Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: LEO Laboratories Limited, Horizon, Honey Lane, Hurley, Maidenhead, Berkshire, SL6 6RJ, UK
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:
Septic endocarditis.
The multidose vial formulations of innohep contain 10 mg/ml of the preservative benzyl alcohol. These formulations must not be given to premature babies or neonates due to the risk of gasping syndrome. The innohep 10,000 IU/ml syringe formulation does not contain the preservative benzyl alcohol.
In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated because the use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis.
Caution is advised when performing neuraxial anaesthesia or lumbar puncture in patients receiving prophylactic doses of innohep due to the risk of spinal haematomas resulting in prolonged or permanent paralysis. A minimum delay of 12 hours should be allowed between the last prophylactic dose of innohep and the needle or catheter placement. For continuous techniques, a similar delay should be observed before removing the catheter. Moreover, 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.
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).
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.
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.
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).
Therapeutic failures have been reported in patients with prosthetic heart valves on full anticoagulant doses of innohep and other low molecular weight heparins. innohep is not recommended for use in this population.
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 administration 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 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.
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.
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.
This medicinal product contains less than 1 mmol sodium (23 mg) per mL, i.e. essentially ‘sodium-free’.
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).
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.
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.
Therapeutic failures and maternal death have been reported in pregnant women with prosthetic heart valves on full anticoagulant 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.
innohep vials contain benzyl alcohol. As this preservative may cross the placenta, innohep formulations without benzyl alcohol (syringes) should be used during pregnancy.
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 breast-feeding for the child and the benefit of therapy for the woman.
There are no clinical studies with innohep regarding fertility.
innohep has no or negligible influence on the ability to drive or 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 to <1/10
Uncommon ≥1/1,000 to <1/100
Rare ≥1/10,000 to <1/1,000
Very rare <1/10,000
Common: Anaemia (incl. haemoglobin decreased)
Uncommon: Thrombocytopenia (type I) (incl. platelet count decreased)
Rare: Heparin-induced thrombocytopenia (type II), Thrombocytosis
Uncommon: Hypersensitivity
Rare: Anaphylactic reaction
Rare: Hyperkalaemia
Common: Haemorrhage, Haematoma
Uncommon: Bruising, ecchymosis and purpura
Uncommon: Hepatic enzyme increased (incl. increased transaminases, ALT, AST and GGT)
Uncommon: Dermatitis (incl. dermatitis allergic and bullous), Rash, Pruritus
Rare: Toxic skin eruption (including Stevens-Johnson syndrome), Skin necrosis, Angioedema, Urticaria
Rare: Osteoporosis (in connection with long-term treatment)
Rare: Priapism
Common: Injection site reaction (incl. injection site haematoma, haemorrhage, pain, pruritus, nodule, erythema and extravasation)
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 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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