Targocid (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Aventis Pharma Ltd. (United Kingdom)

Manufactured By

Gruppo Lepetit, S.R.L. (Italy)

ATC Code

J01XA02 (Teicoplanin)

Active Substance

Teicoplanin (Rec.INN registered by WHO)

Dosage Forms

	Targocid	Lyophilisate for preparation of solution for intravenous and intramuscular administration 200 mg: vial.
		Lyophilisate for preparation of solution for intravenous and intramuscular administration 400 mg: vial.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous and intramuscular administration in the form of a porous, homogeneous mass of light yellow color.

Excipients: sodium chloride 24 mg, sodium hydroxide to pH 7.5.

Solvent composition: water for injections 3 ml.

200 mg – vials of colorless glass (1) in a kit with solvent 3 ml vial 1 pc. – cardboard packs.

Lyophilisate for preparation of solution for intravenous and intramuscular administration in the form of a porous, homogeneous mass of light yellow color.

Excipients: sodium chloride 24.8 mg, sodium hydroxide to pH 7.5.

Solvent composition: water for injections 3 ml.

400 mg – vials of colorless glass (1) in a kit with solvent 3 ml vial 1 pc. – cardboard packs.

Clinical-Pharmacological Group

Antibiotic of the glycopeptide group

Pharmacotherapeutic Group

Antibiotic-glycopeptide

Pharmacological Action

Teicoplanin is an antibiotic of glycopeptide structure, demonstrating in vitro bactericidal activity against anaerobic and aerobic gram-positive microorganisms.

Teicoplanin inhibits the growth of microorganisms sensitive to it by inhibiting the biosynthesis of the microbial cell wall at sites different from those in the microbial cell wall affected by beta-lactam antibiotics.

Teicoplanin is active against Staphylococcus spp. (including strains resistant to methicillin and other beta-lactam antibiotics), Streptococcus spp., Enterococcus spp., Listeria monocytogenes, Micrococcus spp, Corynebacterium spp. of group J/K and gram-positive anaerobes, including Clostridium difficile, Peptococcus spp.

In vitro, synergism regarding the bactericidal effect on Staphylococcus aureus was demonstrated when teicoplanin was combined with aminoglycosides or imipenem. In vitro, additive and synergistic effects against Staphylococcus aureus were shown by the combination of teicoplanin with rifampicin. Synergism of teicoplanin with ciprofloxacin was observed against Staphylococcus epidermidis.

In vitro, one-step resistance to teicoplanin was not obtained, and only after multiple in vitro passages was multi-step resistance developed. Increases in the minimum inhibitory concentrations (MIC) of teicoplanin for some strains of hemolytic staphylococci have been reported.

As a rule, teicoplanin does not exhibit “cross” resistance with antibiotics of other groups, however, slight “cross” resistance to teicoplanin and another glycopeptide – vancomycin – has been observed in Enterococcus spp.

When determining the sensitivity of microorganisms to teicoplanin, discs (sensi-discs) containing 30 micrograms of teicoplanin are used. Strains with a growth inhibition zone diameter of 14 mm or more are considered sensitive, while those with a growth inhibition zone diameter of 10 mm or less are considered resistant.

Pharmacokinetics

The bioavailability after a single intramuscular injection of teicoplanin at a dose of 3-6 mg/kg of body weight is about 90%.

When taken orally, Teicoplanin is not absorbed and, in the absence of lesions of the digestive tract organs, does not enter the systemic circulation; 40% of the orally administered dose is present in feces in a microbiologically active form.

A study of the plasma concentration profile of teicoplanin in humans after its intravenous administration at a dose of 3-6 mg/kg showed a biphasic distribution of teicoplanin (with a rapid distribution phase with a plasma half-life of about 0.3 hours, followed by a slower distribution phase with a plasma half-life of about 3 hours), after which a slow elimination of teicoplanin is observed with a terminal half-life of approximately 150 hours.

Such a long half-life allows the drug to be administered once a day.

When the drug Targocid is administered intravenously at a dose of 6 mg/kg body weight as a 30-minute infusion three times at 12-hour intervals and then once a day (every 24 hours), the minimum plasma concentration of teicoplanin, calculated to be 10 mg/l, could be achieved by day 4.

The calculated maximum and minimum plasma concentrations at steady state, 64 mg/l and 16 mg/l, could be achieved by day 28 of treatment. Teicoplanin is rapidly distributed into the skin (subcutaneous adipose tissue) and blister fluid, myocardium, lung tissue and pleural fluid, bone tissue and synovial fluid, but penetrates poorly into the cerebrospinal fluid.

