Innohep (Tinzaparin Sodium)

INNOHEP®

Leo

Tinzaparin Sodium

Anticoagulant – Antithrombotic

Action And Clinical Pharmacology: Tinzaparin is a low molecular weight (LMW) heparin, produced by enzymatic depolymerization of conventional heparin from porcine mucosa. It possesses antithrombotic activity mediated through antithrombin III.

Pharmacokinetics: The pharmacokinetics of tinzaparin after a single s.c. injection have been studied in clinical trials by the measurement of plasma levels of anti-Xa activity, anti-IIa activity and APTT activity

Results from clinical trials, however, have not demonstrated that plasma levels of any of these activities correlate to either the antithrombotic effect or the bleeding risk. The plasma level of anti-Xa activity may only be used as a measure of the amount of tinzaparin anti-Xa active molecules in plasma. It is not recommended as a tool for monitoring treatment efficacy with tinzaparin.

In orthopedic hip or knee replacement surgery, patients may have a very high risk of developing postoperative deep venous thrombosis and also may have a high risk of bleeding. Therefore, careful precise dosing of conventional unfractionated heparin is required. Results from clinical trials with tinzaparin indicate that there is a close relationship between plasma levels of anti-Xa activity and body weight. This indicates that dosing according to body weight is the best way to obtain precise dosing.

Tinzaparin, 75 anti-Xa IU/kg s.c. once daily following hip or knee replacement surgery, has been shown to be safe and effective for the prevention of deep-vein thrombosis in a randomized double-blind trial versus adjusted dose warfarin. Tinzaparin was equally effective as warfarin treatment in hip surgery and superior to warfarin in preventing thromboembolic events in knee replacement.

Indications And Clinical Uses: For the treatment of deep vein thrombosis.

In the management of the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery.

Tinzaparin may be used in the management of the prevention of postoperative venous thromboembolism in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism (see Precautions, Selection of General Surgery Patients).

Postoperative administration of tinzaparin does not preclude other prophylactic modalities including physical and mechanical methods of adjunct therapy.

Contra-Indications: Tinzaparin must not be administered by i.m. injection due to the risk of hematoma. Where possible, i.m. injections should be avoided in patients during anticoagulant treatment. Allergy and hypersensitivity to tinzaparin. Acute or subacute septic endocarditis. History of thrombocytopenia or in patients in whom an in vitro platelet-aggregation test in the presence of tinzaparin is positive. Uncontrolled severe hypertension. Generalized hemorrhage tendency and other conditions/diseases involving an increased risk of hemorrhage. Hemophilia or major blood clotting disorders. Severe liver damage. Uremia. Acute cerebral insults. Active bleeding from a local lesion such as an acute ulcer or ulcerating carcinoma.

Manufacturers’ Warnings In Clinical States: Tinzaparin should be used with care in patients with severe liver or kidney insufficiency, uncontrolled arterial hypertension or a history of gastrointestinal ulceration.

Children and Pregnancy: There is currently no clinical experience with tinzaparin in pregnant women and children. In two clinical studies performed in pregnant women during second trimester using tinzaparin in a dose of 35 to 40 anti-Xa IU/kg, no transplacental passage of anti-Xa and anti-IIa activities was demonstrated. In rabbits no placental passage of anti-Xa and anti-IIa activity could be demonstrated after s.c. doses of 1 750 anti-Xa IU/kg body weight of tinzaparin. Toxicological studies have shown that no embryotoxic or teratogenic effects were found. Tinzaparin should not be used in pregnant women and in children unless the therapeutic benefits to the patients outweigh the possible risks to the fetus and the patients.

Lactation: It is not known whether tinzaparin is excreted in breast milk of nursing mothers. Mothers receiving tinzaparin should avoid breast-feeding.

Innohep contains sodium bisulfite, which may cause allergic reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatics than in nonasthmatic people.

There have been cases of intraspinal hematomas with the concurrent use of LMW heparin and spinal/epidural anesthesia resulting in long-term or permanent paralysis. The risk of these events may be higher with the use of postoperative indwelling epidural catheters. Tinzaparin should be used concurrently with spinal/epidural anesthesia only when therapeutic benefits to the patient outweigh the possible risks. Appropriate guidelines, precautions, monitoring and followup procedures should be followed (see Adverse Effects, Spinal/Epidural Anesthesia).

Precautions: Tinzaparin should not be administered by i.m. injection due to the risk of hematoma. Where possible i.m. injections should be avoided in patients during anticoagulant treatment.

Tinzaparin should be used with caution in conjunction with drugs which affect either platelet function or the coagulation system (i.e., salicylates, vitamin K antagonists and dextran).

