Dsuvia

Patient Information

Increased Risk Of Overdose And Death In Children Due To Accidental Exposure

Inform patients that accidental exposure, especially by children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS].

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting DSUVIA [see WARNINGS AND PRECAUTIONS].

Addiction, Abuse, And Misuse

Inform patients that the use of DSUVIA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share DSUVIA with others and to take steps to protect DSUVIA from theft or misuse.

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS AND PRECAUTIONS].

Important Administration Of Instructions

Advise patients to allow DSUVIA to dissolve under the tongue and not to chew or swallow the tablet. Advise patients not to eat or drink and to minimize talking for 10 minutes after each dose of DSUVIA.

Hypotension

Inform patients that DSUVIA may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in DSUVIA. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS and ADVERSE REACTIONS].

Pregnancy

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that DSUVIA can (or may) cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see Use In Specific Populations].

Lactation

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use In Specific Populations].

Description

DSUVIA contains one 30 mcg sufentanil tablet housed in a disposable single-dose applicator (SDA). The DSUVIA tablet is an immediate release formulation intended for sublingual administration. Each tablet is blue, flat-faced with a diameter of 3 mm.

The IUPAC chemical name for sufentanil is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-Nphenylpropanamide citrate. Sufentanil citrate has a molecular weight of 578.4 (molecular weight of free sufentanil base is 386.55), its empirical formula is C₂₈H₃₈N₂O₉S • C₆H₈N₂O₇, and its chemical structure is shown below:

DSUVIA tablets inactive ingredients are: mannitol; dicalcium phosphate anhydrous; hypromellose; croscarmellose sodium; FD&C Blue #2; stearic acid and magnesium stearate.

DSUVIA 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. The use of DSUVIA beyond 72 hours has not been studied. Only to be administered by a healthcare provider.
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see WARNINGS AND PRECAUTIONS], 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.

Dosage And Admintisration

Important Administration Instructions

DSUVIA is only to be administered by the healthcare provider.

DSUVIA is only to be used in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments.

DSUVIA treatment must be discontinued prior to the patient leaving the certified medically supervised setting.

Dosage Information

The recommended dosage of DSUVIA is 30 mcg sublingually as needed with a minimum of 1 hour between doses. Do not exceed 12 tablets in 24 hours.

The maximum cumulative daily dose of sufentanil is 360 mcg or 12 tablets (12 tablets x 30 mcg/dose).

Administration Of DSUVIA

• Single-use product / Do not reuse.
• Do not use if pouch seal is broken.
• Do not use if the Single-Dose Applicator (SDA) is damaged.
• Wear gloves when administering DSUVIA.
• Instruct the patient to not chew or swallow the tablet.
• Instruct the patient to not eat or drink and minimize talking for 10 minutes after receiving the tablet. If a patient experiences excessive dry mouth, ice chips should be provided prior to administration of DSUVIA.

Administration Instructions

The pouch contains one clear plastic SDA with a single blue-colored tablet housed in the tip, and an oxygen absorber packet. See Figure 1.

Figure 1. DSUVIA Pouch Contents

REMOVE SDA from pouch.

DISCARD the oxygen absorber packet.

Figure 2. Lock Removal

DISCARD the Lock.

NOTE: To prevent ejecting the tablet accidentally:

Figure 3. SDA Placement for Administration

NOTE: Avoid direct mucosal contact with the SDA tip.

1. Only when ready to administer the medication, TEAR OPEN the notched pouch across the top.
2. REMOVE the white Lock from the green Pusher by squeezing the sides together and detaching from Pusher. See Figure 2.
   • Do not remove Lock until ready to administer
   • Avoid touching the green Pusher before placing the SDA in the patient’s mouth for administration
3. TELL the patient to open their mouth and touch their tongue to the roof of their mouth if possible.
4. REST the SDA lightly on the patient’s lower teeth or lips. See Figure 3.
5. PLACE the SDA tip under the tongue and aim at the floor of the patient’s mouth or sublingual space. See Figure 3.
6. GENTLY DEPRESS the green Pusher to deliver the tablet to the patient’s sublingual space. See Figure 3.
7. VISUALLY CONFIRM tablet placement in the sublingual space. See Figure 4.

