TARGOSID is indicated in adults and in 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),
• bacteraemia that occurs in association with any of the indications listed above.
TARGOSID is also indicated as an alternative oral treatment for Clostridium difficile infection-associated diarrhoea and colitis.
Where appropriate, teicoplanin should be administered in combination with other antibacterial agents.

Consideration should be given to the official guidelines on the appropriate use of antibacterial agents.

Posology
The dose and duration of treatment should be adjusted according to the underlying type and severity of the infection, the clinical response of the patient, and patient factors such as age and renal function.
Measurement of serum concentrations
Teicoplanin trough serum concentrations should be monitored at steady state after completion of the loading dose regimen in order to ensure that a minimum trough serum concentration has been reached:
• For most Gram-positive infections, teicoplanin trough levels of 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) method.
• 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 treatment, teicoplanin trough serum concentrations monitoring may be
performed at least once a week to ensure that these concentrations are stable.
Adults and elderly patients with normal renal function

Duration of treatment
The duration of treatment should be decided based on the clinical response. For infective endocarditis a minimum of 21 days is usually considered appropriate. Treatment should not exceed 4 months.
Combination therapy
Teicoplanin has a limited spectrum of antibacterial activity (Gram positive). It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a strong suspicion that the most likely pathogen(s) would respond to treatment with teicoplanin.
Clostridium difficile infection-associated diarrhoea and colitis
The recommended dose is 100-200 mg administered orally twice a day for 7 to 14 days.
Elderly patients
No dose adjustment is required, except in case of renal impairment (see below).
Adults and elderly patients with impaired renal function
Dose adjustment is not required until the fourth day of treatment, at which time dosing should be adjusted to maintain a serum trough concentration of at least 10 mg/L.
After the fourth day of treatment:
• In mild and moderate renal insufficiency (creatinine clearance 30-80 mL/min): the maintenance dose should be halved, either by administering the dose every two days or by
administering half of the dose once a day.
• In severe renal insufficiency (creatinine clearance less than 30 mL/min) and in
haemodialysed patients: the dose should be one-third of the usual dose, either by administering the initial unit dose every third day or by administering one-third of the dose once a day.
Teicoplanin is not removed by haemodialysis.
Patients in continuous ambulatory peritoneal dialysis (CAPD)
After a single intravenous loading dose of 6 mg/kg bodyweight, 20 mg/L is administered in all the bags of the dialysis solution in the first week, 20 mg/L in alternate bags the second week and then 20 mg/L in the overnight bag in the third week.

Paediatric patients
The dose recommendations are the same in adults and children above 12 years of age.
Neonates and infants up to the age of 2 months: Loading dose
One single dose of 16 mg/kg body weight, administered intravenously by infusion on the first day.
Maintenance dose
One single dose of 8 mg/kg body weight administered intravenously by infusion once a day.
Children (2 months to 12 years): Loading dose
One single dose of 10 mg/kg body weight administered intravenously every 12 hours, repeated 3 times.
Maintenance dose
One single dose of 6-10 mg/kg body weight administered intravenously once a day.
Method of administration
Teicoplanin should be administered by the intravenous or intramuscular route. The intravenous injection may be administered either as a bolus over 3 to 5 minutes or as a 30-minute infusion. Only the infusion method should be used in neonates.
For instructions regarding the reconstitution and dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to teicoplanin or to any of the excipients listed in section 6.1.

Hypersensitivity reactions
Serious, life-threatening hypersensitivity reactions, sometimes fatal, have been reported with teicoplanin (e.g. anaphylactic shock). If an allergic reaction to teicoplanin occurs, treatment should be discontinued immediately and appropriate emergency measures should be initiated.
Teicoplanin must be administered with caution in patients with known hypersensitivity to vancomycin, as crossed hypersensitivity reactions, including fatal anaphylactic shock, may occur.
However, a prior 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 complex of symptoms including pruritus, urticaria, erythema, angioneurotic oedema, tachycardia, hypotension, dyspnoea) has
been observed.
Stopping or slowing the infusion may result in cessation of these reactions. Infusion-related reactions can be limited if the daily dose is not given via bolus injection but infused over a 30-
minute period.

