Prophylaxis of venous thromboembolism in adult patients undergoing surgery, particularly ortho- paedic, 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 can- cer, as well as exacerbation of rheumatic diseases.

 

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

0.1                   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:

4500 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 receiv- ing prophylactic doses of Innohep (see section 4.4 regarding neuraxial anaesthesia). If neuraxial anaesthesia is planned, a minimum delay of 12 hours should be allowed between the last prophy- lactic dose and the needle or catheter placement. Innohep 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 Innohep is not compatible with neurax- ial anaesthesia.

 

Haemodialysis and haemofiltration in adults:

 

Duration of 4 hours or less:

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

 

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

 

Dose monitoring:

Determination of plasma anti-Xa activity can be used to monitor the Innohep dose during haemo- dialysis/haemofiltration. The plasma anti-Xa level should be approximately 0.5 anti-Xa IU/mL one hour after administration.

 

Interchangeability

For interchangeability with other low molecular weight heparins (LMWHs), see section 4.4. Special populations

Paediatric population

The safety and efficacy of Innohep 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 pa- tients with creatinine clearance levels down to 20 mL/minute. When required in these patients, Innohep administration can be initiated with anti-Xa monitoring, if the benefit outweighs the risk (see section 4.4 regarding renal impairment).

 

Elderly

Innohep 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 regarding patients with renal impairment and section 4.4 regarding 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.

 

Innohep is given subcutaneously, for thrombosis prophylaxis in adults. This can be done in ab- dominal 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 be- tween 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 is to be given into the arterial side of the dialyser or in- travenously. The dialyser can be flushed with 500–1,000 mL isotonic sodium chloride

(9 mg/mL) containing 5,000 anti-Xa IU Innohep per litre.

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Current or history of immune-mediated heparin-induced thrombocytopenia (type II) (see section 4.4). 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 two 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 and neonates due to the risk of gasping syndrome.

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 per- manent paralysis. A minimum delay of 12 hours should be allowed between the last prophylactic dose 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

Caution is advised when administering Innohep to patients at risk of haemorrhage. For patients at risk of major haemorrhage, see section 4.3. The combination with medicinal products affecting platelet function or the coagulation system should be avoided or carefully monitored (see section 4.5).

 

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 dis- continued in patients who develop immune-mediated heparin-induced thrombocytopenia (type II), see section 4.3 and 4.8. 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 potas- sium, 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 re- versible 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-coagu- lant 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 pa- tients 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 (see section 4.2). 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 (see section 4.4: Renal impairment); there- fore caution should be exercised when prescribing Innohep to the elderly.

 

Interchangeability

Low molecular weight heparins should not be used interchangeably because of differences in phar- macokinetics and biological activities. Switching to an alternative low molecular weight heparin,

 

especially during extended use, must be exercised with particular caution and specific dosing in- structions 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 allergic reactions. Benzyl alcohol may cause toxic and anaphylactoid reactions in infants and children up to 3 years old. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of ac- cumulation and toxicity (metabolic acidosis).

 

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

 

The anticoagulant effect of Innohep may be enhanced by other drugs affecting the coagulation sys- tem, 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 (see section 4.4).

Pregnancy

Anticoagulant treatment of pregnant women requires specialist involvement.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive tox- icity (see section 5.3).

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 be- tween the last administration of Innohep and the needle or catheter placement.

 

Pregnant women with prosthetic heart valves

Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full an- ticoagulant doses of Innohep and other low molecular weight heparins. Innohep cannot be recom- mended for use in this population.

 

Excipients

Innohep vials contain benzyl alcohol. As this preservative may cross the placenta and may cause accumulation and toxicity (metabolic acidosis), {name} formulations without benzyl alcohol (pre- filled 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 mo- lecular 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 six weeks after

 

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

 

Excipients

Innohep vials contain benzyl alcohol. Due to a risk of accumulation and toxicity (metabolic acido- sis), Innohep formulations without benzyl alcohol (pre-filled syringes) are the preferred choice dur- ing breast-feeding.

 

Fertility

There are no clinical studies with Innohep regarding fertility.

innohep^® has no or negligible influence on the ability to drive and 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 uncom- mon, 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 pre- viously 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 im- mune-mediated heparin-induced thrombocytopenia (see section 4.4).

 

In rare cases, Innohep may cause hyperkalaemia due to hypoaldosteronism. Patients at risk include those with diabetes mellitus or renal impairment (see section 4.4).

 

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.

