Dsuvia

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.3 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.4 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.7 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.10 )] Severe Hypotension [see Warnings and Precautions ( 5.11 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13 )] Seizures [see Warnings and Precautions ( 5.14 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.16 )] The most commonly reported adverse reactions (≥ 2%) were nausea, headache, vomiting, dizziness and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertical Pharmaceuticals, LLC at 1-855-925-8476 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 Possibly or Probably Related Adverse Reactions DSUVIA n=107 Placebo * n=54 Nausea 29.0% 22.2% Headache 12.1% 11.1% Vomiting 5.6% 1.9% Dizziness 5.6% 3.7% Hypotension 4.7% 3.7% *Morphine 1 mg IV was permitted as rescue medication 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. 6.2 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 use of opioids for an extended period of time. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

4 CONTRAINDICATIONS Use of DSUVIA is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.4 )] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 )] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.13 )] • Known hypersensitivity to sufentanil or components of DSUVIA [see Adverse Reactions ( 6.1 , 6.2 )]. • Significant Respiratory Depression. ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) • Known hypersensitivity to sufentanil or components of DSUVIA. ( 4 )

11 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]-N-phenylpropanamide citrate. Sufentanil citrate has a molecular weight of 578.4 (molecular weight of free sufentanil base is 386.55), its empirical formula is C 28 H 38 N 2 O 9 S ● C 6 H 8 N 2 O 7 , 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. sufentanil-figure-06

2 DOSAGE AND ADMINISTRATION Recommended dosage is 30 mcg sublingually as needed with a minimum of one hour between doses. ( 2.2 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve the use of additional doses of DSUVIA for patients in whom a single dose is insufficiently effective and in whom the expected benefits of using additional doses of an opioid clearly outweigh the substantial risks ( 2.2 , 5 ). Respiratory depression can occur at any time during opioid therapy, especially when initiating and following additional doses of DSUVIA. Consider this risk when initiating dosing and when making dose adjustments ( 2.2 , 5 ). Do not exceed 12 tablets in 24 hours. ( 2.2 ) See the Full Prescribing Information for administration information. ( 2.3 ) Do not discontinue DSUVIA abruptly in a physically-dependent patient. ( 9.3 ) 2.1 Important Administration Instructions DSUVIA is only to be administered by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. 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. 2.2 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. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve the use of additional doses of DSUVIA for patients in whom a single dose is insufficiently effective and in whom the expected benefits of using additional doses of an opioid clearly outweigh the substantial risks. The maximum cumulative daily dose of sufentanil is 360 mcg or 12 tablets (12 tablets x 30 mcg/dose). Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addition, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following additional doses of DSUVIA. Consider this risk when initiating dosing and when making dose adjustments [see Warnings and Precautions ( 5 )] . 2.3 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 sufentanil-figure-01 sufentanil-figure-02 sufentanil-figure-03

9.2 Abuse DSUVIA contains sufentanil, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.3 )] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of DSUVIA increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of DSUVIA with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of DSUVIA abuse include those with a history of prolonged use of any opioid, including products containing sufentanil, those with a history of drug or alcohol abuse, or those who use DSUVIA in combination with other abused drugs. “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 people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. DSUVIA, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

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

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance DSUVIA contains sufentanil citrate, a Schedule II controlled opioid agonist that can be abused and may produce drug dependence. 9.2 Abuse DSUVIA contains sufentanil, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.3 )] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of DSUVIA increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of DSUVIA with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of DSUVIA abuse include those with a history of prolonged use of any opioid, including products containing sufentanil, those with a history of drug or alcohol abuse, or those who use DSUVIA in combination with other abused drugs. “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 people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. DSUVIA, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )] .

10 OVERDOSAGE Clinical Presentation Acute overdose with sufentanil 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, hypoglycemia, 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 ( 12.2 )] . 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 measures. Opioid antagonists, such as naloxone, 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. 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.

7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with DSUVIA. Table 2 : Clinically Significant Drug Interactions with DSUVIA Inhibitors of CYP3A4 Clinical Impact: The concomitant use of DSUVIA and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil. Intervention: If concomitant use is necessary, consider an alternate medication that permits dose titration. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider an alternate medication that permits dose titration. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of DSUVIA and CYP3A4 inducers can decrease the plasma concentration of sufentanil [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil [see Warnings and Precautions ( 5.6 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider an alternate medication that permits dose titration. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider less frequent dosing of DSUVIA and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions ( 5.5 )] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation . Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.8 )] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DSUVIA if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (e.g., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.4 )]. Intervention: The use of DSUVIA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of DSUVIA and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of the muscle relaxant as necessary or consider discontinuing use of DSUVIA. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DSUVIA is used concomitantly with anticholinergic drugs. • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with DSUVIA because they may reduce analgesic effect of DSUVIA or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 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 opioid-specific receptors throughout the CNS. Like all full opioid agonists, there is no ceiling effect to analgesia. 12.2 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 ( 6.2 )]. Use of opioids for an extended period of time 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 ( 6.2 )]. 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 ( 5.4 )]. 12.3 Pharmacokinetics Absorption A single sublingual administration of DSUVIA has a bioavailability of approximately 53% relative to a one-minute IV sufentanil infusion of 30 mcg. Compared to IV administration, sublingual C max 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 AUC 0-inf is 278 h*pg/mL, the average C max of 63.1 pg/mL occurs at a median T max of 1.00 hour. After 12 multiple hourly doses over 11 hours, the geometric mean for the AUC within a dosing interval (AUC 0-60min ) and C max 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 AUC 0-inf and C max values of sufentanil, respectively, compared to its administration alone. sufentanil-figure-04

12.1 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 opioid-specific receptors throughout the CNS. Like all full opioid agonists, there is no ceiling effect to analgesia.