Severe bullous reactions
Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with the use of teicoplanin. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present,
teicoplanin treatment should be discontinued immediately.
Spectrum of antibacterial activity
Teicoplanin has a limited spectrum of antibacterial activity (Gram-positive). It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a strong suspicion that the most likely
pathogen(s) would respond to treatment with teicoplanin.
The rational use of teicoplanin should take into account the bacterial spectrum of activity, the safety profile and the suitability of standard antibacterial therapy for treating the individual patient. On this basis it is expected that, in many instances, teicoplanin will be used to treat severe infections in patients for whom standard antibacterial activity is considered to be unsuitable.
Loading dose regimen
Since data on safety are limited, patients should be carefully monitored for adverse reactions
when teicoplanin doses of 12mg/kg body weight twice a day are administered. Under this regimen, blood creatinine values should be monitored in addition to the recommended periodic
haematological examination.
Teicoplanin should not be administered by intraventricular use.
Thrombocytopenia
Thrombocytopenia has been reported with teicoplanin. Periodic haematological examinations are recommended during treatment, including complete cell blood count.
Nephrotoxicity
Renal failure has been reported in patients treated with teicoplanin (see section 4.8). Patients with renal insufficiency, and/or those receiving teicoplanin in conjunction with or sequentially with
other medicinal products with known nephrotoxic potential (aminoglycosides, colistin, amphotericin B, ciclosporin, and cisplatin) should be carefully monitored, and the tests performed
should include auditory tests.
Since teicoplanin is mainly excreted by the kidney, the dose of teicoplanin must be adapted in patients with renal impairment (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 disorders of the inner ear during treatment with teicoplanin should be carefully evaluated and monitored, especially in case of prolonged treatment and in patients with renal insufficiency. Patients receiving teicoplanin in conjunction with or sequentially with other
medicinal products with known neurotoxic/ototoxic potential (aminoglycosides, ciclosporin, cisplatin, furosemide and ethacrynic acid) should be carefully monitored and the benefit of teicoplanin evaluated if hearing deteriorates.
Special precautions must be taken when administering teicoplanin to patients who require concomitant treatment with ototoxic and/or nephrotoxic medicinal products, for which it is recommended that regular haematology, liver and kidney function tests are carried out.
Superinfection

As with other antibiotics, the use of teicoplanin, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

No specific interaction studies have been performed.
Teicoplanin and aminoglycoside solutions are incompatible and must not be mixed for injection; however, they are compatible with dialysis fluids and may be freely used in the treatment of CAPD-related peritonitis.
Teicoplanin should be used with care in conjunction with or sequentially with other medicinal products with known nephrotoxic or ototoxic potential. These include aminoglycosides, colistin, amphotericin B, ciclosporin, cisplatin, furosemide, and ethacrynic acid (see section 4.4).
However, there is no evidence of synergistic toxicity in combinations with teicoplanin.
In clinical studies, teicoplanin has been administered to many patients already receiving various medications including other antibiotics, antihypertensives, anaesthetic agents, cardiac medicinal products and antidiabetic agents without evidence of adverse interaction.
Paediatric population
Interaction studies have only been performed on adults.

Pregnancy
There is a limited amount of data on the use of teicoplanin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3): in rats there was an increased incidence of stillbirths and neonatal mortality. The potential risk for humans is unknown. Therefore, teicoplanin should not be used during pregnancy unless clearly necessary. A potential risk of inner ear and renal damage to the foetus cannot be excluded (see section 4.4).
Breast-feeding
It is unknown whether teicoplanin is excreted in human milk. There is no information on the
excretion of teicoplanin in animal milk. A decision on whether to continue/discontinue breast- feeding or to continue/discontinue therapy with teicoplanin should be made taking into account the benefit of breast-feeding for the child and the benefit of teicoplanin therapy for the mother.
Fertility
Animal reproduction studies have not shown evidence of impairment of fertility.

