Sufentanil Sublingual Tablet (Dsuvia)

Number: 0944

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Aetna considers sufentanil sublingual tablet (Dsuvia) as not medically necessary for the treatment of acute pain severe enough to require an opioid analgesic because the safety for this indication has not been established.
   
   
2. Aetna considers sufentanil sublingual tablet (Dsuvia) experimental and investigational for all other indications because the safety and effectiveness have not been established in the peer-reviewed published medical literature.

Dosage and Administration

Note: Aetna considers Dsuvia as not medically necessary. The dosing recommendations are for informational purposes.

The recommended dosage of Dsuvia (sufentanil) is 30 mcg sublingually, administered by a healthcare provider in a certified medically supervised healthcare setting.  Dsuvia is available in a disposable, single-dose applicator (SDA), as needed with a minimum of 1 hour between doses, not to exceed 12 tablets in 24 hours, with maximum cummulative daily dose of 360 mcg or 12 tablets (12 tablets x 30 mcg/dose).

It is recommended that individuals not eat or drink and minimize talking for 10 minutes after receiving the tablet.

Source: AcelRx Pharmaceuticals, Inc., 2021

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
HCPCS codes not covered for indications listed in the CPB:
Sufentanil (Dsuvia) - no specific code :
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
G89.11 - G89.18	Acute pain

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Dsuvia contains sufentanil, an opioid agonist, and is indicated for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
  

  Limitations of Use:

  • Not for home use or for use in children. Discontinue treatment with Dsuvia before patients leave the certified medically supervised healthcare setting.
  • Not for use for more than 72 hours.
  • Only to be administered by a healthcare provider.
  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Dsuvia for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:
    
    
    • Have not been tolerated, or are not expected to be tolerated,
    • Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

Sublingual sufentanil is available as Dsuvia (AcelRx Pharmaceuticals, Inc) in the United States. Sufentanil is a Schedule II controlled synthetic opioid analgesic that has been marketed for intravenous (IV) and epidural anesthesia and analgesia. The principle therapeutic action of sufentanil is analgesia and sedation, thought to be mediated through opioid-specific receptors throughout the central nervous system (CNS). Like all full opioid agonists, there is no ceiling effect to analgesia.

Sufentanil is 5 to 10 times more potent than its analogue, fentanyl, and 1000 times more potent than morphine (Brooks, 2018). In efforts to offer acute pain management for persons unable to take anything by mouth and have difficulty achieving IV access, sufentanil sublingual tablet was developed. This includes potential uses on the battlefield. For this reason, the Department of Defense (DoD) worked in collaboration with AcelRX Pharmaceuticals on the development of sublingual sufentanil. This opioid formulation was a priority medical product for the Pentagon because it fills an unmet medical need in treating the nation’s soldiers on the battlefield (FDA, 2018). The sufentanil pharmacokinetic profile when delivered sublingually avoids the high peak plasma levels and short duration of action observed with IV administration (AcelRx, 2018a). The high lipophilicity of sufentanil allows it to be administered subligually and achieve a rapid onset of analgesic effect (NICE, 2016).

On November 2, 2018, AcelRx Pharmaceuticals, Inc., announced the U.S. Food and Drug Administration (FDA) approval of Dsuvia, a single-strength solid dosage form of sufentanil administered sublingually via a single-dose applicator, for the management of acute pain in adults that is severe enough to require an opioid analgesic in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments.

Because of the potential for life-threatening respiratory depression due to accidental exposure, Dsuvia (sufentanil) is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) program and is only to be administered by a healthcare professional in a certified medically supervised setting. In addition, Dsuvia must be discontinued prior to the patient leaving the certified medically supervised setting. As with all opioid usage, individuals require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use (FDA, 2018).

Contraindications to Dsuvia include significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, and known hypersensitivity to sufentanil or components of Dsuvia. Labeled warnings and precautions include life-threatening respiratory depression in those with chronic pulmonary disease or in elderly, cachectic, or debilitated persons; serotonin syndrome; adrenal insufficiency; severe hypotension; and risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness. The most commonly reported adverse reactions (2 % or greater) were nausea, headache, vomiting, dizziness and hypotension (AcelRx, 2018b). 

In September 2015, the European Commission (EU) granted approval for a sufentanil suglingual tablet system (Zalviso) which is a type of patient controlled analgesia (PCA) that delivers a 15 mcg sufentanil tablet dose for the management of acute moderate to severe post-operative pain. However, in August 2022, the EU withdrew the marketing authorization at the request of the marketing authorization holder, FGK Representative Service GmbH, which notified the European Commission of its decision to permanently discontinue the marketing of the product for commercial reasons (European Medicines Agency, 2022). In addition, Zalviso (AcelRx Pharmaceuticals) is not FDA-approved in the United States. Of note, the sufentanil suglingual tablet system (SSTS) entails a different dose and delivery system than Dsuvia, which is a healthcare administered 30 mcg sublingual dose.

