Lincomycin-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINCOMYCIN-DARNITSA

Composition:

Active substance: lincomycin;

1 ml of solution contains 300 mg of lincomycin hydrochloride calculated as anhydrous lincomycin;

Excipients: disodium edetate, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or slightly yellowish liquid with a mild specific odor.

Pharmacotherapeutic group. Antibacterials for systemic use. Lincosamides. Lincomycin. ATC code J01F F02.

Pharmacological properties.

Pharmacodynamics.

Lincomycin is an antibiotic of the lincosamide class, produced by Streptomyces lincolniensis. It inhibits bacterial protein synthesis by reversible binding to the 50S ribosomal subunit, thereby disrupting the formation of peptide bonds.

Depending on microbial sensitivity and antibiotic concentration, lincomycin may exhibit either bacteriostatic or bactericidal activity. The in vitro spectrum of activity includes the following pathogens:

Sensitive microorganisms (minimum inhibitory concentration (MIC) ≤ 2 mcg/mL):

• anaerobic gram-positive, non-spore-forming bacteria, including Propionibacterium spp., Eubacterium spp., and Actinomyces spp.;
• anaerobic and microaerophilic gram-positive cocci, including Peptococcus spp., Peptostreptococcus spp., and microaerophilic streptococci;
• aerobic gram-positive microorganisms, including staphylococci, streptococci (except S. faecalis), and pneumococci.

Microorganisms with moderate sensitivity (MIC = 2–4 mcg/mL):

• anaerobic, non-spore-forming, gram-negative bacteria, including Bacteroides spp., Fusobacterium spp.;
• anaerobic, spore-forming, gram-positive bacteria, particularly Clostridium spp.

Resistant microorganisms or microorganisms with low sensitivity (MIC ≥ 8 mcg/mL), including Streptococcus faecalis, Neisseria, most strains of Haemophilus influenzae, Pseudomonas, and other gram-negative microorganisms.

Although Shigella species are in vitro resistant to lincomycin (MIC approximately 200–400 mcg/mL), lincomycin is effective in treating this infection due to the very high concentrations achieved in the intestinal tract (approximately 3000–7000 mcg/g of feces).

Cross-resistance between clindamycin and lincomycin has been established. Resistance most commonly arises due to methylation of specific nucleosides in the 23S ribosomal RNA of the 50S ribosomal subunit, which may confer cross-resistance to macrolides and streptogramin B (MLS_B phenotype). Macrolide-resistant isolates of these microorganisms should be tested for inducible resistance to lincomycin/clindamycin using the D-test or another acceptable method. Currently, there are no established interpretive criteria for susceptibility testing to lincomycin.

Pharmacokinetics.

Absorption. Intramuscular administration of a single 600 mg dose achieves a mean peak serum concentration of 11.6 mcg/mL within 1 hour and maintains therapeutic levels for 17–20 hours against most susceptible gram-positive microorganisms.

Intravenous infusion of 600 mg lincomycin over 2 hours achieves a mean peak serum concentration of 15.9 mcg/mL and maintains therapeutic levels for 14 hours against most susceptible gram-positive microorganisms.

Distribution. Based on direct and indirect evidence, protein binding in blood decreases with increasing serum concentration (saturable binding to plasma proteins).

Concentrations in fetal blood, peritoneal, and pleural fluids may reach 25–50% of serum levels; in breast milk, concentrations range from 50–100%; in bone tissue, approximately 40%; and in surrounding soft tissues, about 75%.

However, lincomycin penetrates poorly into cerebrospinal fluid (CSF), reaching only 1–18% of serum levels. In cases of meningitis, CSF levels may reach up to 40% of serum concentrations.

Elimination. A significant portion of the drug is metabolized, primarily in the liver. The normal serum half-life is 5.4 ± 1 hour. However, this half-life may be prolonged in patients with impaired liver and/or kidney function. Therefore, the dosing frequency of lincomycin should be reduced in patients with hepatic or renal impairment.

After intramuscular administration of 600 mg, urinary excretion of microbiologically active drug ranges from 1.8–24.8% (mean 17.3%), and fecal excretion ranges from 4–14%. After intravenous administration of 600 mg over 2 hours, urinary excretion of microbiologically active drug ranges from 4.9–30.3% (mean 13.8%). The remainder of the drug is excreted as microbiologically inactive metabolites. Hemodialysis and peritoneal dialysis do not significantly affect the elimination of lincomycin from blood.

