Zalviso (in US)
- Phase 1
- Phase 2
- Phase 3
- NDA Filed
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 surgery1. Approximately 12 million surgical procedures per year result in moderate-to-severe acute 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 conditions3.
Inadequate treatment of moderate-to-severe acute 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 stays4.
IV Patient-Controlled Analgesia (PCA)
Currently, patients experiencing moderate-to-severe acute pain in the hospital may have intravenous (IV) PCA as an option to treat their pain, typically utilizing morphine or hydromorphone5. Patient-controlled treatments for pain result in higher patient satisfaction.1 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 metabolites6;
- medication delivery errors typically associated with misprogramming IV PCA pumps7; and
- complications associated with IV delivery such as infection risk and decreased mobility associated with the invasive nature of IV delivery.5
According to published literature, an estimated 407 errors occur per 10,000 people treated with IV PCA each year in the United States. The most common and serious types of errors involve human factors, such as misprogramming the PCA pump or administering the wrong dose9. In 2009, approximately 6.5% of errors associated with PCA pumps were due to operator error and nearly half of these events (~19,000) led to patient harm10. 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 These issues have resulted in the issuance of new draft guidance by the FDA, significantly increasing the data required to be submitted by manufacturers to address safety problems.11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 Zalviso Benefits
Zalviso is a drug/device combination product designed to deliver 15 mcg sufentanil, a high therapeutic index opioid, formulated in a proprietary noninvasive sublingual dosage form via a novel hand-held, pre-programmed, patient-controlled analgesia system. Zalviso is approved in the European Union, it remains an investigational product in the United States.12
Zalviso has the potential to address several key disadvantages of IV PCA, including:
- Lowering the risk of infections related to IV access; Zalviso is noninvasive
- Enhancing ease of mobility; Zalviso does not tether the patient
- Lowering the risk of pump programming errors; Zalviso is pre-programmed
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.
U.S. Development Status
AcelRx filed a New Drug Application with the Food and Drug Administration (FDA) in November 2013 based on the results of three Phase 3 Studies (IAP309, 310, and 311) and received a complete response letter (CRL) in July 2014. In response to the CRL and in consultation with the FDA, AcelRx developed a protocol for a fourth Phase 3 study (IAP312) that is designed to evaluate the overall performance of the Zalviso System. A summary of these studies follows:
Zalviso was shown to be non-inferior (p<0.001) to IV PCA morphine in this open-label, active-comparator trial. The primary endpoint was 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 difference to baseline, 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.13
Studies IAP310 and 311
In addition, Zalviso met the FDA-agreed primary endpoints in two randomized, placebo-controlled Phase 3 registration studies conducted in patients who had undergone major open-abdominal surgery (IAP310) or orthopedic surgery (IAP311) 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, the primary endpoint) 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 were similar between Zalviso- and placebo-treated patients in the IAP310 study. In the IAP311 study, nausea and itching were significantly greater in the Zalviso-treated group (p<0.05).14,15
AcelRx designed IAP312 in consultation with the Division of Anesthesia, Analgesia, and Addiction Products of the U.S. Food and Drug Administration. The study enrolled 320 hospitalized, post-operative patients who used Zalviso to self-administer sublingual tablets containing 15 micrograms of sufentanil as often as once every 20 minutes for 24 to 72 hours to manage their moderate-to-severe acute pain. In addition to the safety and efficacy measures, IAP312 collected information on device usability, including any incidence of Zalviso failure to dispense medication, as well as the incidence of misplaced or dropped tablets. The trial results achieved the study's objectives: the device-dispense failure rate was 2.2 percent (7 out of 320), demonstrating a significant improvement in reliability with the device modifications made since IAP311.
- 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.
- In-house commissioned market research. Rosetta "AcelRx ARX-01 Market Assessment" January 2012.
- Hefland, M and Freeman, M. Assessment and management of acute pain in adult medical inpatients: a systematic review. Pain Medicine. 2009; 10 (7) 1183-1199
- Overdyk FJ, DeVita MA, Pasero C. Postoperative opioid-induced respiratory depression: current challenges and new developments in patient monitoring. Anesthes News. 2012;1-8.
- Lisi DM. Patient-Controlled Analgesia and the Older Patient. US Pharm. 2013;38(3):HS2-HS6
- Smith, HS. Opioid Metabolism. Mayo Clin Proc. July 2009;84(7):613-624
- McKeen MJ, Quraishi SA. Clinical review of intravenous opioids in acute care. J Anesthesiol Clin Sci 2013, 2:1
- Meissner B, et al. The rate and costs attributable to intravenous patient-controlled analgesia errors. Hosp Pharm 2009;44:312-24
- Adamson RT, et al. Clinical and Economic Implications Related to Postsurgical Analgesic Devices. Hosp Pharm 2011;46(6 Suppl 1):S12–S20
- AAMI/FDA. (2010). Infusing Patients Safely: Priority Issues from the AAMI/FDA Infusion Device Summit. Retrieved 10/20/2015 from Link
- 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
- Mather LE. Opioids: a pharmacologist’s delight! Clin Exp Pharmacol Physiol 1995; 22:833-6
- Melson TI, Boyer DL, Minkowitz HS et al. Sufentanil sublingual tablet system vs. intravenous patient-controlled analgesia with morphine for postoperative pain control: a randomized, active-comparator trial. Pain Practice 2014;14: 679‑88
- Ringold FG, Minkowitz HS, Gan TJ et al. Sufentanil sublingual tablet system for the management of postoperative pain following open abdominal surgery. A randomised, placebo-controlled study. Regional Anesthesia and Pain Medicine 2015;40: 22–30
- Jove M, Griffin DW, Minkowitz HS et al. Sufentanil sublingual tablet system for the management of postoperative pain after knee or hip arthroplasty. A randomised, placebo-controlled study. Anesthesiology 2015;123: 434‑43
- AcelRx (September 27, 2016). AcelRx Initiates Phase 3 Study of Zalviso in Patients with Moderate-to-Severe Acute Post-Operative Pain [Press Release]