Active ingredients: Teicoplanin
TARGOSID 200 mg powder and solvent for solution for injection / infusion or oral solution
TARGOSID 400 mg powder and solvent for solution for injection / infusion or oral solution
Indications Why is Targosid used? What is it for?
Targosid is an antibiotic that contains the active substance "teicoplanin". It works by killing the bacteria responsible for infections in the body.
Targosid is used in adults and children (including infants) to treat bacterial infections of:
- skin and underlying tissues (sometimes called "soft tissues")
- bones and joints
- lungs
- urinary tract
- heart (endocarditis)
- abdominal area (peritonitis)
- blood, when caused by any of the conditions listed above.
Targosid can be used to treat certain infections caused by Clostridium difficile bacteria in the intestine. For this, the solution is taken by mouth.
Contraindications When Targosid should not be used
Do not use Targosid if:
- you are allergic to teicoplanin or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Targosid
Talk to your doctor, pharmacist or nurse before you are given Targocid if:
- you are allergic to an antibiotic called "vancomycin"
- have redness of the upper body (red neck syndrome)
- have a decrease in the number of platelets (thrombocytopenia)
- have kidney problems
- you are taking other medicines that may cause hearing and / or kidney problems. You may need to have regular tests to check if your blood, kidneys and liver are working properly (see "Other medicines and Targosid")
If any of the above apply to you (or if you are not sure), talk to your doctor, pharmacist or nurse before being given Targosid.
Exams
You may need to have tests to check your kidneys and / or hearing during treatment. This is more likely if:
- the treatment will last a long time
- have kidney problems
- you are taking or might take other medicines that can affect the nervous system, kidneys or hearing.
In patients who are given Targosid for a long time, bacteria that are not affected by the antibiotic may grow more than normal - the doctor will check for this.
Interactions Which drugs or foods can modify the effect of Targosid
Tell your doctor, pharmacist or nurse if you are taking or have recently taken or might take any other medicines. This is because Targosid can affect the way some other medicines work. Also some medicines can affect the way Targosid works.
In particular, tell your doctor, pharmacist or nurse if you are taking any of the following medicines:
- aminoglycosides, which must not be mixed with Targosid in the same injection. They can also cause hearing problems and / or kidney problems.
- amphotericin B - a medicine to treat fungal infections which can cause hearing problems and / or kidney problems
- cyclosporine - a medicine that affects the immune system which can cause hearing problems and / or kidney problems
- cisplatin - a medicine to treat malignant tumors which can cause hearing problems and / or kidney problems
- diuretic tablets (such as furosemide) which can cause hearing problems and / or kidney problems
If any of the above apply to you (or if you are not sure), talk to your doctor or pharmacist or nurse before you are given Targosid.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before being given this medicine.
They will decide whether you will be given this medicine while you are pregnant. There may be a potential risk of inner ear and kidney problems.
Tell your doctor if you are breast-feeding before you are given this medicine. You will decide whether or not you can continue breastfeeding while Targosid is being given to you. Reproduction studies in animals have shown no evidence of fertility problems.
Driving and using machines
You may have a headache or dizziness while being treated with Targosid. If this happens, do not drive vehicles or use machines.
Targosid contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially sodium-free.
Dose, Method and Time of Administration How to use Targosid: Posology
The recommended dose is
Adults and children (12 years of age and older) without kidney problems
Infections of the skin and subcutaneous tissue, lungs and urinary tract
- Starting dose (for the first 3 doses): 400 mg (corresponding to 6 mg for every kg of body weight) given every 12 hours, by injection into a vein or muscle
- Maintenance dose: 400 mg (corresponding to 6 mg for each kg of body weight) administered once daily by injection into a vein or muscle
Infections of the bones and joints, and of the heart
- Starting dose (for the first 3-5 doses): 800 mg (corresponding to 12 mg for every kg of body weight) given every 12 hours, by injection into a vein or muscle
- Maintenance dose: 800 mg (corresponding to 12 mg for each kg of body weight) administered once daily by injection into a vein or muscle
To treat infections caused by Clostridium difficile bacteria
The recommended dose is 100-200 mg by mouth twice a day for 7 to 14 days
Adults and elderly patients with kidney problems
If you have kidney problems, your dose will usually be decreased after the fourth day of treatment:
- For people with mild and moderate kidney problems the maintenance dose will be given every 2 days, or half the maintenance dose will be given each day.
