Gliteyk

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLITEIK (GLITEIK)

Composition:

Active substance: teicoplanin;

1 vial contains teicoplanin 400.0 mg;

Excipients: sodium chloride;

Solvent: water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: porous mass of white with a brownish-yellow hue.

Pharmacotherapeutic group. Glycopeptide antibiotics. ATC code J01XA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Teicoplanin inhibits the growth of susceptible microorganisms by interfering with cell wall synthesis at a site different from that of beta-lactam antibiotics. Peptidoglycan synthesis is blocked through specific binding to D-alanyl-D-alanine residues.

Resistance to teicoplanin may develop via the following mechanisms:

• Modified target site: this form of resistance is particularly characteristic of Enterococcus faecium. The modification involves replacement of the terminal D-alanine-D-alanine moiety of the peptidoglycan precursor with D-ala-D-lactate, resulting in reduced affinity for vancomycin. The enzymes responsible for this change are newly synthesized D-lactate dehydrogenase or ligase.
• Reduced susceptibility or resistance of staphylococci to teicoplanin is due to overproduction of peptidoglycan precursors to which teicoplanin binds.

Cross-resistance may occur between teicoplanin and the glycopeptide vancomycin. However, some vancomycin-resistant enterococci remain susceptible to teicoplanin (Van-B phenotype).

Clinical breakpoints for antimicrobial susceptibility testing

The minimal inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are presented in Table 1.

Table 1.

Minimal inhibitory concentration (MIC) breakpoints established by EUCAST

Microorganisms	Susceptible	Resistant
Staphylococcus aureus a Coagulase-negative staphylococci a Enterococcus species (Enterococcus spp.) Streptococcus species (Streptococcus spp.) (A, B, C, G) b Streptococcus pneumoniae b Viridans group streptococci b Gram-positive anaerobes, except Clostridium difficile Breakpoints for PK/PD determination (not species-specific) c,d	≤2 mg/L ≤4 mg/L ≤2 mg/L ≤2 mg/L ≤2 mg/L ≤2 mg/L ND ND	>2 mg/L >4 mg/L >2 mg/L >2 mg/L >2 mg/L >2 mg/L ND ND

a The minimum inhibitory concentration (MIC) for glycopeptides depends on the method used and should be determined by the broth microdilution method (ISO 20776). Staphylococcus aureus (S. aureus) with vancomycin MIC values of 2 mg/L are at the breakpoint between wild-type and non-wild-type isolates and may negatively affect clinical response. The susceptibility breakpoints for S. aureus have been reduced to 2 mg/L to avoid reporting isolates with intermediate susceptibility to glycopeptides (Glycopeptide Intermediate-Resistant Staphylococcus aureus, GISA), as serious infections caused by GISA isolates do not respond to higher doses of vancomycin or teicoplanin.

b Isolates with MIC values exceeding the susceptibility breakpoints are very rare or have not yet been reported. Susceptibility testing for any such isolates should be repeated, and if the result is confirmed, the isolate should be referred to a reference laboratory. Until clinical evidence of response to the drug is available for confirmed isolates with MIC values exceeding the current resistance breakpoint, these isolates should be reported as resistant.

c "ND" means that there is currently insufficient evidence to support that the disputed species are a suitable target for therapy with this agent.

d An MIC value may be reported with a comment but without an accompanying categorical interpretation: S (susceptible), I (intermediate), or R (resistant).

Pharmacokinetic/Pharmacodynamic Relationship

The antimicrobial activity of teicoplanin is largely dependent on the duration of time during which drug concentrations exceed the minimum inhibitory concentration (MIC) for the causative pathogen of the specific infection.

Susceptibility

For certain bacterial species, resistance prevalence may vary depending on geographical region and over time; therefore, it is advisable to obtain local resistance data, especially when treating severe infections. Expert consultation should be sought if local resistance prevalence renders the utility of this agent at least questionable for certain types of infections.