12.2 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 ( 6.2 )]. Use of opioids for an extended period of time 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 ( 6.2 )]. 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 ( 5.4 )].

12.3 Pharmacokinetics Absorption A single sublingual administration of DSUVIA has a bioavailability of approximately 53% relative to a one-minute IV sufentanil infusion of 30 mcg. Compared to IV administration, sublingual C max 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 AUC 0-inf is 278 h*pg/mL, the average C max of 63.1 pg/mL occurs at a median T max of 1.00 hour. After 12 multiple hourly doses over 11 hours, the geometric mean for the AUC within a dosing interval (AUC 0-60min ) and C max 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 AUC 0-inf and C max values of sufentanil, respectively, compared to its administration alone. sufentanil-figure-04

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3 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. • Sublingual tablet: 30 mcg tablet housed in a disposable, single-dose applicator (SDA). ( 3 )

Dsuvia Sufentanil SUFENTANIL SUFENTANIL MANNITOL CROSCARMELLOSE SODIUM FD&C BLUE NO. 2 STEARIC ACID MAGNESIUM STEARATE ANHYDROUS DIBASIC CALCIUM PHOSPHATE HYPROMELLOSE, UNSPECIFIED Flat-Faced

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of sufentanil have not been conducted. Mutagenesis: Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micro-nucleus assay. Impairment of Fertility Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rates were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.6 and 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (2.2 times the maximum human daily dose of 360 mcg/60 kg, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of sufentanil have not been conducted. Mutagenesis: Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micro-nucleus assay. Impairment of Fertility Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rates were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.6 and 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (2.2 times the maximum human daily dose of 360 mcg/60 kg, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

NDA209128

Dsuvia

Sufentanil

61621-430

HUMAN PRESCRIPTION DRUG

SUBLINGUAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SUFENTANIL CARTON SUFENTANIL CONTAINER POUCH BACK FOLDOUT SUFENTANIL CONTAINER POUCH BACK BASE PANEL SUFENTANIL CONTAINER POUCH FRONT DSUVIA Carton DSUVIA DFU DSUVIA Back Pouch Label DSUVIA Front Pouch Label

Boxed Warning 12/2023 Indications and Usage ( 1 ) 12/2023 Dosage and Administration ( 2.2 ) 12/2023 Warnings and Precautions ( 5.7 ) 12/2023

17 PATIENT COUNSELING 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 ( 5.1 )] . 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 ( 5.4 )] . Instruct patients not to share DSUVIA with others and to take steps to protect DSUVIA from theft or misuse. 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 ( 5.4 )] . Hyperalgesia and Allodynia Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.7 ), and Adverse Reactions ( 6.2 )] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome 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 after discharge from the hospital. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see Warnings and Precautions ( 5.8 ), and Drug Interactions ( 7 )] . Important Administration 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. 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 ( 5.10 )] . 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 ( 4 ), and Warnings and Precautions ( 5.11 )] . 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 ( 4 ), and Adverse Reactions ( 6 )] . 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 ( 8.3 )] . Lactation Advise nursing mothers to carefully observe 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 ( 8.2 )] . Marketed By: AcelRx Pharmaceuticals, Inc., Hayward, CA PL-6410 Rev E

14 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 sufentanil-figure-05

8.5 Geriatric Use No special population studies were performed using DSUVIA in elderly patients. Of the 646 patients exposed to 30 mcg sufentanil or higher in the first hour of treatment, approximately 11% (72) of patients were ≥ 75 years of age and approximately 20% (126) patients were 65 to 75 years of age. The overall rate of adverse events and most common adverse events, such as nausea, tended to increase with age in patients who received sublingual sufentanil, although vomiting was less common in patients aged ≥ 75 years than in younger patients. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. As the dose of DSUVIA cannot be titrated, monitor geriatric patients closely for signs of central nervous system and respiratory depression or consider an alternate medication that can be titrated [see Warnings and Precautions ( 5.4 )] .

8.4 Pediatric Use The safety and efficacy of the use of DSUVIA in pediatric patients has not been established. The ability of pediatric patients to comply with the sublingual dosing instructions for DSUVIA has not been evaluated. Use of DSUVIA in younger children is not recommended as younger children may not be able to comply with the sublingual dosing instructions for DSUVIA and could swallow the tablet or spit it out, which could impact the efficacy and safety of DSUVIA.