   Figure 4. Tablet Placement in Sublingual Space

    

   NOTE: If the tablet is NOT in the patient’s mouth, it is important to retrieve and dispose of the tablet according to institutional CII waste procedures.

8. DISCARD the used SDA in biohazard waste after administration.

How Supplied

Dosage Forms And Strengths

Sublingual Tablets

DSUVIA is a single 30 mcg sufentanil tablet housed in a disposable, single-dose applicator (SDA). The tablet is blue-colored, flat-faced with rounded edges and is 3 mm in diameter.

Each DSUVIA tablet 30 mcg is housed in a single-dose applicator (SDA) and packaged within a tamper-evident laminate foil pouch. For distribution there is one presentation:

• NDC 61621-430-11 (10 pouches per carton)

The SDA should be disposed in biohazard waste after administration of DSUVIA.

Instruct the healthcare provider to take steps to store DSUVIA securely and to dispose of any dropped or misplaced DSUVIA tablets according to institutional CII procedures.

Storage And Handling

Store DSUVIA at room temperature 20-25 °C, excursions allowed 15-30 °C in a secure, limited access location, in accordance with institutional procedures for CII products.

Marketed By: AcelRx Pharmaceuticals, Inc., Hayward, CA. Revised: May 2021.

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
• Severe hypotension [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In controlled and uncontrolled studies, the safety of DSUVIA was evaluated in a total of 646 patients with moderate-to-severe acute postoperative pain or pain due to trauma which required opioid analgesia.

The most frequently reported adverse reactions ≥ 2% that were probably or possibly related to study treatment in the one pivotal, placebo-controlled trial (Study SAP301) are presented in Table 1.

Discontinuation of study drug due to adverse events occurred in 0.9% of DSUVIA-treated patients (1 out of 107 patients) and 3.7% of placebo-treated patients (2 out of 54 placebo treated patients). The most common reasons for discontinuation of study drug due to adverse reactions in SAP301 were oxygen saturation decreased (0.9% in the DSUVIA group), and dizziness, hemiparesis, somnolence and syncope in the placebo group (1.9% each).

Table 1: Adverse Reactions Occurring in ≥ 2% of Patients and for Which Rate is Higher in DSUVIA than Placebo Group: Placebo-Controlled Study SAP301

Other Reported Adverse Reactions

Additional treatment related adverse drug reactions which occurred in at least 0.1% of the patients exposed to 30 mcg or higher of sublingual sufentanil are described below.

Cardiac Disorders: sinus tachycardia, bradycardia.

Gastrointestinal Disorders: constipation, dyspepsia, flatulence, diarrhea, dry mouth, eructation, retching, abdominal discomfort, abdominal distension, abdominal pain upper, gastritis, postoperative ileus, hypoesthesia oral.

Investigations: oxygen saturation decreased, respiratory rate decreased, urine output decreased, aspartate aminotransferase increased, electrocardiogram abnormal, hepatic enzyme increased.

Musculoskeletal and Connective Tissue Disorders: muscle spasms.

Nervous System Disorders: somnolence, sedation, presyncope, lethargy, memory impairment.

Psychiatric Disorders: insomnia, confusional state, anxiety, agitation, disorientation, euphoric mood, hallucination, mental status changes.

Renal and Urinary Disorders: urinary retention, urinary hesitation, oliguria, renal failure.

Respiratory, Thoracic and Mediastinal Disorders: hypoxia, bradypnea, hiccups, apnea, atelectasis, hypoventilation, respiratory distress, respiratory failure.

Skin and Subcutaneous Tissue Disorders: pruritus,hyperhidrosis, rash.

Vascular Disorders: hypotension, hypertension, orthostatic hypotension, flushing.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of sufentanil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in DSUVIA.

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].

Table 2 includes clinically significant drug interactions with DSUVIA.

Table 2: Clinically Significant Drug Interactions with DSUVIA

Drug Abuse And Dependence

Controlled Substance

DSUVIA contains sufentanil citrate, a Schedule II controlled opioid agonist that can be abused and may produce drug dependence.

Abuse

DSUVIA contains sufentanil, a substance with a high potential for abuse similar to other opioids including (fentanyl, morphine, oxycodone, hydromorphone). DSUVIA can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].

All patients treated with opioids 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.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

DSUVIA, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

WarningS

Included as part of the PRECAUTIONS section.

