INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DALLACIN C (Dalacin C)

Composition:

Active substance: clindamycin;

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

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

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

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

Pharmaceutical form. Capsules.

Main physicochemical properties:

150 mg capsules: hard, opaque gelatin capsules containing white powder, size №1, with white cap and body, marked with black ink with the Pfizer logo and code "CLIN 150";

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

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

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

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

Mechanism of resistance development. Resistance to clindamycin most commonly arises due to mutations in the antibiotic binding site of rRNA or methylation of specific nucleotides within the 23S rRNA of the 50S subunit. These changes may lead to in vitro cross-resistance to macrolides and streptogramin B (MLS_B phenotype). Resistance may sometimes be caused by alterations in ribosomal proteins.

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 resistant to clindamycin. Thus, infections caused by macrolide-resistant staphylococci should not be treated with clindamycin, even if in vitro susceptibility has been demonstrated, due to the risk of selecting mutant strains with constitutive MLS_B resistance during therapy.

Strains with constitutive MLS_B resistance show complete cross-resistance between clindamycin and lincomycin, macrolides (e.g., azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin), as well as streptogramin B. Resistance to clindamycin may be induced by macrolides in macrolide-resistant bacterial isolates. Inducible resistance can be detected using the disk diffusion D-test method or broth dilution method.

Less commonly, resistance mechanisms include antibiotic modification and active efflux. There is complete cross-resistance between clindamycin and lincomycin. As with many antibiotics, the frequency of resistance development depends on the bacterial species and geographical region. Resistance to clindamycin is higher among methicillin-resistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than among organisms susceptible to these agents.

Clinical breakpoints. The prevalence of acquired resistance may vary among species depending on geographical location and time, and local resistance data are therefore required, especially when treating severe infections. If the efficacy of clindamycin against certain types of infections is questionable due to local resistance patterns, expert advice should be sought. Particularly in cases of severe infections or treatment failure, microbiological diagnosis should be established, including identification of the pathogen and determination of its susceptibility to clindamycin.

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

Table 1.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) Breakpoints

EUCAST clinical breakpoints in table form.

1Induced resistance to clindamycin (MLSB resistance) is detected as an antagonistic effect between clindamycin and macrolides. If resistance is not detected, susceptibility to clindamycin is reported. If resistance is detected, resistance to clindamycin is reported.

2In cases of confirmed induced MLSB resistance, the following recommendations apply:

1. The clindamycin test result is not reported.
2. Instead, the following comment is added:

Induced MLSB resistance detected. Clindamycin is not suitable for monotherapy but may be used in combination therapy with a β-lactam or glycopeptide.

3Breakpoints are based on the epidemiological cutoff value (ECOFF), which distinguishes wild-type isolates from isolates with reduced susceptibility.

AFor detection of induced clindamycin resistance, place erythromycin and clindamycin disks at a distance of 12–20 mm (edge to edge) and determine antagonism (D-zone phenomenon).

BFor detection of induced clindamycin resistance, place erythromycin and clindamycin disks at a distance of 12–16 mm (edge to edge) and determine antagonism (D-zone phenomenon).

Table 2.

EUCAST quality control ranges for MIC and disk diffusion testing

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

Prevalence of acquired resistance. Prevalence of acquired resistance based on data from the past 5 years obtained within national antimicrobial resistance surveillance projects and studies (as of April 2022).

Generally susceptible organisms.

Aerobic Gram-positive microorganisms:

• Actinomyces israelii °
• Gardnerella vaginalis °
• Staphylococcus aureus (methicillin-sensitive)
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Viridans group streptococci ○^

Anaerobic microorganisms:

• Bacteroides species ° (except B. fragilis)
• Clostridium perfringens °
• Fusobacterium necrophorum °
• Peptoniphilus species °
• Peptostreptococcus species °
• Prevotella species ○
• Cutibacterium acnes °
• Veillonella species °

Other microorganisms:

• Chlamydia trachomatis °
• Chlamydia pneumoniae °
• Mycoplasma hominis °

Organisms 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

° Updated data were not available at the time of publication. Primary literature, standard references, and treatment guidelines assume susceptibility.

