New Medicines

Zalviso · Acute moderate-to-severe postoperative pain in adults


New formulation
AcelRx Pharmaceuticals

Development and Regulatory status

Not recommended for approval (Negative opinion)
July 2017
01. Mar 12: PIII programme started [1].
02. Mar 12: Plan to file in US mid-2013 [1]
03. Mar 13: Company now plans to file in the US Q3 2013 [6]
04. Oct 13: Filed in the US for management of moderate-to-severe acute pain in adult pts in the hospital setting. The NDA submission is based primarily on data from a PIII registration program that included two double-blind randomized placebo-controlled clinical trials, one conducted in pts following major abdominal surgery, the other in pts following major joint replacement surgery. Additionally, a PIII open-label active-comparator trial was conducted in pts following either major abdominal or orthopedic surgery, comparing Zalviso to the current standard of care, intravenous patient-controlled analgesia (IV PCA) with morphine. Zalviso successfully achieved the primary efficacy endpoints for each of these studies [8].
05. Mar 14: PDUFA action date of 27/07/2014 assigned by FDA for Post-operative pain. [10]
06. July 14: Marketing Authorisation Application submitted to EMA for the management of moderate to severe acute pain in adult patients in a medically supervised environment. [11].
07. July 14: US FDA issued Complete Response Letter requesting additional information on the Zalviso System to ensure proper use of the device. [12]
08. May 15: The FDA refuses a request for a Type B meeting on Zalviso to discuss a new study. AcelRx will meet with its lawyers to determine a pathway forward including the possibility of dispute resolution through one of the FDA prescribed pathways as well as conducting additional clinical or Human Factors studies. AcelRx had intended to share with the FDA results of the bench testing and Human Factors studies they had requested as part of the CRL and Type A meeting, and further discuss their desire for additional clinical work. AcelRx continue to believe that an additional clinical study should not be required to demonstrate the safety and efficacy of the Zalviso System beyond what has already been established in the PIII clinical studies, as well as the bench testing and Human Factors studies [15].
09. Jul 15: EU positive opinion for management of acute moderate to severe post-operative pain in adult patients [17].
10. Jul 15: Zalviso is a hybrid of Sufenta, which has been authorised in the Netherlands since 1978 as an anaesthetic-analgesic [17].
11. Sep 15: The FDA reiterates its demand for a new trial of Zalviso before it can reconsider a marketing application [18].
12. Sep 15: Approved in EU [19].
13. Sep 15: Grunenthal predict that Zalviso will be available to Western European patients in the first half of next year [20]
14. Aug 17: Launched in UK. Price 15 microgram sublingual tab, 40 per cartridge x 20 cartridges=£1065.00 (hospital only). Self-administration device available from company [23]


Opioid analgesic, 15microgram sublingual tablet
The incidence of severe acute postoperative pain has been estimated at 11% of all patients in the first 24 hours after major surgery.
Acute moderate-to-severe postoperative pain in adults