Clinical characteristics.

Indications.

Use for the treatment of severe infections caused by streptococcal, pneumococcal, and staphylococcal strains sensitive to lincomycin.

This medicinal product should be used in patients with allergy to penicillin or in other patients for whom, in the opinion of the physician, penicillin therapy is inappropriate.

Contraindications.

Lincomycin is contraindicated in patients who have previously demonstrated hypersensitivity to lincomycin, clindamycin, or any other component of the medicinal product.

Meningitis.

Interaction with other medicinal products and other forms of interaction.

An antagonism between lincomycin and erythromycin has been observed in vitro. These two medicinal products should not be co-administered due to the possibility of clinically significant interaction.

Lincomycin has the ability to block neuromuscular transmission, which may potentiate the effect of other neuromuscular blocking agents; therefore, lincomycin should be administered with caution to patients receiving such medicinal products.

Special precautions for use.

Lincomycin must be diluted before intravenous infusion. The medicinal product may be administered intravenously only by means of drip infusion lasting not less than 60 minutes (see section "Method of administration and dosage"). Undiluted Lincomycin must not be administered intravenously as a bolus. Severe cardiorespiratory reactions have occurred when the recommended concentration and rate of administration were exceeded.

Prescribing Lincomycin-Darnytsia in the absence of confirmed or highly suspected bacterial infection is unlikely to benefit the patient and increases the risk of development of bacteria resistant to the medicinal product.

To prevent the development of aseptic necrosis, intramuscular injections should be administered deeply into the muscle.

Antibiotic use is frequently associated with the development of diarrhea, which usually resolves after discontinuation of antibiotic therapy. Occasionally, watery or bloody stools may occur in patients after initiation of antibiotic therapy, with or without abdominal cramps and fever, and may appear even 2 or more months after the last dose of antibiotic. In such cases, the patient should seek medical advice as soon as possible.

Certain infections may require incision and drainage or other indicated procedures in addition to antibacterial therapy.

Microbiological testing should be performed to identify causative organisms and determine their susceptibility to lincomycin.

Surgical procedures, when indicated, should be performed in conjunction with antibiotic therapy.

The efficacy of lincomycin in treating staphylococcal infections resistant to other antibiotics but susceptible to lincomycin has been demonstrated. Strains of staphylococci resistant to lincomycin have been identified; therefore, during therapy with Lincomycin-Darnytsia, bacteriological cultures and susceptibility testing of pathogens should be performed. Partial, rather than complete, cross-resistance may occur with macrolide antibiotics. If clinically indicated, the medicinal product may be used concomitantly with other antibacterial agents.

Lincomycin is not indicated for the treatment of minor bacterial infections or viral infections.

To reduce the rate of emergence of drug-resistant bacteria and preserve the effectiveness of lincomycin and other antibacterial agents, Lincomycin-Darnytsia should be used only to treat or prevent infections proven or strongly suspected to be caused by susceptible bacteria. When bacteriological culture and susceptibility results are available, they should be considered when selecting or modifying antibacterial therapy. In the absence of such data, empirical selection of therapy should be based on local epidemiological information and local patterns of susceptibility.

Risk of colitis.

Due to the risk of developing pseudomembranous colitis associated with antibacterial agents, before deciding to prescribe lincomycin, the physician should evaluate the nature of the infection and consider the possibility of using less toxic alternative agents (e.g., erythromycin).

The medicinal product should be used with caution in patients with gastrointestinal disorders, particularly colitis.

Antibacterial therapy may disrupt the normal flora of the colon and lead to overgrowth of clostridia. Studies have shown that the toxin produced by Clostridium difficile is a primary cause of antibiotic-associated colitis. Treatment should be initiated immediately upon diagnosis of pseudomembranous colitis. In mild cases, discontinuation of the medicinal product is usually sufficient. Moderate to severe cases require treatment with electrolyte and protein solutions and administration of antibacterial agents effective against Clostridium difficile in colitis.

Clostridium difficile-associated diarrhea (CDAD) has been linked to the use of nearly all antibacterial agents, including lincomycin, and ranges in severity from mild diarrhea to fatal colitis. Antibacterial therapy disrupts the normal colonic flora, leading to overgrowth of Clostridium difficile.