Precautions

None.

Patient Counseling Information

Advise patients to read the FDA-approved Patient Labeling (Instructions for Use).

Storage And Handling Information

Instruct patients on the proper techniques to store and handle PULMOZYME. PULMOZYME must be stored in the refrigerator at 2 to 8°C (36 to 46°F) and protected from light. It should be kept refrigerated during transport and should not be exposed to room temperatures for a total time of 24 hours.

Advise patients to squeeze each ampule prior to use in order to check for leaks. The solution should be discarded if it is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.

Instruct patients in the proper use and maintenance of the jet nebulizer/compressor system or eRapid Nebulizer System used in PULMOZYME delivery.

Instruct patients not to dilute or mix PULMOZYME with other drugs in the nebulizer. Mixing of PULMOZYME with other drugs could lead to adverse physicochemical and/or functional changes in PULMOZYME or the admixed compound.

Use With The eRapid Nebulizer System

Instruct patients and caregivers to read and follow the directions in both the PULMOZYME Instructions for Use and in the Manufacturer’s eRapid Nebulizer System Instruction Booklet.

Instruct patients and caregivers to clean the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each use. Instruct patients and caregivers to disinfect the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each day of use.

Instruct patients to replace the handset after 90 uses, regardless of whether the EasyCare cleaning aid is used. Since delivery data are not available for PULMOZYME administered with the eRapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of PULMOZYME cannot be assured beyond 90 administrations.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

PULMOZYME produced no treatment-related increases in the incidence of tumors in a lifetime study in Sprague Dawley rats that were administered inhaled doses up to 0.246 mg/kg/day (approximately 30 times the MRHD in adults). There was no increase in the development of benign or malignant neoplasms and no occurrence of unusual tumor types in rats after lifetime exposure.

PULMOZYME tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo mouse bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats that received intravenous doses up to 10 mg/kg/day (approximately 600 times the MRHD in adults).

Use In Specific Populations

Pregnancy

Risk summary

There are no adequate and well-controlled studies with PULMOZYME in pregnant women. However, animal reproduction studies have been conducted with dornase alfa. In these studies, no evidence of fetal harm was observed in rats and rabbits at doses of dornase alfa up to approximately 600 times the maximum recommended human dose (MRHD).

The background risk of major birth defects and miscarriage for the cystic fibrosis population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

Reproductive studies have been performed in rats and rabbits at intravenous doses of dornase alfa up to 10 mg/kg/day (approximately 600 times the MRHD in adults). In a combined embryo-fetal development and preand post-natal development study, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when dornase alfa was administered to dams throughout organogenesis (Gestation days 6 to 17). Dornase alfa did not elicit adverse effects on fetal or neonatal growth when administered to dams throughout most of gestation and delivery (Gestation days 6 to 25) and nursing (Post-partum days 6 to 21).

A pharmacokinetic study in Cynomolgus monkeys found no detectable levels of dornase alfa in fetal blood or amniotic fluid on gestation day 150 (end of gestation) from mothers that were administered an intravenous bolus dose (0.1 mg/kg) followed by an intravenous infusion dose (0.080 mg/kg) over a 6-hour period during pregnancy.

Lactation

Risk Summary

It is not known whether PULMOZYME is present in human milk. In a pharmacokinetic study in Cynomolgus monkeys, levels of dornase alfa detected in milk were less than 0.1% of the maternal serum concentration at 24 hours after dosing [intravenous bolus dose (0.1 mg/kg) of dornase alfa followed by an intravenous infusion (0.080 mg/kg/hr) over a 6-hour period] on post-partum day 14. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PULMOZYME and any potential adverse effects on the breastfed child from PULMOZYME or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of PULMOZYME have been established in pediatric patients 5 years of age and older [see ADVERSE REACTIONS and Clinical Studies]. The safety of PULMOZYME, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 65 patients with cystic fibrosis aged 3 months to < 5 years [see ADVERSE REACTIONS]. While clinical trial data are limited in pediatric patients younger than 5 years of age, the use of PULMOZYME should be considered for pediatric CF patients who may experience potential benefit in pulmonary function or who may be at risk of respiratory tract infection.

Geriatric Use

Cystic fibrosis is primarily a disease of children and young adults. Clinical studies of PULMOZYME did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.

