sufentanil

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 ] , 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. 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.

Recommended dosage is 30 mcg sublingually as needed with a minimum of one hour between doses. 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 . 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 . Do not exceed 12 tablets in 24 hours. See the Full Prescribing Information for administration information. Do not rapidly reduce or abruptly discontinue DSUVIA in a physically-dependent patient. 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 ] . 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 ] . 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 ] .

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

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.

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ] Life-Threatening Respiratory Depression [see Warnings and Precautions ] Opioid-Induced Hyperalgesia and Allodynia [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 ] The most commonly reported adverse reactions (≥ 2%) were nausea, headache, vomiting, dizziness and hypotension. 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 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 ] . 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). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 15 to 6% of participants across the two cohorts newly meet criteria for addiction, as assessed with two validated interview-based measures of moderate-to-sever opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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 ] , 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 ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil [see Warnings and Precautions ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase [see Clinical Pharmacology ] , 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 ] . 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 ]. 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 ] . 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 ]. 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. Examples: Cyclobenzaprine, metaxolone. 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.

• Hepatic and/or Renal Impairment : Monitor for signs of sedation and respiratory depression. 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 ] . 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 ] . 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 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 , Clinical Pharmacology , Nonclinical Toxicology ] . 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% of patients were ≥ 75 years of age and approximately 20% 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 ] . 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 ] . 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 ].