Clindamycin-m

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLINDAMYCIN-M (CLINDAMYCIN-M)

Composition:

Active substance: clindamycin;

Each capsule contains clindamycin hydrochloride equivalent to clindamycin 0.15 g (150 mg);

Excipients: calcium stearate, lactose monohydrate, colloidal anhydrous silicon dioxide, sodium methylparaben (E 219), sodium propylparaben (E 217), gelatin, titanium dioxide (E 171), tartrazine (E 102), erythrosine (E 127), brilliant blue, amaranth (E 123).

Pharmaceutical form. Capsules.

Main physico-chemical properties: hard gelatin capsules with pink cap and body; the contents of the capsules are white powder.

Pharmacotherapeutic group. Antibacterials for systemic use. Lincosamides. Clindamycin. ATC code J01F F01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. The mechanism of action of clindamycin is based on the inhibition of protein biosynthesis by binding to the 50S subunit of the bacterial ribosome, resulting in a predominantly bacteriostatic effect.

Pharmacokinetic/pharmacodynamic relationship. Efficacy will significantly depend on the duration of time during which the drug concentration exceeds the minimum inhibitory concentration (MIC) for the causative pathogen.

Mechanism of resistance development. The following mechanisms may underlie the development of resistance to clindamycin. Resistance in staphylococci and streptococci is primarily due to increased methylation of 23S rRNA (so-called constitutive MLS(_B)-resistance), which greatly reduces the binding affinity of clindamycin to the ribosome. Most methicillin-resistant S. aureus (MRSA) strains exhibit a constitutive MLS(_B) phenotype and are therefore clindamycin-resistant. Thus, infections caused by macrolide-resistant staphylococci should not be treated with clindamycin, even if in vitro susceptibility is demonstrated, due to the risk of selecting during therapy mutant strains with constitutive MLS(_B)-resistance.

Strains with constitutive MLS(_B)-resistance demonstrate complete cross-resistance between clindamycin and lincomycin, macrolides (e.g., azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin), and streptogramin B.

Pharmacokinetics.

Absorption, distribution, and protein binding.

The difference between the administered clindamycin derivatives lies only in the rate of absorption and hydrolysis of esters. After this, clindamycin is present in the body as the free base (active form). Its esters should be considered prodrugs.

Following oral administration, clindamycin hydrochloride and clindamycin 2-palmitate hydrochloride are rapidly and almost completely absorbed from the gastrointestinal tract. Concomitant food intake slightly delays absorption. When administered on an empty stomach, peak serum concentrations are reached within approximately 45–60 minutes, and when administered after food, within approximately 2 hours. After a single oral dose of 150 mg or 300 mg, serum concentrations range from 1.9 to 3.9 µg/mL and from 2.8 to 3.4 µg/mL, respectively (administered fasting).

Plasma protein binding of clindamycin depends on its concentration and ranges from 60% to 94% within the therapeutic range.

Clindamycin readily penetrates tissues, crosses the placental barrier, and enters breast milk. Diffusion into the subarachnoid space is insufficient even in the presence of meningitis. High concentrations are achieved in bone tissue.

Metabolism and elimination.

Clindamycin is primarily metabolized in the liver. Some metabolites are microbiologically active. Medicinal products acting as inducers of hepatic enzymes shorten the mean elimination half-life of clindamycin.

Elimination of clindamycin occurs approximately 2/3 via feces and 1/3 via urine.

The elimination half-life of clindamycin in serum is approximately 3 hours in adults and about 2 hours in children. In renal impairment and moderate to severe hepatic insufficiency, the elimination half-life is prolonged.

Clindamycin is not removed by dialysis.

Clinical characteristics.

Indications.

Acute and chronic bacterial infections caused by pathogens sensitive to clindamycin, in particular:

• infections of bones and joints;
• infections of the ear, nose, and throat area;
• infections of the teeth and jaw area;
• lower respiratory tract infections;
• pelvic and abdominal infections;
• female genital tract infections;
• skin and soft tissue infections;
• scarlet fever.

In severe clinical cases, initial treatment should be performed with medicinal products containing clindamycin administered intravenously by slow infusion.

Contraindications.

Clindamycin-M should not be used in patients with hypersensitivity to clindamycin, lincomycin, or to any other component of the medicinal product.

Clindamycin-M is not suitable for the treatment of meningitis, since the concentration of the antibiotic achieved in cerebrospinal fluid is too low.

Generally, the capsule dosage form is not suitable for use in children under 6 years of age.

Interaction with other medicinal products and other types of interactions.

Whenever possible, Clindamycin-M should not be combined with erythromycin, as an antagonistic effect on antibacterial activity has been observed in vitro.

Pathogenic microorganisms show cross-resistance to clindamycin and lincomycin.

Since the medicinal product Clindamycin-M has the property of blocking neuromuscular transmission, it may potentiate the effect of muscle relaxants (e.g. ether, tubocurarine, pancuronium bromide). This may lead to unexpected life-threatening situations during surgery. Therefore, Clindamycin-M should be used with caution in patients receiving the aforementioned medicinal products.