Overdose

Clinical Presentation

Acute overdose with DSUVIA can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY].

Treatment Of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to sufentanil overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to sufentanil overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of sufentanil in DSUVIA, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

Contraindications

Use of DSUVIA is contraindicated in patients with:

• Significant respiratory depression [see WARNINGS AND PRECAUTIONS]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS AND PRECAUTIONS]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS AND PRECAUTIONS]
• Known hypersensitivity to sufentanil or components of DSUVIA [see ADVERSE REACTIONS].

Mechanism Of Action

Sufentanil is an opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses.

The principle therapeutic action of sufentanil is analgesia and sedation, thought to be mediated through opioidspecific receptors throughout the CNS. Like all full opioid agonists, there is no ceiling effect to analgesia.

Pharmacodynamics

Effects On The Central Nervous System

Sufentanil produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Sufentanil causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects On The Gastrointestinal Tract And Other Smooth Muscle

Sufentanil causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects On The Cardiovascular System

Sufentanil produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects On The Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see ADVERSE REACTIONS].

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].

Effects On The Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Effects On The Respiratory System

All opioid mu-receptor agonists, including DSUVIA, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects.

Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with DSUVIA in the clinical trial, sufentanil given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

A single sublingual administration of DSUVIA has a bioavailability of approximately 53% relative to a oneminute IV sufentanil infusion of 30 mcg. Compared to IV administration, sublingual Cmax values were 17-fold lower. The sublingual route of administration of sufentanil avoids intestinal and hepatic first-pass effects, both which severely limit bioavailability of swallowed (oral) sufentanil sublingual tablet (9%). Following a single dose of DSUVIA, the mean AUC0-inf is 278 h*pg/mL, the average Cmax of 63.1 pg/mL occurs at a median Tmax of 1.00 hour. After 12 multiple hourly doses over 11 hours, the geometric mean for the AUC within a dosing interval (AUC0-60min) and Cmax values were increased by 3.7-fold and 2.3-fold greater compared to single-dose administration, respectively. Steady-state plasma concentrations were achieved after 7 doses (Figure 1).

Figure 1: Sufentanil Concentration-Time Values: Single vs. Consecutive Repeat Doses (12 DSUVIA Doses)

Distribution

Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates.

Elimination

Following a single dose of DSUVIA, the mean terminal half-life is 13.4 hours, and the mean apparent plasma clearance is 108 L/hour.

Metabolism

The liver and small intestine are the major sites of biotransformation

Excretion

Approximately 80% of the IV administered dose of sufentanil is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.

Specific Populations

Clearance is not significantly affected by race, sex, mild or moderate renal impairment based on the population pharmacokinetics.

Drug Interaction Study

Co-administration of a single dose of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC0-inf and Cmax values of sufentanil, respectively, compared to its administration alone.

Clinical Studies

The efficacy and safety of DSUVIA were evaluated in one randomized, double-blind, placebo-controlled trial which enrolled 161 patients (age 18 to 69 years) with acute postoperative pain (pain intensity of ≥ 4 on a 0-10 Numeric Rating Scale [NRS]) after abdominal surgery (studied up to 48 hours) (Study SAP301, NCT# 02356588). Patients were dosed with DSUVIA 30 mcg or placebo as needed with a minimum of 60 minutes between doses. Morphine sulfate 1 mg IV was available as rescue medication.

The primary efficacy endpoint was the time-weighted summed pain intensity difference over 12 hours (SPID12). Patients using DSUVIA had a statistically significantly higher SPID12 than patients using placebo. Least squares means of pain intensity difference from baseline over 24 hours for the abdominal surgery study are shown in Figure 2. Median time to onset of meaningful pain relief (measured using the double stopwatch method) was 54 minutes for the DSUVIA group and 84 minutes for the placebo group. Approximately 22% of patients in the DSUVIA group and 65% of patients in the placebo group took rescue medication within the first 12 hours of the treatment phase.

Figure 2: Least Squares Mean of Pain Intensity Difference by Evaluation Time Point over the 24-Hour Study Period: Abdominal Surgery ITT Population

PID = pain intensity difference; ITT = intent-to-treat; LS = least squares; SEM = standard error of the mean