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.16 )] . There are no available data with sufentanil in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 4.4 times the maximum human daily dose of 360 mcg/60 kg/day, based on a body surface area comparison during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human daily dose of 360 mcg. No malformations were observed in either rats or rabbits at doses below the human daily dose of 360 mcg [see Data] . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or non-medical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.16 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. DSUVIA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DSUVIA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.14, 0.6, or 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group). Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.2, 1.0, or 4.4 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group). No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.2, 1.4, or 2.8 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps. Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.14, 0.6, or 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups).

8 USE IN SPECIFIC POPULATIONS • Hepatic and/or Renal Impairment : Monitor for signs of sedation and respiratory depression. ( 8.6 , 8.7 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.16 )] . There are no available data with sufentanil in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 4.4 times the maximum human daily dose of 360 mcg/60 kg/day, based on a body surface area comparison during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human daily dose of 360 mcg. No malformations were observed in either rats or rabbits at doses below the human daily dose of 360 mcg [see Data] . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or non-medical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.16 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. DSUVIA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DSUVIA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.14, 0.6, or 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group). Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.2, 1.0, or 4.4 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group). No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.2, 1.4, or 2.8 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps. Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.14, 0.6, or 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups). 8.2 Lactation Risk Summary The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DSUVIA and any potential adverse effects on the breastfed infant from DSUVIA or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to DSUVIA through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. DSUVIA is not intended for chronic use [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.2 ), Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and efficacy of the use of DSUVIA in pediatric patients has not been established. The ability of pediatric patients to comply with the sublingual dosing instructions for DSUVIA has not been evaluated. Use of DSUVIA in younger children is not recommended as younger children may not be able to comply with the sublingual dosing instructions for DSUVIA and could swallow the tablet or spit it out, which could impact the efficacy and safety of DSUVIA. 8.5 Geriatric Use No special population studies were performed using DSUVIA in elderly patients. Of the 646 patients exposed to 30 mcg sufentanil or higher in the first hour of treatment, approximately 11% (72) of patients were ≥ 75 years of age and approximately 20% (126) patients were 65 to 75 years of age. The overall rate of adverse events and most common adverse events, such as nausea, tended to increase with age in patients who received sublingual sufentanil, although vomiting was less common in patients aged ≥ 75 years than in younger patients. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. As the dose of DSUVIA cannot be titrated, monitor geriatric patients closely for signs of central nervous system and respiratory depression or consider an alternate medication that can be titrated [see Warnings and Precautions ( 5.4 )] . 8.6 Hepatic Impairment Because sufentanil is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Monitor closely for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] . 8.7 Renal Impairment Sufentanil and its metabolites are known to be excreted by the kidney. No significant changes have been observed in subjects with mild or moderate renal impairment. Monitor closely for adverse events such as respiratory depression, sedation, and hypotension in patients with severe renal impairment [see Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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. 16.2 Storage and Handling Store DSUVIA at room temperature 20-25 ºC, excursions allowed 15-30 ºC in a secure, limited access location, in accordance with institutional procedures for CII products.

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF DSUVIA Accidental Exposure and DSUVIA Risk Evaluation and Mitigation Strategy (REMS) Program Accidental exposure to or ingestion of DSUVIA, especially in children, can result in respiratory depression and death. Because of the potential for life-threatening respiratory depression due to accidental exposure, DSUVIA is only available through a restricted program called the DSUVIA REMS Program [see Warnings and Precautions ( 5.1 , 5.2 )] . DSUVIA must only be dispensed to patients in a certified medically supervised healthcare setting. Discontinue use of DSUVIA prior to discharge or transfer from the certified medically supervised healthcare setting. Addiction, Abuse, and Misuse Because the use of DSUVIA exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing DSUVIA, and reassess all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions ( 5.2 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of DSUVIA. Monitor for respiratory depression, especially during initiation of DSUVIA [see Warnings and Precautions ( 5.4 )] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of DSUVIA and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.5 ) and Drug Interactions ( 7 )] . Cytochrome P450 3A4 Interaction The concomitant use of DSUVIA with all cytochrome P450 3A4 inhibitors may result in an increase in sufentanil plasma concentrations, which could increase or prolong adverse drug reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in sufentanil plasma concentration. Monitor patients receiving DSUVIA and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF DSUVIA See full prescribing information for complete boxed warning. Accidental exposure to or ingestion of DSUVIA, especially in children, can result in respiratory depression and death. Because of the risk of life-threatening respiratory depression from accidental exposure, DSUVIA is available only through a restricted program called the DSUVIA REMS Program [see Warnings and Precautions ( 5.1 , 5.2 )] . DSUVIA should only be administered by a healthcare provider in a certified medically supervised healthcare setting. Discontinue use of DSUVIA prior to discharge or transfer from the certified medically supervised setting. ( 5.1 , 5.2 ) DSUVIA exposes users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing, and reassess regularly for these behaviors and conditions. ( 5.3 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially during initiation. ( 5.4 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.5 , 7 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of sufentanil. ( 5.6 , 7 , 12.3 )