TARGOSID has minor influence on the ability to drive and use machines.
Teicoplanin can cause dizziness and headache. The ability to drive or use machines may be
affected. Patients experiencing these undesirable effects should not drive or use machines.

Tabulated list of adverse reactions

In the table below all the adverse reactions, which occurred at an incidence greater than placebo and in more than one patient are listed using the following convention:
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 (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Adverse reactions should be monitored when teicoplanin doses of 12 mg/kg body weight twice a day are administered (see section 4.4).

To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at the web address www.agenziafarmaco.gov.it/it/responsabili.

Symptoms
Cases of accidental administration of excessive doses to paediatric patients have been reported. In one case agitation occurred in a 29-day-old newborn who had been administered 400 mg intravenously (95 mg/kg).
Management
Treatment of teicoplanin overdose should be symptomatic.
Teicoplanin is not removed by haemodialysis and only slowly by peritoneal dialysis.

Pharmacotherapeutic group: Glycopeptide Antibacterials, ATC code: J01XA 02
Mechanism of action
Teicoplanin inhibits the growth of susceptible organisms by interfering with cell-wall biosynthesis at a site different from that affected by beta-lactams.
Peptidoglycan synthesis is blocked by specific binding to D-alanyl-D-alanine residues.
Mechanism of resistance
Resistance to teicoplanin can be based on the following mechanisms:
• Modified target structure: this form of resistance has occurred particularly in Enterococcus faecium. The modification is based on exchange of the terminal D-alanine-D-alanine
function of the amino-acid chain in a murein precursor with D-Ala-D-lactate, thus reducing the affinity to vancomycin. The responsible enzymes are a newly synthesised D-lactate dehydrogenase or ligase.
• The reduced sensitivity or resistance of staphylococci to teicoplanin is based on the overproduction of murein precursors to which teicoplanin is bound.
Cross-resistance between teicoplanin and the glycoprotein vancomycin may occur. A number of vancomycin-resistant enterococci are sensitive to teicoplanin (Van-B phenotype).
Susceptibility testing breakpoints
The MIC breakpoints which divide sensitive organisms from resistant ones according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), version 3.1, February 11, 2013 are displayed in the following table:

a Glycopeptide MICs are method-dependent and should be determined by broth microdilution (reference ISO 20776). S. aureus with vancomycin MIC values of 2 mg/L are on the edge of the wild type MIC distribution and there may be an impaired clinical response. The resistance breakpoint for S. aureus has been reduced to 2 mg/L to avoid reporting of GISA isolates intermediate as serious infections with GISA isolates are not treatable with increased doses of vancomycin or teicoplanin.
b Isolates with MIC values above the susceptible 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 must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current
resistant breakpoint they should be reported as resistant.
c IE indicates that there is insufficient evidence that the species in question is a good target for therapy with the drug.
d An MIC with a comment but without an accompanying S, I or R categorisation may be reported.
Pharmacokinetic/Pharmacodynamic relationship
Teicoplanin antimicrobial activity depends essentially on the duration of time during which the
substance level is higher than the minimum inhibitory concentration (MIC) of the pathogen.
Susceptibility
The prevalence of resistance may vary geographically and over time for selected species and so local information on resistance is desirable, particularly when treating severe infections.
As necessary, expert advice should be sought when the local prevalence of resistance is such that
the utility of the agent in at least some of types of infections is questionable.
Commonly susceptible species 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 Streptococci in the viridans group a b Anaerobic Gram-positive bacteria
Clostridium difficile a
Peptostreptococcus spp.a
Species for which acquired resistance may be a problem
Aerobic Gram-positive bacteria Enterococcus faecium Staphylococcus epidermidis Staphylococcus haemolyticus Staphylococcus hominis

