Lincocin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINCOCIN (LINCOCIN®)

Composition:

Active substance: lincomycin;

1 ml contains lincomycin 300 mg (as lincomycin hydrochloride);

Excipients: benzyl alcohol, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless solution.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Lincosamides. ATC code J01F F02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Lincomycin inhibits bacterial protein synthesis by binding to the 23S rRNA of the 50S ribosomal subunit. Lincomycin has predominantly bacteriostatic activity in vitro.

Resistance

Cross-resistance has been observed between lincomycin and clindamycin. Resistance is most commonly due to methylation of specific nucleotides in the 23S rRNA of the 50S ribosomal subunit, which may result in cross-resistance to macrolides and streptogramins 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 appropriate method.

Antibacterial activity

Lincomycin is active in vitro and in clinical infections (see section “Indications”) against most strains of the following bacteria:

Staphylococcus aureus;

Streptococcus pneumoniae.

Lincomycin has been shown to be active in vitro against the following microorganisms; however, the safety and efficacy of Lincomycin in treating clinical infections caused by these organisms have not been established in adequate and well-controlled studies.

Gram-positive bacteria:

Corynebacterium diphtheriae;

Streptococcus pyogenes;

Viridans group streptococci.

Anaerobic bacteria:

Clostridium tetani;

Clostridium perfringens.

Pharmacokinetics.

Absorption

Intramuscular administration of a single 600 mg dose results in a mean peak serum concentration of 11.6 µg/mL achieved within 60 minutes, with therapeutic concentrations maintained for 17–20 hours against most susceptible gram-positive organisms.

A two-hour intravenous infusion of 600 mg lincomycin achieves a mean peak serum concentration of 15.9 µg/mL, which remains therapeutic against most susceptible gram-positive organisms for 14 hours.

Distribution

Significant concentrations have been achieved in most body tissues.

Although lincomycin penetrates into cerebrospinal fluid (CSF), CSF levels may be insufficient for the treatment of meningitis.

Elimination

The elimination half-life after intramuscular or intravenous administration is 5.4 ± 1 hour. The serum elimination half-life of lincomycin may be prolonged in patients with severe renal impairment compared to patients with normal renal function. In patients with hepatic impairment, the serum elimination half-life may be twice as long as in patients with normal liver function. Hemodialysis and peritoneal dialysis are ineffective in removing lincomycin from the blood.

Tissue distribution studies indicate that an important route of elimination is via bile.

After a single 600 mg intramuscular dose of lincomycin, urinary excretion of the drug ranges from 1.8–24.8% (mean 17.3%). Following a 600 mg intravenous dose administered over 2 hours, urinary excretion ranges from 4.9–30.3% (mean 13.8%).

Clinical characteristics.

Indications.

Treatment of severe infections caused by strains of streptococci, pneumococci, and staphylococci sensitive to lincomycin. This drug should be administered to patients with penicillin allergy or to patients for whom, in the physician’s opinion, penicillin use is inappropriate.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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

Special precautions for use.

Lincoycin may be used concomitantly with other antimicrobial agents when indicated.

Lincoycin is not indicated for the treatment of mild bacterial infections or viral infections.

Due to the risk of Clostridioides difficile-associated diarrhea, before deciding on the use of lincomycin, the physician should analyze the nature of the infection and assess the appropriateness of using alternative agents.

Clostridioides difficile-associated diarrhea

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

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

If CDAD is diagnosed or suspected, discontinuation of ongoing antibacterial therapy not directed against C. difficile may be necessary. Appropriate management should be initiated as clinically indicated, including correction of fluid and electrolyte imbalances, protein supplementation, antibacterial therapy directed against C. difficile, and surgical evaluation.

Hypersensitivity

Severe hypersensitivity reactions, including anaphylactic reactions and serious skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythema multiforme, have been reported in patients receiving Lincoycin. If anaphylactic or severe skin reactions occur, Lincoycin should be discontinued and appropriate therapy initiated (see section "Adverse reactions").