- For people with severe kidney problems or on hemodialysis: the maintenance dose will be given every 3 days, or one third of the maintenance dose will be given each day.
Peritonitis in patients on peritoneal dialysis
The starting dose is 6 mg for every kg of body weight, given as a single injection into a vein, followed by:
- week one: 20 mg / L in each dialysis bag
- week two: 20 mg / L in alternate bags
- week three: 20 mg / L in the overnight bag.
Infants (from birth to 2 months)
- Starting dose (on the first day): 16 mg for each kg of body weight, given as an infusion by drops into a vein
- Maintenance dose: 8 mg for each kg of body weight, given as an infusion into a vein once a day.
Children (2 months to 12 years)
- Starting dose (for the first three doses): 10 mg for every kg of body weight, given every 12 hours by injection into a vein
- Maintenance dose: 6 - 10 mg for each kg of body weight, given once daily by injection into a vein
How Targosid is given
This medicine is usually given by a doctor or nurse
- it is given by injection into a vein (intravenous) or into a muscle (intramuscular)
- it can also be given by infusion with drops into a vein.
Infants from birth to 2 months of age should only be given as an infusion.
To treat some infections, the solution can be taken by mouth (oral use).
Overdose What to do if you have taken too much Targosid
If you receive more Targosid than you should
It is unlikely that your doctor or nurse will give you too much medicine. However, if you think you have been given too much Targosid or if you feel agitated, tell your doctor or nurse immediately.
If you forget to receive Targosid
Your doctor or nurse will have instructions on when to give Targosid. It is unlikely that they will not give you the medicine as prescribed. However, if you are concerned, tell your doctor or nurse.
If you stop taking Targosid
Do not stop taking this medicine without first talking to your doctor, pharmacist or nurse.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Targosid
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
Stop the treatment and tell your doctor or nurse straight away if you notice any of the following serious side effects - you may need urgent medical treatment:
Uncommon (may affect up to 1 in 100 patients)
- sudden allergic reaction which may be life-threatening - the signs may include: difficulty in breathing or wheezing, sweating, rash, itching, fever, chills
Rare (may affect up to 1 in 1,000 patients)
- flushing in the upper body Not known (frequency cannot be estimated from the available data)
- lesions of the skin, mouth, eyes or genitals - these may be signs of a condition called "toxic epidermal necrolysis" or "Stevens-Johnson syndrome"
Tell your doctor or nurse immediately if you notice any of the side effects listed above.
Tell your doctor or nurse straight away if you notice any of the following serious side effects - you may need urgent medical treatment:
Uncommon (may affect up to 1 in 100 patients)
- swelling and coagulation in a vein
- difficulty in breathing or wheezing (bronchospasm)
- increased number of infections - these could be signs of a decrease in the number of blood cells
Not known (frequency cannot be estimated from the available data)
- lack of white blood cells - the signs may include: fever, severe chills, sore throat or mouth ulceration (agranulocytosis)
- kidney problems or changes in the way your kidneys work - shown in tests
- Seizures
Tell your doctor or nurse immediately if you notice any of the side effects listed above.
Other side effects
Tell your doctor, pharmacist or nurse if you notice any of the following:
Common (may affect up to 1 in 10 patients)
- Rash, erythema, itching
- Ache
- Fever
Uncommon (may affect up to 1 in 100 patients)
- decrease in the number of platelets
- increased levels of liver enzymes in the blood
- increased blood creatinine levels (to check the kidneys)
- hearing loss, ringing in your ears or a feeling that you, or things around you are moving
- feeling or being sick (vomiting), diarrhea
- feeling dizzy or headache
Rare (may affect up to 1 in 1,000 patients)
- infection (abscess)
Not known (frequency cannot be estimated from the available data)
- problems at the injection site - such as redness of the skin, pain or swelling
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP / EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Information on storage and usage time of Targosid, after it has been reconstituted and ready for use, is described in the "Practical Information for Healthcare Professionals on Preparation and Handling of Targosid"
What Targosid contains
- The active ingredient is teicoplanin. Each vial contains 200 mg or 400 mg of teicoplanin.
- The other ingredients are sodium chloride and sodium hydroxide in the powder, and water for injections in the solvent.
What Targosid looks like and contents of the pack
Targosid is a powder and solvent for solution for injection / infusion or oral solution. The powder is a spongy homogeneous mass of ivory color. The solvent is a clear, colorless liquid.
