these drugs is recommended; dose adjustment may be necessary when used concomitantly with chloramphenicol.

Cyclophosphamide: prolonged elimination half-life of cyclophosphamide from 7.5 to 11.5 hours.

Cycloserine: enhanced neurotoxicity of chloramphenicol.

Estrogen-containing oral contraceptives: possible reduction in contraceptive efficacy and increased frequency of breakthrough bleeding. Therefore, non-hormonal contraceptive methods are recommended during treatment with chloramphenicol.

Penicillin, cephalosporins, macrolides (erythromycin, oleandomycin), lincosamides (clindamycin, lincomycin), polyene antibiotics (nystatin, levorin): mutual reduction in antimicrobial activity, as 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.

Vitamin B12, iron preparations, folic acid: possible antagonism of vitamin B12-stimulated hemopoiesis, reduced efficacy of these agents.

Ethanol: development of a disulfiram-like reaction (skin flushing, tachycardia, nausea, vomiting, reflex cough, seizures).

Special precautions.

Due to the possibility of developing severe hematopoietic organ disorders caused by the drug's toxic effects, peripheral blood counts should be monitored during treatment, and the condition of the liver and kidneys should be closely observed.

Levomycetin should be discontinued immediately upon the appearance of leukopenia, thrombocytopenia, anemia, or other pathological blood changes. Although regular monitoring of peripheral blood composition during chloramphenicol therapy may detect early hematological changes (leukopenia, reticulocytopenia, or granulocytopenia) before they become irreversible, it does not eliminate the risk of developing 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, fever, unusual bleeding, or weakness—even if they occur several weeks or months after discontinuation of the drug—require urgent medical attention.

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

Antibacterial agents may lead to overgrowth of nonsusceptible microorganisms, including fungi, and may result in superinfection, requiring appropriate interventions.

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, have been reported with nearly all antibacterial agents, including chloramphenicol. This diagnosis should be considered in any patient who develops diarrhea during or after antibiotic use.

If not properly treated, toxic megacolon, peritonitis, or shock may develop. The risk of colitis is particularly high in elderly patients and in those who are debilitated.

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, liver, and cardiovascular function, the presence of comorbid conditions, and concomitant medication use, dosage selection for elderly patients should be cautious, generally starting at the lower end of the dosing range.

In patients with impaired liver and/or kidney function, serum chloramphenicol levels may increase, and the risk of toxic reactions may be higher; therefore, dosage adjustments are necessary. Periodic measurement of drug concentration in blood, as well as monitoring of liver and kidney function, is advisable.

Chloramphenicol should be administered with caution in patients with a history of allergic reactions or cardiovascular disorders.

Chloramphenicol may also interfere with the development of post-vaccination immunity; therefore, it should not be used during active immunization.

Concomitant ethanol intake leads to a disulfiram-like reaction (skin hyperemia, tachycardia, nausea, vomiting, reflex coughing, seizures).

Uncontrolled prescription of chloramphenicol and its use in mild infectious conditions, acute respiratory illnesses, or as a prophylactic agent to prevent bacterial infections—especially in pediatric practice—is unacceptable.

Repeated courses of chloramphenicol therapy should be avoided. Treatment should last no longer than necessary to achieve therapeutic benefit without risking complications or disease relapse.

Use during pregnancy or breastfeeding.

The safety of using the drug during pregnancy has not been established; therefore, the drug is contraindicated during pregnancy.

Chloramphenicol passes into breast milk; therefore, breastfeeding must 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 neurological adverse effects may occur during Levomycetin therapy.

Dosage and Administration

Chloramphenicol should be taken orally, 30 minutes before meals; in case of nausea or vomiting – one hour after meals.

The dosage regimen is determined individually by a physician depending on the severity of the disease and the patient's condition.

For adults: 250–500 mg should be administered 3–4 times daily. The daily dose is 2 g. In particularly severe infections (e.g., typhoid fever), under hospital conditions, the dose may be increased up to 4 g per day (the maximum daily dose for adults), under strict monitoring of blood parameters and liver and kidney function.

For children: children aged 3 to 8 years should receive a single dose of 125 mg; children aged 8 years and older – 250 mg. The drug should be taken 3–4 times daily. If a 125 mg dose is required, tablets with a lower content of the active substance should be used.

The usual duration of treatment is 7–10 days. If necessary and provided the drug is well tolerated without changes in peripheral blood composition, the treatment course may be extended up to 2 weeks.

Children.

Chloramphenicol in this pharmaceutical form should not be used in children under 3 years of age.

For the treatment of children aged 3 years and older, chloramphenicol should be prescribed with particular caution and only if no alternative therapy is available.

Due to the content of the active substance in the tablet, the use of this drug is possible in children aged 8 years and older.

Overdose.

Symptoms. Severe hematological complications are usually associated with prolonged administration of high doses (over 3 g per day) – pale skin, sore throat and fever, unusual bleeding or bruising, unusual 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," primarily observed in newborns (born to mothers who received chloramphenicol during labor or in whom chloramphenicol therapy was initiated within the first 48 hours of life), but it may also occur in older children or particularly sensitive individuals in cases of overdose (abdominal distension, vomiting, respiratory distress with severe metabolic acidosis, bluish-gray skin color, hypothermia, decreased neurological responsiveness, myocardial conduction depression, cardiovascular collapse, circulatory shock, coma, and fatal outcome).

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

Treatment. Discontinuation of the drug, gastric lavage, administration of enterosorbents (including activated charcoal), saline laxative, high cleansing enema, and symptomatic therapy. In severe cases – hemoadsorption.

Side effects.

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

Immune system disorders: hypersensitivity reactions, including fever, itching, skin rashes (including macular and vesicular), dermatoses, anaphylactic reactions such as urticaria and angioneurotic edema. Cases of Jarisch-Herxheimer reaction (bacteriolysis reaction) have been reported during treatment of typhoid fever (more commonly associated with parenteral forms of chloramphenicol).

Blood and lymphatic system disorders: toxic effects on the hematopoietic system and bone marrow suppression (reticulocytopenia, thrombocytopenia, granulocytopenia, pancytopenia, erythrocytopenia, decreased hemoglobin levels, anemia). Rarely, in severe cases, hypoplastic anemia, aplastic anemia, thrombocytopenic purpura, agranulocytosis, leukopenia, and cytoplasmic vacuolization of early erythroid forms may develop.

Gastrointestinal disorders: dyspeptic symptoms (bloating, nausea, vomiting); the likelihood of these effects is reduced when the drug is taken 1 hour after meals. Other effects include diarrhea, dry mouth, stomatitis, glossitis, irritation of oral and pharyngeal mucous membranes, suppression of intestinal microflora, dysbiosis, and enterocolitis.

Hepatobiliary disorders: liver function abnormalities.

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

Other: superinfection (including fungal infections), dermatitis (including perianal dermatitis), hyperthermia, collapse (in children). Cases of paroxysmal nocturnal hemoglobinuria have also been reported.

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 strip; 1 strip in a paper envelope;

10 tablets in a strip; 2 or 10 strips in a cardboard package;

10 tablets in a blister; 1, 2, or 10 blisters in a cardboard package;

10 tablets in strips or blisters.

Prescription status.

Prescription only.

Manufacturer. JSC "Monfarm".

Manufacturer's address and location of business activity.

8 Zavodska Street, Avramivka village, Uman district, Cherkasy region, 19161, Ukraine.