Dalacin C capsules 300 mg blister No. 16

Instructions for Dalacin C capsules 300 mg blister No. 16

Composition

active ingredient: clindamycin;

1 capsule contains 177.515 mg of clindamycin hydrochloride, equivalent to 150 mg of clindamycin;

1 capsule contains 355.030 mg of clindamycin hydrochloride, equivalent to clindamycin 300 mg;

excipients: corn starch; lactose monohydrate; talc; magnesium stearate; capsule shell 150 mg: titanium dioxide (E 171), gelatin;

300 mg capsule shell: titanium dioxide (E 171), gelatin, indigo carmine (E 132), erythrosine (E 127).

Dosage form

capsules.

Main physicochemical properties:

150 mg capsules: hard opaque gelatin capsules containing white powder, size No. 1, with white cap and body, printed in black ink with the Pfizer logo and the code “CLIN 150”;

300 mg capsules: hard opaque gelatin capsules containing white powder, size No. 0, with lavender cap and body, printed in black ink with the Pfizer logo and the code “CLIN 300”.

Pharmacotherapeutic group

Antibacterials for systemic use. Lincosamides. ATX code J01F F01.

Pharmacological properties

Pharmacodynamics

Mechanism of action. Clindamycin belongs to the lincosamide group of antibiotics. The mechanism of action of clindamycin is based on the inhibition of protein biosynthesis by binding to the 50S subunit and affecting both ribosome formation and translation. Although clindamycin phosphate is inactive in vitro, rapid hydrolysis in vivo converts it to the antibacterially active clindamycin. At usual doses, clindamycin exhibits bacteriostatic activity.

Pharmacokinetic/pharmacodynamic relationship: Efficacy will depend significantly on the time during which the level of the active substance exceeds the minimum inhibitory concentration (MIC) of the pathogen (%C/MIC).

Mechanism of resistance. Resistance to clindamycin most often occurs due to mutations in the antibiotic-binding site of rRNA or methylation of specific nucleotides in the 23S rRNA subunit of the 50S. These changes can result in in vitro cross-resistance to macrolides and streptogramins type B (MLSB phenotype). Resistance is sometimes due to changes in ribosomal proteins.

Resistance in staphylococci and streptococci will mainly result from increased incorporation of methyl groups into 23S rRNA (so-called constitutive MLSB resistance), which greatly reduces the binding affinity of clindamycin to the ribosome. Most methicillin-resistant S. aureus (MRSA) strains have a constitutive MLSB phenotype and are therefore clindamycin resistant. Therefore, infections caused by macrolide-resistant staphylococci should not be treated with clindamycin even when demonstrated in vitro susceptibility due to the risk of selection during treatment of mutant strains with constitutive MLSB resistance.

Strains with constitutive MLSB resistance demonstrate complete cross-resistance between clindamycin and lincomycin, macrolides (e.g. azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin), and streptogramin B. Resistance to clindamycin can be induced by macrolides in macrolide-resistant bacterial isolates. Induced resistance can be determined by the disk method (disco-diffusion D-test) or the broth dilution method.

Less common mechanisms of resistance include antibiotic modification and active efflux. There is complete cross-resistance between clindamycin and lincomycin. As with many antibiotics, the incidence of resistance varies with the bacterial species and geographic area. The incidence of resistance to clindamycin is higher in methicillin-resistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than in organisms susceptible to these agents.

Breakpoints. The prevalence of acquired resistance may vary for individual species depending on geographical location and time, and therefore local information on resistance is required, particularly in the treatment of severe infections. If the efficacy of clindamycin in at least some types of infections is questionable due to local resistance patterns, expert advice should be sought. Particularly in cases of severe infections or failure of therapy, microbiological diagnosis should be made to determine the pathogen and its susceptibility to clindamycin.

Resistance is generally determined by susceptibility interpretation criteria (breakpoints) established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for systemic antibiotics. Clindamycin testing was performed using the conventional serial dilution method.

Table 1.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints

EUCAST clinical breakpoints in tabular form.