When using Clindamycin-M concomitantly, the reliability of the contraceptive effect of oral contraceptives is questionable. Therefore, during treatment with Clindamycin-M, additional contraceptive methods should be used.

Vitamin K antagonists. In patients who have used clindamycin in combination with vitamin K antagonists (e.g. warfarin, acenocoumarol, and fluindione), increased coagulation parameters (prothrombin time/international normalized ratio) and/or bleeding have been observed. Therefore, coagulation parameters should be monitored in such patients.

Special precautions for use.

Clindamycin-M should be used with caution in the following patient groups:

• with impaired liver function;
• with neuromuscular transmission disorders (myasthenia gravis, Parkinson's disease);
• with a history of gastrointestinal disorders (e.g. colitis);
• with atopy;
• with allergies and asthma.

Note: Clindamycin-M should not be used in patients with acute respiratory tract infections if they are caused by viruses. Clindamycin-M is not suitable for the treatment of meningitis, as the concentrations of the antibiotic achieved in cerebrospinal fluid are too low.

Severe hypersensitivity reactions have been reported in patients receiving clindamycin therapy, including serious skin reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens–Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. If a hypersensitivity reaction or serious skin reaction occurs, clindamycin therapy should be discontinued and appropriate treatment initiated (see sections "Contraindications" and "Side effects").

During prolonged treatment (more than 10 days), clinical blood tests and liver and kidney function should be monitored regularly.

Prolonged and repeated use of Clindamycin-M may lead to the development of superinfection or colonization of the skin and mucous membranes by resistant microorganisms or yeast fungi.

During treatment with nearly all antibacterial agents, including clindamycin, cases of Clostridium difficile-associated diarrhea (CDAD) have been reported, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters 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 and are the primary cause of "antibiotic-associated colitis." C. difficile strains producing hyper-toxins are associated with increased morbidity and mortality, as these infections may be unresponsive to antimicrobial therapy and may require colectomy.

CDAD should be considered as a possible diagnosis in all patients who develop diarrhea following antibiotic use. A careful medical history is essential, as cases of CDAD have been reported up to two months after antibiotic administration. Progression to colitis, including pseudomembranous colitis, may occur, with severity ranging from mild to fatal.

If antibiotic-associated diarrhea or antibiotic-associated colitis is diagnosed or suspected, antibacterial agents, including clindamycin, should be discontinued and appropriate therapeutic measures initiated. Antiperistaltic drugs are contraindicated in this situation.

In cases of moderate to severe pseudomembranous colitis, consideration should be given to fluid and electrolyte replacement, protein supplementation, and administration of antibacterial agents clinically effective against Clostridium difficile-induced colitis.

If therapy is continued, liver and kidney function tests should be performed.

Acute kidney injury, including acute renal failure, has been infrequently reported. Therefore, monitoring of kidney function should be considered in patients receiving prolonged therapy, those with pre-existing kidney impairment, or those receiving concomitant nephrotoxic drugs (see section "Side effects").

Clindamycin therapy may sometimes be used as an alternative in patients with penicillin allergy (hypersensitivity to penicillin). Cross-allergy between clindamycin and penicillin is not known and not expected due to structural differences between these agents. However, anaphylactic reactions (hypersensitivity) to clindamycin have been reported in rare cases in individuals with a history of penicillin allergy. This should be taken into account when using clindamycin in patients with penicillin allergy.

If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medication.

Clindamycin-M contains 121 mg of lactose monohydrate per capsule. When used according to instructions, the patient receives up to 484 mg of lactose monohydrate. This corresponds to the total amount of lactose contained in 4 capsules of Clindamycin-M. Clindamycin-M should not be used in patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Excipients: tartrazine (E 102), amaranth (E 123), sodium methylparaben (E 219), and sodium propylparaben (E 217), components of the capsule coating, may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Use during pregnancy.

Results from a large study involving pregnant women who used clindamycin during the first trimester of pregnancy (approximately 650 newborns exposed to clindamycin) did not demonstrate an increased incidence of congenital malformations. However, available data on the safety of clindamycin use during pregnancy are insufficient.

Results from experimental animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonic/fetal development, course of delivery, or postnatal development.

Clindamycin crosses the placenta. Therapeutic, effective concentrations in the fetal organism are expected. When using the drug during pregnancy, the benefits should be carefully weighed against potential risks associated with treatment.

Use during breastfeeding.

Clindamycin passes into breast milk. Therefore, sensitization, diarrhea, and colonization of mucous membranes by yeast fungi cannot be excluded in newborns who are breastfed. Due to the risk of severe adverse reactions in breastfed newborns, clindamycin should not be used in women who are breastfeeding.

Reproductive function.

Animal studies have not shown any signs of impaired reproductive function. There are no data on the effect of clindamycin on human reproductive function.

Ability to affect reaction speed when driving or operating machinery.

Clindamycin has a mild or moderate effect on the ability to drive or operate machinery. Some adverse reactions (particularly dizziness, somnolence; see section "Side effects") may affect the ability to concentrate and reaction speed; therefore, they may impair the ability to drive vehicles or operate machinery.

