Innohep

innohep 10,000 IU/ml

Tinzaparin sodium 10,000 anti-Factor Xa IU/ml

Excipients with known effect:

Benzyl alcohol (10 mg/ml) and sodium (in total < 23 mg/dose).

Solution for injection.

Vials of 2 ml filled with a colourless to straw coloured liquid, free from turbidity and from matter that deposits on standing.

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.

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

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 innohep dose during haemodialysis/haemofiltration. The plasma anti-Xa level should be approximately 0.5 anti-Xa IU/ml one hour after administration.

Interchangeability

Special populations

Paediatric population

The safety and efficacy of innohep in children below 18 years have not yet been established.

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, innohep administration can be initiated with anti-Xa monitoring, if the benefit outweighs the risk.

Elderly

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 innohep 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 innohep per litre.

-

- Current or history of immune-mediated heparin-induced thrombocytopenia (type II).

- Active major haemorrhage or conditions predisposing to major haemorrhage. Major haemorrhage is defined as fulfilling any one of these three criteria: a) occurs in a critical area or organ (e.g. intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, intra-uterine or intramuscular with compartment syndrome), b) causes a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or c) leads to transfusion of 2 or more units of whole blood or red blood cells.

- Septic endocarditis.

- The multidose vial formulations of innohep contain 10 mg/ml of the preservative benzyl alcohol. These formulations must not be given to premature babies or neonates due to the risk of gasping syndrome.

The innohep 10,000 IU/ml syringe formulation does not contain the preservative benzyl alcohol.

- In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated because the use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis.

Neuraxial anaesthesia

Caution is advised when performing neuraxial anaesthesia or lumbar puncture in patients receiving prophylactic doses of innohep due to the risk of spinal haematomas resulting in prolonged or permanent paralysis. A minimum delay of 12 hours should be allowed between the last prophylactic dose of innohep and the needle or catheter placement. For continuous techniques, a similar delay should be observed before removing the catheter. Moreover, innohep should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed. Patients should be closely monitored for signs and symptoms of neurological injury.

Haemorrhage

Intramuscular injections

innohep should not be administered by intramuscular injection due to the risk of haematoma. Due to the risk of haematoma, concomitant intramuscular injections should also be avoided.

Heparin-induced thrombocytopenia

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

Hyperkalaemia

Heparin products can suppress adrenal secretion of aldosterone, leading to hyperkalaemia. Risk factors include diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium at pre-treatment, concomitant therapy with drugs that may elevate plasma potassium, and long-term use of innohep. In patients at risk, potassium levels should be measured before starting innohep and monitored regularly thereafter. Heparin-related hyperkalaemia is usually reversible upon treatment discontinuation, though other approaches may need to be considered if innohep treatment is considered lifesaving (e.g. decreasing potassium intake, discontinuing other drugs that may affect potassium balance).

Prosthetic heart valves

Therapeutic failures have been reported in patients with prosthetic heart valves on full anti-coagulant doses of innohep and other low molecular weight heparins. innohep is not recommended for use in this population.

Renal impairment

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/minute. When required in these patients, innohep administration can be used cautiously with anti-Xa monitoring, if the benefit outweighs the risk. Although anti-Xa monitoring remains a poor predictor of haemorrhage risk, it is the most appropriate measure of the pharmacodynamic effects of innohep.

Elderly

Elderly are more likely to have reduced renal function ; therefore caution should be exercised when prescribing innohep to the elderly.

Interchangeability

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.

Excipients warnings

The multidose vial formulations of innohep contain 10 mg/ml of the preservative benzyl alcohol. Benzyl alcohol may cause toxic and anaphylactoid reactions in infants and children up to 3 years old.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

The anticoagulant effect of innohep may be enhanced by other drugs affecting the coagulation system, such as those inhibiting platelet function (e.g. acetylsalicylic acid and other non-steroidal anti-inflammatory drugs), thrombolytic agents, vitamin K antagonists, activated protein C, direct factor Xa and IIa inhibitors. Such combinations should be avoided or carefully monitored.

Pregnancy

Anticoagulant treatment of pregnant women requires specialist involvement.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

A large amount of data on pregnant women (more than 2,200 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of tinzaparin. Tinzaparin does not cross the placenta. innohep can be used during all trimesters of pregnancy if clinically needed.

Epidural anaesthesia:

Due to the risk of spinal haematoma, treatment doses of innohep (175 IU/kg) are contraindicated in patients who receive neuraxial anaesthesia. Therefore, epidural anaesthesia in pregnant women should always be delayed until at least 24 hours after administration of the last treatment dose of innohep. Prophylactic doses may be used as long as a minimum delay of 12 hours is allowed between the last administration of innohep and the needle or catheter placement.