Typically Susceptible Microorganisms

Aerobic Gram-Positive Bacteria

Corynebacterium jeikeium a

Enterococcus faecalis

Staphylococcus aureus (including methicillin-resistant strains)

Streptococcus agalactiae

Streptococcus dysgalactiae subsp. equisimilis a

(Group C & G streptococci)

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci a, b

Anaerobic Gram-Positive Bacteria

Clostridium difficile a

Peptostreptococcus species a

Species for Which Acquired Resistance May Occur

Aerobic Gram-Positive Bacteria

Enterococcus faecium

Staphylococcus epidermidis

Staphylococcus haemolyticus

Staphylococcus hominis

Resistant Microorganisms

All Gram-negative bacteria

Chlamydiae

Chlamydophila

Legionella pneumophila

Mycoplasma

a Recommendations regarding standard dosing and treatment are based on predicted susceptibility.

b Resistance rates may vary depending on the specific streptococcal species.

Pharmacokinetics

Absorption

After intramuscular administration, the bioavailability of teicoplanin (compared to intravenous administration) is nearly complete (90%). After administration of six daily intramuscular doses of 200 mg, the mean (with standard deviation, SD) maximum teicoplanin concentration (Cmax) is 12.1 (0.9) mg/L, reached 2 hours after dosing.

After intravenous administration of a loading dose of 6 mg/kg given every 12 hours for 3 to 5 doses, Cmax values ranged from 60 to 70 mg/L, and the trough concentration (Ctrough) usually exceeds 10 mg/L. After intravenous administration of a loading dose of 12 mg/kg given every 12 hours for 3 doses, mean Cmax and Ctrough values are estimated to be approximately 100 mg/L and 20 mg/L, respectively.

After administration of a maintenance dose of 6 mg/kg given once daily, Cmax and Ctrough values are approximately 70 mg/L and 15 mg/L, respectively. After administration of a maintenance dose of 12 mg/kg given once daily, Ctrough values range from 18 to 30 mg/L.

Distribution

Protein binding to human serum ranges from 87.6% to 90.8% without concentration-dependent changes. Teicoplanin binds primarily to human serum albumin. It does not penetrate erythrocytes.

The volume of distribution at steady state (Vss) ranges from 0.7 to 1.4 L/kg. The highest Vss values were observed in recent studies where samples were collected more than 8 days after the start of treatment.

Teicoplanin distributes predominantly into the lungs, myocardium, and bone tissue, with tissue-to-serum ratios exceeding 1. In blister fluid, synovial fluid, and peritoneal fluid, tissue-to-serum ratios range from 0.5 to 1. Elimination of teicoplanin from peritoneal fluid occurs at the same rate as from serum. In pleural fluid and subcutaneous adipose tissue, tissue-to-serum ratios range from 0.2 to 0.5. Teicoplanin penetrates poorly into cerebrospinal fluid (CSF).

Biotransformation

Unchanged teicoplanin is the main compound found in plasma and urine, indicating minimal metabolism. Two metabolites are formed, likely via hydroxylation, accounting for 2–3% of the administered dose.

Elimination

Teicoplanin is excreted unchanged primarily in urine (80% within 16 days), and 2.7% of the administered dose is excreted in feces (via biliary excretion) within 8 days after administration.

The elimination half-life of teicoplanin ranges from 100 to 170 hours, based on recent studies where blood samples were collected approximately 8–35 days after the start of treatment.

Teicoplanin has a low total clearance ranging from 10 to 14 mL/h/kg, with renal clearance ranging from 8 to 12 mL/h/kg, indicating that teicoplanin is primarily eliminated via the kidneys.

Linearity

Teicoplanin exhibits linear pharmacokinetics when administered at doses ranging from 2 to 25 mg/kg.

Special Patient Populations

• Renal impairment:

Since teicoplanin is eliminated by the kidneys, its elimination decreases proportionally with the degree of renal impairment. Total and renal clearance of teicoplanin depend on creatinine clearance.

• Elderly patients:

In elderly patients, the pharmacokinetics of teicoplanin are not altered, except in cases of renal impairment.

