Zalviso™

AcelRx Zalviso AcelRx Zalviso

Moderate-to-severe acute pain management in the hospital remains a challenge for healthcare providers with up to 75% of patients reporting inadequate pain relief following surgery. Inadequate treatment of moderate-to-severe pain can lead to decreased mobility, which increases the risks for serious medical complications, including deep vein thrombosis and partial lung collapse, potentially resulting in extended hospital stays. Approximately 12 million surgical procedures per year result in moderate-to-severe pain in the U.S., with an additional 7.4 million hospital inpatients in the U.S. annually experiencing moderate-to-severe acute pain from other, non-post surgical, medical conditions. Currently, patients experiencing moderate-to-severe acute pain in the hospital may have IV PCA treatment, typically utilizing morphine or hydromorphone1. However, there are deficiencies associated with the current use of IV PCA that can negatively impact patient safety, well-being and recovery. These include drug-related side effects associated with morphine or hydromorphone, complications associated with IV delivery and medication delivery errors typically associated with misprogramming of the complex IV PCA pumps. Inadequate pain relief can lead to decreased mobility, which increases the risks of other medical complications, including deep vein thrombosis and partial lung collapse, and can result in extended hospital stays.

There are many deficiencies associated with the current use of IV PCA that can negatively impact patient safety, well-being and recovery, including:

  • Side effects associated with the most commonly used opioids, morphine and hydromorphone, and their active metabolites
  • Infection risk, analgesic gaps and decreased mobility associated with the invasive nature of IV delivery, and
  • Medication errors, which in some instances may be fatal, due to the complexity of IV PCA pumps. Many IV PCA medication errors are the result of human factors such as programming errors.

According to published literature, the estimated annual error rates are 407 errors per 10,000 people treated with IV PCA in the United States. The most common and serious types of errors involve human factors, such as mis-programming the PCA pump or administering the wrong dose3. In 2002 and 2003, approximately 5% of operator errors reported to the FDA resulted in patient deaths. Approximately 56,000 adverse events were reported to the FDA between 2005 and 2009, prompting 70 Class II infusion pump recalls of devices that could cause temporary or reversible adverse effects and 14 Class I infusion pump recalls of devices that could cause serious injury or death. These issues with infusion pumps have resulted in the issuance of new draft guidance by the FDA, significantly increasing the data required to be submitted by manufacturers to address safety problems.

Zalviso has the potential to address many of the key disadvantages of IV PCA, including:

  • Lowering the risk of IV PCA-related infections, reducing analgesic gaps and enhancing mobility, and
  • Lowering the risk of pump programming errors.

Zalviso is designed to provide a favorable safety, efficacy and tolerability profile, potentially enabling Zalviso to become the new standard of care for patient-controlled analgesia.


Key Features and Potential Benefits of Zalviso as Compared to IV PCA Standard of Care:

Key Features and Potential Benefits of Zalviso Unmet Need with Current Standard of Care (IV PCA)
Sublingual route of delivery is being evaluated to reduce the risk if IV-related analgesic gaps and reduce the risk of IV complications.8 IV catheters can become infiltrated, kinked or dislodged resulting in analgesic gaps and other complications.2 Peripheral IV catheters are associated with bacteremia and phlebitis.8
Preprogrammed PCA system designed for sufentanil tablet delivery, may reduce the risk of pump programming errors by the end user.

Zalviso produced a significantly faster onset of pain relief and reduction in pain intensity compared to IV PCA morphine that separated at 45 minutes and achieved statistical significance at 1, 2 and 4 hours (p<0.01).
Due to the narrow therapeutic window for opioids and the complexity of IV PCA, the potential for patient harm due to medication delivery errors is high.3 The most common and serious types of errors involve human factors, such as mistakes in programming or administering the wrong dose.3
In three Phase 3 studies completed with sufentanil tablets, the average time interval between doses was approximately 80-90 minutes. This compares favorably to the typical redosing intervals for IV PCA of 20-40 minutes demonstrating the durability of analgesic effect. Due to the brief duration of effective analgesia that results from each IV PCA dose, patients need to frequently re-dose to maintain analgesia. Based on the mean use of morphine during the first 24 hours of PCA use, a retrospective study of patients receiving IV PCA morphine suggested that patients needed to redose every 20-40 minutes to maintain analgesia.4 We believe this can be demanding for patients and result in interruptions in analgesia, especially when patients fall asleep and wake up in pain.
In our active comparator phase 3 study, there was statistically fewer patients in the Zalviso group that experienced oxygen desaturation to a level less than 95% compared to the IV PCA morphine group (p=0.028). Published data indicates a high rate of somnolence (approximately 50%) and oxygen desaturation (approximately 10%) using standard IV PCA with standard opioids such as morphine.5,6

