Contact: Breanna Burkart or Anna Sussman
720/564-9150
Innohep® (tinzaparin sodium injection) is a once-daily low molecular weight heparin medication for the treatment of acute symptomatic deep vein thrombosis (DVT) with or without pulmonary embolism when administered in conjunction with the oral anticoagulant warfarin sodium (such as Coumadin®) in hospitalized patients. Innohep® was approved by the U.S. Food and Drug Administration (FDA) in July 2000.
Deep Vein Thrombosis
Deep vein thrombosis (DVT) is a term used to describe a blood clot in a major vein, most frequently in the legs. According to the American Heart Association, approximately 2 million Americans develop deep vein thrombosis annually, and an estimated 600,000 of these develop pulmonary embolism, a potentially fatal complication in which the blood clot breaks free and travels to the pulmonary artery or one of its branches and obstructs blood flow to the lungs. Research shows that pulmonary emboli are a major contributory factor in some 10 percent of all hospital deaths.
A number of factors may contribute to DVT including decreased blood flow in the veins, injury to the veins, and increases in the clotting ability of the blood. DVT is a major complication in orthopedic, pelvic, abdominal and thoracic surgical patients, as well as those other chronic diseases such as congestive heart failure, lung disease and diabetes. Hospitalized patients are at high risk for DVT since many of them have one or more risk factors. Other risk factors include obesity, smoking, varicose veins and the use of oral contraceptives or hormone replacement therapy. Age is also a risk factor; incidence of DVT increases sharply with age.
Cancer patients have an especially high risk of DVT. They are twice as likely to develop postoperative thrombosis than their counterparts without cancer undergoing the same surgical procedure and to experience a recurrent thromboembolic event after an initial episode. Studies indicate that thrombosis is one of the most frequent complications and the second leading cause of death in patients with known cases of cancer.
DVT Treatment
Deep vein thrombosis is usually treated with anticoagulants to prevent further clotting of the blood. There are a number of injectable and oral anticoagulant drugs available, and many are used in combination. The anticoagulant heparin has been the standard treatment for DVT since the 1960s. While heparin is an effective therapy, it is most frequently given by intravenous injection and requires careful patient monitoring and dose-adjustment to ensure adequate coagulation without increasing a patient’s risk of bleeding.
Treatment of DVT has been transformed with the recent introduction of low molecular weight heparins (LMWH), a modified form of the drug heparin. Studies indicate that LMWHs are as safe and effective as heparin but have several advantages over heparin therapy. LMWHs have a more predictable anticoagulant dose response. In addition, the greater bioavailability and longer half-life of LMWHs allow convenient once- or twice-daily dosing via subcutaneous (under the skin) injection.
DVT Treatment with Innohep® (tinzaparin sodium injection)
The low molecular weight heparin Innohep® (tinzaparin sodium injection) has been used for over 15 years to treat approximately 30 million patients worldwide (estimated based on number of units sold). Studies show it to be as effective as continuous intravenous, adjusted dose heparin in hospitalized patients for reducing the risk of recurrent thromboembolic events. In addition, studies indicate that Innohep® significantly reduces the risk of major bleeding compared with intravenous heparin. The absolute risk reduction was 1.9% during initial treatment period. There was no statistical significance in the long-term reduction of bleeding at Day 90. The 95 percent confidence interval of the difference in major bleeding event rates was 0.33 percent, 3.47 percent.
Innohep® is convenient for patients. It is formulated for once-a-day administration and is dosed based on body weight. Dose adjustments are not required for renally impaired, elderly or weight extreme patients. Elderly patients and patients with renal insufficiency may show reduced elimination of Innohep®. Innohep® should be used with care in these patients.
Innohep®’s Mechanism of Action
Like other LMWHs and standard heparin, Innohep® does not break up existing blood clots but rather inhibits the formation of new clots by blocking reactions in the blood that lead to clots. Innohep® acts as a potent co-inhibitor of several activated coagulation factors, especially Factors Xa and IIa (thrombin). Its primary inhibitory activity is mediated through an enzyme inhibitor, antithrombin. Innohep® also induces the release of tissue factor pathway inhibitor (TFPI), which may contribute to its anticoagulant effect.