The weak affinity binding to plasma proteins is 90-95%. The volume of distribution at steady state after intravenous administration of teicoplanin at a dose of 3-6 mg is 0.94 – 1.41 l/kg. The volume of distribution in children does not differ significantly from that in adults.

After parenteral administration of teicoplanin, its metabolism is minimal (about 3%). 97% of the administered teicoplanin is excreted from the body unchanged. Approximately 80% of the administered dose is excreted by the kidneys.

Renal clearance after intravenous administration of 3-6 mg/kg is in the range of 10.4 – 12.1 mg/h/kg. Total plasma clearance is in the range of 11.9-14.7 ml/h/kg.

Indications

Severe infections caused by gram-positive bacteria sensitive to the drug, including those resistant to other antibiotics (such as penicillins, including methicillin, and cephalosporins), including these infections in patients with allergies to penicillins and cephalosporins

• Endocarditis;
• Septicemia;
• Bone and joint infections;
• Lower respiratory tract infections;
• Skin and soft tissue infections;
• Urinary tract infections;
• Peritonitis occurring during continuous ambulatory peritoneal dialysis (CAPD).

Prophylaxis of infectious complications in dental and orthopedic surgeries when there is a risk of developing infections caused by gram-positive microorganisms.

For oral administration of the solution: pseudomembranous colitis caused by Clostridium difficile (associated with the use of antibacterial drugs).

ICD codes

Dosage Regimen

Teicoplanin is administered parenterally (intravenously or intramuscularly). Intravenous (IV) administration can be carried out either by IV injection over 3-5 minutes, or by IV infusion over 30 minutes. In newborns, the drug should be administered only as an intravenous infusion.

Dosage regimen in adults and adolescents 16-18 years of age with normal renal function

Treatment of infections caused by gram-positive bacteria sensitive to the drug (endocarditis; septicemia; bone and joint infections; lower respiratory tract infections; skin and soft tissue infections; urinary tract infections)

For moderate to severe skin and soft tissue infections, urinary tract infections, lower respiratory tract infections, the initial dose of teicoplanin is 400 mg as a single IV dose on the first day, followed by a maintenance dose of 200 mg once a day IV or intramuscularly (IM).

For the treatment of severe bone and joint infections, septicemia, endocarditis, the initial dose is 400 mg IV every 12 hours for the first three doses, followed by a maintenance dose of 400 mg IV or IM once a day. In severe infections, the minimum serum concentration should not be below 10 mg/l.

Maximum concentrations, determined 1 hour after IV administration of 400 mg, are usually in the range of 20 to 50 mg/l.

In some cases (in burn patients or in patients with endocarditis), the maintenance dose may be up to 12 mg/kg of body weight per day. The standard doses of 200 mg and 400 mg correspond to doses of 3 mg/kg and 6 mg/kg of body weight. In patients weighing more than 85 kg, it is recommended to adjust the drug dose based on body weight, following the same therapeutic regimen: moderate to severe infections 3 mg/kg, severe infections 6 mg/kg.

Patients with peritonitis that developed as a complication of continuous ambulatory peritoneal dialysis

After a single loading dose of 400 mg intravenously, 20 mg/l is administered into each reservoir with peritoneal dialysis solution in the first week, 20 mg/l is administered into every second reservoir with peritoneal dialysis solution in the second week, and 20 mg/l is administered into the reservoir with peritoneal dialysis solution for overnight dialysis in the third week.

Antimicrobial prophylaxis in orthopedic surgeries, in dental surgeries (e.g., prophylaxis of endocarditisin patients with artificial heart valves): 400 mg of teicoplanin (or 6 mg/kg if the patient’s weight is more than 85 kg) as a single IV injection during induction anesthesia.

Pseudomembranous colitis caused by C.difficile 200 mg of teicoplanin orally twice a day.

Dosage regimen in children

Children over 2 months to 16 years old for most gram-positive infections, the recommended initial dose is 10 mg/kg body weight IV at 12-hour intervals for the first three doses, switching to a maintenance dose of 6 mg/kg body weight, administered IM or IV once a day.

For severe infections and neutropenia, the recommended initial dose is 10 mg/kg body weight IV at 12-hour intervals for the first three doses, switching to a maintenance dose of 10 mg/kg body weight, administered IV once a day.

