Zalviso™

AcelRx Zalviso AcelRx Zalviso

Moderate-to-Severe Acute Pain in a Hospital Setting

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 (1). Approximately 12 million surgical procedures per year result in moderate-to-severe pain in the U.S. (2), 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 (3).

 

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 atelectasis (lung collapse), potentially resulting in extended hospital stays (4). 

IV Patient-Controlled Analgesia (PCA)

Currently, patients experiencing moderate-to-severe acute pain in the hospital may have IV PCA as an option to treat their pain, typically utilizing morphine or hydromorphone (5). However, the use of IV PCA has been associated with deficiencies that can negatively impact patient safety and recovery. These include:

  • drug-related side effects associated with morphine or hydromorphone and their active metabolites (6);
  • medication delivery errors typically associated with misprogramming IV PCA pumps (7); and
  • complications associated with IV delivery such as infection risk and decreased mobility associated with the invasive nature of IV delivery. (8)

According to published literature, an estimated 407 errors occur per 10,000 people treated with IV PCA each year in the United States (9). The most common and serious types of errors involve human factors, such as mis-programming the PCA pump or administering the wrong dose (9). In 2009, approximately 6.5% of errors associated with PCA pumps were due to operator error and that nearly half of these events (~19,000) lead to patient harm (10). Between 2005 and 2009, errors associated with infusion pumps led to 70 Class II recalls of devices that could cause temporary or reversible adverse effects and 14 Class I recalls of devices that could cause serious injury or death. These issues have resulted in the issuance of new draft guidance by the FDA, significantly increasing the data required to be submitted by manufacturers to address safety problems. (11)

Potential Zalvisio Benefits Zalviso has the potential to address several key disadvantages of IV PCA, including:

  • Lowering the risk of IV PCA-related infections;
  • 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 a strong treatment option for patient-controlled analgesia. For a comparison of Zalviso and IV PCA features, click here (opens pop-up table – see slide 2).


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

Key Features of Zalviso 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

U.S. Development Status

A New Drug Application (NDA) was filed with the US FDA in November 2013 based on results of three Phase 3 studies. In response to a complete response letter that was received July 2014 and subsequent communications with the FDA, AcelRx has submitted a protocol to the FDA for a fourth study that will be designed to evaluate the overall performance of the Zalviso System. Pending the Agency’s review of this protocol, AcelRx is prepared to initiate this study in the first quarter of 2016.

Study IAP309

As previously reported, 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 (p<0.001).  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.

Studies IAP310 and 310

In addition, Zalviso met the FDA-agreed primary endpoints in 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.

Zalviso® (15 micrograms sufentanil sublingual tablet system) was approved in September 2015 by the European Commission (EC) for the management of acute moderate-to-severe post-operative pain in adult patients in a hospital setting.

Zalviso is to be administered in a hospital setting only and should only be prescribed by physicians who are experienced in the management of opioid therapy. Zalviso sublingual tablets are to be self-administered by the patient in response to pain using the Zalviso administration device. Zalviso should not be used in patients with hypersensitivity to the active substance or with significant respiratory depression.

The marketing authorization is granted for the 28 EU member states as well as for the European Economic Area (EEA) countries, Norway, Iceland and Liechtenstein. Grünenthal Group, AcelRx's licensee in Europe and Australia, expects the product to be available to Western European patients in the first half of 2016.

In the United States and other geographies, Zalviso remains an investigational product.

References

1: Apfelbaum JL, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003 Aug;97(2):534-40.

2: Triple Tree LLC. (2014) Pain Management – Industry Perspective.

3: Connors AF, Jr, et al. A Controlled Trial to Improve Care for Seriously III Hospitalized Patients: The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). JAMA. 1995;274(20):1591-1598.

4: Overdyk FJ, DeVita MA, Pasero C. Postoperative opioid-induced respiratory depression: current challenges and new developments in patient monitoring. Anesthes News. 2012;1-8.

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

6: Smith, HS. Opioid Metabolism. Mayo Clin Proc. July 2009;84(7):613-624

7: McKeen MJ, Quraishi SA. Clinical review of intravenous opioids in acute care. J Anesthesiol Clin Sci 2013, 2:1

8: Lisi DM. Patient-Controlled Analgesia and the Older Patient. US Pharm. 2013;38(3):HS2-HS6

9: Meissner B, et al. The rate and costs attributable to intravenous patient-controlled analgesia errors. Hosp Pharm 2009;44:312-24

10: Adamson RT, et al. Clinical and Economic Implications Related to Postsurgical Analgesic Devices. Hosp Pharm 2011;46(6 Suppl 1):S12–S20

11: AAMI/FDA. (2010). Infusing Patients Safely: Priority Issues from the AAMI/FDA Infusion Device Summit. Retrieved 10/20/2015 from http://tinyurl.com/46l7ynq

12: 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

13: 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

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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