Bleeding :  Bleeding is the most common adverse event associated with INNOHEP (tinzaparin sodium injection); however, the incidence of major bleeding is low. In clinical trials, the definition of major bleeding included bleeding accompanied by ≥2 gram/dL decrease in hemoglobin, requiring transfusion of 2 or more units of blood products, or bleeding which was intracranial, retroperitoneal, or into a major prosthetic joint. The data are provided in Table 4.

Fatal or nonfatal hemorrhage from any tissue or organ can occur. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as, but are not limited to, paralysis; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypoptension, shock, or coma. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis (see WARNINGS, Hemorrhage).

Thrombocytopenia :  In clinical studies thrombocytopenia was identified in 1% of patients treated with INNOHEP. Severe thrombocytopenia (platelet count <50,000/mm ³ ) occurred in 0.13% (see WARNINGS , Thrombocytopenia ).

Elevations of Serum Aminotransferases :  Asymptomatic increases in aspartate (AST [SGOT]) and/or alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in up to 8.8% and 13% for AST and ALT, respectively, of patients receiving tinzaparin sodium for the treatment of DVT. Similar increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are reversible and are rarely associated with increases in bilirubin (see PRECAUTIONS , Laboratory Tests ).

Local Reactions :  Mild local irritation, pain, hematoma, and ecchymosis may follow SC injection of INNOHEP. Injection site hematoma has been reported in approximately 16% of INNOHEP treated patients.

Hypersensitivity :  Anaphylactic/anaphylactoid reactions may occur in association with INNOHEP use (see CONTRAINDICATIONS and WARNINGS).

Adverse Events :  Adverse events with INNOHEP or heparin reported at a frequency of ≥1% in clinical trials with patients undergoing treatment for proximal DVT with or without PE, are provided in Table 5.

Other Adverse Events in Completed or Ongoing Trials : Other adverse events reported at a frequency of ≥1% in 4,000 patients who received INNOHEP in completed or ongoing clinical trials are listed by body system:

Body as a Whole:   injection site hematoma, reaction unclassified.

Cardiovascular Disorders, General:   hypotension, hypertension.

Central and Peripheral Nervous System Disorders:   dizziness.

Gastrointestinal System Disorders:    flatulence, gastrointestinal disorder (not otherwise specified), dyspepsia.

Heart Rate and Rhythm Disorders:   tachycardia.

Myo-, Endo-, Pericardial and Valve Disorders:   angina pectoris.

Platelet, Bleeding and Clotting Disorders:    hematoma, thrombocytopenia.

Psychiatric Disorders:   insomnia, confusion.

Red Blood Cell Disorders:   anemia.

Resistance Mechanism Disorders:   healing impaired, infection.

Respiratory System Disorders:   pneumonia, respiratory disorder.

Skin and Appendages Disorders:   rash erythematous, pruritus, bullous eruption, skin disorder.

Urinary System Disorders:   urinary retention, dysuria.

Vascular (Extracardiac) Disorders:   thrombophlebitis deep, thrombophlebitis leg deep.

Serious adverse events reported in clinical trials or from post-marketing experience are included in Table 6 and 7, respectively.

Ongoing Safety Surveillance :  When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis (see boxed WARNING ).

INNOHEP was first introduced in foreign markets in 1991. There have been no reports of spinal epidural hematoma in association with neuraxial anesthesia or spinal puncture with INNOHEP in clinical trials or in post-marketing surveillance.

There has been one case of spinal epidural hematoma with INNOHEP administered at a therapeutic dose in a patient who had not received neuraxial anesthesia or spinal puncture.

Because of increased risk of bleeding, INNOHEP should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, and NSAIDs including ketorolac tromethamine), and thrombolytics. If co-administration is essential, close clinical and laboratory monitoring of these patients is advised (see PRECAUTIONS , Laboratory Tests ).

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