1Induced clindamycin resistance (MLSB resistance) is the result of antagonism between clindamycin and macrolides. If resistance is not found, clindamycin susceptibility is reported. If resistance is found, clindamycin resistance is reported.

2 In case of proven induced MLSB resistance, the following recommendations are given:

1. Clindamycin test result not provided.

2. Instead of the result, the following comment is added:

Induced MLSB resistance has been identified. Clindamycin is not suitable for monotherapy, but can be used in combination therapy with a β-lactam or glycopeptide.

To detect induced resistance to clindamycin, place disks with erythromycin and clindamycin at a distance of 12–20 mm (edge to edge) and determine antagonism (phenomenon D).

BTo detect induced resistance to clindamycin, place disks with erythromycin and clindamycin at a distance of 12–16 mm (edge to edge) and determine antagonism (phenomenon D).

Table 2.

EUCAST quality control ranges for MIC and disc zone determination

ATCC® is a registered trademark of the American Type Culture Collection.

Prevalence of acquired resistance. Prevalence of acquired resistance based on data from the last 5 years from national resistance surveillance projects and research (as of April 2020).

Usually sensitive species.

Aerobic gram-positive microorganisms:

Actinomyces israelii °

Gardnerella vaginalis °

Staphylococcus aureus (methicillin-sensitive)

Streptococcus pneumoniae

Streptococcus pyogenes

Streptococci of the "viridians" group ○^

Anaerobic microorganisms:

Bacteroides species ° (except B. fragilis)

Clostridium perfringens °

Fusobacterium species °

Peptoniphilus species °

Species of Peptostreptococcus °

Prevotella species ○

Propionibacterium species °

Veillonella species °

Other microorganisms:

Chlamydia trachomatis °

Chlamydophila pneumoniae °

Mycoplasma hominis °

Species for which acquired resistance may be a problem.

Aerobic gram-positive microorganisms:

Staphylococcus aureus

Staphylococcus aureus (methicillin-resistant) +

Staphylococcus epidermidis #

Staphylococcus haemolyticus #

Staphylococcus hominis #

Streptococcus agalactiae

Anaerobic microorganisms:

Bacteroides fragilis °

Resistant microorganisms.

Aerobic gram-positive microorganisms:

Enterococcus species

Listeria monocytogenes

Aerobic Gram-negative microorganisms:

Escherichia coli

Haemophilus influenzae

Klebsiella species

Pseudomonas aeruginosa

Anaerobic microorganisms:

C. difficile

Other microorganisms:

Mycoplasma pneumoniae

Ureaplasma urealyticum

° No updated data were available at the time of publication. Primary literature, standard literature, and treatment guidelines suggest susceptibility.

+ In at least one region, the frequency of resistance exceeds 50%.

^A general term for a heterogeneous group of streptococcal species. The frequency of resistance may vary depending on the streptococcal species involved.

# In intensive care units, the resistance rate is ≥ 50%.

Pharmacokinetics

Absorption, distribution and protein binding. The difference between the clindamycin derivatives used is only in the time of absorption and cleavage of the esters. After this, clindamycin is present in the body as the free base (active form). Its esters should be considered precursors of the drug.

After oral administration, clindamycin hydrochloride and clindamycin 2-palmitate hydrochloride are rapidly and almost completely absorbed from the gastrointestinal tract. Simultaneous food intake slightly slows down absorption. When administered in the fasting state, maximum serum concentrations are reached after approximately 45-60 minutes, and when administered after a meal - after approximately 2 hours. After oral administration of a single dose of 150 mg or 300 mg, the concentrations are 1.9 to 3.9 μg/ml and 2.8 to 3.4 μg/ml, respectively (fasting state).

The binding of clindamycin to plasma proteins depends on its concentration and ranges from 60% to 94% within the therapeutic range.

Clindamycin readily penetrates tissues, crosses the placental barrier and is excreted in breast milk. Diffusion into the subarachnoid space is insufficient even in meningeal inflammation. High concentrations are achieved in bone tissue.

Biotransformation and elimination. Clindamycin is primarily metabolized in the liver. Some metabolites are microbiologically active. Drugs that act as inducers of hepatic enzymes reduce the mean residence time of clindamycin in the body.

