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1. Innohep 10 000 Iu/Ml
2. Innohep 10 000 Iu/Ml

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

INNOHEP 10,000 IU/ml.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

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

3.    PHARMACEUTICAL FORM

Solution for Injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the prevention of thromboembolic events, including deep vein thrombosis, in adults undergoing general and orthopaedic surgery.

For the prevention of clotting in the extracorporeal circuit during haemodialysis in adults with chronic renal insufficiency.

4.2    Posology and method of administration

For prevention of thromboembolic events:

Administration is by subcutaneous injection.

Adults at low to moderate risk, e.g. patients undergoing general surgery:

3,500 anti-Factor Xa IU two hours before surgery and then once daily for 7 to 10 days post-operatively.

Adults at high risk, e.g. patients undergoing orthopaedic surgery:

In this high risk group the recommended dose is either a fixed dose of 4,500 anti-Factor Xa IU given 12 hours before surgery followed by a once daily dose, or 50 anti-Factor Xa IU/kilogram body weight 2 hours before surgery followed by a once daily dose for 7 to 10 days post-operatively.

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-Factor Xa IU innohep per litre.

Patients with chronic renal insufficiency:

a)    Short-term haemodialysis (up to 4 hours)

A bolus dose of 2,000 - 2,500 anti-Factor Xa IU into the arterial side of the dialyser (or intravenously).

b)    Long-term haemodialysis (more than 4 hours)

A bolus dose of 2,500 anti-Factor Xa IU into the arterial side of the dialyser (or intravenously) followed by 750 anti-Factor Xa IU/hour infused into the extracorporeal circuit.

Dosage adjustment

The bolus innohep dose may be adjusted (increased or decreased) by 250 -500 anti-Factor Xa IU until a satisfactory response is obtained.

Additional innohep (500-1,000 anti-Factor Xa IU) may be given if concentrated red cells or blood transfusions (which may increase the likelihood of clotting in the dialyser) are given during dialysis or additional treatment beyond the normal dialysis duration is employed.

Dose monitoring

Determination of plasma anti-Factor Xa may be used to monitor the innohep dose during haemodialysis. Plasma anti-Factor Xa, one hour after dosing should be within the range 0.4 - 0.5 IU/ml.

Elderly

No dose modifications are necessary.

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.

4.3 Contraindications

•    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 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.

4.4 Special warnings and precautions for use

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).

Neuraxial anaesthesia

In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the use of a peridural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture.

In decision making on the interval between the last administration of heparin at prophylactic doses and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account. Subsequent dose should not take place before at least 4 hours have elapsed. Readministration should be delayed until the surgical procedure is completed.

Should a physician decide to administer anti-coagulation in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits and bowel or bladder dysfunction. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.

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

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 section 4.3 and 4.8). Platelet counts will usually normalise within 2 to 4 weeks after withdrawal.

Hvperkalaemia

Heparin products can suppress adrenal secretion of aldosterone, leading to hyperkalaemia. Risk factors include diabetes mellitus, chronic renal failure, preexisting 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

There have been no adequate studies to assess the safe and effective use of innohep in preventing valve thrombosis in patients with prosthetic heart valves. The use of innohep cannot be recommended for this purpose.

Renal impairment (also see Section 4.2, Posology and method of administration) Available evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 ml/minute. Although anti-Xa monitoring is the most appropriate measure if the pharmacodynamics 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.

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.

Interchangeability with other LMWHs:

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, should be avoided.

Special attention and compliance with the instructions for use specific to each proprietary medicinal product are required.

Hypersensitivity to heparin or other LMWHs

innohep should be used with caution in patients with hypersensitivity to heparin or to other low molecular weight heparins.

Excipient warnings

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

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. (See section 4.3 for premature babies and neonates.)

4.5 Interaction with other medicinal products and other forms of interaction

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 (see section 4.4).

4.6 Fertility, pregnancy and lactation

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 breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical studies with innohep regarding fertility.

4.7. Effects on ability to drive and use machines

No adverse effects to be expected.

Undesirable effects

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 (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

>1/100 and < 1/10 >1/1,000 and <1/100 >1/10,000 and <1/1,000 <1/10,000

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 decreased)

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 transaminases, 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 treatment)
Reproductive system and breast disorders
Rare >1/10,000 and <1/1,000	Priapism
General disorders and administration sit	e conditions
Common >1/100 and < 1/10	Injection site reaction (incl. injection site haematoma, haemorrhage, pain, pruritus, nodule, erythema 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Haemorrhage is the main complication of overdose. Due to the relatively short halflife of innohep (see section 5.2), minor haemorrhages can be managed conservatively following treatment discontinuation. Serious haemorrhage may require the administration of the antidote protamine sulphate. 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.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

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

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Benzyl alcohol, Sodium acetate, Sodium hydroxide, Water for Injections.

6.2    Incompatibilities

Innohep should not be mixed with any other injection.

6.3    Shelf life

2 years.

6.4    Special precautions for storage

Do not store above 25 °C.

6.5    Nature and contents of container

2ml glass vial containing 10,000 anti-Factor Xa IU/ml in packs of 1, 2, 5 and 10 vials.

6.6    Instructions for use/handling

The vial should be discarded 14 days after first use.

7 MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited

Horizon

Honey Lane

Hurley Maidenhead Berkshire SL6 6RJ UK

8. MARKETING AUTHORISATION NUMBER(S)

PL 00043/0205

9. DATE OF FIRST AUTHORISATION/RENEWAL AUTHORISATION

30^th September 1998

10 DATE OF REVISION OF THE TEXT

06/03/2015