Trial or other data

01. ARX-01 is a pre-programmed, handheld system that allows post-operative patients to self-dose with sublingual Sufentanil NanoTabs to manage their post-operative pain [1].
02. Mar 12: The first PIII double-blind RCT started Mar 12 (NCT01539642). 150 adults who have had open abdominal surgery will receive ARX-01 15mcg NanoTabs or placebo (2:1) for post-operative pain for a minimum of 48 hours and, as needed, up to 72 hours after randomization. The primary outcome is time-weighted summed pain intensity difference (SPID) over 48-hours. The study is due to complete Dec 12. The PIII programme includes a second RCT for post-operative pain control following major joint replacement surgery, and an open-label active-comparator study comparing ARX-01 to IV morphine PCA [1,2].
03. Apr 12: The second study has started. The multicentre, randomized, open-label study will compare the Sufentanil NanoTab PCA System to IV PCA with morphine, in the treatment of acute post-operative pain immediately after major abdominal or orthopaedic surgery in 400 patients. The primary objective is to demonstrate non-inferiority of ARX-01 as determined by patient global satisfaction with the method of pain relief. Patients will be treated for post-operative pain for a minimum of 48 hours after randomization. Top-line data expected in H2 2012.The third PIII study will start in the Q3 2012, will be an RCT comparing ARX-01 to placebo in treating post-operative pain following major joint replacement surgery [3].
04. Aug 2012: Dosing in third PIII study started. This third study will randomise 400 pts 3:1 to receive 15 mcg Sufentanil NanoTabs or placebo NanoTabs, both delivered via the ARX-01 system at a maximum dosing rate of one NanoTab every 20 minutes to control pain. Patients will be followed for a minimum of 48 hours and, as needed, up to 72 hours. The primary endpoint is the sum of the pain intensity difference to baseline, over the 48 hour study period, or SPID-48. Secondary endpoints include pain relief scores, patient global satisfaction ratings, and use of rescue medication. The ease of set up and operation of the ARX-01 system for nursing staff and patients, respectively, will also be measured through questionnaires. Topline results are expected to be available during the first quarter of 2013. [4]
05. Nov 12: Top line results from a PIII study reported. The randomized, open-label study enrolled 359 adult patients compared the ARX-01 sublingual Sufentanil NanoTab PCA System (15mcg/dose) vs IV PCA with morphine (1mg/dose) for the treatment of acute post-operative pain immediately following major abdominal or orthopaedic surgery. Patients were treated for a minimum of 48 hours and up to 72 hours. The Sufentanil NanoTab PCA System was non-inferior (p<0.001) to IV PCA morphine for the primary endpoint of PGA over the 48-hour study period as determined by the combined % of patients with PGA ratings of ‘good’ or ‘excellent’ (78.5% vs. 66.1% respectively) the non-inferiority assessment was based on a lower limit of -15% for the 95% CI around the difference between these percentages. The 95% CI was +3.2% to +21.6% for the 48 hour PGA and a statistical analysis for superiority could be performed. This found the NanoTab System was statistically superior to IV PCA morphine for the PGA endpoint (p=0.009). Similar number of patients dropped out of the study prematurely due to lack of efficacy (7.3% vs. 8.3% respectively) or due to an adverse event (7.9% vs. 11.1% respectively). Nurses setting up treatments and managing patients in the study reported a greater Overall Satisfaction (3.93 vs. 3.32 out of 5, p<0.001) and Overall Ease of Care (4.26 vs. 3.82, p=0.018) with the Sufentanil NanoTab PCA System. Likewise, patients in the study reported that they had greater Overall Satisfaction (4.15 vs. 3.83 out of 5, p=0.003) and greater Overall Ease of Care (4.45 vs. 4.07, p<0.001) with the NanoTab System [5]
06. Mar 13: Top-line data results reported from the first of two pivotal placebo-controlled PIII studies. The randomized, double-blind, placebo-controlled study enrolled 178 adult patients immediately following major abdominal surgery. Patients were treated for post-operative pain for a minimum of 48 hours, and up to 72 hours. Morphine was allowed as rescue medication; pre-rescue pain scores were imputed to minimize the impact of rescue opioid on efficacy evaluations. The primary endpoint was pain intensity over the 48-hour vs baseline (Summed Pain Intensity Difference [SPID-48]), which was significantly greater in patients receiving sufentanil NanoTabs (105.6 vs 55.6, p=0.001). SPID was also significantly greater in the sufentanil group at 24 and 72 hours (p<0.001 and p=0.004, respectively). 70.2% of the sufentanil group completed the 48-hour study period vs 51.7% of placebo patients. Reasons for drop-out in the sufentanil and placebo groups included adverse events (5.3% and 6.9%) and lack of efficacy (16.7% and 31.0%) [6].
07. May 13: Top-line data showed that primary efficacy endpoint was achieved in a placebo-controlled PIII study (n=426) of investigational sublingual Sufentanil NanoTab PCA System for treatment of moderate -to-severe acute pain immediately following major orthopaedic surgery. Pts were randomized 3:1, with 315 pts randomised to sufentanil treatment and 104 to placebo treatment; treated for a minimum of 48 hours, and up to 72 hours. Both treatments were delivered by the pt, as needed, using the NanoTab System with a 20-minute lock-out period. Results demonstrated that pts receiving sufentanil NanoTabs realized a significantly greater SPID-48 during the study period than placebo-treated pts (+76.1 vs -11.5, p<0.001). Secondary endpoint data showed that SPID at 24 hours and 72 hours was also significantly greater in the sufentanil-treated patients than in the placebo group (<0.001 in each case). Adverse events reported in the study were generally mild or moderate in nature and were similar in both placebo and treatment groups for the majority of adverse events [7].
08. Dec 13: AcelRx Pharmaceuticals has signed an agreement giving Germany´s Grünenthal European and Australian marketing rights [9]
09. Oct 14: Publication of Zalviso (sufentanil sublingual tablet system, SSTS) PIII trial (IAP310) which evaluated safety and efficacy in pts with post-operative pain following open abdominal surgery. Zalviso was better at managing pain over 48 hrs as measured by Summed Pain Intensity Difference to Baseline (SPID-48), than placebo (p=0.001). Treatment-related adverse events were similar between groups, with fewer Zalviso patients dropping out of the study due to inadequate analgesia compared to placebo (17.4% vs 31.8%; p=0.035) and using approximately half as much rescue morphine (1.8 doses vs. 3.8 doses).[13,14]
10. Jun 15: Results of PIII (n=419) trial published in Anesthesiology. Summed pain intensity difference from baseline to 48 hours was reported to be better in the sufentanil group compared with placebo (p<0.001), although patients on sufentanil reported a higher incidence of nausea and pruritus [16].
11. Nov 15: AcelRx pharmaceuticals present a subgroup analysis from three PIII studies at Obesity Week 2015 - titled "Efficacy and Safety of the Sufentanil Sublingual Tablet System (SSTS) in Class I and II Obese Patients: The Effect of BMI on Analgesic Response". Overall the data showed that Zalviso provides faster onset of pain relief in obese post-surgical pts vs. IV PCA of morphine. Significant differences in pain intensity were observed as early as 45 mins after the first dose (p<0.05), a trend that continued until 6 hours after the initial dose (p<0.001), after which time pain intensity scores equilibrated between the two groups. Results of the sub-group analysis also show that obese pts using Zalviso experienced statistically fewer adverse events than did those receiving IV PCA morphine. While overall adverse event rates were comparable, incidence rates of anaemia, leukocytosis (increase in white blood cells), vomiting, hypoalbuminaemia (decrease in albumin levels), hyponatraemia (decrease in sodium levels), urinary retention and pruritus (itching) were all significantly lower in the Zalviso arm compared to the morphine arm (p=0.05) [21].

