innohep 4,500 IU syringe (Prophylaxis and Haemodialysis)

The SmPC has been updated following an EU harmonisation work-sharing procedure.

Sections 4.1 and 4.2 have been updated, with consequential changes to sections 4.4. Information on prophylactic use in VTE for non-surgical patients is also included.

Changes are detailed below:

 

4.1     Therapeutic indications – revised wording

Prophylaxis of venous thromboembolism in adult patients undergoing surgery, particularly orthopaedic, general or oncological surgery.

Prophylaxis of venous thromboembolism in non-surgical adult patients immobilised due to acute medical illness including: acute heart failure, acute respiratory failure, severe infections, active cancer, as well as exacerbation of rheumatic diseases.

Prevention of clotting in extracorporeal circuits during haemodialysis and haemofiltration in adults.

 

4.2     Posology and method of administration – revised wording

Posology

Prophylaxis of thromboembolic events in adults:

Administration is by subcutaneous injection.

Surgical patients at moderate risk of thromboembolic events:

3,500 anti-Xa IU given SC 2 hours before surgery and then once daily for as long as the patient is considered to be at risk of VTE.

Surgical patients at high risk of thromboembolic events e.g. undergoing orthopaedic or cancer surgery:

4,500 anti‑Xa IU given SC 12 hours before surgery and then once daily for as long as the patient is considered to be at risk of VTE.

Non-surgical patients immobilised due to acute medical illness:

3,500 anti-Xa IU given SC once daily in patients at moderate risk of VTE, or 4,500 anti-Xa IU given SC once daily in patients at high risk of VTE. Administration should continue for as long as the patient is considered to be at risk of VTE.

Neuraxial anaesthesia

Caution is advised when performing neuraxial anaesthesia or lumbar puncture in patients receiving prophylactic doses of tinzaparin sodium, see section 4.4: Neuraxial anaesthesia. If neuraxial anaesthesia is planned, a minimum delay of 12 hours should be allowed between the last prophylactic dose and the needle or catheter placement. Tinzaparin sodium should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed. Thus, the 2 hours preoperative initiation of thromboprophylaxis with tinzaparin sodium is not compatible with neuraxial anaesthesia.

Haemodialysis and haemofiltration in adults:

 

Duration of 4 hours or less:

A bolus injection of 2,000 to 2,500 anti-Xa IU at the start of dialysis.

Duration of more than 4 hours:

A bolus injection of 2,500 anti-Xa IU at the start of dialysis/filtration, followed by 750 anti-Xa IU/hour as a continuous infusion.

Dose adjustment:

If necessary, the bolus dose may be increased or decreased gradually in increments of 500 anti-Xa IU until a satisfactory response is obtained. The usual dose is within 2,000–4,500 anti-Xa IU.

In case of concomitant transfusion of blood or concentrated red corpuscles, an extra bolus injection of 500–1,000 anti-Xa IU can be administered.

Dose monitoring:

Determination of plasma anti-Xa activity can be used to monitor the tinzaparin sodium dose during haemodialysis/haemofiltration. The plasma anti-Xa level should be approximately 0.5 anti-Xa IU/ml one hour after administration.

Interchangeability

For interchangeability with other LMWHs, see section 4.4.

Special populations

Paediatric population

The safety and efficacy of tinzaparin sodium in children below 18 years have not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Renal impairment

If renal impairment is suspected, renal function should be assessed using a formula based on serum creatinine to estimate creatinine clearance level.

Use in patients with a creatinine clearance level < 30 ml/minute is not recommended, as dosage in this population has not been established. Available evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/min. When required in these patients, tinzaparin sodium administration can be initiated with anti-Xa monitoring, if the benefit outweighs the risk (see section 4.4: Renal impairment).

Elderly

Tinzaparin sodium should be used in the elderly in standard doses. Precaution is recommended in the treatment of elderly patients with renal impairment. If renal impairment is suspected, see section 4.2: Renal impairment and section 4.4: Renal impairment.

Weight

For patients with very low or very high body weight, 50 anti-Xa IU per kg body weight once daily may be considered as an alternative to fixed dosing. For surgical patients, the first dose is given SC 2 hours before surgery. The administration should continue once daily for as long as the patient is considered to be at risk of VTE.