 

Very common (≥1/10) Common (≥1/100 and < 1/10)

Uncommon (≥1/1,000 and <1/100) Rare (≥1/10,000 and <1/1,000)

Very rare (<1/10,000), unknown (could not be estimated from currently available data)

 

Blood and lymphatic system disorders
Common ≥1/100 and < 1/10	Anaemia (incl. haemoglobin decreased)
Uncommon ≥1/1,000 and <1/100	Thrombocytopenia (type I) (incl. platelet count de- creased)

 

 

Rare ≥1/10,000 and <1/1,000	Heparin-induced thrombocytopenia (type II) Thrombocytosis
Immune system disorders
Uncommon ≥1/1,000 and <1/100	Hypersensitivity
Rare ≥1/10,000 and <1/1,000	Anaphylactic reaction
Metabolism and nutrition disorders
Rare ≥1/10,000 and <1/1,000	Hyperkalaemia
Vascular disorders
Common ≥1/100 and < 1/10	Haemorrhage Haematoma
Uncommon ≥1/1,000 and <1/100	Bruising, ecchymosis and purpura
Hepatobiliary disorders
Uncommon ≥1/1,000 and <1/100	Hepatic enzyme increased (incl. increased trans- aminases, ALT, AST and GGT)
Skin and subcutaneous tissue disorders
Uncommon ≥1/1,000 and <1/100	Dermatitis (incl. dermatitis allergic and bullous) Rash Pruritus
Rare ≥1/10,000 and <1/1,000	Toxic skin eruption (including Stevens-Johnson syndrome) Skin necrosis Angioedema Urticaria
Musculoskeletal and connective tissue disorders
Rare ≥1/10,000 and <1/1,000	Osteoporosis (in connection with long-term treat- ment)
Reproductive system and breast disorders
Rare ≥1/10,000 and <1/1,000	Priapism
General disorders and administration site conditions
Common ≥1/100 and < 1/10	Injection site reaction (incl. injection site haema- toma, haemorrhage, pain, pruritus, nodule, ery- thema and extravasation)

 

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:

 

Danish Medicines Agency Axel Heides Gade 1

DK-2300 Copenhagen S

Homepage: www.meldenbivirkning.dk

Haemorrhage is the main complication of overdose. Due to the relatively short half-life of Innohep (see section 5.2), minor haemorrhages can be managed conservatively following treatment discon- tinuation. Serious haemorrhage may require the administration of the antidote protamine sulfate.

Patients should be carefully monitored.

Tinzaparin sodium is a low molecular weight heparin of porcine origin with an anti-Xa/anti-IIa ra- tio between 1.5 and 2.5. Tinzaparin sodium is produced by enzymatic depolymerisation of conven- tional unfractionated heparin. Like conventional heparin, tinzaparin sodium acts as an anticoagu- lant by potentiating antithrombin III’s inhibition of activated coagulation factors, primarily factor Xa.

 

The biological activity of tinzaparin sodium is standardised against the current “International stand- ards for low molecular weight heparins”, and expressed in anti-Xa international units (IU).

 

The anti-Xa activity of tinzaparin sodium is not less than 70 and not more than 120 IU/mg. The anti-IIa activity of tinzaparin sodium is approximately 55 IU/mg. The characteristic value of mass- average molecular mass of tinzaparin sodium is about 6,500. The mass percentage of chains lower than 2,000 is not more than 10.0 per cent. The mass percentage of chains between 2,000 and 8,000 ranges between 60.0 % and 72.0 % (typical 66%). The mass percentage of chains above 8,000 ranges between 22.0 % and 36.0 %.

 

The absolute bioavailability based on anti-Xa activity after subcutaneous administration is approximately 90% and time to reach maximal activity is 4-6 hours. The terminal elimination half-life is approximately 3.7 hours. Due to the long half-life of the pharmacological effect for Innohep, once daily administration is sufficient.

 

Tinzaparin sodium undergoes minor metabolisation in the liver through a depolymerisation and is excreted via the kidneys as an unchanged or almost unchanged form.

 

The pharmacokinetic activity of Innohep has been studied in pregnant women. Data from sequen- tial pharmacokinetic monitoring of 55 pregnant women indicate that the pharmacokinetic proper- ties do not differ from the pharmacokinetic properties in non-pregnant women. There was a slight, but non-statistically significant drop in the anti-Xa levels as the pregnancy progressed. Some moni- toring of peak anti-Xa levels 4 hours after administration of tinzaparin sodium is recommended in the first weeks of treatment as well as later in the pregnancy.

 

Following a bolus IV injection of 2,500 anti-Xa IU, administered to dialysis patients, the observed half-life is about 2.5 hours. The pharmacokinetic properties are monitored by anti-Xa activity de- termination. There is a linear connection between plasma anti-Xa 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.

However, data are not sufficient to allow for dosing recommendations, see section 4.2.

Heparins and low molecular weight heparins (LMWH) are generally only slightly toxic, and this applies for tinzaparin sodium as well. The most important effect observed in studies of acute, sub- acute and chronic toxicity, reproduction toxicity and mutagenicity is haemorrhaging caused by the very high doses administered.

 

After intramuscular administration of LMWH in animals necrotising haematoma was observed. Osteoporotic effects were revealed in a 12 month study in rats. Animal studies in rats and rabbits did not show a teratogenic potential of LMWH in doses up to 25 mg/kg body weight. Fetuses which were prenatally exposed to 10 mg/kg body weight were found to have lower body weights than controls.

 

Benzyl alcohol

Sodium acetate trihydrate

Sodium hydroxide

Water for injections

This medicinal product must not be mixed with other medicinal products.

2 years Chemical and physical in use stability has been demonstrated for 28 days at 30°C. From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days at 30°C. Other in-use storage times and conditions are the responsibility of the user.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Multi-dose vials of 2 mL and 5 mL Pack size: 10

 

Not all pack sizes may be marketed.

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