Dsuvia Sufentanil 30 ug Tablet, 1 tablet — NDC 61621-430-01 (Billing 61621-0430-01)

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 )

5.1Risk 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.

5.2DSUVIA 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.

5.3Addiction, 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… [Excerpted — this section continues on DailyMed.]

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.

6.1Clinical 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.

6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of sufentanil. Because these reactions are reported voluntaril… [Excerpted — this section continues on DailyMed.]

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… [Excerpted — this section continues on DailyMed.]

9 DRUG ABUSE AND DEPENDENCE

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

9.2Abuse 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.

9.3Dependence 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, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinic… [Excerpted — this section continues on DailyMed.]

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