The powder is packaged:
- in colorless type I glass vials with usable volume 10 mL for 200 mg closed by a bromobutyl rubber stopper, a yellow aluminum cap and a plastic tear-off tab.
- in colorless type I glass vials with usable volume 22 mL for 400 mg closed by a bromobutyl rubber stopper, a green aluminum cap and a plastic tear-off tab.
The solvent is packaged in a colorless type I glass vial.
Packaging:
- 1 vial of powder with 1 vial of solvent
Not all pack sizes may be marketed
The following information is intended for medical or healthcare professionals only:
Practical information for healthcare professionals on the preparation and handling of Targosid.
This medicine is for single use only.
Method of administration
The reconstituted solution can be injected directly or alternatively further diluted.
The injection can be given as a 3-5 minute bolus or as a 30 minute infusion.
Infants from birth to 2 months of age should only be given as an infusion.
The reconstituted solution can also be given by mouth (oral use).
Preparation of the reconstituted solution
- Slowly inject the entire contents of the solvent vial into the vial of powder
- gently swirl the vial between your hands until the powder has completely dissolved. If the solution becomes foamy, let it sit for about 15 minutes.
The reconstituted solutions contain 200 mg of teicoplanin in 3.0 mL and 400 mg in 3.0 mL.
Only clear and yellowish solutions should be used.
The final solution is isotonic with plasma and has a pH of 7.2-7.8.
Preparation of the diluted solution before the infusion
Targosid can be administered in the following infusion solutions:
- sodium chloride solution 9 mg / mL (0.9%)
- Ringer's solution
- lactated Ringer's solution
- 5% dextrose solution
- 10% dextrose solution
- solution containing 0.18% sodium chloride and 4% glucose
- solution containing 0.45% sodium chloride and 5% glucose
- peritoneal dialysis solution containing 1.36% or 3.86% glucose solution.
Shelf life of the reconstituted solution
The chemical-physical stability in use of the reconstituted solution prepared according to the recommendations has been demonstrated for 24 hours at a temperature between 2 and 8 ° C.
From a microbiological point of view, the product should be used immediately. If this does not happen, the user is responsible for the storage period and conditions of the product which should normally not exceed 24 hours at a temperature between 2 and 8 ° C, unless reconstitution is carried out under controlled and validated conditions. of asepsis.
Shelf life of the diluted medicinal product
The chemical-physical stability in use of the reconstituted solution prepared according to the recommendations has been demonstrated for 24 hours at a temperature between 2 and 8 ° C. From a microbiological point of view, the product should be used immediately. If this is not the case, the user is responsible for the storage period and conditions of the product and should normally not exceed 24 hours at a temperature between 2 and 8 ° C, unless the reconstitution / dilution is carried out under controlled conditions. and validated by asepsis.
Disposal
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TARGOSID POWDER AND SOLVENT FOR INJECTABLE SOLUTION / INFUSION OR ORAL SOLUTION
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 200mg of teicoplanin equivalent to not less than 200,000 IU.
After reconstitution, the solution will contain 200 mg of teicoplanin in 3.0 mL.
Each vial contains 400mg of teicoplanin equivalent to not less than 400,000 IU.
After reconstitution, the solution will contain 400 mg of teicoplanin in 3.0 mL.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder and solvent for solution for injection / infusion or oral solution.
Powder for solution for injection / infusion or oral solution: ivory-colored spongy homogeneous mass.
Solvent: clear, colorless liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Targosid is indicated in adults and children from birth for the parenteral treatment of the following infections (see sections 4.2, 4.4 and 5.1):
• complicated skin and soft tissue infections,
• bone and joint infections,
• hospital-acquired pneumonia,
• community-acquired pneumonia,
• complicated urinary tract infections,
• infective endocarditis,
• peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD),
• bacteremia occurring in association with any of the indications listed above.
Targosid is also indicated as an alternative oral therapy in the treatment of diarrhea and colitis associated with infection Clostridium difficile.
Where appropriate, teicoplanin can be administered in combination with other antibacterial drugs.
Official guidelines on the appropriate use of antibacterial drugs should be considered.
04.2 Posology and method of administration
Dosage
The dose and duration of treatment should be individually adjusted according to the type and severity of the current infection, the patient's clinical response and patient-related parameters such as age and renal function.