Method of administration

Parenteral products should be inspected visually prior to administration. Do not use if cloudiness or precipitate is observed. The liquid may turn yellow during storage but is still useable.

Administration is by subcutaneous injection when given as prophylaxis of thromboembolic events in adults. This can be done in abdominal skin, the outer side of the thigh, lower back, upper leg or upper arm. Do not inject in the area around the navel, near scars or in wounds.

For abdominal injections, the patient should be in a supine position, alternating the injections between the left and right side. The air-bubble within the syringe should not be removed. During the injection, the skin should be held in a fold.

For haemodialysis, the dose of tinzaparin sodium should be given into the arterial side of the dialyser or intravenously. The dialyser can be primed by flushing with 500-1,000 ml isotonic sodium chloride (9 mg/ml) containing 5,000 anti-Xa IU tinzaparin sodium per litre.

 

4.4     Special warnings and precautions for use

The following subsections have been updated in line with the revised statements in Section 4.2.

·       Renal impairment

 

Interchangeability: Following wording added.

Low molecular weight heparins should not be used interchangeably because of differences in pharmacokinetics and biological activities. Switching to an alternative low molecular weight heparin, especially during extended use, must be exercised with particular caution and specific dosing instructions for each proprietary product must be followed.

 

Heparin-induced thrombocytopenia: Revision to the wording.

 

10 Date of revision of SmPC

Updated to March 2017

The SmPC has been updated following an EU harmonisation work-sharing procedure.

Sections 4.1 and 4.2 have been updated, with consequential changes to sections 4.4. Information on prophylactic use in VTE for non-surgical patients is also included.

Changes are detailed below:

 

4.1     Therapeutic indications – revised wording

Prophylaxis of venous thromboembolism in adult patients undergoing surgery, particularly orthopaedic, general or oncological surgery.

Prophylaxis of venous thromboembolism in non-surgical adult patients immobilised due to acute medical illness including: acute heart failure, acute respiratory failure, severe infections, active cancer, as well as exacerbation of rheumatic diseases.

Prevention of clotting in extracorporeal circuits during haemodialysis and haemofiltration in adults.

 

4.2     Posology and method of administration – revised wording

Posology

Prophylaxis of thromboembolic events in adults:

Administration is by subcutaneous injection.

Surgical patients at moderate risk of thromboembolic events:

3,500 anti-Xa IU given SC 2 hours before surgery and then once daily for as long as the patient is considered to be at risk of VTE.

Surgical patients at high risk of thromboembolic events e.g. undergoing orthopaedic or cancer surgery:

4,500 anti‑Xa IU given SC 12 hours before surgery and then once daily for as long as the patient is considered to be at risk of VTE.

Non-surgical patients immobilised due to acute medical illness:

3,500 anti-Xa IU given SC once daily in patients at moderate risk of VTE, or 4,500 anti-Xa IU given SC once daily in patients at high risk of VTE. Administration should continue for as long as the patient is considered to be at risk of VTE.

Neuraxial anaesthesia

Caution is advised when performing neuraxial anaesthesia or lumbar puncture in patients receiving prophylactic doses of tinzaparin sodium, see section 4.4: Neuraxial anaesthesia. If neuraxial anaesthesia is planned, a minimum delay of 12 hours should be allowed between the last prophylactic dose and the needle or catheter placement. Tinzaparin sodium should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed. Thus, the 2 hours preoperative initiation of thromboprophylaxis with tinzaparin sodium is not compatible with neuraxial anaesthesia.

Haemodialysis and haemofiltration in adults:

 

Duration of 4 hours or less:

A bolus injection of 2,000 to 2,500 anti-Xa IU at the start of dialysis.

Duration of more than 4 hours:

A bolus injection of 2,500 anti-Xa IU at the start of dialysis/filtration, followed by 750 anti-Xa IU/hour as a continuous infusion.

Dose adjustment:

If necessary, the bolus dose may be increased or decreased gradually in increments of 500 anti-Xa IU until a satisfactory response is obtained. The usual dose is within 2,000–4,500 anti-Xa IU.

In case of concomitant transfusion of blood or concentrated red corpuscles, an extra bolus injection of 500–1,000 anti-Xa IU can be administered.

