innohep

10 Vials of 2 mL: Tinzaparin sodium 10,000 IU anti-Xa/mL, preserved with benzyl alcohol (10 mg/mL).
Formulation: Tinzaparin sodium 10,000 IU anti-Xa, Benzyl alcohol 10 mg.

Properties: 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 depolymerization 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 standardized against the 1st "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 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 percent. The mass percentage of chains between 2,000 and 8,000 ranges between 60.0 and 72.0 percent (typical 66%). The mass percentage of chains above 8,000 ranges between 22.0 and 36.0 percent.
The maximum anti-Xa activity is seen after 4-6 hours following subcutaneous injection. The elimination half-life of anti-Xa activity after i.v. injection is approx. 90 minutes. Bioavailability of anti-Xa activity is 90%. Due to the very long biological half-life of Tinzaparin sodium (innohep), administration once daily is sufficient.
Tinzaparin undergoes minor metabolization in the liver through a depolymerization and is excreted via the kidneys as an unchanged or almost unchanged form. The pharmacokinetic activities of Tinzaparin sodium (innohep) have been studied in pregnancy.
Data from sequential pharmacokinetic monitoring in 55 pregnancies suggests that pharmacokinetic properties do not differ from the non-pregnant state. There was a small, but non-statistically significant, decrease in anti-Xa levels with advancing gestation. Some monitoring of peak anti-Xa levels four hours following administration of tinzaparin is recommended in the first weeks of administration and in late pregnancy.
Toxicology: Preclinical Safety Data: Heparins and LMW-heparins 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 LMW-heparin in animals necrotising haematoma were observed. Osteoporotic effects were revealed in a 12-months study in rats. Animal studies in rats and rabbits failed to find a teratogenic potential of LMW-heparin in doses up to 25 mg/kg bodyweight. Foetuses which were prenatally exposed to 10 mg/kg body weight were found to have lower bodyweights than controls.

Treatment of venous thrombosis and thromboembolic disease including deep vein thrombosis and pulmonary embolus.
Note: Tinzaparin sodium (innohep) is not indicated for the treatment of serious pulmonary embolism, i.e. high-risk patients with hemodynamic instability.

175 anti-Xa IU/kg body weight given subcutaneously once daily.
Oral anticoagulation should be commenced on the second day of treatment.
175 anti-Xa IU/kg body weight once daily for at least 6 days and until adequate oral anti-coagulation is established.
Prefilled syringes: The Tinzaparin sodium (innohep) syringes have a graduation of 0.05 mL which makes it possible to choose the most suitable syringe for the individual patient depending on the patient's body weight. In order to achieve the correct dosage for the individual patient the average volume is ejected before s.c. injection holding the syringe in a vertical position.
Different low molecular weight heparins are not necessarily equivalent. Therefore, specific posology and instructions for use of each one should be followed.
Children: There is no experience of use in children.
Elderly: Renal function should be assessed with e.g. the Cockcroft-Gault formula to estimate creatinine clearance levels.
No dose reduction is needed in elderly patients with normal renal function.
Renal impairment: No dose reduction is needed in patients having creatinine clearance levels down to 20 mL/min. However, precaution is recommended when treating patients with severe renal impairment (creatinine clearance < 30 mL/min).

Bleeding is the leading sign and symptom of tinzaparin overdosage.
Should bleeding occur, Tinzaparin sodium (innohep) should be discontinued in dependence on the severity of the bleeding and the risk of thrombosis.
In case of severe bleeding tinzaparin may be neutralised by protamine. After subcutaneous administration of different dosages of tinzaparin the anti-IIa-activity was neutralised to up to 85% and the anti-Xa-activity was neutralised up to 60% (47-74%) by intravenous administration of protamine sulphate (1 mg per 100 anti-Xa-I.U. tinzaparin). Repeated doses of protamine or a continuous infusion may be necessary.
Note that protamine overdosage has an anticoagulant effect in itself and that protamine may cause anaphylactoid reactions.

Hypersensitivity to tinzaparin, heparin or constituents of Tinzaparin sodium (innohep) (e.g. sodium metabisulfite); current or history of heparin-associated thrombocytopenia (type II); uncontrolled severe hypertension; septic endocarditis; intracranial or intraocular bleeding or other current active bleeding process; haemorrhagic diathesis (inherited or acquired), deficiency of coagulation factors, severe thrombocytopenia; severe impairment of liver or pancreas; active gastric and/or duodenal ulcer disease; surgery involving the brain, spinal cord or eye; lumbar puncture, spinal or epidural anaesthesia; haemorrhagic stroke, cerebral aneurysm; retinopathy, vitreous haemorrhage; in women with abortus imminens.
For vials only: Because of its content of benzyl alcohol, this formulation is contraindicated in newborns.

