Ultrex capsules 300 mg No. 16

Instructions for Ultrex capsules 300 mg No. 16

Composition

active ingredient: clindamycin;

1 capsule contains 150 mg or 300 mg of clindamycin;

excipients: lactose monohydrate; corn starch; talc; magnesium stearate;

150 mg capsule shell: hard gelatin Capsugel size 1 (titanium dioxide (E 171), gelatin, dye 10A1 black);

capsule shell 300 mg: hard gelatin Capsugel size 0e1 (titanium dioxide (E 171), gelatin, dye 10A1 black);

composition of dye 10A1 black: shellac, black iron oxide (E 172), propylene glycol (E 1520), ammonium hydroxide (E 527).

Dosage form

capsules.

Main physicochemical properties:

150 mg capsules: white hard gelatin capsules, size 1, imprinted with “CLIN 150”, filled with white crystalline powder;

300 mg capsules: white hard gelatin capsules, size 0e1, with the inscription "CLIN 300", filled with white crystalline powder.

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 assembly 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 substance exceeds the minimum inhibitory concentration (MIC) for the causative pathogen (%C/MIC).

Mechanism of resistance. Resistance to clindamycin most often occurs due to mutations in the rRNA antibiotic binding site 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 the 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 confirmed 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 among methicillin-resistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than among 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.

EUCAST breakpoints (see table 1). (European Committee on Antimicrobial Susceptibility Testing).

Table 1.

EUCAST Clinical Breakpoints in Tabular Form, Version 8.0

1 Induced resistance to clindamycin can be detected by determining the antagonistic effect between clindamycin and macrolides. If resistance is not detected, it is reported that testing was performed according to clinical breakpoints. If resistance is detected, “resistance” is reported and the following comment may be added to the report: “Clindamycin may be used for short-term therapy of less serious skin and soft tissue infections, as the development of constitutive resistance during such therapy is unlikely.”

2 The clinical significance of induced resistance to clindamycin in combination therapy for severe S. pyogenes infections is unknown.

3 Induced resistance to clindamycin can be detected by determining the antagonism between clindamycin and macrolides. If resistance is not detected, testing according to clinical breakpoints is reported. If resistance is detected, “resistance” is reported.

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

B To 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).

a Disk content – 2 mcg of clindamycin

The EUCAST quality control ranges for MIC and disc zone determination are presented in Table 2.

Table 2

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 February 2018).

Usually sensitive species.

Aerobic Gram-positive microorganisms: no p\f

Actinomyces israelii ° Gardnerella vaginalis ° Staphylococcus aureus (methicillin sensitive) Streptococcus pneumoniae Streptococcus pyogenes Streptococci of the "viridians" group ○^

Anaerobic microorganisms: no

Bacteroides species ° (except B.fragilis) Clostridium perfringens ° Fusobacterium species ° Peptoniphilus species ° Peptostreptococcus species ° 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 Staphylococcus agalactiae

Aerobic Gram-negative microorganisms:

Moraxella catarrhalis $

Anaerobic microorganisms:

Bacteroides fragilis °

Resistant microorganisms.

Aerobic gram-positive microorganisms:

Types of Enterococcus Listeria monocytogenes

Aerobic Gram-negative microorganisms:

Escherichia coli Haemophilus influenzae Klebsiella species Pseudomonas aeruginosa

Anaerobic microorganisms:

Clostridium 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.

$ The natural susceptibility of most strains is in the intermediate range.

+ 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.

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.

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.

In vitro studies in human liver and intestinal microsomes have demonstrated that the oxidation of clindamycin occurs primarily by CYP3A4 with minor involvement of CYP3A5 to form clindamycin sulfoxide and the minor metabolite N-desmethyl-clindamycin.

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 impaired renal function and moderate to severe hepatic impairment.

Clindamycin is not removed by dialysis.

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.

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

Table 3.

Indication

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

bone and joint infections; ear, nose and throat infections; teeth and jaw infections; lower respiratory tract infections; pelvic and abdominal infections; female genital infections; skin and soft tissue infections; scarlet fever.

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

Contraindication

Hypersensitivity to clindamycin, lincomycin or to any of the excipients of the drug.

Ultrex 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, Ultrex may potentiate the effects of muscle relaxants (e.g. ether, tubocurarine, pancuronium halide). This may lead to unexpected life-threatening situations during surgery. Ultrex should therefore be used with caution in patients receiving the above-mentioned drugs.

The reliability of the contraceptive effect of oral contraceptives is questionable when used concomitantly with Ultrex. Therefore, other methods of contraception should be used in addition during treatment with Ultrex.

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

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

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

Ultrex 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).

Acute kidney injury.

Rare cases of acute kidney injury, including acute renal failure. Therefore, monitoring of renal function should be considered in patients receiving long-term therapy, who have pre-existing renal impairment, or who are taking concomitant nephrotoxic drugs (see section 4.8).

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 Ultrex 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 CDAD has been reported up to two months after the use of antibacterial agents. Progression to colitis, including pseudomembranous colitis, may occur, and the severity of the disease may range 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. 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.

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, anaphylactic reactions (hypersensitivity) to clindamycin have been reported in isolated cases in individuals who are already allergic to penicillin. This should be considered when using clindamycin to treat patients with penicillin allergy.

Ultrex contains 214.08 mg or 283.24 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 856.32 mg of lactose with each dose. This corresponds to the total amount of lactose contained in 4 capsules of Ultrex 150 mg. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Ultrex.

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.

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

Use during breastfeeding.

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, adverse effects on the gastrointestinal microflora of breast-fed infants, such as diarrhoea or blood in the stool, sensitisation, rash and mucosal yeast colonization, cannot be excluded. Due to the risk of serious adverse reactions in breast-fed infants, clindamycin should not be used by breastfeeding women.

Reproductive function.

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

Ultrex 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 medicines with a higher content of the active substance.

Capsules of 300 mg.

Depending on the location and severity of the infection, adults and children over 14 years of age should use 0.6-1.8 g of clindamycin per day. The daily dose is divided into 2, 3 or 4 separate doses.

Therefore, 2-6 capsules of Ultrex 300 mg should be used per day (equivalent to 0.6-1.8 g of clindamycin).

For children under 14 years of age, there are medicines 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 Ultrex is administered every 8 hours, no dose reduction is necessary. However, patients with severe hepatic impairment should be monitored for clindamycin plasma levels. Depending on the results obtained, a dose reduction or prolongation of the dosing intervals 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.

Ultrex capsules are not suitable for use in children who cannot swallow them whole. Capsules do not allow for accurate dosing 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

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 presented in order of decreasing seriousness within each category.

Infections and invasions.

Common: pseudomembranous colitis*.

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.*

Kidney and urinary dysfunction.

Frequency unknown: acute kidney injury (see section "Special warnings and precautions for use").

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.

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 of antibiotics (class effect).

Pseudomembranous enterocolitis may often develop with Ultrex. Immediately after the detection (diagnosis) of pseudomembranous enterocolitis, the doctor should consider discontinuing Ultrex 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 Ultrex should be discontinued immediately and the usual 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

Ultrex, 150 mg capsules, – 36 months.

Ultrex, 300 mg capsules, – 36 months.

Storage conditions

Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

No. 16 (8x2): 8 capsules of 150 mg or 300 mg in a blister; 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Rivopharm SA.

Address

Centro Insema, 6928 Manno, Switzerland.