Dose monitoring:

Determination of plasma anti-Xa activity can be used to monitor the tinzaparin sodium dose during haemodialysis/haemofiltration. The plasma anti-Xa level should be approximately 0.5 anti-Xa IU/ml one hour after administration.

Interchangeability

For interchangeability with other LMWHs, see section 4.4.

Special populations

Paediatric population

The safety and efficacy of tinzaparin sodium in children below 18 years have not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Renal impairment

If renal impairment is suspected, renal function should be assessed using a formula based on serum creatinine to estimate creatinine clearance level.

Use in patients with a creatinine clearance level < 30 ml/minute is not recommended, as dosage in this population has not been established. Available evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/min. When required in these patients, tinzaparin sodium administration can be initiated with anti-Xa monitoring, if the benefit outweighs the risk (see section 4.4: Renal impairment).

Elderly

Tinzaparin sodium should be used in the elderly in standard doses. Precaution is recommended in the treatment of elderly patients with renal impairment. If renal impairment is suspected, see section 4.2: Renal impairment and section 4.4: Renal impairment.

Weight

For patients with very low or very high body weight, 50 anti-Xa IU per kg body weight once daily may be considered as an alternative to fixed dosing. For surgical patients, the first dose is given SC 2 hours before surgery. The administration should continue once daily for as long as the patient is considered to be at risk of VTE.

Method of administration

Parenteral products should be inspected visually prior to administration. Do not use if cloudiness or precipitate is observed. The liquid may turn yellow during storage but is still useable.

Administration is by subcutaneous injection when given as prophylaxis of thromboembolic events in adults. This can be done in abdominal skin, the outer side of the thigh, lower back, upper leg or upper arm. Do not inject in the area around the navel, near scars or in wounds.

For abdominal injections, the patient should be in a supine position, alternating the injections between the left and right side. The air-bubble within the syringe should not be removed. During the injection, the skin should be held in a fold.

For haemodialysis, the dose of tinzaparin sodium should be given into the arterial side of the dialyser or intravenously. The dialyser can be primed by flushing with 500-1,000 ml isotonic sodium chloride (9 mg/ml) containing 5,000 anti-Xa IU tinzaparin sodium per litre.

 

4.4     Special warnings and precautions for use

The following subsections have been updated in line with the revised statements in Section 4.2.

·       Renal impairment

 

Interchangeability: Following wording added.

Low molecular weight heparins should not be used interchangeably because of differences in pharmacokinetics and biological activities. Switching to an alternative low molecular weight heparin, especially during extended use, must be exercised with particular caution and specific dosing instructions for each proprietary product must be followed.

 

Heparin-induced thrombocytopenia: Revision to the wording.

 

10 Date of revision of SmPC

Updated to March 2017

Update to SmPC in line with Article 45 paediatric workshare variation:$0Section 4.1: addition of adult to the 2 indications$0$0Section 4.2: addition of paragraph relating to paediatric population$0$0Section 4.8: addition of paragraph relating to paediatric population$0$0Section 5.2: addition of paragraph relating to paediatric population$0

Update to SmPC in line with Article 45 paediatric workshare variation:$0Section 4.1: addition of adult to the 2 indications$0$0Section 4.2: addition of paragraph relating to paediatric population$0$0Section 4.8: addition of paragraph relating to paediatric population$0$0Section 5.2: addition of paragraph relating to paediatric population$0

Section 4.2:

QRD and editorial updates.

 

Additional information related to the elderly and patients with renal impairment:

 

Elderly:

innohep should be used in the elderly in standard doses. Caution is recommended in the treatment of elderly patients with renal impairment.

If renal impairment is suspected, see section 4.2 Patients with Renal Impairment and section 4.4 Renal impairment.

No dose modifications are necessary

 

Patients with Renal Impairment:

If renal impairment is suspected, renal function should be assessed using a formula based on serum creatinine to estimate creatinine clearance level. Available evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/minute. However, caution is recommended when treating patients with severe renal impairment (creatinine clearance < 30 ml/minute).

There is limited data available in patients with an estimated creatinine clearance level below 20 ml/minute. See section 4.4 Renal impairment.

Section 4.3: ‘bleeding’ changed to ‘haemorrhage’

Section 4.4:

Editorial updates throughout.