In addition, like standard heparin, Innohep® has a variety of other actions including interactions with endothelial cell growth factors and inhibition of smooth muscle cell proliferation. At this time, the clinical significance of these actions is unknown.
Safety and Efficacy of Innohep®
In controlled clinical trials comparing treatment with Innohep® to standard heparin therapy, including a landmark study of 435 hospitalized patients with symptomatic proximal DVT published in the New England Journal of Medicine, Innohep® was shown to be at least as safe and effective as heparin for the treatment of DVT with or without pulmonary embolism when administered in conjunction with warfarin sodium. Total recurrent thromboembolic events (DVTs and pulmonary embolisms) occurred in six of 216 patients (2.8 percent) in the Innohep® treatment arm and 15 of 219 patients (6.8 percent) receiving intravenous heparin. The 95 percent confidence interval for the total thromboembolic event rate difference (4.0 percent) was 0.07 percent, 8.07 percent. This difference was not statistically significant. Deaths with Innohep® occurred in 4.6 percent (10 patients) and with heparin in 9.6 percent (21 patients). The 95 percent confidence interval for the mortality difference was 0.16 percent, 9.76 percent.
While bleeding is the most common side effect with Innohep®, clinical studies demonstrated a low incidence of major bleeding among DVT patients (0.8 percent of 519 patients treated with subcutaneous Innohep® (tinzaparin sodium injection) as compared to 2.7 percent of 524 patients treated with intravenous heparin).
Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins and spinal/epidural anesthesia or spinal puncture, which can result in long-term or permanent paralysis. The risk of hematomas is increased by the use of postoperative, indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis such as NSAIDs (non-steroidal anti-inflammatory drugs), platelet inhibitors or other anticoagulants. Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Please see Full Prescribing Information.
Patients with active major bleeding, patients with (or a history of) heparin-induced thrombocytopenia, or patients with known sensitivity to heparin, tinzaparin sodium injection (Innohep® or any of its constituents) or pork products should not be treated with Innohep®. Innohep® should be used with extreme caution in conditions with increased risk of hemorrhage.
Bleeding is the most common adverse event associated with Innohep® and can occur in any tissue or organ. The most common adverse events in controlled clinical trials with Innohep® were injection site hematomas (16 percent), abnormal elevations of AST (8.8 percent) and ALT (13 percent), urinary tract infection (3.7 percent), pulmonary embolism (2.3 percent) and chest pain (2.3 percent). Other bleeding events associated with Innohep® at a frequency of greater than or equal to 1 percent were epistaxis (1.9 percent), hemorrhage (1.5 percent), hematuria (1 percent) and thrombocytopenia (1 percent).
Innohep® cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosage. Each of these medications has its own instructions for use. Please see Full Prescribing Information for Innohep®.
Administration of Innohep®
Innohep® is administered by deep subcutaneous injection in the abdominal area. One dose of Innohep® every 24 hours is safe and effective for the treatment of DVT with or without pulmonary embolism. Most patients receive Innohep® for at least six daysand until their blood is adequately anticoagulated with warfarin sodium. (Warfarin sodium therapy is usually initiated within one to three days following the start of Innohep® and continues for some time following the termination of Innohep® treatment). Innohep® is dosed based on the patient’s body weight.
Commercial Status of Innohep®
Pharmion Corporation acquired exclusive U.S. marketing rights to Innohep® (tinzaparin sodium injection) from LEO Pharma of Denmark in July 2002and re-launched the product to the U.S. hematology and oncology markets in October 2002.
For more information about Innohep®, please visit the Innohep website at www.innohepusa.com or call Breanna Burkart or Anna Sussman, Directors, Investor Relations and Corporate Communications (720) 564-9150. Innohep® is a registered trademark of LEO Pharma.