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.

Some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alterna- tive treatment, such as surgery or thrombolysis, may be indicated.

Posology

Adults

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

 

Extended treatment in cancer patients

175 IU anti-Xa/kg dose given subcutaneously once daily. The recommended treatment duration is 6 months. Anticoagulant treatment beyond 6 months should be evaluated.

 

Neuraxial anaesthesia

Treatment doses of Innohep (175 IU/kg) are contraindicated in patients who receive neuraxial an- aesthesia, 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 low molecular weight heparins, 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. Availa- ble 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 monitor- ing, 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 re- spectively, 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 treat- ment 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 in- jections between left and right side. The air-bubble within the syringe should not be removed. Dur- ing the injection, the skin should be held in a fold.

 

Doses are administered in 1,000 IU increments facilitated by theInnohep 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 ap- propriate dosage before subcutaneous injection.

 

Guide to appropriate dosages for different body weights - 175 IU/kg body weight subcuta- neously once daily
	Kg*	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 estab- lish the appropriate dose/volume

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, itra- 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. Treatment doses of Innohep (175 IU/kg) are contraindicated in patients who receive neuraxial an- aesthesia. If neuraxial anaesthesia is planned, Innohep should be discontinued at least 24 hours be- fore 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 moni- tored 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 with- drawal.

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.

 

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 treatment 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 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

Innohep 20,000 anti-Xa IU/mL contains sodium metabisulfite. Metabisulfites may rarely cause se- vere hypersensitivity reactions and bronchospasm. Innohep formulations containing sodium meta- bisulfite must be used with caution in patients with asthma.

 

This medicinal product contains up to 40 mg sodium per mL. The amount 40 mg is equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 and lactation

 

Fertility

There are no clinical studies with Innohep regarding fertility.

 

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.

 

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.

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

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)

 

Patients with cancer on extended treatment

In a trial of patients with cancer on extended (6 months) treatment with Innohep, the overall fre- quency of adverse reactions was comparable to that seen in other patients treated with Innohep. Pa- tients 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 post-marketing 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 sulphate. 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 the 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 %. 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 anti-Xa levels as the pregnancy progressed. Some monitor- ing 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.

 

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 months 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.

Sodium metabisulfite (E223)

Sodium hydroxide

 

Water for injections

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

3 years

This medicinal product does not require any special storage conditions.

Pre-filled syringe (graduated), with protective cap, plunger and needle safety device Pack sizes: 2, 6, 10, 30, 50 and 100 injection syringes.

Not all pack sizes may be marketed.

 

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