Clindamycin is excreted approximately 2/3 in the feces and 1/3 in the urine.

The serum half-life of clindamycin is approximately 3 hours in adults and approximately 2 hours in children. The half-life is prolonged in patients with renal impairment and moderate to severe hepatic impairment.

Clindamycin is not removed by dialysis.

Obese Pediatric Patients 2 to 18 Years of Age and Obese Adults 18 to 20 Years of Age. Pharmacokinetic data analysis in obese patients: in children 2 to 18 years of age and adults 18 to 20 years of age – demonstrated that clindamycin clearance and volume of distribution, normalized to total body weight, were comparable to those in subjects with normal body weight.

Bioavailability: The absolute bioavailability of clindamycin was determined in a clinical study (1994). Sixteen healthy male volunteers each received 600 mg of clindamycin intravenously (as clindamycin phosphate) and orally (2 capsules, each containing 300 mg of clindamycin hydrochloride).

The prerequisite for use is on an empty stomach.

Table 3.

Arithmetic mean (mA), standard deviation(s) (s) and geometric mean (mG) after oral and intravenous (IV) administration

Indication

Acute and chronic bacterial infections caused by clindamycin-sensitive pathogens, including:

bone and joint infections;

ear, nose and throat infections;

infections of the teeth and jaw area;

lower respiratory tract infections;

pelvic and abdominal infections;

infections of the female genital organs;

skin and soft tissue infections;

scarlet fever.

In severe clinical conditions, treatment should initially be carried out with drugs containing clindamycin, which are slowly injected into the blood vessel (via infusion).

Contraindication

Dalacin C should not be used in patients with known sensitivity to clindamycin, lincomycin or any other component of the drug.

Dalacin C is not suitable for the treatment of meningitis because the concentration of the antibiotic achieved in the cerebrospinal fluid is too low.

Interaction with other medicinal products and other types of interactions

Antagonism (induced resistance) has been observed in vitro between clindamycin and erythromycin against a subset of macrolide-resistant bacterial isolates. The two drugs should not be used concomitantly due to potential clinical significance, unless appropriate susceptibility testing has been performed.

Pathogenic microorganisms demonstrate cross-resistance to clindamycin and lincomycin.

Due to its neuromuscular blocking properties, clindamycin may potentiate the effects of muscle relaxants (e.g., ether, tubocurarine, pancuronium halide). This may lead to unexpected life-threatening situations during surgery. Therefore, Dalacin C should be used with caution in patients receiving the above-mentioned drugs.

Vitamin K Antagonists: Elevated coagulation tests (prothrombin time/international normalized ratio) and/or bleeding have been reported in patients receiving clindamycin in combination with vitamin K antagonists (e.g., warfarin, acenocoumarol, and fluindione). Therefore, coagulation tests should be monitored frequently in such patients.

Clindamycin is metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5 to form the major metabolite clindamycin sulfoxide and the minor metabolite N-desmethyl-clindamycin. Therefore, inhibitors of CYP3A4 and CYP3A5 may decrease clindamycin clearance, and inducers of these isoenzymes may increase clindamycin clearance. When potent inducers of CYP3A4, such as rifampicin, should be monitored for loss of efficacy.

In vitro studies demonstrate that clindamycin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1, or CYP2D6 and only moderately inhibits CYP3A4. Therefore, clinically significant interactions between clindamycin and concomitantly administered drugs metabolized by these CYP enzymes are unlikely.

Application features

Dalacin C should be used with caution in the following categories of patients:

with impaired liver function;

with disorders of neuromuscular transmission (myasthenia gravis, Parkinson's disease);

with a history of gastrointestinal diseases (for example, inflammation of the colon);

with atopy;

with allergies and asthma.

Dalacin C is not suitable for the treatment of meningitis because the antibiotic concentrations achieved in the cerebrospinal fluid are too low.

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

During long-term treatment (more than 10 days), clinical blood tests and liver and kidney function should be checked regularly.