Because lincomycin therapy has been associated with the development of severe colitis, which may be fatal, it should be used only for serious infections when less toxic antimicrobial agents are ineffective. It should not be used in patients with nonbacterial infections, such as most upper respiratory tract infections.

Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. Hyper-toxin-producing strains of Clostridium difficile are associated with increased morbidity and mortality, as this infection may be refractory to antibacterial therapy and require colectomy. Clostridium difficile-associated diarrhea should be considered in patients who develop diarrhea after antibiotic use. A detailed medical history is also necessary, as cases of CDAD have been reported up to 2 months after administration of antibacterial agents.

In cases of suspected or confirmed CDAD, ongoing antibacterial therapy not directed against Clostridium difficile should be discontinued. Depending on clinical indications, fluid and electrolyte replacement, protein supplementation, antibacterial treatment targeting Clostridium difficile, and surgical evaluation should be initiated.

Allergy.

Lincomycin-Darnytsia should be used with caution in patients with a history of bronchial asthma or severe allergies, or in patients with atopy.

Hypersensitivity.

Serious hypersensitivity reactions, including anaphylactic reactions and severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythema multiforme, have been reported during lincomycin use. If an allergic reaction to lincomycin occurs, treatment should be discontinued and appropriate therapy initiated (see section "Adverse reactions").

Unsuitability for use in meningitis.

Although lincomycin penetrates into cerebrospinal fluid (CSF), the concentration of lincomycin in CSF may be insufficient for the treatment of meningitis; therefore, the medicinal product should not be prescribed in such cases.

Superinfections.

Lincomycin use may lead to overgrowth of nonsusceptible organisms, particularly fungal organisms. If superinfections occur, appropriate measures should be taken according to the clinical situation. If patients with pre-existing fungal infections require lincomycin treatment, concomitant antifungal therapy should be administered.

In patients with severe renal impairment, the elimination half-life of lincomycin from plasma may be prolonged compared to patients with normal renal function. In patients with hepatic impairment, the plasma elimination half-life may be doubled compared to patients with normal liver function.

In patients with severe renal and/or hepatic impairment, the dose of the medicinal product should be selected with caution, and serum levels of lincomycin should be monitored during high-dose therapy.

During prolonged treatment, periodic liver and kidney function tests and blood analyses should be performed.

Use in elderly patients.

Current clinical experience indicates that the incidence of diarrhea is higher in elderly patients with severe underlying diseases. If the medicinal product is prescribed to patients in this group, changes in bowel frequency should be carefully monitored.

Pediatric use.

Low-birth-weight infants and premature neonates are more susceptible to toxicity.

Important information on excipients.

This medicinal product contains sodium compounds; therefore, patients on a sodium-controlled diet should exercise caution when using this product.

Use during pregnancy or breastfeeding.

Studies on the teratogenic potential of lincomycin in animals and adequate, well-controlled studies on the effects of lincomycin in pregnant women have not been conducted. Lincomycin should not be used during pregnancy except when treatment is clearly necessary.

Lincomycin has been reported to be present in human breast milk at concentrations ranging from 0.5 to 2.4 mcg/mL. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the benefit of the drug to the mother.

Ability to influence reaction rate when driving or operating machinery.

No specific effect on reaction rate when driving or operating machinery has been observed; however, isolated cases of dizziness have been reported.

Administration and Dosage

Lincomycin should not be administered intravenously as an undiluted bolus. The drug may be given intravenously only by means of drip infusion lasting at least 1 hour.

If severe diarrhea develops during therapy, administration of this antibacterial agent should be discontinued.

Adults.

Intramuscular administration.

Usual dose:

600 mg intramuscularly every 24 hours.

Severe infections: 600 mg intramuscularly every 12 hours (or more frequently), depending on the severity of the infection.

Intravenous administration.

Usual dose:

From 600 mg to 1 g every 8–12 hours.

These doses may be increased in severe infections.

In life-threatening conditions, the daily intravenous dose may be up to 8 g.

Children (aged 1 month and older).

Intramuscular injections.

10 mg/kg per day as a single injection.

Severe infections: 10 mg/kg every 12 hours or more frequently.

Intravenous injections.

From 10 to 20 mg/kg per day, depending on the severity of the infection, may be administered in several doses according to the described dilution and infusion rate guidelines.

Dosage in patients with hepatic or renal impairment.