Measurement of serum concentrations
To optimize treatment, steady-state serum teicoplanin concentrations should be monitored after completion of the loading regimen to ensure that the required minimum concentrations have been reached:
• For most Gram-positive infections, teicoplanin trough levels of at least 10 mg / L measured by High Liquid Performance Chromatography (HPLC), or 15 mg / L measured by Fluorescence Polarization Immunoassay (FPIA).
• For endocarditis and other severe infections, teicoplanin trough levels of 15-30 mg / L when measured by HPLC, or 30-40 mg / L when measured by FPIA method.
During maintenance therapy, monitoring of the required trough concentrations can be done at least once a week to ensure that these concentrations are stable.
Adults and the elderly with normal renal function
1 Measured with FPIA
Duration of treatment
The duration of treatment should be based on the clinical response. A minimum of 21 days is usually considered appropriate for infective endocarditis. Treatment should not exceed 4 months.
Combination treatment
Teicoplanin has a limited spectrum of antibacterial activity (Gram positive). It is not suitable for use as a single agent for the treatment of certain types of infections, unless the pathogen is already known and of known susceptibility or there is a high suspicion that the most likely pathogen (s) is (not) susceptible to treatment with teicoplanin.
Diarrhea and colitis associated with Clostridium difficile infection
The recommended dose is 100-200 mg administered orally twice daily for 7 to 14 days.
Elderly patients
No dosage adjustment is required unless renal insufficiency is present (see below).
Adults and elderly patients with renal insufficiency
No dosage adjustment is required until the fourth day of treatment, from which the dosage must be adjusted to maintain trough serum concentrations of at least 10 mg / L.
After the fourth day of treatment:
• in mild and moderate renal insufficiency (creatinine clearance between 30 and 80 mL / min): the maintenance dose should be halved, by administering the dose every other day or by administering half the dose once a day.
• in severe renal insufficiency (creatinine clearance less than 30 mL / min) and in patients undergoing hemodialysis: the dose should be one third of the normal dose, given the dose every 3 days or one third of the dose once a day.
Teicoplanin is not removed by hemodialysis.
Continuous outpatient peritoneal dialysis (CAPD) patients
After a single intravenous loading dose of 6 mg / kg body weight, 20 mg / L is administered in all dialysis solution bags in the first week, 20 mg / L in alternate bags in the second week, and 20 mg / L thereafter. in the night bag during the third week.
Pediatric population
The recommended doses are the same in adults and children over 12 years of age.
Babies and children from birth to 2 months :
Loading dose
A single dose of 16 mg / kg body weight, administered by intravenous infusion on the first day
Maintenance dose
A single dose of 8 mg / kg body weight, administered by intravenous infusion once daily.
Children (2 months to 12 years) :
Loading dose
A single dose of 10 mg / kg body weight, administered intravenously every 12 hours, repeated 3 times
Maintenance dose
A single dose of 6-10 mg / kg body weight administered intravenously once daily
Method of administration
Teicoplanin must be administered intravenously or intramuscularly.
The intravenous injection can be given either as a 3-5 minute bolus or as a 30 minute infusion.
In infants only infusion should be used.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
04.3 Contraindications
Hypersensitivity to teicoplanin or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Hypersensitivity reactions
Serious hypersensitivity reactions have been reported with teicoplanin, which have been life-threatening and have sometimes been fatal (e.g. anaphylactic shock). If an allergic reaction to teicoplanin occurs, treatment should be stopped immediately and appropriate emergency measures taken.
Teicoplanin should be administered with caution in patients with known hypersensitivity to vancomycin, as cross-hypersensitivity reactions, including fatal anaphylactic shock, may occur.
However, a history of "red man syndrome" with vancomycin is not a contraindication to the use of teicoplanin.
Infusion related reactions
In rare cases (even at the first dose), "red man syndrome" (a symptom complex including pruritus, urticaria, erythema, angioneurotic edema, tachycardia, hypotension, dyspnoea) has been observed.
Stopping or slowing the infusion may stop these reactions. Infusion-related reactions may be limited if the daily dose is not administered as a bolus injection but as a 30 minute infusion.
Severe bullous reactions
Skin reactions such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with the use of teicoplanin which have exposed the patient to life-threatening or proved fatal. If symptoms or signs of SJS are present o TEN (e.g. progressive skin rash often with ulceration or mucosal lesions) treatment with teicoplanin should be stopped immediately.