Tinzaparin sodium (innohep) should be given with caution to patients with: hepatic and renal insufficiency; uncontrolled arterial hypertension; gastrointestinal ulceration; suspicion of malignoma with bleeding tendency; history of peptic ulcer disease; nephrolith and/or ureterolith; concomitant use of drugs which increase the serum potassium levels, oral anticoagulants, platelet inhibitors (e.g. ASA).
Precaution is recommended in the treatment of patients with severe renal impairment (creatinine clearance < 30 mL/min).
Precaution is recommended in the treatment of elderly patients with renal impairment. Renal function should be assessed and in patients with severe renal impairment (creatinine clearance < 30 mL/min), monitoring of anti-factor Xa activity should be considered.
Platelet counts are recommended before administration of tinzaparin, on the first day of therapy and then regularly every 3 or 4 days and at the end of therapy.
As with other LMWHs, the administration of Tinzaparin sodium (innohep) in some patients undergoing surgical procedures (especially orthopaedic) or presenting a concomitant inflammatory process, has coincided with an asymptomatic increase of platelet count, which in many cases subsided without stopping administration of Tinzaparin sodium (innohep). If an increase in platelet count occurs, evaluation of the benefit/risk of continuing therapy for that patient should be made.
Due to the content of sodium metabisulfite, Tinzaparin sodium (innohep) should not be used in patients with asthma and hypersensitivity to sulphites.
Caution in the treatment of elderly patients.
Must not be administered by intramuscular or intravenous injection.
Due to the risk of haematoma during Tinzaparin sodium (innohep) therapy the intramuscular injection of other agents should be avoided.

Anticoagulant treatment of pregnant women requires specialist involvement.
Data on a limited number (637) of exposed pregnancies indicate no additional risk of tinzaparin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. No transplacental passage was demonstrated in two clinical studies. Animal data do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing tinzaparin to pregnant women.
There are no data available concerning lactation.
Pregnant patients with prosthetic heart valves: Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anticoagulant doses of tinzaparin and other LMWHs. Tinzaparin is not recommended for use in pregnant women with prosthetic heart valves.
In the absence of clear dosing, efficacy and safety information in this circumstance, any attempt to anti-coagulate such patients must only be undertaken by medical practitioners with expertise and experience in this clinical area, and only if no safer alternative is available.
The use of Tinzaparin sodium (innohep) in women with abortus imminens is contraindicated.
An epidural anaesthesia during birth in pregnant women treated with LMW-heparin is contraindicated.
For vials only: Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/Kg/day). Therefore the use of this formulation in newborns especially in preterm babies is contraindicated.
The 2 mL vial of Tinzaparin sodium (innohep) 20,000 IU/mL contains 20mg of benzyl alcohol (10mg of benzyl alcohol per mL). As benzyl alcohol may cross the placenta, the use of Tinzaparin sodium (innohep) formulations containing benzyl alcohol is not recommended during pregnancy.

Frequent: Bleeding complications (skin, mucous membrane, wounds, gastrointestinal, urogenital).
Increase in aminotransferases, gamma-GT, LDH, lipase.
Injection site haematoma and pain, rarely skin necrosis.
Increase of serum potassium concentration.
Occasional: A mild transient thrombocytopenia (type I) at the beginning of heparin therapy with platelet counts between 100,000/μl and 150,000/μl due to temporary platelet activation. As a rule no complications occur, therefore, treatment can be continued.
Rare: Cases of antibody-mediated severe thrombocytopenia (type II) with platelet counts clearly below 100,000/μl or a rapid decrease to less than 50% of baseline have been observed. In patients not sensitised the decrease in platelet count generally sets in 6-14 days after the beginning of treatment. In sensitised patients this may happen within few hours. This severe type of thrombocytopenia can be related to arterial and venous thromboses/thromboembolisms, consumption coagulopathy, possibly skin necroses at injection site, petechiae, purpura and melaena. The anticoagulant effect of heparin may be reduced (heparin tolerance). In such cases use of Tinzaparin sodium (innohep) is to be discontinued immediately. The patient must be informed of the fact that he/she must also avoid taking heparin-containing medicinal products in the future.
Anaphylactic reactions, in rare cases anaphylactic shock.
Allergic reactions with symptoms such as e.g. nausea, vomiting, fever, headache, urticaria, pruritus, dyspnoea, bronchospasm, hypotension.
Transient hair loss.
Rare cases of serious adverse drug reactions for Tinzaparin sodium (innohep) such as subdural or epidural haematoma, intracranial haemorrhage, retroperitoneal haemorrhage, metrorrhagia, angioedema, epidermal necrolysis, Stevens-Johnson-Syndrome, priapism have been reported.
In very rare cases: hypoaldosteronism, associated with hyperkalaemia and metabolic acidosis (especially in patients with renal impairment and diabetes mellitus).
Note: Due to the sodium metabisulfite content hypersensitivity reactions can occur in individual cases, especially in patients suffering from bronchial asthma, which can be expressed as vomiting, diarrhoea, dyspnoea, acute asthmatic attack, disturbance of consciousness or shock.

Concomitant administration of drugs affecting the haemostasis, e.g. NSAID, acetylsalicylic acid, salicylates, vitamin K antagonists, dipyridamole and dextran should be used with caution in patients receiving Tinzaparin sodium (innohep).
Interaction of heparin with intravenous nitroglycerine (which can result in a decrease in efficacy) cannot be ruled out for tinzaparin.
Drugs that increase the serum potassium concentration should only be taken concomitantly under especially careful medical supervision.

Incompatibilities: Tinzaparin sodium (innohep) should be given by subcutaneous injection only. It should not be mixed with any other injections.

Do not store above 30°C.
Shelf-Life: 2 years.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AB10 - tinzaparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.

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