DepoDur found to be innovative option for postoperative pain relief

10/25/04

Data show single-shot epidural can improve treatment of pain following major surgery

CHADDS FORD, Pa., October 26, 2004 – Data from two clinical trials presented at the American Society of Anesthesiologists' Annual Meeting in Las Vegas this week support the safety and efficacy of DepoDurTM (morphine sulfate extended-release liposome injection) CII -- an innovative single-dose epidural injection designed to improve postoperative pain control. DepoDurTM will be commercially available in the U.S. by the end of 2004.

DepoDurTM was approved by the U.S. Food and Drug Administration (FDA) in May 2004 for the treatment of pain following major surgery. It is given as a single epidural injection before or during surgery in procedures such as hip and knee replacement, lower abdominal surgery and elective Caesarean section. Unlike currently available epidural morphine formulations, DepoDurTM can provide up to 48 hours of effective pain relief with a single shot. Furthermore, DepoDurTM does not require an indwelling catheter for continuous infusion, which may limit patient mobility and present obstacles for administering anticoagulant (blood thinning) therapy. This new therapeutic option may help physicians overcome challenges associated with current postoperative pain treatment options while providing safe and effective pain control.

"DepoDurTM has been shown to offer effective pain control while streamlining the process of peri-operative pain management," said Gavin Martin, M.D., assistant clinical professor of anesthesiology, Duke University and an investigator in clinical trials. "Soon patients will be able to experience up to 48 hours of pain relief post-surgery with a single shot. This product will help enable healthcare professionals to achieve optimal pain control for their patients without the many challenges commonly associated with postoperative pain relief."

The majority of surgical patients experience moderate-to-severe postoperative pain, but the treatment of this pain is still often inadequate. Studies show that patients who use pain medication early and aggressively after surgery have shorter hospital stays, suffer fewer chronic pain problems, and end up using fewer painkillers overall than those who avoid pain medication. The current methods for treating moderate-to-severe postoperative pain include intravenous patient-controlled analgesia (IV PCA), epidural morphine sulfate infusions, and intramuscular opioid injections.

A recent meta-analysis reported in the Journal of the American Medical Association, encompassing three decades of research, showed that epidural analgesia provides significantly better postoperative pain control compared to IV PCA. Until recently, all available forms of epidural analgesia required continuous delivery via an indwelling catheter if extended pain relief was required. Such catheters can interfere with patient mobility, be a potential source of infections, and limit options for administration of anticoagulant therapy. Prior to the advent of DepoDurTM, the most common alternative to epidural analgesia was intravenous patient-controlled analgesia (IV PCA), which is prone to possible equipment malfunction or patient error, leading to under- or over-delivery of medication and resulting in variable pain control.

Data Presented at ASA Meeting

In one randomized, double-blind, parallel-group, dose-ranging study, single epidural doses of DepoDurTM 5*, 10, 15, 20, or 25* mg or 5 mg standardized conventional morphine sulfate (MS; Astramorph/PF® or Duramorph®) were administered to 487 adult patients 18 years of age or over approximately 30 minutes before lower abdominal surgery and before the induction of general or regional anesthesia. The study found that a single dose provided significant dose-related improvements in pain control for up to 48 hours while significantly reducing postoperative IV fentanyl use. Higher doses significantly reduced the number of patients requiring any postoperative IV fentanyl.

In another study with 164 patients undergoing knee replacement surgery, patients 18 years of age or over were randomized to receive either an epidural injection of DepoDurTM 20 mg, DepoDurTM 30* mg, or a placebo epidural before or during surgery. At the first request for pain medication after surgery, patients in the DepoDurTM group were given an IV bolus of hydromorphone and placebo via IV patient-controlled analgesia (PCA). Those patients randomized to the control group (IV PCA group) were given an IV bolus of morphine and morphine via IV PCA for pain relief. Pain intensity recall scores (100-mm Visual Analog Scale [VAS]) were assessed at 4, 8, 12, 24, 30, 36, and 48 hours. The results demonstrated DepoDurTM to be a safe and effective alternative to IV opioid PCA for postoperative pain, providing effective pain control with less use of supplemental opioids over the 48-hour postoperative period. In the DepoDurTM group, patient pain intensity ratings were significantly lower than in the IV PCA group.

About DepoDurTM

Previously referred to as DepoMorphineTM, DepoDurTM is the first single-dose extended-release epidural formulation of morphine sulfate approved by the FDA for the treatment of pain following major surgery. DepoDurTM employs SkyePharma's (LSE: SKP; Nasdaq: SKYE) proprietary DepoFoamTM technology and is supplied as a ready-to-use suspension. DepoDurTM is intended for single-dose administration by the epidural route, at the lumbar level, for the treatment of pain following major surgery. DepoDurTM is administered prior to surgery or after clamping the umbilical cord during cesarean section. DepoDurTM is not intended for intrathecal, intravenous, or intramuscular administration. Administration of DepoDurTM into the thoracic epidural space or higher has not been evaluated and therefore is not recommended.

The FDA approval of DepoDurTM was based on clinical data showing significantly improved outcomes in 876 patients undergoing major surgical procedures such as hip replacement, lower abdominal surgery and elective Caesarean section. In clinical trials, patients given DepoDurTM demonstrated lower pain intensity scores and reduced need for rescue medication. In these trials, efficacy was assessed for at least 48 hours and safety was assessed for up to 30 days after DepoDurTM administration.

As with all opioids, the chief hazard of morphine sulfate is respiratory depression, especially in elderly and debilitated patients and in those with compromised respiratory function; therefore, patients must be monitored for a least 48 hours and the facility must be equipped to resuscitate patients. No other medication should be administered in the epidural space for at least 48 hours. DepoDurTM is contraindicated in patients with known hypersensitivity to morphine or the product's components, and in those patients with respiratory depression, acute or severe bronchial asthma, upper airway obstruction, those who have or are suspected of having paralytic ileus, head injury or increased intracranial pressure and those who are in circulatory shock. Any contraindications for an epidural injection preclude the administration of DepoDurTM. Patients with depleted blood volume receiving DepoDurTM may experience severe hypotension. The most common adverse events reported in clinical studies (>10%) were: decreased oxygen saturation, hypotension, urinary retention, vomiting, constipation, nausea, pruritus, pyrexia, anemia, headache, and dizziness. DepoDurTM is a Schedule II controlled substance and is subject to abuse and diversion.

DepoDurTM was developed by SkyePharma Inc. Under an agreement with SkyePharma, Endo Pharmaceuticals has exclusive rights to market DepoDurTM in the U.S. and Canada. For complete prescribing information, please visit www.depodur.com.

* DepoDurTM is not FDA-approved at the 5, 25 or 30 mg doses. It is FDA-approved at the 10, 15 and 20 mg doses.

About Endo

A wholly owned subsidiary of Endo Pharmaceuticals Holdings Inc. (Nasdaq: ENDP), Endo Pharmaceuticals is a fully integrated specialty pharmaceutical company with market leadership in pain management products. The company researches, develops, produces and markets a broad product offering of branded and generic pharmaceuticals, meeting the needs of healthcare professionals and consumers alike. More information, including this and past press releases of Endo Pharmaceuticals Holdings Inc., is available online at www.endo.com.

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