Spectrum of antibacterial activity
Teicoplanin has a spectrum of antibacterial activity (Gram positive) limited. It is not suitable for use as a single agent for the treatment of certain types of infections, unless the pathogen is already known and of known susceptibility or there is a high suspicion that the most likely pathogen (s) is (not) susceptible to treatment with teicoplanin.
The rational use of teicoplanin must take into account the spectrum of antibacterial activity, the safety profile and the adequacy of the standard antibacterial therapy for the treatment of the individual patient. On this basis it is expected that in many cases teicoplanin will be used to treat severe infections in patients for whom standard antibacterial therapy is considered inappropriate.
Loading dose regimen
As safety data are limited, patients should be closely monitored for adverse reactions when teicoplanin doses of 12 mg / kg body weight are administered twice daily. With this regimen, in addition to the recommended periodic haematological monitoring, blood creatinine values should be monitored.
Teicoplanin must not be administered intraventricularly.
Thrombocytopenia
Thrombocytopenia has been reported with teicoplanin. Periodic haematological evaluations, including a complete blood count, are recommended during treatment.
Nephrotoxicity
Renal failure has been reported in patients treated with teicoplanin (see section 4.8). Patients with renal insufficiency, and / or receiving teicoplanin together or sequentially with other medicinal products with known potential nephrotoxicity (aminoglycosides, colistin, amphotericin B, cyclosporine and cisplatin) should be closely monitored, and hearing tests included.
Since teicoplanin is mainly excreted via the kidney, the dose of teicoplanin should be adjusted in patients with renal insufficiency (see section 4.2).
Ototoxicity
As with other glycopeptides, ototoxicity (deafness and tinnitus) has been reported in patients treated with teicoplanin (see section 4.8). Patients who develop signs and symptoms of impaired hearing or inner ear disorders during treatment with teicoplanin should be carefully monitored and evaluated, especially in the case of prolonged treatment and in patients with renal insufficiency. Patients receiving teicoplanin together or sequentially with other medicinal products with known potential neurotoxicity / ototoxicity (aminoglycosides, cyclosporine, cisplatin, furosemide and ethacrynic acid) should be closely monitored, and, if hearing deteriorates, the benefit of teicoplanin should be evaluated.
Particular caution should be exercised when teicoplanin is administered to patients requiring concomitant treatment with ototoxic and / or nephrotoxic drugs for which regular haematological tests and evaluation of hepatic and renal function are recommended.
Superinfection
As with other antibiotics, the use of teicoplanin could cause the growth of non-sensitive organisms, particularly with prolonged treatment. Should superinfection occur during therapy, appropriate measures should be taken.
04.5 Interactions with other medicinal products and other forms of interaction
No specific interaction studies have been conducted.
Solutions of teicoplanin and aminoglycosides are incompatible and should not be mixed for injection, however they are compatible with dialysis fluids and can be used freely in the treatment of CAPD-related peritonitis.
Teicoplanin should be used with caution in concomitant or subsequent therapy with drugs with known nephrotoxic or ototoxic potential. These include aminoglycosides, colistin, amphotericin B, cyclosporine, cisplatin, furosemide and ethacrynic acid (see section 4.4). However, there is no evidence of synergistic toxicity in combination with teicoplanin.
In clinical studies, teicoplanin has been administered to many patients already receiving various medicinal products including other antibiotics, antihypertensives, anesthetic, cardiovascular and antidiabetic drugs without evidence of adverse interactions.
Pediatric population
Interaction studies have only been conducted in adults.
04.6 Pregnancy and lactation
Pregnancy
There are limited data on the use of teicoplanin in pregnant women. Animal studies have shown reproductive toxicity at high doses (see section 5.3): in rats there was an increased incidence of stillbirth and neonatal mortality. The potential risk to humans is unknown. Therefore, teicoplanin should not be used during pregnancy unless clearly necessary. A potential risk of kidney and inner ear damage to the fetus cannot be excluded (see section 4.4).
Feeding time
It is not known whether teicoplanin is excreted in human breast milk. There is no information on the excretion of teicoplanin in milk in animals. The decision whether to continue / discontinue breastfeeding or to continue / discontinue teicoplanin therapy must be made taking into account the benefit of breastfeeding for the child and the benefit of teicoplanin therapy for the mother.