Long-term and repeated use of Dalacin C may lead to the development of superinfection or colonization of the skin and mucous membranes with resistant microorganisms or yeast fungi.

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including clindamycin, and may range 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 and are the primary cause of antibiotic-associated colitis. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and require colectomy.

The possibility of CDAD should be considered in all patients with antibiotic-associated diarrhea. A careful history should be taken, as cases of CDAD have been reported up to two months after the use of antibacterial agents. Progression to colitis, including pseudomembranous colitis (see section 4.8), which may range in severity from mild to fatal, is possible.

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

In cases of moderate to severe pseudomembranous colitis, consideration should be given to fluid and electrolyte management, protein supplementation, and the use of antibacterial agents clinically effective for the treatment of Clostridium difficile colitis.

In case of prolonged therapy, liver and kidney function tests should be performed.

Acute kidney injury, including acute renal failure, has been reported uncommonly. In patients with pre-existing renal dysfunction and in patients taking concomitant nephrotoxic drugs, monitoring of renal function should be considered (see section 4.8).

Clindamycin treatment is sometimes a possible alternative in cases of penicillin allergy (hypersensitivity to penicillin). Cross-allergy between clindamycin and penicillin is not known and is not expected due to the structural differences between these substances. However, in isolated cases, anaphylactic reactions (hypersensitivity) to clindamycin have been reported in individuals who were already allergic to penicillin. This should be considered when using clindamycin to treat patients with penicillin allergy.

Dalacin C contains 209.49 mg or 253.97 mg of lactose monohydrate per 1 capsule of 150 mg or 300 mg, respectively. When the drug is used according to the dosage instructions, the patient receives up to 837.96 mg of lactose with each dose. This corresponds to the total amount of lactose contained in 4 capsules of the drug Dalacin C 150 mg. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Dalacin C.

Use during pregnancy or breastfeeding

Use during pregnancy.

A large study of pregnant women exposed to clindamycin during the first trimester of pregnancy (approximately 650 infants) did not show an increased incidence of birth defects. However, there is insufficient evidence to support the safety of clindamycin use during pregnancy.

The results of experimental studies in animals do not suggest direct or indirect harmful effects on the course of pregnancy, embryonal/fetal development, the course of childbirth or postnatal development.

Clindamycin crosses the placenta. It is assumed that therapeutically effective concentrations are reached in the fetus. When using the drug during pregnancy, the benefits and possible risks associated with treatment should be carefully weighed.

Clindamycin is excreted in human milk. Clindamycin has been reported to be present in human milk at concentrations ranging from < 0.5 to 3.8 μg/mL following systemic administration. Therefore, gastrointestinal adverse reactions such as diarrhea or blood in the stool, sensitization, rash, and mucosal colonization with yeasts cannot be excluded in breastfed infants. Because of the risk of serious adverse reactions in breastfed infants, clindamycin should not be used by breastfeeding women.

Fertility.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

Clindamycin has minor or moderate influence on the ability to drive and use machines. Some side effects (including dizziness, drowsiness, see section "Adverse reactions") may affect the ability to concentrate and react; therefore, they may affect the ability to drive and use machines.

Method of administration and doses

Dalacin C should be taken with sufficient fluid (at least 1 large glass of water) to avoid possible irritation of the esophagus.

If an infection caused by β-hemolytic streptococcus is suspected or if there are signs of β-hemolytic streptococcus, treatment should be carried out for at least 10 days.

Capsules of 150 mg.

Adults: Depending on the location and severity of the infection, adults and children aged 14 years and over should take 4–12 capsules per day (equivalent to 0.6–1.8 g of clindamycin).

The daily dose is divided into 4 doses.

To provide higher doses, there are also dosage forms with a higher content of the active substance.

Capsules of 300 mg.

Depending on the location and severity of the infection, adults and children aged 14 and over should take 2–6 capsules per day (equivalent to 0.6–1.8 g of clindamycin).

The daily dose is divided into 2, 3 or 4 separate doses.

Children and adolescents.

The dose of clindamycin should be prescribed based on total body weight, regardless of obesity.

The maximum daily dose should not exceed the adult dose.

