Dsuvia

• 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.

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 Risks of
Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and
Inducers

Concomitant use of DSUVIA with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g. erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of sufentanil and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression

[see Warnings and Precautions ]

, particularly when an inhibitor is added after a stable dose of DSUVIA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in DSUVIA-treated patients may increase sufentanil plasma concentrations and prolong opioid adverse reactions. When using DSUVIA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DSUVIA-treated patients, monitor patients closely at frequent intervals for respiratory depression and sedation

[see Drug Interactions ]

.

Concomitant use of DSUVIA with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease sufentanil plasma concentrations, decrease opioid efficacy or, possibly lead to a withdrawal syndrome in a patient who had developed physical dependence to sufentanil. When using DSUVIA with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals for adequate analgesia and for symptoms of opioid withdrawal

[see Drug Interactions ]

.

), Drug Interactions (

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.

), and Clinical Pharmacology (

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_maxvalues 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-infis 278 h*pg/mL, the average C_maxof 63.1 pg/mL occurs at a median T_maxof 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_maxvalues 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-infand C_maxvalues of sufentanil, respectively, compared to its administration alone.

)]

.

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.

• Not for home use or for use in children. Discontinue treatment with DSUVIA before patients leave the certified medically supervised healthcare setting.
• Not for use for more than 72 hours. The use of DSUVIA beyond 72 hours has not been studied.
• Only to be administered by a healthcare provider.
• Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration

  [see Warnings and Precautions (

  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 ]

  .

  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.

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DSUVIA, and monitor all patients receiving DSUVIA for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DSUVIA but use in such patients necessitates intensive counseling about the risks and proper use of DSUVIA along with intensive monitoring for signs of addiction, abuse, and misuse.

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing DSUVIA. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

  
  
  

  )]

  , reserve DSUVIA for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):

- Have not been tolerated, or are not expected to be tolerated,

- Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

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.

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 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 ]

  .

  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.

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DSUVIA, and monitor all patients receiving DSUVIA for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DSUVIA but use in such patients necessitates intensive counseling about the risks and proper use of DSUVIA along with intensive monitoring for signs of addiction, abuse, and misuse.

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing DSUVIA. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

  
  
  

  )]
• Life-Threatening Respiratory Depression
  [see Warnings and Precautions (

  5.4 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status

  [see Overdosage ]

  . Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of DSUVIA, the risk is greatest during the initiation of therapy. Monitor patients closely for respiratory depression while on treatment with DSUVIA.

  Accidental exposure to or ingestion of even one dose of DSUVIA, especially in children, can result in respiratory depression and death due to an overdose of sufentanil.

  Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider minimizing the use of DSUVIA and carefully monitor the patient for signs of respiratory depression

  [see Dosage and Administration ]

  .

  )]
• Opioid-Induced Hyperalgesia and Allodynia
  [see Warnings and Precautions (

  5.7 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. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

  [see Dependence ]

  . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

  Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety).

  
  
  

  )]
• Adrenal Insufficiency
  [see Warnings and Precautions (

  5.10 Adrenal Insufficiency

  Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

  
  
  

  )]
• Severe Hypotension
  [see Warnings and Precautions (

  5.11 Severe Hypotension

  DSUVIA may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)

  [see Drug Interactions ]

  . Monitor these patients for signs of hypotension after initiating DSUVIA. In patients with circulatory shock, DSUVIA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DSUVIA in patients with circulatory shock.

  
  
  

  )]
• Gastrointestinal Adverse Reactions
  [see Warnings and Precautions (

  5.13 Risks of Use in Patients with Gastrointestinal Conditions

  DSUVIA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

  The sufentanil in DSUVIA may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

  
  
  

  )]
• Seizures
  [see Warnings and Precautions (

  5.14 Increased Risk of Seizures in Patients with Seizure Disorders

  The sufentanil in DSUVIA may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during DSUVIA therapy.

  )]
• Neonatal Opioid Withdrawal Syndrome
  [see Warnings and Precautions (

  5.16 Neonatal Opioid Withdrawal Syndrome

  Use of opioids for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

  [see Use in Specific Populations ]

  .

  )]