Laboratory Tests: Administration of 75 anti Xa IU/kg in hip and knee surgery patients may be associated with bleeding. In the event of excessive blood loss from the surgical wound, the first injection of tinzaparin should be deferred, until the bleeding has stopped. Clinical studies found no correlation between anti-Xa, anti-IIa, or APTT ratios and bleeding complications. Therefore, there is no need for extensive monitoring of these activities. A fall in thrombocyte counts has been observed yet no direct association to tinzaparin has been identified.

As a precautionary measure, platelet counts should be determined prior to the start of treatment with tinzaparin and, subsequently, twice weekly for the duration of treatment. An in vitro platelet-aggregation test in the presence of tinzaparin should be performed in patients with a history of heparin-induced thrombocytopenia. In case of negative results, treatment with tinzaparin may be instituted but the patient must be closely monitored and platelet counts determined at least once daily. A positive result contraindicates tinzaparin.

In the case of minor bleeding, the drug should be postponed or withdrawn. When serious bleeding requires reversal of tinzaparin, protamine sulfate (1% solution) by slow infusion will neutralize tinzaparin. The effect of protamine sulfate should be monitored by the APTT. (For more information, please see Overdose: Symptoms and Treatment.)

Selection of General Surgery Patients: Tinzaparin may be used as an adjunct in the prevention of postoperative venous thromboembolism in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism.

General surgery patients, who have one or more of the following risk factors, are at high risk of developing postoperative thromboembolism: previous venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of lower limb, bed rest more than 5 days prior to surgery, predicted duration of surgery more than 30 minutes, and age 60 years or above.

Drug Interactions: There has been no clinical experience with the possible interaction between tinzaparin and other drugs other than ASA. No evidence of an interaction between tinzaparin and ASA on the anti-Xa or anti-IIa activities was found. The bleeding time increased on the combined treatment in 7/8 subjects as expected with regard to the ASA intake, though no significant influence on the platelet aggregation was found. The bleeding time was prolonged by an average of 3 to 4 minutes (within a variance of 4 to 7.25 minutes) on the final day of 3 consecutive days of ASA intake (300 mg daily). Bleeding time did not exceed 10 to 12 minutes (upper normal limit), nor did any patient experience clinically evident bleeding. Tinzaparin alone or in combination with ASA was well tolerated in clinical studies with only occasional bruising at the injection site seen.

ASA inhibits platelet aggregation and is often recommended in the prevention of arterial thrombi formation. Heparin and LMW heparin primarily inhibit fibrin formation on the surface of platelet aggregates. Theoretically, maximal antithrombotic effect of the two compounds may be achieved when combined. The combined use of several substances influencing hemostasis will increase the risk of bleeding complications, and caution must be exercised particularly in patients at risk of developing bleeding complications. Many patients presenting for thromboprophylaxis may be ASA consumers since ASA is recommended as prophylaxis against myocardial infarction in many countries. Therefore, tinzaparin should be used with caution in conjunction with drugs which affect the platelet function or the coagulation system (i.e., oral anticoagulants, inhibitors of platelet aggregation, nonsteroidal anti-inflammatory agents, preparations containing ASA, vitamin K antagonists and dextran).

Adverse Reactions: Hemorrhage is the main complication that can result from tinzaparin treatment. However, the clinical trials with tinzaparin in the dosages recommended have not been associated with hemorrhage to any clinically significant degree.

Frequent reactions (>1/100): General: hematoma at injection site – uncomplicated. Liver: transient increase in aminotransferase levels – not clinically relevant.

Less frequent reactions: Skin: rash – uncomplicated.

Liver: As with conventional heparin, a significant but transient increase of the liver transaminases has been noted following administration of tinzaparin in doses of 50 anti-Xa IU/kg body weight once daily, as well as in higher doses. The increased levels of liver transaminases observed in the tinzaparin studies were most probably induced by the treatment. The conclusion agrees with observations made in association with treatment using heparins. The exact mechanism associated with the increased levels of liver transaminases has not been fully elucidated. However, no consistent irreversible liver damage has ever been demonstrated due to this known heparin effect.

Clinical studies have suggested that the transaminase increase seems to be dose dependent and requires more than 3 days of treatment to appear. Following the administration of tinzaparin in a dose of 150 anti-Xa IU/kg twice daily; however, all subjects showed increased plasma levels of AST and ALT from a mean of 17.8 to 128.5 U/mL and 19.3 to 257 U/mL respectively. These elevations correspond to a 7- to 12-fold increase as compared to the post-study evaluation performed within 7 days of study completion. Transaminase levels normalized within 2 weeks of the last dose of tinzaparin.