^General term for a heterogeneous group of streptococcal species. Resistance rates may vary depending on the specific streptococcal species involved.

Resistance rates in intensive care units are ≥ 50%.

Pharmacokinetics.

Absorption, distribution, and protein binding. The only difference between the clindamycin derivatives used lies 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 about 2 hours after administration with food. After single oral doses 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 is concentration-dependent and ranges from 60% to 94% within the therapeutic range.

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

Biotransformation and elimination. Clindamycin is primarily metabolized in the liver. Some metabolites exhibit microbiological activity. Drugs acting as inducers of hepatic enzymes reduce the mean residence time of clindamycin in the body.

In vitro studies using human liver and intestinal microsomes have demonstrated that oxidation of clindamycin occurs primarily via CYP3A4, with minor contribution from CYP3A5, forming clindamycin sulfoxide and the minor metabolite N-desmethyl-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.

Paediatric patients aged 2 to 18 years and adults aged 18 to 20 years with obesity. Analysis of pharmacokinetic data in obese patients — children aged 2 to 18 years and adults aged 18 to 20 years — demonstrated that clindamycin clearance and volume of distribution, normalized to total body weight, are comparable to those in patients with normal body weight.

Bioavailability. Absolute bioavailability of clindamycin was determined in a clinical study (1994). Each of 16 healthy male volunteers received 600 mg clindamycin intravenously (as clindamycin phosphate) and orally (2 capsules, each containing 300 mg clindamycin hydrochloride).

Prerequisite for administration: on an empty stomach.

Table 3.

Arithmetic mean values (mA), standard deviation(s), and geometric mean values (mG) after oral and intravenous (i.v.) administration

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 dental and jaw area;
• infections of the lower respiratory tract;
• pelvic and abdominal infections;
• female genital tract infections;
• skin and soft tissue infections;
• scarlet fever.

In severe clinical cases, treatment should initially be started with medicinal products containing clindamycin administered intravenously by infusion.

Contraindications.

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

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

Interaction with other medicinal products and other forms of interaction.

Antagonism (induced resistance) has been observed in vitro between clindamycin and erythromycin against a subgroup of macrolide-resistant bacterial isolates. Both agents should not be used concomitantly due to potential clinical significance, except when appropriate sensitivity testing has been performed.

Pathogenic microorganisms exhibit cross-resistance between clindamycin and lincomycin.

Due to the inherent properties of clindamycin to block 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, Dalacin C should be used with caution in patients receiving the aforementioned medicinal products.

Vitamin K antagonists. Increased coagulation test parameters (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, frequent monitoring of coagulation parameters should be performed in such patients.

Clindamycin is primarily metabolized by CYP3A4 and to a lesser extent by CYP3A5, forming the main metabolite clindamycin sulfoxide and the minor metabolite N-desmethylclindamycin. Therefore, inhibitors of CYP3A4 and CYP3A5 may reduce clindamycin clearance, while inducers of these isoenzymes may increase clindamycin clearance. When using strong CYP3A4 inducers, such as rifampicin, monitoring for loss of efficacy should be performed.

In vitro studies show 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.

Special precautions for use.

Dalacin C should be used with caution in the following patient groups:

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

Note: Dalacin C should not be used in patients with acute respiratory tract infections if they are caused by viruses.

Dalacin C 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.

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

During the use of almost all antibacterial agents, including clindamycin, Clostridium difficile-associated diarrhea (CDAD) has been reported, with manifestations ranging 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. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be unresponsive to antimicrobial therapy and may require colectomy.

CDAD should be considered in all patients presenting with 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 (see section "Side effects"), 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 agents are contraindicated in this situation.

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

With prolonged therapy, liver and kidney function tests should be performed.