Children under 2 months, including newborns the recommended initial dose is 16 mg/kg body weight IV on the first day, switching to a maintenance dose of 8 mg/kg body weight IV once a day. IV administration should be carried out by IV infusion over 30 minutes.

Dosage regimen in elderly patients

No adjustment of the dosage regimen is required in case of normal renal function.

Dosage regimen in adults with renal impairment

No adjustment of the dosage regimen is required until day 4 of treatment with teicoplanin. Starting from the fourth day, the administered dose should maintain the teicoplanin serum concentration at a level of 10 mg/l.

In moderate renal impairment (creatinine clearance 40-60 ml/min): the maintenance dose should be reduced by half, either by administering the previous dose once every two days, or by administering half the dose once a day. In severe renal impairment (creatinine clearance less than 40 ml/min) and in patients on hemodialysis: the maintenance dose should be reduced to one-third, either by administering the previous dose every third day, or by administering 1/3 of the previous dose once a day. Teicoplanin is not removed by hemodialysis.

Duration of treatment

A therapeutic response in most patients with infections caused by antibiotic-sensitive pathogens is observed within 48-72 hours after starting the drug. The total duration of treatment is determined individually and depends on the type and severity of the infection and the clinical response of the particular patient. For endocarditis and osteomyelitis, treatment for 3 weeks or more is recommended; however, Targocid should not be administered for more than 4 months.

Preparation of the solution

The entire contents of the ampoule with sterile water should be slowly introduced into the vial of the drug Targocid, gently rocking the vial until the powder is completely dissolved, avoiding foam formation. It is very important that the entire drug is dissolved, even the part that is near the stopper. Shaking the solution produces foam, which makes it difficult to withdraw the required volume of solution. However, if Teicoplanin is completely dissolved, the foam does not change the concentration of the remaining solution of 200 mg/3 ml in the Targocid 200 mg vial and 400 mg/3 ml in the Targocid 400 mg vial. If the solution turns out to be foamy, then it should be left to stand for about 15 minutes to reduce the amount of foam.

The teicoplanin solution should be slowly withdrawn from the vial, trying to withdraw it completely, by piercing the needle into the center of the rubber stopper.

The resulting solution will contain 200 mg of teicoplanin in 3 ml in the Targocid 200 mg vial and 400 mg in 3 ml in the Targocid 400 mg vial. It is important that the preparation of the solution is carried out correctly and the solution is carefully withdrawn from the vial; improper preparation of the solution may lead to the administration of a lower dose than required.

The prepared solution is isotonic and has a pH of 7.2-7.8. The prepared solution can be administered directly by injection or further diluted with 0.9% sodium chloride solution, Ringer’s solution, Hartmann’s solution, 5% dextrose solution, peritoneal dialysis solution containing 1.36% or 3.86% dextrose.

Adverse Reactions

Usually, Targocid is well tolerated. Adverse reactions rarely require discontinuation of treatment and are mostly moderate and transient; severe adverse reactions are rare. The adverse reactions listed below have been reported.

Local reactions

Erythema, pain at the injection site, thrombophlebitis, abscess at the IM injection site.

Allergic reactions

Rash, itching, fever, chills, bronchospasm, anaphylactic reactions, anaphylactic shock, urticaria, angioedema, rare reports of exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

In addition, infusion-related reactions such as erythema or “flushing” of the upper body have been reported, with no history of prior treatment with teicoplanin, and they did not recur upon subsequent administration of the drug at a reduced rate or concentration. These cases were not specific to any particular concentration of the infusion solution or infusion rate.

Gastrointestinal side effects

Nausea, vomiting, diarrhea.

Blood side effects

Agranulocytosis, leukopenia, neutropenia, thrombocytopenia, eosinophilia.

Liver and biliary tract side effects

Increased activity of “liver” transaminases and/or alkaline phosphatase in the blood serum.

Kidney side effects

Increased serum creatinine concentrations, renal failure.

Central nervous system side effects

Dizziness; headache, seizures with intravenous administration.

Hearing and labyrinth disorders

Hearing loss, tinnitus and vestibular disorders.

Other

Superinfection (overgrowth of microorganisms not sensitive to the drug).

Contraindications

• hypersensitivity to teicoplanin and other components of the drug.