In summary, tinzaparin administered in doses of 50 anti-Xa IU/kg body weight once daily, 75 anti-Xa IU/kg once daily, and 150 anti-Xa IU/kg twice daily, for 5 consecutive days results in markedly increased but reversible liver transaminases levels (especially ALT). Normalization of these levels occurred within 2 to 4 weeks. Clinical studies involving administration of standard heparin in doses up to 10 000 IU given i.v. every 6 hours or s.c. in doses of 5 000 IU every 8 hours or twice daily, have yielded the same effect.

Spinal/Epidural Anesthesia: There have been cases of intraspinal hematomas with the concurrent use of LMW heparin and spinal/epidural anesthesia resulting in long-term or permanent paralysis (incidence: 1:45 000). Tinzaparin should only be used concurrently with spinal/epidural anesthesia when the therapeutic benefits to the patient outweigh the possible risks. If LMW heparin is used concurrently with spinal/epidural anesthesia, experts have suggested that no spinal invasion should be attempted for 12 hours following the dose of LMW heparin and that the next dose should be held until at least 2 hours after the spinal/epidural anesthesia procedure. The same rules are applied to the withdrawal or manipulation of the catheter. Careful vigilance for neurological signs is recommended, with rapid diagnosis and treatment, if such signs occur.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Bleeding is a symptom of tinzaparin overdose. In recommended doses, there should be no need for an antidote but in the event of accidental administration of an overdose, protamine sulfate should be given. There is no clinical experience with overdose, but studies in animals indicate that the dose of protamine sulfate required to neutralize the hemorrhagic effects is greater for tinzaparin than for unfractionated heparin. The effect of protamine sulfate should be monitored by the APTT. Excess bleeding is not seen in animal experiments when the APTT is brought within the normal range. If transfusions are required, fresh frozen plasma is preferred.

In the case of minor bleeding, the drug should be postponed or withdrawn. When serious bleeding requires reversal of tinzaparin, protamine sulfate (1% solution) by slow infusion will neutralize tinzaparin. No more than 50 mg should be administered, using a very slow i.v., during a 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 anti-Xa IU tinzaparin.

Dosage And Administration: Prevention of postoperative venous thromboembolism in general surgery patients: tinzaparin 3 500 anti-Xa IU (available in a prefilled syringe) given by s.c. injection 2 hours before surgery followed by 3 500 anti-Xa IU once daily for 7 to 10 days.

Prevention of postoperative venous thromboembolism in orthopedic surgery patients: Hip Surgery: Tinzaparin 50 anti-Xa IU/kg body weight given by s.c. injection 2 hours before surgery followed by 50 anti-Xa IU/kg body weight once daily for 7 to 10 days; or tinzaparin 75 anti-Xa IU/kg body weight given postoperatively by s.c. injection once daily for 7 to 10 days.

Knee Surgery: Tinzaparin 75 anti-Xa IU/kg body weight given postoperatively by s.c. injection once daily for 7 to 10 days.

Treatment of deep vein thrombosis: tinzaparin 175 anti-Xa IU/kg of body weight, once daily.

No dose modifications are necessary for the use of tinzaparin in elderly patients. There is no experience of use in children.

Availability And Storage: Syringes: 10 000 anti-Xa IU/mL: Each mL of sterile solution contains: tinzaparin sodium 10 000 anti-Xa IU. Nonmedicinal ingredients: sodium acetate•3H2O, sodium hydroxide* and water for injection (*quantity sufficient for pH adjustment). pH range of the final solution is 5.0 to 7.5. Preservative-free. Unit dose syringes of 0.35 mL and 0.45 mL.

20 000 anti-Xa IU/mL: Each mL of sterile solution contains: tinzaparin sodium 20 000 anti-Xa IU. Nonmedicinal ingredients: sodium metabisulfite, sodium hydroxide* and water for injection (*quantity sufficient for pH adjustment). pH range of the final solution is 5.0 to 7.5. Preservative-free. Unit dose graduated syringes of 0.5 mL, 0.7 mL and 0.9 mL.

Vials: 10 000 anti-Xa IU/mL: Each mL of sterile solution contains: tinzaparin sodium 10 000 anti-Xa IU. Nonmedicinal ingredients: benzyl alcohol, sodium hydroxide*, sodium metabisulfite and water for injection (*quantity sufficient for pH adjustment). pH range of the final solution is 5.0 to 7.5. Multi-dose vials of 2 mL.

20 000 anti-Xa IU/mL: Each mL of sterile solution contains: tinzaparin sodium 20 000 anti-Xa IU. Nonmedicinal ingredients: benzyl alcohol, sodium hydroxide*, sodium metabisulfite and water for injection (*quantity sufficient for pH adjustment). pH range of the final solution is 5.0 to 7.5. Multidose vials of 2 mL.

Store at 15 to 25°C. Protect from light.

INNOHEP® Leo Tinzaparin Sodium Anticoagulant – Antithrombotic

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