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

Clindamycin therapy may be 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 structural differences between these substances. However, in rare cases, anaphylactic reactions (hypersensitivity) to clindamycin have been reported in individuals with a history of penicillin allergy. This should be taken into account when using clindamycin to treat patients with penicillin allergy.

Dalacin C contains 209.49 mg or 253.97 mg of lactose monohydrate per 150 mg or 300 mg capsule, respectively. When used according to dosage instructions, each dose delivers up to 837.96 mg of lactose. This corresponds to the total amount of lactose contained in 4 capsules of Dalacin C 150 mg. Dalacin C should not be administered to patients with rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption syndrome.

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, 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 the potential risks associated with treatment.

Use during breastfeeding.

Clindamycin is excreted in human breast milk. Clindamycin has been detected in human breast milk at concentrations ranging from < 0.5 to 3.8 µg/mL following systemic administration. Therefore, adverse gastrointestinal effects in breastfed newborns, such as diarrhea or blood in stool, sensitization, rash, and mucosal colonization by yeast fungi, cannot be excluded. Due to the risk of severe adverse reactions in breastfed newborns, women who are breastfeeding should not use clindamycin.

Fertility.

Animal studies have not shown any evidence 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 to moderate effect on the ability to drive vehicles or operate machinery. Some side effects (e.g. dizziness, drowsiness; 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

Dalacin C should be taken with plenty of fluid (at least one full glass of water) to reduce the risk of esophageal irritation.

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

150 mg capsules

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

The daily dose should be divided into 4 doses.

For higher dosage requirements, medicinal formulations with a higher content of active substance are available.

300 mg capsules

Depending on the site and severity of infection, the recommended dose for adults and children aged 14 years and older is 2–6 capsules daily (equivalent to 0.6–1.8 g of clindamycin).

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

Children and adolescents.

Clindamycin dosage should be 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, medicinal formulations with lower content of active substance are available.

Hepatic impairment. In patients with moderate to severe hepatic impairment, the elimination half-life of clindamycin is prolonged. Generally, when Dalacin C is administered every 8 hours, dosage reduction is not required. However, in patients with severe hepatic insufficiency, plasma levels of clindamycin should be monitored. Depending on the results, dosage reduction or prolonged dosing intervals may be necessary.

Renal impairment. In renal impairment, the elimination half-life of clindamycin is prolonged; however, dosage adjustment is not usually required in mild to moderate renal dysfunction. Nevertheless, in patients with severe renal impairment or anuria, plasma levels of clindamycin should be monitored. Depending on the results, dosage reduction or, alternatively, prolongation of 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.

Dalacin C capsules are not suitable for children who cannot swallow them whole. Capsules do not allow precise dosing in mg/kg; therefore, in some cases, it may be necessary to use an alternative, more appropriate dosage form.

Depending on the site and severity of infection, children under 14 years of age should receive 8–25 mg of clindamycin per kg of body weight per day; see Table 4.

Table 4.

The daily dose is divided into 3–4 separate doses. Administration in the form of 4 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 for removing clindamycin from blood serum. A specific antidote is unknown.

Adverse Reactions

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

By frequency, adverse reactions are classified into the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), 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, 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 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.

Renal and urinary disorders.

Frequency not known: acute renal failure.

Investigations.

Common: abnormalities in liver function biochemical parameters.

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

Adverse reactions associated with antibiotic use (class effect).

Pseudomembranous colitis may commonly develop during treatment with Dalacin C. Upon detection (diagnosis) of pseudomembranous colitis, the physician should consider discontinuing Dalacin C and initiate appropriate therapy (using antibiotics/chemotherapeutic agents with clinically proven efficacy). Medicinal products that inhibit peristalsis are contraindicated.

Clindamycin use 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, Dalacin C 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 of the medicinal product. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Physicians should report any suspected adverse reactions in accordance with applicable legislative requirements.

Shelf life. 5 years.

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

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

Prescription status. Prescription only.

Manufacturer.

Fareva Amboise / Fareva Amboise.

Manufacturer's address.

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