Innohep 20 000 Iu/Ml
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
INNOHEP 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 in adults.
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 antifactor Xa activity may 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).
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), 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. This formulation must not be given to premature babies and neonate due to the risk of gasping syndrome.
The innohep® 20,000 IU/ml syringe formulation does not contain the preservative benzyl alcohol.
• 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 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
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.
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 (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 of the pharmacodynamic 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).
Some formulations of innohep contain sodium metabisulphite. Metabisulphites may rarely cause severe hypersensitivity reactions and bronchospasm. innohep formulations containing sodium metabisulphite 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 Ila 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.
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 >1/10
Common Uncommon Rare Very rare
>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.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 18 October 1994 Date of latest renewal: 25 March 2007
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, 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 pre-clinical 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
Sodium metabisulphite, Benzyl alcohol, Sodium hydroxide, Water for Injections.
6.2 Incompatibilities
Innohep should be given by subcutaneous injection only. It 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 20,000 anti-Factor Xa IU/ml in packs of 1 or 10 vials.
6.6 Special precautions for disposal
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 0043/0192.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18 October 1994.
10 DATE OF REVISION OF THE TEXT
06/03/2015