• Pediatric population:

Higher total clearance (15.8 mL/h/kg in neonates; 14.8 mL/h/kg in children with a mean age of 8 years) and shorter elimination half-life (40 hours in neonates; 58 hours in children with a mean age of 8 years) are observed compared to adult patients.

Clinical characteristics.

Indications.

Infections caused by Gram-positive bacteria, including those sensitive or resistant to methicillin, as well as in patients with allergy to beta-lactam antibiotics.

In adults and children:

skin and soft tissue infections;

complicated upper and lower urinary tract infections;

respiratory tract infections;

bone and joint infections;

septicaemia;

endocarditis;

peritonitis associated with ambulatory continuous peritoneal dialysis.

When necessary, teicoplanin should be used in combination with other antibacterial agents. Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to teicoplanin or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

No specific interaction studies have been conducted for this medicinal product.

Teicoplanin and aminoglycoside solutions are incompatible and should not be mixed during injection; however, they are compatible in dialysis fluid and may be used in the treatment of patients with peritonitis undergoing continuous ambulatory peritoneal dialysis.

Teicoplanin should be used with caution when administered concomitantly with, or after, other medicinal products known to have nephrotoxic and/or neurotoxic/ototoxic effects. Such agents include, for example, aminoglycosides, colistin, amphotericin B, cyclosporine, cisplatin, furosemide, and ethacrynic acid (see section "Special warnings and precautions for use", "Nephrotoxicity" and "Ototoxicity"). However, there is no evidence of synergistic toxic effects of these agents in combination with teicoplanin.

In clinical trials, teicoplanin was administered to many patients who were already receiving various medicinal products, including other antibiotics, antihypertensive agents, anaesthetics, cardiac medications, and antidiabetic agents, without any adverse interactions observed.

Paediatric population

Interaction studies have been conducted only in adult patients.

Special precautions.

Hypersensitivity reactions

Severe, life-threatening hypersensitivity reactions, sometimes with fatal outcomes (e.g., anaphylactic shock), have been reported during treatment with teicoplanin. If an allergic reaction to teicoplanin occurs, therapy must be discontinued immediately and appropriate emergency measures initiated.

Teicoplanin should be administered with caution in patients with known hypersensitivity to vancomycin, as cross-reactivity may occur, including fatal anaphylactic shock.

However, a history of pseudoallergic reactions associated with vancomycin use is not a contraindication for the use of teicoplanin.

Infusion reactions

Rarely (even after the first dose), pseudoallergic reactions (a constellation of symptoms including pruritus, urticaria, erythema, angioedema, tachycardia, hypotension, and dyspnea) have been observed. Discontinuation or slowing of the infusion may lead to resolution of these reactions. Infusion-related reactions can be minimized by administering the daily dose not as a bolus injection but by infusion over a 30-minute period.

Severe bullous reactions

Life-threatening or even fatal skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with teicoplanin use. If symptoms or signs of SJS or TEN occur (e.g., progressive skin rash, often with blistering or mucosal involvement), teicoplanin must be discontinued immediately.

Antibacterial spectrum of activity

Teicoplanin has a limited antibacterial spectrum (gram-positive bacteria). It is not suitable as monotherapy for certain types of infections unless the causative pathogen has been definitively identified and shown to be susceptible to this agent, or there is strong clinical suspicion that the pathogen(s) are likely to be susceptible to teicoplanin therapy.

For rational use of teicoplanin, consideration should be given to its antibacterial spectrum, safety profile, and the appropriateness of standard antibacterial therapy for the individual patient. Based on this, teicoplanin is expected to be used primarily for the treatment of serious infections in patients for whom standard antibacterial therapy is considered unsuitable.

Teicoplanin must not be administered intrathecally.

Thrombocytopenia

Cases of thrombocytopenia have been reported during teicoplanin use (see section "Adverse reactions"). During treatment, periodic hematological monitoring, including complete blood count, is recommended.