Fertility
Reproduction studies in animals have shown no evidence of decreased fertility.
04.7 Effects on ability to drive and use machines
Targosid slightly affects the ability to drive and use machines.
Teicoplanin can cause dizziness and headache. The ability to drive or use machines may therefore be impaired. Patients who have experienced such side effects should not drive or operate machinery.
04.8 Undesirable effects
Table of adverse reactions
The table below lists all adverse reactions that occurred with an incidence greater than placebo and in more than 1 patient, according to the following convention:
very common (≥ 1/10), common (≥ 1/100,
Within the different frequency groups, undesirable effects are reported in order of decreasing severity.
Adverse reactions should be monitored when teicoplanin doses of 12 mg / kg body weight are administered twice daily (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Symptoms
There have been reports of overdoses mistakenly administered to pediatric patients. In one case, agitation was reported in a 29-day-old infant who received 400 mg intravenously (95 mg / kg).
Treatment
In the event of an overdose of teicoplanin, treatment should be symptomatic.
Teicoplanin is not removed from the circulation by hemodialysis and only slowly by peritoneal dialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Glycopeptide antibacterials. A.T.C Code: J01XA02.
Mechanism of action
Teicoplanin inhibits the growth of sensitive microorganisms by interfering with cell wall biosynthesis at a site other than the target site of beta-lactams.
The synthesis of peptidoglycans is blocked by specific binding with the D-alanyl-D-alanine residues.
Resistance mechanism
Resistance to teicoplanin can be based on the following mechanisms:
• modified target structure: this form of resistance occurred in particular with the "Enterococcus faecium. The modification is based on the substitution of the terminal group D-alanine-D-alanine of the amino acid chain in a precursor of murein with D-ala-D-lactate, with consequent reduction of the affinity for vancomycin. The enzymes responsible are D-lactate dehydrogenase or newly synthesized ligases.
• The reduced sensitivity or resistance of staphylococci to teicoplanin is based on an overproduction of precursors of the murein to which teicoplanin binds.
Cross-resistance between teicoplanin and the glycoprotein vancomycin may occur. Several vancomycin-resistant enterococci are susceptible to teicoplanin (Van-B phenotype).
Susceptibility - breakpoint values
The following table shows the Minimum Inhibitory Concentration (MIC) breakpoint values that divide susceptible from resistant organisms according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) version 3.1, 11 February 2013:
to The MICs of the glycopeptides are method-dependent and must be determined by micro-dilution of the broth (reference ISO 20776). S. aureus with vancomycin MICs of 2 mg / L it is at the extreme of the wild-type MIC distribution and there may be an impaired clinical response. The resistance breakpoint for S. aureus was reduced to 2 mg / L to avoid reporting of intermediate GISA isolates as serious infections with GISA isolates are not treatable with higher doses of vancomycin or teicoplanin.
b Isolates with MIC values above the susceptibility breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. As long as there is no evidence of clinical response for confirmed isolates with MICs above current breakpoints, such isolates should be reported resistant.
c EI indicates that there is insufficient evidence that the target species is a good target for drug therapy.
d A MIC may be reported with a comment but not accompanied by an S, I or R categorization
Pharmacokinetic / pharmacodynamic relationship
The antimicrobial activity of teicoplanin essentially depends on the time the substance levels are above the MIC of the pathogen.
Susceptibility
The prevalence of acquired resistances can vary geographically and as a function of time for selected species, so local information on resistances is desirable, particularly when treating severe infections.
If necessary, an expert should be consulted when the local prevalence of resistance phenomena, at least in some types of infections, is such that the usefulness of teicoplanin is questioned.
Commonly sensitive species
Aerobic Gram-positive bacteria
Corynebacterium jeikeima
Enterococcus faecalis
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilisa
(Group C and G streptococci)
Streptococcus pneumoniae
Streptococcus pyogenes
Viridans group streptococci a b
Gram-positive anaerobic bacteria
Clostridium difficile
Peptostreptococcus sppa.
Species for which acquired stamina can be a problem
Aerobic Gram-positive bacteria
Enterococcus faecium
Staphylococcus epidermidis
Staphylococcus haemolyticus
Staphylococcus hominis
Inherently resistant strains
All Gram-negative bacteria
Other bacteria
Chlamydia spp.
Chlamydophila spp.
