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.
Table 4 : Major Bleeding Events1 in Treatment of Acute Deep
Vein Thrombosis With or Without Pulmonary Embolism
|Treatment of Acute DVT With or Without PE||INNOHEP® (tinzaparin)
|Major Bleeding Events2||0.83||2.73|
|1 INNOHEP® (tinzaparin) 175 IU/kg once
daily SC. Unfractionated heparin initial IV bolus of 5,000 IU followed
by continuous IV infusion adjusted to an aPTT of 1.5 to 2.5 or initial
IV bolus of 50 IU/kg followed by continuous IV infusion adjusted to an
aPTT of 2.0 to 3.0. In all groups treatment continued for approximately
6 to 8 days, and all patients received oral anticoagulant treatment commencing
in the first 2 to 3 days.
2 Bleeding accompanied by ≥ 2 gram/dL decline in hemoglobin, requiring transfusion of or more units of blood products, or bleeding which was intracranial, retroperitoneal, or into a major prosthetic joint.
3 The 95% CI on the difference in major bleeding event rates (1.9%) was 0.33%, 3.47%.
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; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; swelling; weakness; hypotension, 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).
In clinical studies thrombocytopenia was identified in 1% of patients treated with INNOHEP® (tinzaparin) . Severe thrombocytopenia (platelet count < 50,000/mm³) 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).
Mild local irritation, pain, hematoma, and ecchymosis may follow SC injection of INNOHEP® (tinzaparin) . Injection site hematoma has been reported in approximately 16% of patients treated with INNOHEP® (tinzaparin) .
Adverse events with INNOHEP® (tinzaparin) 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.
Table 5 : Adverse Events Occurring in ≥ 1% in Treatment
of Acute Deep Vein Thrombosis With or Without Pulmonary Embolism Studies
|Adverse Events||Treatment Group1|
|Urinary Tract Infection||19 (3.7%)||18 (3.4%)|
|Pulmonary Embolism||12 (2.3%)||12 (2.3%)|
|Chest Pain||12 (2.3%)||8 (1.5%)|
|Epistaxis||10 (1.9%)||7 (1.3%)|
|Headache||9 (1.7%)||9 (1.7%)|
|Nausea||9 (1.7%)||10 (1.9%)|
|Hemorrhage NOS||8 (1.5%)||23 (4.4%)|
|Back Pain||8 (1.5%)||2 (0.4%)|
|Fever||8 (1.5%)||11 (2.1%)|
|Pain||8 (1.5%)||7 (1.3%)|
|Constipation||7 (1.3%)||9 (1.7%)|
|Rash||6 (1.2%)||8 (1.5%)|
|Dyspnea||6 (1.2%)||9 (1.7%)|
|Vomiting||5 (1.0%)||8 (1.5%)|
|Hematuria||5 (1.0%)||6 (1.1%)|
|Abdominal Pain||4 (0.8%)||6 (1.1%)|
|Diarrhea||3 (0.6%)||7 (1.3%)|
|NOS = not otherwise specified
1 INNOHEP® (tinzaparin) 175 IU/kg once daily SC. Unfractionated heparin initial IV bolus of 5,000 IU followed by continuous IV infusion adjusted to an aPTT of 1.5 to 2.5 or initial IV bolus of 50 IU/kg followed by continuous IV infusion adjusted to an aPTT of 2.0 to 3.0. In all groups treatment continued for approximately 6 to 8 days, and all patients received oral anticoagulant treatment commencing in the first 2 to 3 days.
Other Adverse Events in Completed or Ongoing Trials
Other adverse events reported at a frequency of ≥ 1% in 4,000 patients who received INNOHEP® (tinzaparin) 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.
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.
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 Tables 6 and 7, respectively:
Table 6 : Serious Adverse Events Associated With INNOHEP® (tinzaparin)
in Clinical Trials
|Category||Serious Adverse Event|
|Injection site bleeding|
|Organ dysfunction||Angina pectoris|
|Myocardial infarction/coronary thrombosis|
|Allergic reactions||Allergic reaction|
|Injection site reaction||Cellulitis|
Table 7 : Other Serious Adverse Events Associated With INNOHEP® (tinzaparin)
from Post-Marketing Surveillance
|Category||Serious Adverse Event|
|Organ dysfunction||Cholestatic hepatitis|
|Increase in hepatic enzymes|
|Cutaneous reactions||Epidermal necrolysis|
|Injection site reactions||Abscess|
|Allergic reactions||Allergic purpura|
|Fetal/neonatal||Cutis aplasia of the scalp|
|General||Acute febrile reaction|
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).
Spinal epidural hematoma in association with neuraxial anesthesia or spinal puncture with INNOHEP (tinzaparin) ® has been reported.
Spinal epidural hematoma with INNOHEP® (tinzaparin) administered at a therapeutic dose has been reported in at least one patient who had not received neuraxial anesthesia or spinal puncture.
Read the Innohep (tinzaparin) Side Effects Center for a complete guide to possible side effects
Because of increased risk of bleeding, INNOHEP® (tinzaparin) should be used with caution in patients receiving oral anticoagulants, platelet inhibitors (e.g., salicylates, dipyridamole, sulfinpyrazone, dextran, NSAIDs including ketorolac tromethamine, ticlopidine, and clopidogrel), and thrombolytics. If coadministration is essential, close clinical and laboratory monitoring of these patients is advised (see PRECAUTIONS, Laboratory Tests).
Laboratory Test Interactions
Elevation of Serum Transaminases
Asymptomatic reversible increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels have occurred in patients during treatment with INNOHEP® (tinzaparin) (see ADVERSE REACTIONS, Elevations of Serum Aminotransferases). Similar increases in transaminase levels have also been observed in patients and volunteers treated with heparin and other low molecular weight heparins.
Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like INNOHEP® (tinzaparin) should be interpreted with caution.
Read the Innohep Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/8/2010
This monograph has been modified to include the generic and brand name in many instances.
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