Inherently resistant bacteria All Gram-negative bacteria Other bacteria
Chlamydia spp.
Chlamydophila spp. Legionella pneumophila Mycoplasma spp.
a No current data were available when the tables were published. The primary literature, standard volumes and treatment recommendations assume sensitivity
b Collective term for a heterogeneous group of Streptococcus species. Resistance rate can vary
depending on the actual Streptococcus species

Absorption
Teicoplanin is administered by parenteral route (intravenously or intramuscularly). After
intramuscular administration, the bioavailability of teicoplanin (as compared to intravenous administration) is almost complete (90%). After six daily intramuscular administrations of
200 mg, the mean (SD) maximum teicoplanin concentration (Cmax) amounts to 12.1 (0.9) mg/L and occurs at 2 hours after administration.
After a loading dose of 6 mg/kg administered intravenously every 12 hours for 3 to 5 administrations, Cmax values range from 60 to 70 mg/L and Ctrough are usually above 10 mg/L. After an intravenous loading dose of 12 mg/kg administered every 12 hours for 3 administrations, mean values of Cmax and Ctrough are estimated to be around 100 mg/L and 20 mg/L, respectively.
After a maintenance dose of 6 mg/kg administered once daily Cmax and Ctrough values are approximately 70 mg/L and 15 mg/L, respectively.
After a maintenance dose of 12 mg/kg once daily Ctrough values range from 18 to 30 mg/L.
When administered by oral route, teicoplanin is not absorbed from the gastrointestinal tract. When administered by oral route at 250 or 500 mg single dose to healthy subjects, teicoplanin is not detected in the serum or urine but only recovered in faeces (about 45% of the administered dose) as an unchanged medicinal product.
Distribution
The binding to human serum proteins ranges from 87.6 to 90.8% without any variation based on
the teicoplanin concentrations. Teicoplanin is mainly bound to human serum albumin. Teicoplanin is not distributed in red cells.
The volume of distribution at steady-state (Vss) varies from 0.7 to 1.4 mL/kg. The highest values
of Vss have been observed in the recent studies where the sampling period was superior to 8 days.
Teicoplanin is mainly distributed in lung, myocardium and bone tissues with tissue/serum ratios
superior to 1. In blister fluids, synovial fluid and peritoneal fluid the tissue/serum ratios ranged from 0.5 to 1. Elimination of teicoplanin from peritoneal fluid occurs at the same rate as from serum. In pleural fluid and subcutaneous fat tissue the tissue/serum ratios are comprised between
0.2 and 0.5. Teicoplanin does not readily penetrate into the cerebrospinal fluid (CSF).

Biotransformation
The unchanged form of teicoplanin is the main compound identified in plasma and urine, indicating a minimal metabolism. Two metabolites are formed probably by hydroxylation and represent 2 to 3% of the administered dose.
Elimination
Unchanged teicoplanin is mainly excreted by urinary route (80% within 16 days) while 2.7% of
the administered dose is recovered in the faeces (via bile excretion) within 8 days following administration.Elimination half-life of teicoplanin varies from 100 to 170 hours in the most recent studies where blood sampling duration is about 8 to 35 days.
Teicoplanin has a low total clearance in the range of 10 to 14 mL/h/kg and a renal clearance in the range of 8 to 12 mL/h/kg indicating that teicoplanin is mainly excreted by renal mechanisms.
Linearity
Teicoplanin exhibited linear pharmacokinetics at dose range of 2 to 25 mg/kg.
Special populations
• Renal impairment:
As teicoplanin is eliminated by renal route, teicoplanin elimination decreases according to the
degree of renal impairment. The total and renal clearances of teicoplanin depend on the creatinine
clearance.
• Elderly patients:
In the elderly population the teicoplanin pharmacokinetics are not modified unless in case of renal impairment.
• Paediatric population
A higher total clearance (15.8 mL/h/kg for neonates, 14.8 mL/h/kg for a mean age of 8 years) and a shorter elimination half-life (40 hours for neonates; 58 hours for 8 years) are observed compared to adult patients.