In July 2018, the European Medicines Agency approved sufentanil sublingual 30 mcg tablet under the brand name Dzuveo. According to the FDA, Dzuveo and Dsuvia entail a feature that allows the drug to be delivered in a stable form, making it a viable option suited for certain special circumstances where patients may not be able to swallow oral medication, and where access to IV pain relief is not possible, such as soldiers on the battlefield. For that reason, the Department of Defense collaborated with the sponsor on the development of this non-invasive opioid analgesic option that could provide rapid pain relief for soldiers (FDA, 2018).

FDA approval of Dsuvia was based on results from one phase-3, prospective, randomized, double-blind, placebo-controlled trial (SAP301, NCT02356588, Minkowitz et al [2017]) evaluating the efficacy and safety of sufentanil subligual 30 mcg tablet (SST) for the management of pain after ambulatory abdominal surgery.

Minkowitz and colleagues (2017) state that SST has shown to be an effective opioid analgesic in postoperative pain management following abdominal surgery. A total of 161 patients (age 18 to 69 years) scheduled to undergo abdominoplasty, open tension-free inguinal hernioplasty, or laparoscopic abdominal surgery under general or spinal anesthesia that did not include intrathecal opioids during the operation, were randomized to SST (n=107) or placebo (n=54). Patients were dosed with SST 30 mcg or placebo as needed with a minimum of 60 minutes between doses. The primary endpoint was the time-weighted summed pain intensity difference to baseline (SPID) over 12 hours. Secondary endpoints included SPID over 24 and 48 hours, total pain relief, and patient and healthcare professional (HCP) global assessments. Pain scores were recorded for up to 48 hours. SPID 12 was higher (greater pain intensity reduction from baseline) in the SST group compared with placebo (p < 0.001). In the SST group, a greater proportion of patients and HCPs responded "good" or "excellent" on the global assessments compared with placebo (p < 0.001 for both). Approximately 22% of patients in the Dsuvia group and 65% of patients in the placebo group took rescue medication (morphine sulfate 1 mg IV) within the first 12 hours of the treatment phase. There was a numerically, but not statistically, higher incidence of nausea and headache in the SST group. The investigators found that Dsuvia (sufentanil) sublingual tablet demonstrated a statistically greater summed pain intensity difference from baseline over the first 12 hours of the study compared to placebo. In addition, the pain intensity difference from baseline was superior to that of the placebo group within 15 minutes and median meaningful pain relief occurred following a single dose. Thus, they concluded that not only was SST an effective opioid analgesic postoperatively, but SST was also well tolerated with mild-to-moderate side effects, similar to those found in placebo-treated patients.

The study had several limitations that required careful interpretation of results. The study was meant to reflect the typical surgical population; however, patient enrollment was not limited by age and the elderly were under-represented (1.2 percent of patients were older than 65 years). The primary endpoint included a 12-hour evaluation period, as ambulatory care surgery typically results in same-day discharge; thus, this study cannot fully interpret the longer term effects of SST in this population. Nonetheless, the majority of patients were followed for 24 hours. In addition, the sample size was limited, which may also affect the generalizability of the results.  Futhermore, all patients, including those in the SST group, were permitted to receive IV opioids in the operating room as well as IV morphine for rescue analgesia. However, according to Mindowitz and colleagues, SST demonstrated superior pain relief compared with placebo despite this potential confound (Minkowitz et al, 2017). 

Hutchins et al (2018) conducted a multicenter, open-label, single-arm study to evaluate sufentanil sublingual tablet 30 mcg (SST 30 mcg) for postoperative pain in an older patient population with comorbidities. Patients with a postoperative pain intensity score greater than or equal to 4 on an 11-point numeric rating scale (NRS) were allowed to enter the study and receive SST 30 mcg as requested for pain (minimum 60-minute redosing interval) over the 12-hour study period. Efficacy was assessed by patient reports of pain intensity on the NRS and a five-point pain relief scale. Safety was monitored throughout the study; plasma sufentanil concentrations were also measured. The primary efficacy endpoint was the time-weighted summed pain intensity difference (SPID) to baseline over 12 hours (SPID12). Of the 140 patients enrolled, 69% were American Society of Anesthesiologists Physical Class II or III, 44% had a body mass index (BMI) ≥30 mg/kg2, and 29% had hepatic and/or renal impairment. Average age was 54.7 years (SD = 9.9 years), and average baseline pain intensity was 6.2 (SD = 1.9). The most common surgeries were abdominal (59%) and orthopedic (20%). The mean SPID12 was 36.0 (standard error of the mean = 2.2); mean scores were similar, regardless of age, sex, race, and BMI. From baseline, mean pain intensity decreased significantly starting 30 minutes postdose, and mean pain relief increased significantly starting 15 minutes postdose, remaining relatively stable through 12 hours (P < 0.001 at each time point). Four (3%) patients discontinued due to inadequate analgesia, and 45 (32%) patients had one or more adverse events that were considered possibly or probably related to the study drug. Mean plasma sufentanil concentrations were generally similar regardless of age, sex, BMI, or organ impairment status. The authors concluded that SST 30 mcg was effective and well tolerated for the management of moderate-to-severe acute postoperative pain.