Nephrotoxicity

Cases of nephrotoxicity and renal failure have been reported in patients receiving teicoplanin (see section "Adverse reactions"). Close monitoring is required in patients with renal impairment, in those receiving high loading doses of teicoplanin, and in patients receiving teicoplanin concomitantly with or following other medicinal products known to have nephrotoxic potential (e.g., aminoglycosides, colistin, amphotericin B, cyclosporine, and cisplatin). Auditory monitoring is also recommended (see “Ototoxicity” below).

Since teicoplanin is primarily excreted via the kidneys, dosage adjustment is necessary in patients with impaired renal function (see section "Dosage and administration").

Ototoxicity

Ototoxicity (hearing loss and tinnitus) has been reported with teicoplanin, as with other glycopeptides, in patients (see section "Adverse reactions"). Patients who develop signs or symptoms of hearing impairment or inner ear disorders during teicoplanin therapy should be carefully evaluated and monitored, particularly during prolonged treatment and in patients with renal impairment.

Close monitoring is required in patients receiving teicoplanin concomitantly with medicinal products known to have nephrotoxic and/or neurotoxic/ototoxic potential (e.g., aminoglycosides, colistin, amphotericin B). If hearing deterioration occurs, the benefit of continuing teicoplanin therapy should be reassessed.

Special precautions should be taken when using teicoplanin in patients requiring concomitant therapy with ototoxic and/or nephrotoxic medicinal products, and regular monitoring of complete blood count, and liver and kidney function tests is recommended.

Superinfection

As with other antibiotics, prolonged use of teicoplanin may result in overgrowth of microorganisms not susceptible to the drug. If superinfection occurs during therapy, appropriate measures should be taken.

This medicinal product contains sodium. The sodium content is less than 1 mmol per dose, i.e., in practice, this medicinal product is considered "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies with teicoplanin have not shown teratogenic effects, and clinical data are limited. However, due to the high therapeutic efficacy of Gliteik, its use may be considered during pregnancy if there is a life-threatening indication (regardless of gestational age). In such cases, neonatal hearing function should be evaluated (otoacoustic emissions), considering the potential ototoxic effects of teicoplanin.

Breastfeeding. There are no data on the passage of teicoplanin into breast milk; therefore, breastfeeding during treatment with Gliteik is not recommended.

Ability to influence the ability to drive or operate machinery.

Gliteik has a negligible influence on the ability to drive vehicles or operate machinery.

Teicoplanin may cause dizziness and headache. These effects may impair the ability to drive vehicles or operate machinery. Patients experiencing these adverse effects should not drive or operate machinery.

Method of Administration and Dosage.

Dosage

The dosage and duration of therapy should be adjusted according to the type and severity of the existing infection, the patient's clinical response, and individual patient characteristics such as age and renal function.

Monitoring of drug concentration in blood serum

Serum trough concentrations of teicoplanin at steady state should be monitored after completion of the loading dose period to ensure achievement of the minimum serum trough concentration:

• For most infections caused by Gram-positive bacteria, trough concentrations of teicoplanin should be at least 10 mg/L when measured by high-performance liquid chromatography (HPLC), or at least 15 mg/L when measured by fluorescence polarization immunoassay (FPIA).
• For endocarditis and other severe infections, trough concentrations of teicoplanin should be 15–30 mg/L when measured by HPLC, or 30–40 mg/L when measured by FPIA.

During maintenance therapy, monitoring of teicoplanin serum trough concentrations should be performed at least once weekly to ensure that concentrations remain stable.