Risk of toxicity associated with benzyl alcohol in children (gasping syndrome)

Lincoycin contains the preservative benzyl alcohol. Benzyl alcohol has been associated with serious adverse reactions, including gasping syndrome. Although typical therapeutic doses of this medicinal product usually result in benzyl alcohol exposure significantly lower than levels reported to cause gasping syndrome, the minimal amount of benzyl alcohol that may lead to toxicity is unknown. The risk associated with benzyl alcohol depends on the amount administered and the liver and kidney capacity to detoxify this chemical compound. Premature infants and newborns with low birth weight may be more susceptible to developing toxicity.

Inadequate 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 drug should not be prescribed in such cases.

Available clinical experience suggests that elderly patients with pre-existing severe illnesses are more prone to diarrhea. If Lincoycin is prescribed to patients in this group, changes in bowel frequency should be closely monitored.

The drug should be used with caution in patients with a history of gastrointestinal disorders, particularly colitis.

Lincoycin should be used with caution in patients with a history of bronchial asthma or severe allergic reactions.

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

Use of Lincoycin may lead to overgrowth of non-susceptible organisms, including fungal organisms such as Candida. If superinfection occurs, appropriate measures should be taken according to the clinical situation. If patients with pre-existing Candida infections require treatment with Lincoycin, concomitant antifungal therapy should be administered.

Patients with renal and/or hepatic impairment

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

Dosage of the drug should be carefully selected and serum levels of lincomycin monitored during high-dose therapy in patients with severe renal impairment and/or hepatic impairment (see section "Dosage and administration").

Liver and kidney function tests and blood analyses should be performed periodically during prolonged treatment with Lincoycin.

Severe cardiovascular and pulmonary reactions may occur if the recommended concentration and rate of administration are exceeded.

Prescribing Lincoycin in the absence of confirmed or highly suspected bacterial infection is unlikely to benefit the patient and increases the risk of developing bacterial resistance.

Antibiotic use is often associated with diarrhea, which usually resolves after discontinuation of antibiotic therapy. However, watery or bloody stools, with or without abdominal cramps and fever, may appear even two or more months after the last dose of antibiotic. In such cases, patients should seek medical advice promptly.

Use during pregnancy or breastfeeding.

Pregnancy

Adequate and well-controlled studies on the use of lincomycin in pregnant women have not been conducted.

Lincoycin contains the preservative benzyl alcohol. Benzyl alcohol can cross the placenta (see section "Special precautions for use"). Lincoycin should not be used during pregnancy except when treatment is absolutely necessary.

Teratogenic effect

In a study involving 60 pregnant women, the concentration of lincomycin in umbilical cord serum was approximately 25% of the maternal serum concentration, indicating that lincomycin crosses the placenta; significant accumulation in amniotic fluid was not observed. Experience with the use of Lincoycin during pregnancy (a study involving 345 women) did not demonstrate adverse outcomes.

In studies where lincomycin was administered orally to pregnant Sprague Dawley rats during the period of major organogenesis at doses up to 5000 mg/kg (approximately 6 times the maximum recommended human dose (MRHD) on a body surface area basis), no evidence of teratogenicity was observed.

Non-teratogenic effects

Reproductive studies in rats that received lincomycin orally for two weeks prior to mating, throughout pregnancy, and lactation showed no adverse effects on offspring survival (up to two generations) from birth to weaning at doses up to 1000 mg/kg (1.2 times the MRHD on a body surface area basis).

Breastfeeding

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 importance of the drug to the mother.

Ability to affect the speed of reaction while driving or operating machinery.

Studies on the ability to affect reaction speed while driving or operating machinery have not been conducted. No specific effects on reaction speed while driving or operating machinery have been noted; however, isolated cases of dizziness have been reported.

Administration and Dosage

Lincomycin MUST be diluted prior to intravenous infusion. The drug should be administered by intravenous infusion over at least 1 hour. DO NOT administer as an intravenous bolus.