 

‘bleeding’ changed to ‘haemorrhage’

 

Updated information on heparin induced thrombocytopenia, renal impairment and the elderly:

Heparin-induced thrombocytopenia

Because of the risk of immune-mediated heparin-induced thrombocytopenia (type II), platelet count should be measured before the start of treatment and periodically thereafter. innohep must be discontinued in patients who develop immune-mediated heparin-induced thrombocytopenia (type II) (see sections 4.3 and 4.8). Platelet counts will usually normalise within 2 to 4 weeks after withdrawal.

 

Renal Iimpairment

All aAvailable evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/minute. Although anti-Xa monitoring is the most appropriate measure of the pharmacodynamic effects of innohep, it remains a poor predictor of haemorrhage risk. Nonetheless, monitoring of anti-factor Xa activity may be considered in patients with severe renal impairment (creatinine clearance <30 ml/minute).

Caution is recommended when treating patients with severe renal impairment (creatinine clearance < 30 ml/minute).

There is limited data available in patients with an estimated creatinine clearance level below 20 ml/minute.

Precaution is recommended in patients with very severe renal impairment (creatinine clearance < 20 ml/min), when using prophylactic doses.

 

Elderly

Elderly are more likely to have reduced renal function (see section 4.4 Renal impairment) therefore caution should be exercised when prescribing innohep to the elderly.

Section 4.8: ‘bleeding’ changed to ‘haemorrhage’; Inclusion of national adverse event reporting statement.

Section 4.9: ‘bleeding’ changed to ‘haemorrhage’

Section 6.1: Editorial

Section 9: Editorial

Section 10: 28 November 2014

Section 4.2:

QRD and editorial updates.

 

Additional information related to the elderly and patients with renal impairment:

 

Elderly:

innohep should be used in the elderly in standard doses. Caution is recommended in the treatment of elderly patients with renal impairment.

If renal impairment is suspected, see section 4.2 Patients with Renal Impairment and section 4.4 Renal impairment.

No dose modifications are necessary

 

Patients with Renal Impairment:

If renal impairment is suspected, renal function should be assessed using a formula based on serum creatinine to estimate creatinine clearance level. Available evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/minute. However, caution is recommended when treating patients with severe renal impairment (creatinine clearance < 30 ml/minute).

There is limited data available in patients with an estimated creatinine clearance level below 20 ml/minute. See section 4.4 Renal impairment.

Section 4.3: ‘bleeding’ changed to ‘haemorrhage’

Section 4.4:

Editorial updates throughout.

 

‘bleeding’ changed to ‘haemorrhage’

 

Updated information on heparin induced thrombocytopenia, renal impairment and the elderly:

Heparin-induced thrombocytopenia

Because of the risk of immune-mediated heparin-induced thrombocytopenia (type II), platelet count should be measured before the start of treatment and periodically thereafter. innohep must be discontinued in patients who develop immune-mediated heparin-induced thrombocytopenia (type II) (see sections 4.3 and 4.8). Platelet counts will usually normalise within 2 to 4 weeks after withdrawal.

 

Renal Iimpairment

All aAvailable evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/minute. Although anti-Xa monitoring is the most appropriate measure of the pharmacodynamic effects of innohep, it remains a poor predictor of haemorrhage risk. Nonetheless, monitoring of anti-factor Xa activity may be considered in patients with severe renal impairment (creatinine clearance <30 ml/minute).

Caution is recommended when treating patients with severe renal impairment (creatinine clearance < 30 ml/minute).

There is limited data available in patients with an estimated creatinine clearance level below 20 ml/minute.

Precaution is recommended in patients with very severe renal impairment (creatinine clearance < 20 ml/min), when using prophylactic doses.

 

Elderly

Elderly are more likely to have reduced renal function (see section 4.4 Renal impairment) therefore caution should be exercised when prescribing innohep to the elderly.

Section 4.8: ‘bleeding’ changed to ‘haemorrhage’; Inclusion of national adverse event reporting statement.

Section 4.9: ‘bleeding’ changed to ‘haemorrhage’

Section 6.1: Editorial

Section 9: Editorial

Section 10: 28 November 2014

SmPC was updated in line with latest clinical information in CCSI_09

SmPC was updated in line with latest clinical information in CCSI_09