Dosage for adult patients and children aged 12 years and older, and elderly patients with normal renal function

Indications	Loading dose		Maintenance dose
	Dosing regimen during loading dose period	Target trough concentrations on day 3–5	Maintenance dose	Target trough concentrations during maintenance therapy
Complicated skin and soft tissue infections Pneumonia Complicated urinary tract infections	3 intravenous or intramuscular administrations of 400 mg (approximately 6 mg/kg body weight) every 12 hours	>15 mg/L1	6 mg/kg body weight intravenously or intramuscularly once daily	>15 mg/L1 once weekly
Bone and joint infections	3–5 intravenous administrations of 800 mg (approximately 12 mg/kg body weight) every 12 hours	>20 mg/L1	12 mg/kg body weight intravenously or intramuscularly once daily	>20 mg/L1
Infective endocarditis	3–5 intravenous administrations of 800 mg (approximately 12 mg/kg body weight) every 12 hours	30–40 mg/L1	12 mg/kg body weight intravenously or intramuscularly once daily	>30 mg/L1

1 Determination by fluorescence polarization immunoassay (FPIA)

Duration of therapy

The duration of therapy is determined based on clinical response. For infective endocarditis, an appropriate duration of therapy is usually considered to be a minimum of 21 days. The duration of therapy should not exceed 4 months.

Combination therapy

Teicoplanin has a limited spectrum of antibacterial activity (gram-positive bacteria). It is not suitable for use as a single agent in the treatment of certain types of infections unless the causative organism has already been documented and is known to be susceptible to this agent, or there is high confidence that the causative organism(s) are most likely to be susceptible to teicoplanin therapy.

Geriatric patients

Dose adjustment is not required if the patient does not have renal impairment (see below).

Adult and geriatric patients with renal impairment

During the first four days of therapy, no dose adjustment is necessary, and the dose should be administered to maintain a trough serum concentration of at least 10 mg/L.

After the fourth day of therapy:

• In mild to moderate renal impairment (creatinine clearance 30–80 mL/min): the maintenance dose should be halved—by administering the dose once every two days or by administering half the dose once daily.
• In severe renal impairment (creatinine clearance less than 30 mL/min) and in patients undergoing hemodialysis: the dose should be one-third of the usual dose, achieved by administering the standard initial dose once every three days or one-third of this dose once daily.

Teicoplanin is not removed from the body by hemodialysis.

Outpatients undergoing continuous ambulatory peritoneal dialysis (CAPD)

After a single intravenous loading dose of 6 mg/kg body weight, administer 20 mg/L into the dialysis solution bag during the first week; 20 mg/L into separate bags during the second week; and then 20 mg/L into the nighttime bag during the third week.

Pediatric patients

The drug is used in children from the age of 2 months.

Dosing recommendations for children aged 2 months to 12 years:

Loading dose: 10 mg/kg body weight administered intravenously every 12 hours for a total of 3 doses.

Maintenance dose: 6–10 mg/kg body weight administered intravenously once daily.

Dosing recommendations for children older than 12 years are the same as for adults.

Route of administration. Administer intravenously or intramuscularly. Intravenous administration should be performed over 3–5 minutes or by intravenous infusion over 30 minutes.

Solution preparation: slowly add the entire volume of solvent into the vial and gently swirl between the palms until the powder is completely dissolved. Avoid formation of bubbles. If foam appears, leave the vial in an upright position until the foam completely disappears, approximately 15 minutes. The resulting ready-to-use isotonic solution (pH 7.5) may be stored for up to 48 hours at room temperature and for 7 days at 4 °C.

The reconstituted solution may be administered by injection or further diluted with:

• 0.9% sodium chloride solution;
• lactated sodium solution (Ringer's lactate, Hartmann's solution). After dilution in these solutions, the preparation may be stored for up to 24 hours at a temperature not exceeding 25 °C or for 7 days at 4 °C;
• 5% glucose solution;
• 0.18% sodium chloride and 4% glucose solution (the resulting solution may be stored for 24 hours at a temperature not exceeding 25 °C);
• peritoneal dialysis solution—1.36% or 3.86% glucose (the resulting solution may be stored for 28 days at 4 °C).

Teicoplanin remains stable for 48 hours at 37 °C when mixed with peritoneal dialysis solutions containing insulin or heparin.

Children.

The drug is used in children from the age of 2 months.

Overdose.

