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) alternative 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 adequate
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 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 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. 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 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 appropriate dosage before subcutaneous injection.

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, itraarticular 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 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.

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 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.
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 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); 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
Innohep 20,000 anti-Xa IU/mL contains 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.
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 system, such as those inhibiting platelet function (e.g. acetylsalicylic acid and other non-steroidal antiinflammatory
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).

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 toxicity
(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 between
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 anticoagulant
doses of Innohep and other low molecular weight heparins. Innohep cannot be recommended
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 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 six 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.

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 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)
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)

 

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 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 discontinuation.
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 ratio between 1.5 and 2.5. Tinzaparin sodium is produced by enzymatic depolymerisation of conventional unfractionated heparin. Like conventional heparin, tinzaparin sodium acts as an anticoagulant
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 standards 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 sequential pharmacokinetic monitoring of 55 pregnant women indicate that the pharmacokinetic properties 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 monitoring 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, subacute 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.