4.1. Therapeutic indications

Teicoplanin Seacross 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.

Teicoplanin Seacross 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 official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

The dose and duration of treatment should be adjusted according to the underlying type and severity of infection and 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

Indications

Loading dose

Maintenance dose

Loading dose regimen

Targeted trough concentrations at day 3 to 5

Maintenance dose

Targeted trough concentrations during maintenance

- Complicated skin and soft tissue infections

- Pneumonia

- Complicated urinary tract infections

6 mg/kg body weight every 12 hours for 3 intravenous or intramuscular administrations

>15 mg/L1

6 mg/kg body weight intravenous or intramuscular once a day

>15 mg/L1 once a week

- Bone and joint infections

12 mg/kg body weight every 12 hours for 3 to 5 intravenous administrations

>20 mg/L1

12 mg/kg body weight intravenous or intramuscular once a day

>20 mg/L1

- Infective endocarditis

12 mg/kg body weight every 12 hours for 3 to 5 intravenous administrations

30-40 mg/L1

12 mg/kg body weight intravenous or intramuscular once a day

>30 mg/L1

1 Measured by FPIA

The dose is to be adjusted on bodyweight whatever the weight of the patient.

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 high suspicion that the most likely pathogen(s) would be suitable for 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 population

No dose adjustment is required, unless there is 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 when measured by HPLC, or at least 15 mg/L when measured by FPIA method.

After the fourth day of treatment:

● In mild and moderate renal insufficiency (creatinine clearance 30-80 mL/min): maintenance dose should be halved, either by administering the dose every two days or by administering half of this dose once a day.

● In severe renal insufficiency (creatinine clearance less than 30 mL/min) and in haemodialysed patients: dose should be one-third the usual dose, either by administering the initial unit dose every third day or by administering one-third of this 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 the bag of the dialysis solution in the first week, 20 mg/L in different bags the second week and then 20 mg/L in the overnight bag in the third week.

Paediatric population

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 Clostridium difficile infection-associated diarrhoea and colitis, the oral route is to be used.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to teicoplanin or to any of the excipients listed in section 6.

4.4. Special warnings and precautions for use

Teicoplanin should not be administered by intraventricular use.

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 cutaneous adverse reactions

Severe cutaneous adverse reactions (SCAR) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal have been reported with the use of teicoplanin (see section 4.8). Acute generalized exanthematous pustulosis (AGEP) has also been reported with the use of teicoplanin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions (e.g. progressive skin rash often with blisters or mucosal lesions or pustular rash, or any other sign of skin hypersensitivity) and be closely monitored. If signs and symptoms suggestive of severe skin reactions appear, teicoplanin should be withdrawn and alternative treatment should be considered.

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 high suspicion that the most likely pathogen(s) would be suitable for 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 to treat the individual patient. On this basis it is expected that in most instances teicoplanin will be used to treat severe infections in patients for whom standard antibacterial activity is considered to be unsuitable.

Thrombocytopenia

Thrombocytopenia has been reported with teicoplanin (see section 4.8). Periodic haematological examinations, including complete cell blood count, are recommended during treatment.

Nephrotoxicity

Nephrotoxicity and renal failure have been reported in patients treated with teicoplanin (see section 4.8). Patients with renal insufficiency, in those receiving the high loading dose regimen of teicoplanin, and those receiving teicoplanin in conjunction with or sequentially with other medicinal products with known nephrotoxic potential (e.g. aminoglycosides, colistin, amphotericin B, ciclosporin, and cisplatin) should be carefully monitored, and should get auditory tests (see “Ototoxicity” below).

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 nephrotoxic and/or neurotoxic/ototoxic potential (e.g. aminoglycosides, colistin, amphotericin B, 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 in 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.

4.5. Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed.

Teicoplanin and aminoglycoside solutions are incompatible and must not be mixed for injection; however, they are compatible in dialysis fluid 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 and/or neurotoxic/ototoxic potential. These include e.g. aminoglycosides, colistin, amphotericin B, ciclosporin, cisplatin, furosemide, and ethacrynic acid (see section 4.4 “Nephrotoxicity” and “Ototoxicity”). 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 in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are a limited amount of data from 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 to the child and the benefit of teicoplanin therapy to the mother.

Fertility

Animal reproduction studies have not shown evidence of impairment of fertility.

4.7. Effects on ability to drive and use machines

Teicoplanin Seacross 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.

4.8. Undesirable effects

Tabulated list of adverse reactions

In the table below all the adverse reactions, which occurred at an incidence greater than placebo and 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.

System organ class

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 available data)

Infections and infestations

Abscess

Superinfection (overgrowth of non-susceptible organisms)

Blood and the lymphatic system disorders

Leucopenia, thrombocytopenia, eosinophilia

Agranulocytosis, neutropenia, pancytopenia

Immune system disorders

Anaphylactic reaction (anaphylaxis) (see section 4.4)

Drug reaction with eosinophilia and systemic symptoms (DRESS), anaphylactic shock (see section 4.4)

Nervous system disorders

Dizziness, headache

Seizures

Ear and Labyrinth disorders

Deafness, hearing loss (see section 4.4), tinnitus, vestibular disorder

Vascular disorders

Phlebitis

Thrombophlebitis

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Gastrointestinal disorders

Diarrhoea, vomiting, nausea

Skin and subcutaneous tissue disorders

Rash, erythema, pruritus

Red man syndrome (e.g. Flushing of the upper part of the body) (see section 4.4).

Toxic epidermal necrolysis, Stevens-Johnson syndrome, Acute generalized exanthematous pustulosis, erythema multiforme, angioedema, dermatitis exfoliative, urticaria (see section 4.4)

Renal and Urinary disorders

Blood creatinine increased

Renal failure (including renal failure acute) (see below description of selected adverse reactions)*

General disorders and administration site conditions

Pain, pyrexia

Injection site abscess, chills (rigors)

Investigations

Transaminases increased (transient abnormality of transaminases), blood alkaline phosphatase increased (transient abnormality of alkaline phosphatase)

Description of selected adverse reactions

*Based on literature reports, the estimated rate of nephrotoxicity in patients receiving low loading dose regimen of average 6 mg/kg twice a day, followed by a maintenance dose of average 6 mg/kg once daily, is around 2%.

In an observational post-authorisation safety study which enrolled 300 patients with a mean age of 63 years (treated for bone and joint infection, endocarditis or other severe infections) who received the high loading dose regimen of 12 mg/kg twice a day (receiving 5 loading doses as a median) followed by a maintenance dose of 12 mg/kg once daily, the observed rate of confirmed nephrotoxicity was 11.0% (95% CI = [7.4%; 15.5%]) over the first 10 days. The cumulative rate 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 receiving more than 5 high loading doses of 12 mg/kg twice a day, followed by a maintenance dose of 12 mg/kg once daily, the observed cumulative rate of nephrotoxicity from the start of treatment up to 60 days after the last administration was 27% (95% CI = [20.7%; 35.3%]) (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.