1. Name Of The Medicinal Product
innohep® 20,000 IU/ml and innohep® Syringe 20,000 IU/ml
2. Qualitative And Quantitative Composition
Tinzaparin sodium 20,000 anti-Factor Xa IU/ml
3. Pharmaceutical Form
Solution for injection
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of deep vein thrombosis and of pulmonary embolus.
4.2 Posology And Method Of Administration
Administration is by subcutaneous injection only.
Adults:
175 anti-Factor Xa IU/kg bodyweight once daily, for at least 6 days and until adequate oral anti-coagulation is established. There is no need to monitor the anticoagulant activity of innohep®.
Patients with renal impairment:
Caution is recommended when treating patients with renal impairment (see Section 4.4, Special warnings and precautions for use). Monitoring of anti-factor Xa activity should be considered in patients with severe renal impairment (creatinine clearance < 30 ml/min); however, available evidence suggests that no dose reduction is needed in patients with creatinine clearance levels down to 20 ml/min.
Elderly:
Renal function should be assessed, for example with the Cockcroft-Gault formula, to estimate creatinine clearance levels. No dose reduction is needed in elderly patients with normal renal function (see Section 4.4, Special warnings and precautions for use).
Children:
There is no experience of use in children.
4.3 Contraindications
• Known hypersensitivity to constituents.
• Current or history of heparin-induced thrombocytopenia.
• Generalised or local haemorrhagic tendency, including uncontrolled severe hypertension, severe liver insufficiency, active peptic ulcer, acute or subacute septic endocarditis, intracranial haemorrhage, or injuries and operations on the central nervous system, eyes and ears, and in women with abortus imminens.
• The innohep® 20,000 IU/ml vial formulation contains 10 mg/ml of the preservative benzyl alcohol. This formulation must not be given to premature babies or neonates.
The innohep® 20,000 IU/ml syringe formulation does not contain the preservative benzyl alcohol.
• An epidural anaesthesia during birth in pregnant women treated with low molecular weight heparin is contraindicated (see section 4.6).
• In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contraindicated 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
Care should be taken when innohep® is administered to patients with increased risk of bleeding complications.
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 four 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.
innohep® should not be administered by intramuscular injection due to the risk of haematoma.
Due to increased bleeding risk care should be taken when giving concomitant intramuscular injections, lumbar puncture and similar procedures.
innohep® should be used with caution in patients with hypersensitivity to heparin or to other low molecular weight heparins.
As there is a risk of antibody-mediated heparin-induced thrombocytopenia, platelet counts should be measured in patients receiving heparin treatment for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.
As with other low molecular weight heparins, in some patients undergoing surgical procedures (especially orthopaedic) or presenting with a concomitant inflammatory process, the administration of innohep® has coincided with an asymptomatic increase of platelet count, which in many cases subsided during continued administration. If an increase in platelet count occurs, evaluation of the benefit/risk of continuing therapy for that patient should be made.
Renal impairment (also see Section 4.2, Posology and method of administration): Caution is recommended in the treatment of patients with renal impairment. Monitoring of anti Xa activity should be considered in patients with severe renal impairment (creatinine clearance < 30 ml/min).
Caution is recommended in the treatment of elderly patients with renal impairment. Renal function should be assessed in all elderly patients. Monitoring of anti-factor Xa activity should be considered in patients with severe renal impairment (creatinine clearance < 30 ml/min).
For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment, such as surgery or thrombolysis, may be indicated.
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium-sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.
The innohep® 20,000 IU/ml syringe and vial formulations contain sodium metabisulphite (E223). This may rarely cause severe hypersensitivity reactions and bronchospasm.
The innohep® 20,000 IU/ml vial formulation contains the preservative benzyl alcohol 10 mg/ml. This should be administered with caution to infants and children up to 3 years old, as there is a risk that benzyl alcohol may cause toxic reactions and allergic reactions (anaphylactoid) in this age group (see section 4.3 for premature babies and neonates).
Drugs affecting platelet function or the coagulation system should in general not be given concomitantly with innohep® (see section 4.5).
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The anticoagulant effect of innohep® may be enhanced by concomitant medication with other drugs affecting platelet function or the coagulation system, e.g. platelet aggregation inhibitors, thrombolytic agents, salicylates, non-steroidal anti-inflammatory drugs, vitamin K antagonists, dextrans, activated protein C.