Evidence based evaluations

Dzuveo (EU); Dsuvia (US) · Acute pain - single-dose sublingual formulation (30 micrograms)


Dzuveo (EU); Dsuvia (US)
New formulation
AcelRx Pharmaceuticals
AcelRx Pharmaceuticals

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Approved (Licensed)

Jan 19: In its 2018 annual filing, AcelRx reports that its strategy with respect to Dzuveo in territories outside of the United States is seek commercial partnerships [10]

Nov 18: AcelRx Pharmaceuticals plans to launch sufentanil sublingual in the US in Q1 19 [9].

Nov 18: Approved in the US, despite a letter to the FDA from the Anesthetic and Analgesic Drug Products Advisory Committee chair pleading for rejection, expressing concerns about its potency and potential for diversion, abuse and death. However the formulation will not be available in retail pharmacies and will require administration by a healthcare professional in a medically supervised setting, such as hospitals and emergency rooms, under a restrictive risk-management plan mandated by the FDA. AcelRx plans to price Dsuvia at $50 to $60 and launch in Q1 2019 [8].

Jun 18: approved in EU [8].

Apr 18: recommended for approval by CHMP: the full indication is "for the management of acute moderate to severe pain in adult patients" [7].

Oct 17: AcelRx Pharmaceuticals announces intention to resubmit NDA to US FDA by end of 2017 [6].

Oct 17: the FDA has issued a Complete Response Letter rejecting the New Drug Application and requesting further data. It requires additional safety data for the maximum dose of the drug from at least 50 trial participants, and it is also recommending changes to the directions for use to address use-related errors, to be validated through a human factors study. AcelRx considers that the requests are manageable and intends to meet with the FDA to discuss the issues and plan resubmission [5].

Mar 17: MAA submitted to EMA for use in patients with moderate to severe acute pain in a medically supervised setting [4].

Dec 13: AcelRx meets with the FDA to identify a PIII programme pathway [2].


a sublingual formulation of the opioid analgesic sufentanil for the treatment of acute pain (ARX 04; single-dose formulation).
Acute pain - single-dose sublingual formulation (30 micrograms)

Trial or other data

Feb 16: AcelRx announces interim PIII results. 40 patients dosed so far with ARX-04 demonstrated a quick, sharp drop in pain scores after turning up at the ER [3].

Sep 15: AcelRx announces positive data from its late-stage study. Sublingual sufentanil tablet ARX-04 met the primary and secondary endpoints set out for patients with moderate-to-severe acute pain following ambulatory abdominal surgery [1].

Mar 15: AcelRx reports initiation of a PIII trial which will evaluate safety and efficacy of ARX-04 for treatment of moderate-to-severe acute pain, in an emergency room setting (SAP302; NCT02447848). The open-label trial is designed to enrol approximately 40 patients in the US [2].

Apr 13: Top-line results from a PII dose-finding study of sublingual sufentanil in patients with acute pain following bunionectomy surgery were reported by AcelRx (NCT01710345). Initiated in November 2012, the trial randomised 101 patients to receive sufentanil 20µg, sufentanil 30µg, or placebo [2].

Evidence based evaluations