Dosage and Administration

Clindamycin-M should be taken with a sufficient amount of liquid (at least one full glass of water) to help prevent possible esophageal irritation.

In suspected infections caused by β-hemolytic streptococci, or when signs of β-hemolytic streptococcal infection are present, treatment should continue for at least 10 days.

Adults.

Depending on the site and severity of infection, adults and children aged 14 years and older should take 4–12 capsules daily (equivalent to 0.6–1.8 g of clindamycin).

The daily dose should be divided into 4 doses.

For higher dosing requirements, medicinal products with a higher content of active substance are also available.

Liver disease. In patients with moderate to severe hepatic impairment, the elimination half-life of clindamycin is prolonged. Usually, when Clindamycin-M is administered every 8 hours, dose reduction is not required. However, patients with severe hepatic insufficiency should be monitored for plasma clindamycin levels. Depending on the results, dose reduction or extended dosing intervals may be necessary.

Renal disease. In renal impairment, the elimination half-life of clindamycin is prolonged; however, dose adjustment is not required in mild to moderate renal dysfunction. Nevertheless, in patients with severe renal insufficiency or anuria, plasma clindamycin levels should be monitored. Depending on the results of these measurements, dose reduction or, alternatively, extending the dosing intervals to 8 or even 12 hours may be necessary.

Hemodialysis. Clindamycin is not removed by hemodialysis. Therefore, no additional dose is required before or after hemodialysis.

Children.

This medicinal formulation may be administered to children aged 6 years and older.

Depending on the site and severity of infection, children under 14 years of age should receive 8–25 mg of clindamycin per kilogram of body weight per day—see the table.

Table.

The daily dose should be divided into 3–4 individual doses. Administration in 4 divided doses is generally preferred.

Overdose.

Symptoms of overdose have not been observed to date. If necessary, gastric lavage may be indicated. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from blood serum. No specific antidote is known.

Adverse Reactions.

The adverse reactions listed below were identified during clinical trials and post-marketing surveillance. Within each category, adverse reactions are listed by frequency and clinical significance.

By frequency, adverse reactions are classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated based on available data). Adverse reactions are listed within each category in decreasing order of severity.

Infections and infestations.

Common: pseudomembranous colitis*.

Frequency not known: colitis due to Clostridium difficile*, vaginal infections.

Blood and lymphatic system disorders.

Common: agranulocytosis*, neutropenia*, thrombocytopenia*, leukopenia*, eosinophilia.

Immune system disorders.

Rare: drug fever.

Very rare: anaphylactic reaction*.

Frequency not known: anaphylactic shock*, anaphylactoid reaction*, hypersensitivity*.

Nervous system disorders.

Uncommon: taste disturbance, neuromuscular blockade.

Frequency not known: dizziness, somnolence, headache.

Gastrointestinal disorders.

Very common: esophageal irritation, esophagitis*, stomatitis, soft stools, diarrhea, abdominal pain, vomiting, nausea.

Frequency not known: esophageal ulcer*.

Hepatobiliary disorders.

Very rare: transient hepatitis with cholestatic jaundice.

Frequency not known: jaundice*.

Skin and subcutaneous tissue disorders.

Common: maculopapular exanthema, morbilliform exanthema*, urticaria.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome*, Lyell's syndrome, Quincke's edema/angioneurotic edema*, exfoliative dermatitis*, bullous dermatitis*, erythema multiforme, pruritus, vaginitis.

Very rare: rash, blistering, hypersensitivity reactions.

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)*, acute generalized exanthematous pustulosis*.

Musculoskeletal and connective tissue disorders.

Very rare: polyarthritis.

Renal and urinary disorders.

Renal function impairment manifested as azotemia, oliguria and/or proteinuria.

Frequency not known: acute kidney injury (see section "Special precautions").

Investigations.

Common: abnormal liver function biochemical parameters.

* Adverse reactions identified during post-marketing use of the medicinal product (see section "Special precautions").

Adverse reactions of antibiotics (class effect).

Pseudomembranous enterocolitis may commonly occur during treatment with Clindamycin-M. Upon diagnosis of pseudomembranous enterocolitis, the physician should consider discontinuing Clindamycin-M and initiate appropriate therapy (administration of antibiotics/chemotherapeutic agents with clinically proven efficacy). Medicinal products that inhibit peristalsis are contraindicated.

Use of clindamycin may lead to overgrowth of other intestinal microorganisms, including fungi.

Allergic reactions may occasionally occur even after the first dose. Severe acute allergic reactions such as anaphylactic shock are very rare. In such cases, Clindamycin-M should be discontinued immediately and appropriate emergency measures initiated (e.g., administration of antihistamines, corticosteroids, sympathomimetics, and artificial ventilation if necessary).

Reporting suspected adverse reactions. It is important to report suspected adverse reactions after marketing authorization. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Physicians should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Incompatibilities.

Due to antagonism between clindamycin and erythromycin, their concomitant use is not recommended. Do not use simultaneously with ampicillin, phenytoin, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

Packaging.

10 capsules in a blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Monpharm".

Manufacturer's name and address.

8 Zavodska Street, Monastyryshche, Cherkasy region, 19100, Ukraine.