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| |  FDA Approves Depodur (Morphine Sulphate) Single Epidural Injection for Post-Surgical Pain Relief LONDON, ENGLAND and CHADDS FORD, PA -- May 19, 2004 -- SkyePharma PLC (LSE: SKP, Nasdaq: SKYE) and Endo Pharmaceuticals (Nasdaq: ENDP) today announced that the US Food & Drug Administration (FDA) has approved SkyePharma's New Drug Application (NDA) for DepoDur™ for the treatment of pain following major surgery. Previously referred to as DepoMorphine™, DepoDur is a novel single dose sustained-release injectable formulation of morphine. Michael Ashton, Chief Executive of SkyePharma, said: "The FDA's decision to approve DepoDur is a tremendous vindication of our faith in the product. DepoDur represents the largest single commitment SkyePharma has made to product development, including funding the product through Phase III trials and building and sustaining a purpose-built manufacturing plant. We expect its commercialisation to have a profound effect on the company's future. Our clinical trial programme for DepoDur involved over 1000 patients in four different pain models and demonstrated the great potential of the product to improve the control of post-operative pain. We and our partners look forward to the benefits this product will bring for many patients after surgery." Endo's Chairman and Chief Executive Officer Carol A. Ammon said: "We are delighted with the FDA's decision on DepoDur. We believe the approval of DepoDur is an important step in fulfilling our vision of building our franchise in pain management as well as extending our reach into complementary therapeutic areas such as anaesthesiology." She added that Endo expects to be in a position to commercialize DepoDur by the end of 2004 provided SkyePharma is able to provide sufficient inventory to support the launch of the product. "We look forward to the commercialization of DepoDur and believe it provides a novel approach to the treatment of post-operative pain benefiting patients undergoing major surgery."
About DepoDur™ DepoDur is a single dose extended-release injectable formulation of morphine sulphate. DepoDur employs SkyePharma's proprietary DepoFoam™ technology and is supplied as a ready-to-use suspension. It is given as a single epidural injection before or during surgery and provides pain relief for up to 48 hours following surgery. There is no need for an in-dwelling catheter for continuous infusion, thereby overcoming a major drawback to the otherwise theoretically desirable epidural route of administration for opioid analgesics. DepoDur is designed for the control of pain after major surgery. SkyePharma and Endo expect that its main use will be in control of post- operative pain in hospitalised patients undergoing major surgical procedures requiring general or regional anaesthesia such as major abdominal surgery, orthopaedic surgery and caesarean section. Currently there are an estimated 6 million such procedures every year in the USA and 5 million in Europe. DepoDur is supplied in a 2 ml vial containing a 10 mg/ml suspension in sterile saline and is administered as a single dose epidural injection at the lumbar level prior to surgery (or after clamping of the umbilical cord during caesarean section). The recommended dose is 10 mg for caesarean section, 10-15 mg for lower abdominal surgery and 15 mg for major orthopaedic surgery of the lower extremities. Some patients may benefit from a dose of 20 mg. It should be appreciated that as with all opioids the incidence of serious adverse respiratory events is dose-related. Respiratory depression is the chief hazard of all opioid preparations and occurs more frequently in elderly or debilitated patients. For elderly patients (age >65 years), the low end of the dosing range for DepoDur is recommended together with vigilant peri-operative monitoring. On 16 September 2003 the FDA formally accepted for filing a New Drug Application ("NDA") for DepoDur, which had been submitted on 18 July 2003. On 20 November 2003 SkyePharma submitted an application for DepoDur to the UK Medicines and Healthcare products Regulatory Agency ("MHRA"). After national approval in the UK, SkyePharma intends to seek approval in other European Union countries under the Mutual Recognition procedure. SkyePharma has licensed DepoDur to Endo for North America and to Medeus Pharma for Europe. SkyePharma has completed seven clinical trials of DepoDur. The Phase IIb and Phase III clinical development programme for DepoDur involved four separate pain models and included more than 1000 patients. In the two Phase III trials, in hip surgery and lower abdominal surgery, DepoDur demonstrated extended dose-related analgesia and achieved its primary endpoint (superiority over study comparators in terms of total demand for opioid analgesics after surgery) with a high degree of statistical significance (p<0.0001 and p=0.0003, respectively). DepoDur also achieved statistical significance on several secondary endpoints. Importantly, statistical significance was achieved for the current pain intensity scores at rest and with activity over a 48 hour period and for the ratings of overall pain control. In two related Phase IIb trials, DepoDur was significantly better than study comparators in the caesarean section study (p=0.0209) and approached statistical significance in the knee arthroplasty study (p=0.0902), which used a novel endpoint: time-weighted pain intensity recall score over 48 hours. DepoDur achieved a high degree of statistical significance in total demand for opioid analgesics after surgery (p=0.001), a secondary endpoint in this trial but the primary endpoint in the three other studies. In all four of these studies the safety profile of DepoDur was typical for an epidural opioid agent. As with all opioid preparations, respiratory depression is the chief hazard associated with DepoDur. The most common adverse events reported during clinical trials were decreased oxygen saturation, hypotension, urinary retention, vomiting, constipation, nausea, pruritus, pyrexia, anemia, headache and dizziness. About DepoFoam™ DepoFoam is SkyePharma's proprietary extended-release injectable delivery technology. This is fully commercialised and approved by regulatory agencies in both the USA and Europe. DepoFoam consists of lipid-based particles containing discrete water-filled chambers dispersed through the lipid matrix. The particles are 10-30 microns in diameter and are suspended in saline. The suspension resembles skimmed milk and can be injected through a fine needle. The water-filled chambers containing active drug account for most of the weight of the particles. The lipids are naturally occurring substances (or close analogues) such as phospholipids and triglycerides. The small amount of lipid is cleared rapidly in the body as the particles deliver their drug payload over a period that can be modified from 1 to 30 days. About post-operative pain After a major surgical operation, the level of pain is usually very high for the first one to two days but the intensity of pain gradually subsides and by the end of the second day pain can normally be satisfactorily controlled with oral analgesics. For the immediate post-operative period, opioid analgesics like morphine (used alone or in combination with other non-opioid analgesics) are likely to remain the "gold standard" for relief of severe acute pain. However the relatively short duration of pain relief with opioids means that they require either continuous infusion or patient-controlled analgesia ("PCA") in which a pump delivers a series of doses of a short-acting opioid analgesic in response to the patient pressing a button (under computer control to prevent over-dosing). Both of these approaches require the patient to have an in-dwelling epidural or intravenous catheter. Such catheters can fall out or interfere with patient mobility and are a potential source of infections. Epidural catheters are also contra-indicated with concomitant use of anticoagulants because of the risk of bleeding in the spinal column that can potentially result in paralysis. There is a growing trend toward routine use of anticoagulants in patients undergoing orthopaedic surgery in order to prevent the formation of blood clots.
SOURCE: SkyePharma PLC; Endo Pharmaceuticals
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