If severe diarrhea develops during therapy, Lincomycin should be discontinued.

The duration of treatment is determined individually by the physician depending on the severity and course of the disease.

Adults

А. Intramuscular Administration

1. Severe infections: 600 mg intramuscularly every 24 hours.
2. More severe forms of infections: 600 mg intramuscularly every 12 hours or more frequently.

В. Intravenous Administration

The intravenous dose is determined by the severity of the infection.

1. Severe infections: 600 mg to 1 g every 8–12 hours.
2. For more severe infections, these doses may be increased.
3. In life-threatening conditions, the daily intravenous dose may reach up to 8 g.

Children from 1 month of age

А. Intramuscular Administration

1. Severe infections: 10 mg/kg as a single intramuscular injection every 24 hours.
2. More severe forms of infections: 10 mg/kg every 12 hours or more frequently.

В. Intravenous Administration

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

Dosing in patients with hepatic or renal impairment. In patients with impaired liver or kidney function, the serum half-life of lincomycin is prolonged, which warrants a reduction in the frequency of lincomycin 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 (see section "Special Warnings and Precautions for Use").

Infections caused by beta-hemolytic streptococcus. 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 an appropriate diluent, and the infusion should last no less than 1 hour.

The indicated doses may be repeated, and the frequency of administration is 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 of the cardiovascular and pulmonary systems may occur if Lincomycin is administered at higher than recommended concentrations or at a faster rate (see section "Special Warnings and Precautions for Use").

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Children.

The medicinal product contains the preservative benzyl alcohol. Benzyl alcohol has been associated with the development of gasping syndrome with fatal outcomes in premature infants (see section "Special Warnings and Precautions for Use").

Safety and efficacy in pediatric patients under 1 month of age have not been established; therefore, this medicinal product is not administered to premature infants or infants under 1 month of age.

May cause toxic and allergic reactions in infants and children under 3 years of age (see section "Special Warnings and Precautions for Use").

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 undiluted high doses. Such reactions have not occurred when the drug was 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 removal of lincomycin from the blood.

Side effects

The following are adverse reactions associated with the use of lincomycin.

Gastrointestinal disorders: diarrhea, nausea, vomiting, glossitis, stomatitis, abdominal pain, abdominal discomfort†, anal pruritus.

Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, bullous dermatitis, exfoliative dermatitis, erythema multiforme (see section "Special precautions for use"), rash, urticaria, pruritus.

Infections and infestations: vaginal infections; pseudomembranous colitis; Clostridioides difficile-associated colitis (see section "Special precautions for use").

Blood and lymphatic system disorders: pancytopenia, agranulocytosis, aplastic anemia, leukopenia, neutropenia, thrombocytopenic purpura.

Immune system disorders: anaphylactic reactions (see section "Special precautions for use"), angioneurotic edema, serum sickness.

Hepatobiliary disorders: jaundice, liver function test abnormalities, increased transaminase levels.

Renal and urinary system disorders: renal dysfunction, oliguria, proteinuria, azotemia.

Cardiac disorders: cardiopulmonary arrest (see section "Method and dosage of administration").

Vascular disorders: hypotension (see section "Method and dosage of administration"), thrombophlebitis†.

Ear and labyrinth disorders: vertigo, tinnitus.

Neurological disorders: headache, dizziness, somnolence.

General disorders and administration site conditions: sterile abscess at injection site‡, induration at injection site‡, pain at injection site‡, irritation at injection site‡.

† Observed during intravenous administration.

‡ Observed during intramuscular administration.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

Lincomycin, solution for injection, is physically incompatible with neomycin, kanamycin, and phenytoin.

Packaging. 2 ml of solution for injection in a vial. 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pfizer Manufacturing Belgium NV

Manufacturer's address and place of business.

Reyksweg 12, Puurs-Sint-Amands, 2870, Belgium.