In patients with impaired hepatic or renal function, the serum half-life of lincomycin is prolonged, which necessitates a reduction in the frequency of administration. If lincomycin therapy is required in patients with significantly impaired renal function, the appropriate dose should be 25% to 30% of the dose recommended for patients with normal renal function.

Duration of treatment is determined individually.

Infections caused by β-hemolytic streptococci.

Treatment should last at least 10 days.

Dilution and infusion rate.

The dose for infusion should be prepared as follows:

1 g of lincomycin should be diluted in no less than 100 mL of a suitable diluent (0.9% sodium chloride solution), and the infusion should last no less than 1 hour.

The indicated doses may be repeated, and the frequency of administration should be determined according to need, provided that the daily dose does not exceed the maximum recommended dose of lincomycin, which is 8 g.

Note. Severe reactions involving the cardiovascular and respiratory systems may occur if this medicinal product is administered at higher than recommended concentrations or too rapidly.

Children.

Lincomycin-Darnitsia may be used in children aged 1 month and older at the recommended doses (see section "Method of administration and dosage").

Overdose.

In case of overdose, secondary gastrointestinal disturbances may occur, including abdominal pain, nausea, vomiting, and diarrhea. Severe cardiorespiratory reactions have been reported following too rapid intravenous administration of high doses of undiluted solution. Such reactions have not occurred when the medicinal product was properly diluted according to recommendations.

Treatment of overdose may include gastric lavage or induction of emesis. There is no known specific antidote.

Hemodialysis and peritoneal dialysis are ineffective for removing lincomycin from the blood.

Adverse Reactions

Auditory and vestibular system disorders: tinnitus, vertigo.

Gastrointestinal disorders: glossitis, stomatitis, nausea, heartburn, vomiting, abdominal discomfort and pain, persistent diarrhea, colitis (including pseudomembranous colitis, Clostridium difficile-associated colitis), monoclonal infections, perianal pruritus, decreased appetite.

Hepatobiliary disorders: jaundice and changes in liver function tests (particularly elevated serum transaminase levels) may also occur during lincomycin therapy.

Renal and urinary system disorders: renal function impairment (azotemia, oliguria, proteinuria), vaginitis.

Nervous system disorders: headache, dizziness.

Cardiovascular system disorders: episodes of arterial hypotension have been reported after parenteral administration of the drug, especially with too rapid infusion. Rarely, episodes of cardiac and respiratory depression, tachycardia, dizziness, asthenia, skeletal muscle relaxation up to cardiopulmonary shock have been observed after too rapid intravenous administration.

Blood and lymphatic system disorders: cases of neutropenia, leukopenia, agranulocytosis, and thrombocytopenic purpura have been reported. There have been isolated reports of aplastic anemia and pancytopenia, in which the influence of lincomycin as the cause of the adverse reaction cannot be excluded.

Immune system disorders: angioneurotic edema, serum sickness, and anaphylactic shock, some of which occurred in patients with hypersensitivity to penicillin. Rare cases of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis associated with lincomycin administration have also been documented.

In the event of acute severe hypersensitivity reactions, immediate medical interventions may be required (when clinically indicated), including administration of adrenaline and other emergency measures such as oxygen therapy, intravenous fluids, antihistamines, corticosteroids, pressor amines, and ensuring airway patency.

Skin and subcutaneous tissue disorders: pruritus, skin rash (vesicular, macular, roseolar, petechial, urticarial, maculopapular), urticaria, vaginitis; rarely – exfoliative dermatitis and vesiculobullous dermatitis.

Local reactions at the site of administration: with intramuscular injections, local irritation (hyperemia, pruritus), pain, swelling, induration, and sterile abscess formation may occur. With intravenous administration, thrombophlebitis may develop.

The likelihood of these reactions can be minimized by administering the drug via deep intramuscular injection and avoiding the use of permanent intravenous catheters.

Reporting of suspected adverse reactions.

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

Shelf life. 2 years.

The shelf life is defined as the use of the medicinal product until the last day of the specified month.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

The medicinal product is pharmaceutically incompatible with kanamycin, ampicillin, barbiturates, theophylline, calcium gluconate, heparin, and magnesium sulfate.

Lincomycin is incompatible in the same syringe or infusion solution with kanamycin, neomycin, or phenytoin.

Packaging.

1 ml or 2 ml in an ampoule; 5 ampoules in a blister pack; 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of its business activity.

13 Borispilska Street, Kyiv, 02093, Ukraine.