Cases of accidental administration of excessively high doses of the drug to pediatric patients have been reported. In one case, excitation was observed in a 29-day-old newborn who received an intravenous dose of 400 mg of the drug (95 mg/kg).

Treatment of overdose should be symptomatic.

Teicoplanin is not removed from the body by hemodialysis and is only slowly eliminated by peritoneal dialysis.

Adverse reactions.

The table below lists all adverse reactions occurring at a frequency greater than placebo and in more than one patient, using the following categories:

Very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

System Organ Class	Common (from ≥1/100 to <1/10)	Uncommon (from ≥1/1000 to <1/100)	Rare (from ≥1/10 000 to <1/1000)	Very rare (<1/10 000)	Frequency not known (cannot be estimated from available data)
Infections and infestations			Abscess		Superinfection (overgrowth of non-susceptible organisms)
Blood and lymphatic system disorders		Leukopenia, thrombocytopenia, eosinophilia			Agranulocytosis, neutropenia, pancytopenia
Immune system disorders		Anaphylactic reaction (anaphylaxis) (see section "Special warnings and precautions for use").			Drug reaction with eosinophilia and systemic symptoms (DRESS), anaphylactic shock (see section "Special warnings and precautions for use").
Nervous system disorders		Dizziness, headache			Seizures
Ear and labyrinth disorders		Deafness, hearing loss (see section "Special warnings and precautions for use"), tinnitus, vestibular disorders
Vascular disorders		Phlebitis			Thrombophlebitis
Respiratory, thoracic and mediastinal disorders		Bronchospasm
Gastrointestinal disorders		Diarrhea, vomiting, nausea
Skin and subcutaneous tissue disorders	Rash, erythema, pruritus		Pseudoallergic reaction (i.e., redness of the upper body) (see section "Special warnings and precautions for use").		Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioneurotic edema, exfoliative dermatitis, urticaria (see section "Special warnings and precautions for use").
Renal and urinary disorders		Increased blood creatinine levels			Renal failure (including acute renal failure) (see description of individual adverse reactions below)*
General disorders and administration site conditions	Pain, pyrexia				Injection site abscess, chills (shivering)
Investigations		Increased transaminase levels (transient transaminase abnormalities), increased alkaline phosphatase levels in blood (transient abnormalities of alkaline phosphatase).

Description of individual adverse reactions

* Based on literature data, the probability of nephrotoxicity in patients who received a regimen with a low loading dose of an average of 6 mg/kg twice daily, followed by a maintenance dose of an average of 6 mg/kg once daily, is approximately 2%.

In an observational post-marketing safety study involving 300 patients with a mean age of 63 years (treated for bone and joint infections, endocarditis, or other serious infections), who received high loading doses of 12 mg/kg twice daily (mean of 5 loading doses), followed by a maintenance dose of 12 mg/kg once daily, the incidence of confirmed nephrotoxicity was 11.0% (95% CI = [7.4%; 15.5%]) within the first 10 days. The probability of nephrotoxicity from the start of treatment up to 60 days after the last dose was 20.6% (95% CI = [16.0%; 25.8%]). In patients who received more than 5 high loading doses of 12 mg/kg twice daily, followed by a maintenance dose of 12 mg/kg once daily, the cumulative incidence of nephrotoxicity from the start of treatment up to 60 days after the last dose was 27% (95% CI = [20.7%; 35.3%]) (see section "Dosage and Administration").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions to the State Expert Center of the Ministry of Health of Ukraine.

Shelf life.

2 years.

Storage conditions.

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

Incompatibilities.

Teicoplanin and aminoglycosides are incompatible when mixed directly; therefore, mixing them prior to injection is not permitted.

If teicoplanin is used in combination with other antibiotics, each drug must be administered separately.

This medicinal product must not be mixed with any other medicinal products except those specified in the section "Dosage and Administration".

Packaging.

Lyophilisate for solution for injection 400 mg in vials No. 1, supplied with 3.2 ml of water for injections in ampoules No. 1, in a blister pack, in a carton.

Prescription status.

By prescription.

Manufacturer.

JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.