Legionella pneumophila
Mycoplasma spp.
to No updated data was available at the time of publication of the table. The main literature, standard texts and treatment recommendations deem it sensitive.
b Collective term for a heterogeneous group of Streptococcus species. The rate of resistance may vary according to the actual Streptococcus species
05.2 Pharmacokinetic properties
Absorption
Teicoplanin is administered parenterally (intravenously or intramuscularly). After intramuscular administration, the bioavailability of teicoplanin (relative to intravenous administration) is almost complete (90%). After 6 daily intramuscular administrations of 200 mg the mean (SD) maximum concentration (Cmax) of teicoplanin is 12.1 mg / L and is achieved 2 hours after administration.
After a 6 mg / kg loading dose administered intravenously every 12 hours for 3-5 administrations, Cmax values range between 60 and 70 mg / L and Cmin values are generally greater than 10 mg / L.
After a loading dose of 12 mg / kg administered intravenously every 12 hours for 3 administrations, the mean values of Cmax and Cmin are estimated to be approximately 100 mg / L and 20 mg / L, respectively.
After a maintenance dose of 6 mg / kg administered once daily, the Cmax and Cmin values are approximately 70 mg / L and 15 mg / L, respectively.
After a maintenance dose of 12 mg / kg once daily the Cmin values range from 18 to 30 mg / L.
Teicoplanin is not absorbed from the gastrointestinal tract following oral administration. After oral administration of a single 250 or 500 mg dose to healthy subjects, teicoplanin was not recovered in serum or urine, but only in faeces (approximately 45% of the administered dose) as unchanged drug.
Distribution
Protein binding in human serum ranges from 87.6 to 90.8% without variation as a function of teicoplanin concentrations. Teicoplanin is primarily bound to serum albumin. Teicpolanin is not distributed in red blood cells.
The steady-state volume of distribution (Vss) ranges from 0.7 to 1.4 mL / kg. The highest values of Vss were observed in recent studies where the sampling period was greater than 8 days.
The drug is distributed mainly in lungs, myocardium and bone tissue, with tissue / serum ratios greater than 1. In blister fluid, synovial fluid and peritoneal fluid the tissue / serum ratio varies from 0.5 to 1. The elimination of teicoplanin from peritoneal fluid occurs at the same rate as from serum In pleural fluid and subcutaneous adipose tissue the tissue / serum ratio is between 0.2 and 0.5 Teicoplanin does not readily penetrate cerebrospinal fluid (CSF).
Biotransformation
The main compound identified in plasma and urine is the unchanged form of teicoplanin, indicating minimal metabolism. Two metabolites are probably formed by hydroxylation, accounting for 2-3% of the administered dose.
Elimination
Unchanged teicoplanin is excreted primarily via the urine (80% within 16 days) while 2.7% of the administered dose is recovered in the faeces (via biliary excretion) within 8 days of administration. In most recent studies with a duration of blood sampling from 8 to 35 days, the elimination half-life of teicoplanin ranges from 100 to 170 hours.
Teicoplanin has low total elimination in the order of 10-14 mL / h / kg and renal elimination in the order of 8-12 mL / h / kg, indicating that teicoplanin is primarily excreted via the kidney.
Linearity
Teicoplanin exhibits linear pharmacokinetics over a dose range of 2 to 25 mg / kg.
Special populations
• Kidney failure
Since teicoplanin is eliminated by the kidney, the elimination of teicoplanin decreases as a function of the degree of renal insufficiency. The total and renal clearance of teicoplanin are dependent on creatinine clearance.
• Elderly patients
In the elderly population, the pharmacokinetics of teicoplanin are unchanged except in cases of renal insufficiency.
• Pediatric population
Compared to adult patients, there is a higher total clearance (15.8 mL / h / kg for neonates, 14.8 mL / h / kg at a mean age of 8 years) and a shorter elimination half-life (40 hours for infants, 58 hours to 8 years).
05.3 Preclinical safety data
After repeated parenteral administration in rats and dogs, effects on the kidney were observed which were shown to be dose-dependent and reversible. Studies to investigate the potential ototoxicity in the guinea pig indicate the possibility of a slight deficit of cochlear and vestibular function, in the absence of morphological damage.
Teicoplanin administered subcutaneously up to 40 mg / kg / day did not alter male and female fertility in rats.