For children under 14 years of age, there are dosage forms with a lower content of active substance.

Liver disease. In patients with moderate to severe liver disease, the half-life of clindamycin is prolonged. Usually, if Dalacin C is administered every 8 hours, no dose reduction is necessary. However, in patients with severe hepatic impairment, clindamycin plasma levels should be monitored. Depending on the results, a dose reduction or prolongation of the dosing interval may be necessary.

Renal disease. The elimination half-life of clindamycin is prolonged in renal disease; however, no dose reduction is necessary in mild to moderate renal impairment. However, plasma clindamycin levels should be monitored in patients with severe renal impairment or anuria. Depending on the results of these measurements, a reduction in dose or, alternatively, an extension of the dosing interval 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.

Dalacin C capsules are not suitable for use in children who cannot swallow them whole. Capsules do not allow for accurate dosing of the drug in mg/kg, so in some cases it may be necessary to use the drug in another, more convenient dosage form.

Depending on the location and severity of the infection, children under 14 years of age should be given 8–25 mg of clindamycin per kilogram of body weight per day, see Table 4.

Table 4.

The daily dose is divided into 3-4 separate doses. As a rule, 4 doses are preferred.

Overdose

No symptoms of overdose have been observed so far. Gastric lavage is indicated if necessary. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the blood serum. A specific antidote is unknown.

Side effects

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

Adverse reactions are ranked under headings of frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (frequency cannot be estimated from the available data). Adverse reactions are listed within each category in order of decreasing seriousness.

Infections and invasions.

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

From the blood and lymphatic system.

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

From the immune system.

Rare: drug fever.

Very rare: anaphylactic reaction*.

Frequency unknown: anaphylactic shock*, anaphylactoid reaction*, hypersensitivity*.

From the nervous system.

Uncommon: taste distortion, neuromuscular blockade.

Frequency unknown: dizziness, drowsiness, headache.

From the gastrointestinal tract.

Very common: esophageal irritation, oesophagitis*, stomatitis, diarrhoea, abdominal pain, vomiting, nausea.

Frequency unknown: esophageal ulcer*.

Hepatobiliary disorders.

Very rare: transient hepatitis with cholestatic jaundice.

Frequency unknown: jaundice.*

On the skin and subcutaneous tissue.

Common: maculopapular rash, crusted rash*, urticaria.

Rare: toxic epidermal necrolysis*, Stevens-Johnson syndrome*, Lyell syndrome, angioedema/angioedema*, exfoliative dermatitis*, bullous dermatitis*, erythema multiforme, pruritus, vaginitis.

Very rare: rash and 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.

On the part of the kidneys and urinary system.

Frequency unknown: acute renal failure.

Laboratory test results.

Common: Abnormal biochemical liver function tests.

*Adverse reactions identified during post-marketing use of the drug (see section "Special warnings and precautions for use").

Adverse reactions to the use of antibiotics (class effect).

Pseudomembranous colitis may often develop when using Dalacin C. Immediately after detecting (diagnosing) pseudomembranous colitis, the doctor should consider discontinuing Dalacin C and initiating appropriate treatment (use of specific antibiotics/chemotherapeutic agents with clinically proven efficacy). Drugs that inhibit peristalsis are contraindicated.

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

Sometimes allergic reactions occur even after the first use. Very rarely, severe acute allergic reactions, such as anaphylactic shock, occur. In such cases, the use of Dalacin C should be discontinued immediately and appropriate emergency measures should be taken (e.g., antihistamines, corticosteroids, sympathomimetics, and, if necessary, artificial ventilation).

Reporting of suspected adverse reactions.

Once a medicinal product has been authorised, it is essential to report suspected adverse reactions. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Physicians should report any suspected adverse reactions as required by law.

Expiration date

5 years.

Storage conditions

Store out of the reach of children at a temperature not exceeding 25 ºС.

Packaging

8 capsules in a blister, 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Fareva Amboise/Fareva Amboise.

Location of the manufacturer and its business address

Zone Industriale, 29 route des Industries, 37530 Poce-sur-Cisse, France/Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.