Zalviso Development Status

The NDA submission for Zalviso is based on a comprehensive development program and includes data from AcelRx’s three Phase 3 clinical trials. As previously reported, Zalviso met the FDA-agreed primary endpoints in the two double-blind, placebo-controlled Phase 3 registration studies conducted in patients who had undergone major open-abdominal surgery or orthopedic surgery that involved either knee or hip replacement procedures. In each of these trials, patients treated with Zalviso to manage their post-surgical pain reported a greater sum of the pain intensity difference to baseline over 48 hours (SPID-48) compared to placebo-treated patients (p=0.001 and p<0.001, respectively). Adverse events considered possibly or probably related to treatment were generally mild-to-moderate in nature and similar for the majority of adverse events between Zalviso- and placebo-treated patients, with the exception of itching, which was significantly greater (p < 0.05) in the Zalviso-treated group.

The third Phase 3 study, an open-label, active-comparator trial comparing Zalviso to IV PCA with morphine demonstrated that:

  • Zalviso was non-inferior (p<0.001) to IV PCA morphine based on the primary endpoint of Patient Global Assessment of method of pain control comparison over the 48-hour trial period (PGA48) as determined by the combined percentage of patients with PGA ratings of “good” or “excellent”.
  • A secondary comparison of the primary endpoint demonstrated that Zalviso was statistically superior to IV PCA morphine for the PGA48 endpoint (p=0.007). Statistically superior and non-inferior PGA comparisons for Zalviso compared to IV PCA morphine were also seen at the 24-hour and 72-hour time points.
  • Secondary endpoints of summed pain intensity, summed pain relief, and dropouts due to inadequate analgesia over the 48-hour study period were similar between treatment groups.

Zalviso had a significantly faster reduction in pain intensity compared to IV PCA morphine in the first 4 hours of treatment. In addition, both nurses and patients rated Zalviso significantly higher for Overall Satisfaction and Ease of Care compared to IV PCA with morphine. Overall, adverse events in the comparison trial were similar and most were mild-to-moderate in nature in both treatment groups. (see publications and press releases)

References

1: Campbell Alliance analysis of post-operative pain market (analysis on file)

2: Panchal SJ, Damaraju CV, Nelson WW, Hewitt DJ, Schein JR. System-related events and analgesic gaps during postoperative pain management with the fentanyl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia. Anesth Analg 2007;105:1437-41

3: Meissner B, Nelson W, Hicks R, Sikirica V, Gagne J, Schein J. The rate and costs attributable to intravenous patient-controlled analgesia errors. Hosp Pharm 2009;44:312-24.

4: Macintyre P.E, Jarvis D.A.Pain, 1996, 64:357-364

5: Dolin SJ and Cashman JN. Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritis, and urinary retention: evidence from published data. Br J Anaesth 2005, 95 (5): 584–91

6: Cashman JN and Dolin SJ. Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data. Br J Anaesth. 2004, 93(2):212-23

7: Wheeler M, Oderda GM, Ashburn MA, Lipman AG. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain 2002;3:159-80.

8: Webster J, Osborne S, Rickard C, Hall J. Clinically-indicated replacement versus routine replacement of peripheral venous catheters. Cochrane Database Syst Rev 2010;3:CD007798.

9. Schein JR, Hicks RW, Nelson, WW, Sikirica V, Doyle DJ, Patient-controlled analgesia-related medication errors in the postoperative period: causes and prevention. Drug Safety 2009; 32(7):549-559

Zalviso Publications and Press Releases

AcelRx presents data at the 19th Annual International Meeting of ISPOR May 31-June 4, 2014 in Montreal

Poster

AcelRx presents clinical data at the American Society of Anesthesiologists (ASA) in October 2013 showing Zalviso met its primary endpoint in a Phase 3 open-label active comparator trial (IAP 309).

Press Release

Abstract

Poster

AcelRx presents data at the American Society of Anesthesiologists (ASA) in October 2013 showing Zalviso met the primary endpoint in a double-blind, placebo-controlled Phase 3 registration study conducted in patients who had undergone major open-abdominal surgery (IAP 310).

Press Release

Abstract

Poster

AcelRx presents data at the American Society of Anesthesiologists (ASA) in October 2013 showing Zalviso met the primary endpoint in a double-blind, placebo-controlled Phase 3 registration study conducted in patients who had undergone major orthopedic surgery (IAP 311).

Press Release

Abstract

Poster

AcelRx presents at the American Society of Anesthesiologists (ASA) in October 2013 pharmacokinetic data from a study describing different routes of sufentanil delivery (IV vs. transmucosal vs. oral/swallowed).

Press Release

PK Abstract

PK Poster

AcelRX

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