Miner et al (2019) evaluated pooled phase III safety analysis of SST for short-term treatment of postoperative patients with moderate-to-severe acute pain. The analysis included studies of healthcare administration of SST 30 mcg following abdominal surgery and studies of patient controlled analgesia (PCA) with SST 15 mcg (30 mcg dose-equivalent) in postoperative patients. Study drug exposure, patient discontinuations, adverse events (AEs) and oxygen desaturation events were included in their analysis. All enrolled patients who received at least one dose of the study drug were included in the analyses and include summaries of safety data. The authors found that the pooled results from 10 clinical trials, in which patients were treated with SST 30 and 15 mcg for 72 hours or less, indicate that SST has a tolerable safety profile, with most AEs considered mild or moderate in severity. The authors state that safety assessments indicate that AEs are similar to those observed with other opioids in postoperative studies and no dose-dependent increases in oxygen desaturation events were observed with SST use. Most of the respiratory events observed were mild to moderate and self-limited, and naloxone was not required for any patient receiving SST 30 mcg and required by 3 patients receiving SST 15 mcg. The authors acknowledged limitations to their findings. Not all studies of SST were placebo-controlled and no study of SST 30 mcg included an active comparator, which may limit the ability to interpret these results. This pooled analysis also included patients in SST 15 mcg PCA studies who received two doses of SST 15 mcg within the first 25 min of the study. Furthermore, 75% of these patients also received a third dose of SST 15 mcg in the first hour of treatment, exceeding by 50% the dose of sufentanil received from a single SST 30-mcg dose given per hour. Overall, the 24-h median (range) SST dose amount utilized was 1.8-times higher for the SST 15-mcg (375 mcg) group compared with the SST 30-mcg (210 mcg) group. The majority of patients in the SST 30 mcg studies were outpatient or short-stay (primarily laparoscopic) surgery and often discharged home at 12–24 hours postoperatively; whereas, the SST 15 mcg PCA studies had undergone longer, more complicated surgeries (knee/hip replacement or open abdominal surgery), requiring 2 to 3 days in a hospital setting. In addition, long-term consequences of opioid treatment, such as tolerance or addiction, were not identified in these short-term studies; however, the labeled use of SST is for no more than 2–3 days duration in medically supervised and monitored settings. Nonetheless, the authors concluded that overall, SST was well-tolerated, with mose AEs considered mild or moderate in severity.

Leiman et al (2021) state that global assessments and treatment-related adverse events (AEs) were analyzed from patients treated with sufentanil sublingual tablets (SST) 30 mcg for moderate-to-severe acute pain following surgery (abdominal, orthopedic, or other) or in the emergency department (ED). A total of 283 patients were included in the HPGA/PGA analyses. Overall, SST 30 mcg was highly rated by both healthcare professionals and patients across the demographic subgroups. A total of 323 patients were included in the safety evaluation. The majority of patients did not experience any SST-related AEs; however, those that did experienced common opioid-related side effects such as nausea, headache, dizziness, and vomiting. No patients experienced unexpected AEs or required the use of naloxone. The potential limitations of this analysis include the relatively smaller percentage of elderly patients and the fact that opioid-tolerant patients were not enrolled in any of these studies. These data highlight the efficacy and safety of SST in non-opioid tolerant patients, but additional evaluation of real-world data may be warranted in opioid-tolerant patients, as well as in larger numbers of elderly patients. Another limitation associated with the interpretation of these data is based on the fact that these scores were obtained in a controlled clinical trial environment. Because healthcare provider communication with patients is commonly associated with increased patient satisfaction scores, simply being in these clinical trials could have resulted in slightly higher patient global assessments. However, in general, the healthcare professional global assessments were largely consistent with the patient global assessments, suggesting minimal bias in patients treated with SST 30 mcg. Future study should focus on global satisfaction scores after treatment with SST 30 mcg in real-world scenarios.

Berg et al (2022) conducted a two-arm, parallel group, randomized prospective outcomes study at a single, free-standing ambulatory surgery center to determine if a single dose of a sublingual sufentanil tablet (SST) is as efficacious as a single dose of intravenous (IV) fentanyl in readiness to discharge. Patients (n=75) aged 18-80 undergoing general anesthesia who developed a postoperative pain score of 4 or more were randomized to receive either 30 mcg SST or 50 mcg IV fentanyl. After their initial randomized dose, rescue IV fentanyl followed by oral oxycodone was allowed if needed. Recovery length of stay from arrival in the postanesthesia care unit until readiness to discharge criteria was based on their facility's phase 2 discharge criteria. The authors found that readiness to discharge from the recovery room was not significantly different between either group (p=0.903). There was no significant difference in the amount of morphine equivalents (MME) of rescue opioids needed (p=0.742). The change in pain from PACU initially, and on discharge was not significantly different (p=0.079). There was no difference in the six-item screener and the Overall Benefit of Analgesic Survey Score. The authors concluded that the patients who received a SST had no significant differences in PACU length of stay or rescue analgesic usage when compared to intravenous fentanyl 50 mcg.

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References