Pregnant women with prosthetic heart valves:

Therapeutic failures and maternal death have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses of innohep and other low molecular weight heparins. In the absence of clear dosing, efficacy and safety information in this circumstance, innohep is not recommended for use in pregnant women with prosthetic heart valves.

Excipients:

innohep vials contain benzyl alcohol. As this preservative may cross the placenta, innohep formulations without benzyl alcohol (syringes) should be used during pregnancy.

Breast-feeding

Animal data indicate that innohep excretion into breast milk is minimal.

It is unknown whether tinzaparin is excreted into human milk. Although oral absorption of low molecular weight heparins is unlikely, a risk to newborns/infants cannot be excluded.

In patients at risk, the incidence of venous thromboembolism is particularly high during the first 6 weeks after child birth.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from innohep therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical studies with innohep regarding fertility.

innohep has no or negligible influence on the ability to drive or use machines.

The most frequently reported undesirable effects are haemorrhage events, anaemia secondary to haemorrhage and injection site reactions.

Haemorrhage may present in any organ and have different degrees of severity. Complications may occur particularly when high doses are administered. Although major haemorrhages are uncommon, death or permanent disability has been reported in some cases.

Immune-mediated heparin-induced thrombocytopenia (type II) largely manifests within 5 to 14 days of receiving the first dose. Furthermore, a rapid-onset form has been described in patients previously exposed to heparin. Immune-mediated heparin-induced thrombocytopenia (type II) may be associated with arterial and venous thrombosis. innohep must be discontinued in all cases of immune-mediated heparin-induced thrombocytopenia.

In rare cases, innohep may cause hyperkalaemia due to hypoaldosteronism. Patients at risk include those with diabetes mellitus or renal impairment.

Serious allergic reactions may sometimes occur. These include rare cases of skin necrosis, toxic skin eruption (e.g. Stevens-Johnson syndrome), angioedema and anaphylaxis. Treatment should be promptly discontinued at the slightest suspicion of such severe reactions.

The estimation of the frequency of undesirable effects is based on a pooled analysis of data from clinical studies and from spontaneous reporting.

Undesirable effects are listed by MedDRA SOC and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Paediatric population

Limited information derived from one study and postmarketing data indicates that the pattern of adverse reactions in children and adolescents is comparable to that in adults.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Haemorrhage is the main complication of overdose. Due to the relatively short half-life of innohep , minor haemorrhages can be managed conservatively following treatment discontinuation. Serious haemorrhage may require the administration of the antidote protamine sulfate. Patients should be carefully monitored.

Any hypovolaemia should be actively managed. Transfusion of fresh plasma may be used, if necessary. Plasma anti-Factor Xa and anti-Factor IIa activity should be measured during the management of overdose situations. Usually, the anticoagulant effects will have reduced to negligible levels after 24 hours, but treatment should be according to the patient's clinical condition.

Pharmacotherapeutic group: Antithrombotic Agents, ATC code: B01AB10

innohep is an antithrombotic agent. It potentiates the inhibition of several activated coagulation factors, especially Factor Xa, its activity being mediated via antithrombin III.

The pharmacokinetics/pharmacodynamic activity of innohep is monitored by anti-Factor Xa activity.

innohep has a bioavailability of around 90% following a subcutaneous injection. The absorption half-life is 200 minutes, peak plasma activity being observed after 4 to 6 hours. The elimination half-life is about 90 minutes.

The half-life of innohep in patients with renal insufficiency given a bolus intravenous dose of 2,500 anti-Factor Xa IU is about 2.5 hours.

There is a linear dose response relationship between plasma activity and the dose administered.

Paediatric population

Preliminary data on the use of tinzaparin suggest that younger children including neonates and infants clear tinzaparin faster and therefore might require higher doses than older children.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

Benzyl alcohol

Sodium acetate

Sodium hydroxide

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years.

The vial should be discarded 14 days after first opening.

Do not store above 25°C.

2 ml multi-dose glass vial containing 10,000 anti-Factor Xa IU/ml.

Pack sizes: 1, 2, 5 or 10 vials.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

LEO Laboratories Limited

Horizon

Honey Lane

Hurley

Maidenhead

Berkshire

SL6 6RJ

UK

PL 00043/0205

Date of first authorisation: 30 September 1998

Date of latest renewal: 26 April 2004

07/03/2017