Innohep Syringe 20 000 Iu/Ml

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

innohep Syringe 20,000 IU/ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tinzaparin sodium 20,000 anti-Factor Xa IU/ml Excipients with known effect:

Sodium metabisulfite (1.83 mg/ml) and sodium (in total < 23 mg/dose).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe.

1 ml syringe holding a colourless to straw coloured liquid, free from turbidity and from matter that deposits on standing.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of venous thrombosis and thromboembolic disease including deep vein thrombosis and pulmonary embolus in adults.

Extended treatment of venous thromboembolism and prevention of recurrences in adult patients with active cancer.

For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment, such as surgery or thrombolysis, may be indicated.

4.2 Posology and method of administration

Posology

Treatment in adults

175 anti-Xa IU/kg body weight given subcutaneously once daily for at least 6 days and until adequate oral anti-coagulation is established.

Extended treatment in adult patients with active cancer 175 IU anti-Xa IU/kg body weight given subcutaneously once daily for a recommended treatment period of 6 months. The benefit of continued anticoagulation treatment beyond 6 months should be evaluated.

Neuraxial anaesthesia

Treatment doses of innohep (175 IU/kg) are contraindicated in patients who receive neuraxial anaesthesia, see section 4.3. If neuraxial anaesthesia is planned, innohep should be discontinued at least 24 hours before the procedure is performed. innohep should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed.

Interchangeability

For interchangeability with other LMWHs, see section 4.4.

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 patients with creatinine clearance levels down to 20 ml/min. When required in these patients, innohep treatment can be initiated with anti-Xa monitoring, if the benefit outweighs the risk (see section 4.4: Renal impairment). In this situation, the dose of innohep should be adjusted, if necessary, based on anti-factor Xa activity. If the anti-factor Xa level is below or above the desired range, the dose of innohep should be increased or reduced respectively, and the anti-factor Xa measurement should be repeated after 3-4 new doses. This dose adjustment should be repeated until the desired anti-factor Xa level is achieved. For guidance, mean levels between 4 and 6 hours after administration in healthy volunteers and patients without severe renal insufficiency have been between 0.5 and 1.5 IU/anti-factor Xa IU/ml. Anti-factor Xa activity determinations were by a chromogenic assay.

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: Renal impairment and section 4.4: Renal impairment.

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 by storage but is still suitable.

Administration is by subcutaneous injection. 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 supine position, alternating the injections between 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.

Doses are administered in 1,000 IU increments facilitated by the 0.05 ml graduations on the syringes. The calculated dose, based on the patient’s body weight, should therefore be rounded up or down as appropriate. If necessary, any excess volume should be expelled, to achieve the appropriate dosage before SC injection.

Guide to appropriate dosages for different body weights - 175 IU/kg body weight subcutaneously once daily

	kg¹	International units (IU)	Injection volume (ml)
20,000 IU/ml in graduated syringes	32-37	6,000	0.30
	38-42	7,000	0.35
	43-48	8,000	0.40
	49-54	9,000	0.45
	55-59	10,000	0.50
	60-65	11,000	0.55
	66-71	12,000	0.60
	72-77	13,000	0.65
	78-82	14,000	0.70
	83-88	15,000	0.75
	89-94	16,000	0.80
	95-99	17,000	0.85
	100-105	18,000	0.90

*For patients weighing < 32 kg or > 105 kg, the same calculation as above should be used to establish the appropriate dose/volume

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).

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. Re-administration 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

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

Regular monitoring of platelet count also applies to extended treatment for cancer-associated thrombosis, especially during the first month, considering that cancer and its treatments such as chemotherapy may also cause thrombocytopenia.

Patients with pulmonary embolism

For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment, such as surgery or thrombolysis, may be indicated.

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 (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 tinzaparin sodium in preventing valve thrombosis in patients with prosthetic heart valves; therefore no dosage recommendations can be given. High doses of tinzaparin sodium (175 IU/kg) may not be sufficient prophylaxis to prevent valve thrombosis in patients with prosthetic heart valves. The use of tinzaparin sodium cannot be recommended for this purpose.

Renal impairment

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

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.

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’.

Some formulations of innohep contain sodium metabisulfite. Metabisulfites may rarely cause severe hypersensitivity reactions and bronchospasm. innohep formulations containing sodium metabisulfite must be used with caution in patients with asthma.

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.

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

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

4.8 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 Common Uncommon Rare

Very rare

>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 disort	ers
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 site conditions
Common >1/100 and < 1/10	Injection site reaction (incl. injection site haematoma, haemorrhage, pain, pruritus, nodule, erythema and extravasation)

Patients with cancer on extended treatment

In a trial of patients with cancer on extended (6 months) treatment with innohep, the overall frequency of adverse reactions was comparable to that seen in other patients treated with innohep. Patients with cancer generally have an increased risk of haemorrhage, which is further influenced by older age, comorbidities, surgical interventions and concomitant medications. Thus, as expected, the incidence of haemorrhagic events was higher than previously observed in short-term use, and similar to the rates seen with extended use of anticoagulants in patients with cancer.

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 half-life 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 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.

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.

A meta-analysis of five studies of innohep in non-cancer and cancer patients showed that, at the end of a 3 to 6 month treatment period, use of innohep in the subpopulation of cancer patients to manage venous thrombo-embolism resulted in a rate of recurrence of venous thrombo-embolism that was not statistically significantly different compared to the rate when oral vitamin K analogues were used. In addition, there was not a statistically significant difference in overall mortality or major bleeding episodes related to treatment.

5.2 Pharmacokinetic properties

The pharmacokinetics/pharmacodynamic activity of innohep is monitored by anti-Factor Xa activity. Following subcutaneous injection of innohep, antiFactor Xa activity reaches a maximum at 4-6 hours (peak anti-Factor Xa activity, after administration of 175 anti-Factor Xa IU/kg bodyweight once daily, is approximately 0.5-1.0 IU/ml). Detectable anti-Factor Xa activity persists for 24 hours.

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 SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium metabisulfite

Sodium hydroxide Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

3 years.

Contains no bactericide, any portion of the contents not used at once should be discarded together with the syringe.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

1 ml pre-filled variable dose graduated syringe (glass Type I) with protective cap, plunger and needle safety device containing:

0.4 ml (8,000 anti-Factor Xa IU)

0.5 ml (10,000 anti-Factor Xa IU)

0.6 ml (12,000 anti-Factor Xa IU)

0.7 ml (14,000 anti-Factor Xa Iu)

0.8 ml (16,000 anti-Factor Xa IU)

0.9 ml (18,000 anti-Factor Xa Iu)

Pack sizes: 2, 6 or 10 syringes.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited

Horizon

Honey Lane

Hurley

Maidenhead

Berkshire

SL6 6RJ

8 MARKETING AUTHORISATION NUMBER(S)

PL 00043/0197

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 3 October 1996 Date of latest renewal: 21 December 2002

10 DATE OF REVISION OF THE TEXT

29/09/2016

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.

• Treatment doses of innohep (175 IU/kg) are contraindicated in patients who receive neuraxial anaesthesia. If neuraxial anaesthesia is planned, innohep should be discontinued at least 24 hours before the procedure is performed. 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.

• In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contraindicated