Dsuvia

1 INDICATIONS AND USAGE 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, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, [see Warnings and Precautions ( 5.3 )] , reserve opioid analgesics, including DSUVIA, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. DSUVIA contains sufentanil, an opioid agonist, and is indicated for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use: Not for home use or for use in children. Discontinue treatment with DSUVIA before patients leave the certified medically supervised healthcare setting. ( 1 ) Not for use for more than 72 hours. Only to be administered by a healthcare provider. Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including DSUVIA, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.3 )

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 rapidly reduce or abruptly discontinue DSUVIA 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

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.7 ) Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue DSUVIA if serotonin syndrome is suspected. ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.9 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of DSUVIA in patients with circulatory shock. ( 5.11 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of DSUVIA in patients with impaired consciousness or coma. ( 5.12 ) 5.1 Risk of Respiratory Depression and Death Due to Accidental Exposure Accidental ingestion or exposure to even one dose of DSUVIA, especially in children, can result in respiratory depression and death due to an overdose of sufentanil. DSUVIA is for use in adult patients only in a certified medically supervised healthcare setting. Use of DSUVIA outside of this setting can increase the risk of accidental exposure in others for whom it is not prescribed, causing fatal respiratory depression. Discontinue use of DSUVIA prior to discharge or transfer from the certified medically supervised healthcare setting. DSUVIA is not for home or pediatric use. Following accidental ingestion of DSUVIA, monitor patients for opioid-related adverse events, such as respiratory depression. 5.2 DSUVIA Risk Evaluation and Mitigation Strategy (REMS) Because of the potential for life-threatening respiratory depression due to accidental exposure, DSUVIA is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the DSUVIA REMS Program. The goal of the DSUVIA REMS is to mitigate the risk of respiratory depression resulting from accidental exposure by: • Ensuring that DSUVIA is dispensed only to patients in certified medically supervised healthcare settings. The requirements of the DSUVIA REMS are as follows: • Healthcare settings that dispense DSUVIA must: - Be able to manage an acute opioid overdose including respiratory depression - Train all relevant staff that DSUVIA must not be dispensed for use outside of the certified healthcare setting - Train all relevant staff involved in administration of DSUVIA to refer to the Directions for Use prior to administration - Establish processes and procedures to verify that DSUVIA is not dispensed for use outside of the certified healthcare setting. • Wholesalers that distribute DSUVIA must: - Establish processes and procedures to ensure that DSUVIA is distributed only to certified medically supervised healthcare settings. - Distribute only to certified medically supervised healthcare settings. Further information about the DSUVIA REMS Program is available at www.DSUVIAREMS.com, or by calling 1-855-925-8476. 5.3 Addiction, Abuse and Misuse DSUVIA contains sufentanil, a Schedule II controlled substance. As an opioid, DSUVIA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DSUVIA. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk …

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 )

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 [see Warnings and Precautions ( 5.5 )]. Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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) [se…

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 overdose reversal agent, such as naloxone or nalmefene, 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 subcutane…

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 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 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 voluntaril…