In embryo-fetal development studies, no malformations were observed after subcutaneous administration up to 200 mg / kg / day in rats and intramuscular administration up to 15 mg / kg / day in rabbits.However, in rats there was an increase in the incidence of stillbirths at doses starting at 100 mg / kg / day and above and neonatal mortality at 200 mg / kg / day. This effect was not seen at 50 mg / day. kg / day.
A peri and postnatality study in rats showed no effects on either the fertility of the F1 generation or the development and survival of the F2 generation after subcutaneous administration up to 40 mg / kg / day.
Teicoplanin did not show potential to cause antigenicity (in mice, guinea pigs or rabbits), genotoxicity or local irritation.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Powder for solution for injection / infusion or oral solution
sodium chloride
sodium hydroxide (for pH adjustment)
Solvent
water for injections.
06.2 Incompatibility
Solutions of teicoplanin and aminoglycosides are incompatible when mixed directly and should not be mixed prior to injection.
If teicoplanin is administered in combination therapy with other antibiotics, the preparations must be administered separately.
This medicinal product must not be mixed with other medicinal products except those listed in section 6.6.
06.3 Period of validity
Validity of the powder in the sales package
3 years.
Shelf life of the reconstituted solution
The chemical-physical stability in use of the reconstituted solution prepared according to the recommendations has been demonstrated for 24 hours at a temperature between 2 and 8 ° C.
From a microbiological point of view, the product should be used immediately. If not used immediately, the user is responsible for the shelf life and conditions of the product, which should normally not exceed 24 hours at 2 to 8 ° C, unless reconstitution is done under controlled conditions. and validated by asepsis.
Shelf life of the diluted medicinal product
The chemical-physical stability in use of the reconstituted solution prepared according to the recommendations has been demonstrated for 24 hours at a temperature between 2 and 8 ° C.
From a microbiological point of view, the product should be used immediately. If not used immediately, the user is responsible for the shelf life and conditions of the product, which should normally not exceed 24 hours at 2 to 8 ° C, unless reconstitution is done under controlled conditions. and validated by asepsis.
06.4 Special precautions for storage
Powder in retail packaging
This medicine does not require any special storage conditions.
For storage conditions of the reconstituted / diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Primary packaging:
The lyophilized medicinal product is packaged in:
Colorless type I glass vials with usable volume 10 mL for 200 mg closed with a bromobutyl rubber stopper, a yellow aluminum cap and a plastic tear-off tab.
Colorless type I glass vials with usable volume 22 mL for 400 mg closed by a bromobutyl rubber stopper, a green aluminum cap and a plastic tear-off tab.
The water for injections is packaged in a colorless type I glass ampoule.
Packs:
• 1 vial of powder with 1 vial of solvent
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
This medicine is for single use only.
Preparation of the reconstituted solution:
• Slowly inject the entire contents of the solvent vial into the vial of powder
• Gently swirl the vial between your hands until the powder has completely dissolved. If the solution becomes foamy, let it sit for about 15 minutes. Only clear and yellowish solutions should be used.
The reconstituted solutions contain 200 mg of teicoplanin in 3.0 mL and 400 mg in 3.0 mL.
The reconstituted solution can be injected directly or alternatively further diluted, or administered orally.
Preparation of the diluted solution before the infusion:
Targocid can be administered in the following infusion solutions:
- sodium chloride solution 9 mg / mL (0.9%)
- Ringer's solution
- lactated Ringer's solution
• 5% dextrose solution
• 10% dextrose solution
• solution containing 0.18% sodium chloride and 4% glucose
• solution containing 0.45% sodium chloride and 5% glucose
• peritoneal dialysis solution containing 1.36% or 3.86% glucose solution.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi S.p.A. - Viale L. Bodio, 37 / B - 20158 Milan
08.0 MARKETING AUTHORIZATION NUMBER
TARGOSID 200 mg powder and solvent for solution for injection / infusion or oral solution
- 1 vial of powder with 1 vial of A.I.C. n. 026458012
TARGOSID 400 mg powder and solvent for solution for injection / infusion or oral solution
- 1 vial of powder with 1 vial of A.I.C. n. 026458024
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
TARGOSID 200 mg powder and solvent for solution for injection / infusion or oral solution
30 July 1987/12 September 2013
TARGOSID 400 mg powder and solvent for solution for injection / infusion or oral solution
13 February 2009/12 September 2013
10.0 DATE OF REVISION OF THE TEXT
October 2015
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