With caution

• In patients with hypersensitivity to vancomycin (risk of “cross” hypersensitivity);
• In patients with renal failure (dosing regimen adjustment is required, see section “Dosage and Administration”, and monitoring of hearing status, hematological parameters, renal and liver function indicators);
• In patients undergoing long-term treatment (monitoring of hearing status, hematological parameters, renal and liver function indicators is required);
• During concomitant treatment with other ototoxic and nephrotoxic drugs: aminoglycosides, colistin, amphotericin B, cyclosporine, cisplatin, furosemide and ethacrynic acid.

Use in Pregnancy and Lactation

Pregnancy

Targocid should not be used during pregnancy or if it is suspected, except in cases where the potential benefit to the mother outweighs the possible harm to the fetus. Animal studies have not revealed teratogenic effects of teicoplanin.

Breastfeeding period

Information on the excretion of teicoplanin into breast milk is not available. If it is necessary to use the drug during lactation, the issue of temporary discontinuation of breastfeeding should be decided.

Use in Hepatic Impairment

Hepatic toxicity of teicoplanin has been reported. Therefore, liver function should be monitored, especially in patients receiving long-term treatment with teicoplanin.

Use in Renal Impairment

Until day 4 of treatment with teicoplanin, no adjustment of the dosing regimen is required. Starting from the fourth day, the administered dose should maintain the teicoplanin serum concentration at a level of 10 mg/l.

In moderate renal failure (creatinine clearance 40-60 ml/min): the maintenance dose should be reduced by half, either by administering the same dose once every two days, or by administering a half dose once a day. In severe renal failure (creatinine clearance less than 40 ml/min) and in patients on hemodialysis: the maintenance dose should be reduced to one third, either by administering the same dose every third day, or by administering 1/3 of the same dose once a day. Teicoplanin is not removed by hemodialysis.

Pediatric Use

Children over 2 months to 16 years: for most Gram-positive infections, the recommended initial dose is 10 mg/kg body weight IV at 12-hour intervals for the first three doses, followed by a maintenance dose of 6 mg/kg body weight, administered IM or IV once a day.

In severe infections and neutropenia, the recommended initial dose is 10 mg/kg body weight IV at 12-hour intervals for the first three doses, followed by a maintenance dose of 10 mg/kg body weight, administered IV once a day.

Children under 2 months, including newborns: the recommended initial dose is 16 mg/kg body weight IV on the first day, followed by a maintenance dose of 8 mg/kg body weight IV once a day. IV administration should be performed by IV infusion over 30 minutes.

Geriatric Use

In elderly patients with normal renal function, no adjustment of the dosing regimen is required.

Special Precautions

Targocid should be administered with caution in case of known hypersensitivity to vancomycin, as “cross” allergy may develop.

Toxic effects on the hearing organ, hematological, hepatic and renal toxicity of teicoplanin have been reported. Therefore, hearing status, hematological parameters, liver and kidney function should be monitored, especially in patients with renal failure, in patients receiving long-term treatment with teicoplanin, and in patients simultaneously receiving treatment with other ototoxic and nephrotoxic drugs (aminoglycosides, colistin, amphotericin B, cyclosporine, cisplatin, furosemide and ethacrynic acid).

Superinfection: as with other antibiotics, the use of teicoplanin, especially if prolonged, may lead to overgrowth of microorganisms (bacteria or fungi) non-susceptible to the drug; in case of superinfection development during treatment with the drug, appropriate measures should be taken.

Effect on ability to drive vehicles or engage in other potentially hazardous activities

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as the drug may cause dizziness and other side effects that may affect these abilities.

Overdose

Human overdose experience

Cases of administration of excessively high doses by mistake to pediatric patients have been reported. In one report, agitation was observed in a 29-day-old newborn who received 400 mg of teicoplanin IV (95 mg/kg body weight). In all other cases, there were no symptoms or laboratory abnormalities associated with teicoplanin overdose. The age of patients with overdose ranged from 1 month to 8 years. Doses from 35.7 mg/kg to 104 mg/kg were administered by mistake.

Overdose treatment

Teicoplanin is not removed by hemodialysis. Overdose treatment should be symptomatic.

Drug Interactions

With nephrotoxic and ototoxic drugs (streptomycin, neomycin, kanamycin, gentamicin, amikacin, tobramycin, cephaloridine, colistin, amphotericin B, cyclosporine, cisplatin, furosemide, ethacrynic acid)

When combined with the drugs listed above, the risk of developing side effects may increase with simultaneous or sequential use of teicoplanin with these drugs.

Teicoplanin is pharmaceutically incompatible with aminoglycosides.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children!

Shelf Life

The shelf life of the drug is 3 years, the solvent is 5 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.