Following repeated parenteral administration to rats and dogs, effects on the kidney were observed and were shown to be dose-dependent and reversible. Studies to investigate the potential to cause ototoxicity in guinea-pigs indicate that a mild impairment of cochlear and vestibular function is possible, in the absence of morphological damage.
Subcutaneous administration of teicoplanin at up to 40 mg/kg/day did not affect male and female fertility in rats.
In embryofetal development studies, no malformations were observed following subcutaneous
administration of up to 200 mg/kg/day in rats and intramuscular administration of up to
15 mg/kg/day in rabbits. However, in the rat, there was an increased incidence of stillbirths at doses of 100 mg/kg/day and above and neonatal mortality at 200 mg/kg/day. This effect was not reported at 50 mg/kg/day
A peri and postnatal study in rats showed no effects on the fertility of the F1 generation or on the
survival and development of the F2 generation following subcutaneous administration of up to 40 mg/kg/day.

Teicoplanin did not show any potential to cause antigenicity (in mice, guinea-pigs or rabbits), genotoxicity or local irritancy.

Powder for solution for injection/infusion or oral solution Sodium chloride
Sodium hydroxide (for pH adjustment)
Solvent
Water for injections

Teicoplanin and aminoglycoside are incompatible when mixed directly and must not be mixed before 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 mentioned in section 6.6.

Shelf life of the powder as packaged for sale: 3 years Shelf life of the reconstituted solution: Chemical and physical in-use stability of the reconstituted solution prepared as recommended has been demonstrated for 24 hours at 2 to 8°C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. Shelf life of the diluted medicinal product: Chemical and physical in-use stability of the reconstituted solution prepared as recommended has been demonstrated for 24 hours at 2 to 8°C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Powder as packaged for sale:
This medicinal product does not require any special storage conditions.

For the storage conditions of the reconstituted/diluted medicinal product, see section 6.3.

Primary packaging:
The freeze-dried medicinal product is packaged in:
Type I, colourless glass vial with a useful volume of 10 mL for 200 mg closed with a bromobutyl
rubber stopper and a yellow aluminium flip-off top with plastic overseal.
Type I, colourless glass vial with a useful volume of 22 mL for 400 mg closed with a bromobutyl rubber stopper and a green aluminium flip-off top with plastic overseal.
Water for injections is packaged in Type I, colourless glass ampoule.
Pack sizes:
- 1 powder vial with 1 solvent ampoule
Not all pack sizes may be marketed.

This medicinal product is for single use only. Preparation of reconstituted solution:
- Slowly inject the entire content of the supplied solvent into the powder vial.
- Gently roll the vial between the hands until the powder is completely dissolved. If the
solution becomes foamy, then it should be left to stand for about 15 minutes. Only clear and yellowish solutions should be used.
The reconstituted solutions will contain 200 mg of teicoplanin in 3.0 mL and 400 mg in 3.0 mL.
Nominal teicoplanin content of vial
200 mg
400 mg
Volume of powder vial
10 mL
22 mL
Volume withdrawable from the
solvent ampoule for reconstitution
3.14 mL
3.14 mL
Volume containing nominal
teicoplanin dose (extracted by 5 mL syringe and 23 G needle)
3.0 mL
3.0 mL
The reconstituted solution may be injected directly or alternatively further diluted, or orally administered.
Preparation of the diluted solution before infusion:
TARGOSID can be administered in the following infusion solutions:
- sodium chloride 9 mg/mL (0.9%) solution
- Ringer solution

Ringer-lactate solution
- 5% dextrose injection
- 10% dextrose injection
- 0.18% sodium chloride and 4% glucose solution
- 0.45% sodium chloride and 5% glucose solution
- Peritoneal dialysis solution containing 1.36% or 3.86% glucose solution.
Any unused product or waste material should be disposed of in accordance with local requirements.