4.6 Pregnancy And Lactation
Pregnancy
No transplacental passage of innohep® was found (assessed by anti-Factor Xa and anti-Factor IIa activity) in patients given a dose of 35 to 40 anti-Factor Xa IU/kg in the second trimester of pregnancy. In rabbits, no transplacental passage of anti-Factor Xa or anti-Factor IIa activity was observed after doses of 1750 anti-Factor Xa IU/kg. Toxicological studies in rats have shown no embryotoxic or teratogenic effects, although a lower birthweight was found.
Although these animal studies show no hazard, as a precaution innohep® should not be used in pregnancy unless no safer alternative is available.
As benzyl alcohol may cross the placenta, the use of innohep® formulations containing benzyl alcohol should be avoided during pregnancy.
The use of innohep® in women with abortus imminens is contraindicated (see section 4.3).
Prosthetic heart valves:
Therapeutic failures and maternal death have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses of low molecular weight heparins. In the absence of clear dosing, efficacy and safety information in this circumstance, tinzaparin sodium is not recommended for use in pregnant women with prosthetic heart valves.
Lactation
It is not known whether innohep® is excreted in breast milk. However, patients are advised to stop breast-feeding while receiving innohep®.
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
Based on reports from clinical trials the frequency rate of all adverse reactions is 17.6%. The most frequently reported undesirable effects are bleeding events, injection site reactions, various skin reactions, reversible thrombocytopenia, allergic reactions, headache and reversible increase in liver enzymes.
Based on pooled study results, from a clinical trial programme where 3167 patients received innohep®, local reactions following subcutaneous administration such as irritation, bruising, pain and ecchymosis were identified in approximately 3.7% of patients. The overall bleeding risk was approximately 11% while the risk of major bleeding was approximately 0.5%. Reversible thrombocytopenia was seen in approximately 0.6% of patients.
A list of undesirable effects is given below. Where frequencies are given, these are based on the clinical trial data, using the stated frequency classification. Where the term 'Not known' is given, these effects are derived from spontaneous reports.
Frequency classification:
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4.9 Overdose
Overdose of innohep® may be complicated by haemorrhage. With recommended dosages there should be no need for an antidote but in the event of accidental administration of an overdose, the effect of innohep® can be reversed by intravenous administration of 1% protamine sulphate solution.
The dose of protamine sulphate required for neutralisation should be accurately determined by titrating with the patient's plasma.
Studies in healthy volunteers indicate that 65-80% of the anti-Xa activity is neutralised by protamine sulphate 1 mg/100 anti-Xa IU of innohep®. A return of innohep® anti-Xa, anti-IIa and APTT activities are seen 3 hours after its reversal probably due to continuous absorption of innohep® from the s.c. depot. It may therefore be necessary to give protamine sulphate intermittently or as a continuous infusion to achieve and maintain neutralisation of s.c. innohep® for at least 24 hours. Potential side-effects of protamine sulphate must be considered and patients carefully observed.
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.
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. Following subcutaneous injection of innohep®, anti-Factor 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.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
innohep® 20,000 IU/ml:
Sodium metabisulphite
Benzyl alcohol
Sodium hydroxide
Water for injections
innohep® Syringe 20,000 IU/ml:
Sodium metabisulphite
Sodium hydroxide
Water for injections
6.2 Incompatibilities
innohep® should be given by subcutaneous injection. It should not be mixed with any other injection.
6.3 Shelf Life
innohep® 20,000 IU/ml:
2 years.
innohep® Syringe 20,000 IU/ml:
3 years.
6.4 Special Precautions For Storage
Do not store above 25°C.
6.5 Nature And Contents Of Container
innohep® 20,000 IU/ml:
2 ml glass vial containing 20,000 anti-Factor Xa IU/ml in packs of 1 vial.
innohep® Syringe 20,000 IU/ml:
A prefilled variable dose graduated syringe with needle safety device containing:
0.5 ml (10,000 anti-Factor Xa IU)
0.7 ml (14,000 anti-Factor Xa IU)
0.9 ml (18,000 anti-Factor Xa IU)
in packs of 2 and 6 syringes
6.6 Special Precautions For Disposal And Other Handling
innohep® 20,000 IU/ml:
The vial should be discarded 14 days after first use.
innohep® Syringe 20,000 IU/ml:
Contains no bactericide, any portion of the contents not used at once should be discarded together with the syringe.
7. Marketing Authorisation Holder
LEO Laboratories Limited
Longwick Road
Princes Risborough
Bucks HP27 9RR
8. Marketing Authorisation Number(S)
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9. Date Of First Authorisation/Renewal Of The Authorisation
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10. Date Of Revision Of The Text
1 September 2011
LEGAL CATEGORY
POM
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