DSUVIA (sufentanil) sublingual tablet, CII

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]-Nphenylpropanamide citrate. Sufentanil citrate has a molecular weight of 578.4 (molecular weight of free sufentanil base is 386.55), its empirical formula is C₂₈H₃₈N₂O₉S ● C₆H₈N₂O₇

DSUVIA tablets inactive ingredients are: mannitol; dicalcium phosphate anhydrous; hypromellose; croscarmellose sodium; FD&C Blue #2; stearic acid and magnesium stearate.

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, and misuse with opioids, even at recommended doses, 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.

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

DOSAGE AND ADMINISTRATION

Important Administration Instructions

DSUVIA is only to be administered by the healthcare provider. 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.

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. The maximum cumulative daily dose of sufentanil is 360 mcg or 12 tablets (12 tablets x 30 mcg/dose).

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

Only when ready to administer the medication, TEAR OPEN the notched pouch across the top. The pouch contains one clear plastic SDA with a single blue-colored tablet housed in the tip, and an oxygen absorber packet. See Figure 1. REMOVE SDA from pouch. DISCARD the oxygen absorber packet.

FIGURE 1

REMOVE the white Lock from the green Pusher by squeezing the sides together and detaching from Pusher. See Figure 2. DISCARD the Lock.
NOTE: To prevent ejecting the tablet accidentally:
Do not remove Lock until ready to administer
Avoid touching the green Pusher before placing the
SDA in the patient’s mouth for administration

Figure 2

TELL the patient to open their mouth and touch their
tongue to the roof of their mouth if possible.
REST the SDA lightly on the patient’s lower teeth or
lips. See Figure 3.
PLACE the SDA tip under the tongue and aim at the
floor of the patient’s mouth or sublingual space. See
Figure 3

NOTE: Avoid direct mucosal contact with the SDA tip.

GENTLY DEPRESS the green Pusher to deliver the
tablet to the patient’s sublingual space. See Figure 3

FIGURE 3

VISUALLY CONFIRM tablet placement in the
sublingual space. See Figure 4.
NOTE: If the tablet is NOT in the patient’s mouth, it is
important to retrieve and dispose of the tablet according
to institutional CII waste procedures.
DISCARD the used SDA in biohazard waste after
administration.

FIGURE 4

CONTRAINDICATIONS

Use of DSUVIA is contraindicated in patients with:

Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
Known or suspected gastrointestinal obstruction, including paralytic ileus
Known hypersensitivity to sufentanil or components of DSUVIA

WARNINGS AND PRECAUTIONS

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.

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

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. 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.

Risks from Concomitant Use with Benzodiazepines or other CNS Depressants:
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DSUVIA with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs:
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of sufentanil, the active opioid ingredient of DSUVIA, with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (e.g., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur at the recommended dosage.

Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one monthBof 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 withphysiologic replacement doses of corticosteroids. Wean the patient off the opioid to allow adrenal function torecover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as somecases reported use of a different opioid without recurrence of adrenal insufficiency. The information availabledoes not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

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). 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.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), DSUVIA may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with DSUVIA.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DSUVIA in patients with impaired consciousness or coma. DSUVIA is not suitable for use in patients who are not alert and able to follow directions.

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.

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.

Bradycardia: DSUVIA may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely forchanges in heart rate, particularly when initiating therapy with DSUVIA.

Neonatal Opioid Withdrawal Syndrome: Prolonged use of DSUVIA during pregnancy can result in withdrawal in the neonate. Neonatal opioidwithdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognizedand treated, and requires management according to protocols developed by neonatology experts. Observenewborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant womenusing opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure thatappropriate treatment will be available

Adverse drug reactions

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 chronic use of opioids

DRUG INTERACTIONS

Inhibitors of CYP3A4: 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, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.

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: The concomitant use of DSUVIA and CYP3A4 inducers can decrease the plasma concentration of sufentanil, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

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: 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.

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: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

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): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma)

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: May reduce the analgesic effect of DSUVIA and/or precipitate withdrawalsymptoms.

Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants: Sufentanil may enhance the neuromuscular blocking action of skeletal musclerelaxants and produce an increased degree of respiratory depression.

Monitor patients for signs of respiratory depression that may be greater thanotherwise expected and decrease the dosage of the muscle relaxant as necessaryor consider discontinuing use of DSUVIA.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release ofantidiuretic hormone.

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase risk of urinaryretention and/or severe constipation, which may lead to paralytic ileus.

Monitor patients for signs of urinary retention or reduced gastric motility when DSUVIA is used concomitantly with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS

Pregnancy: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Thereare no available data with sufentanil in pregnant women to inform a drug-associated risk for major birth defectsand miscarriage.

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical 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

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 depressionin 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 prolonglabor 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.

Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinicalneed for DSUVIA and any potential adverse effects on the breastfed infant from DSUVIA or from theunderlying maternal condition.

Infants exposed to DSUVIA through breast milk should be monitored 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.

Infertility: Chronic use of opioids 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.

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.

Hepatic Impairment: Because sufentanil is extensively metabolized in the liver, its clearance may decrease in patients with hepaticimpairment. Monitor closely for adverse events such as respiratory depression, sedation, and hypotension

Renal Impairment: Sufentanil and its metabolites are known to be excreted by the kidney. No significant changes have beenobserved in subjects with mild or moderate renal impairment. Monitor closely for adverse events such asrespiratory depression, sedation, and hypotension in patients with severe renal impairment

Controlled Substance

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

Abuse

DSUVIA contains sufentanil, a substance with a high potential for abuse similar to other opioids including fentanyl, morphine, oxycodone, hydromorphone. DSUVIA can be abused and is subject to misuse, addiction, and criminal diversion

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

OVERDOSAGE

Acute overdose with DSUVIA 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations

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 techniques.

The opioid antagonists, naloxone or nalmefene, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to sufentanil overdose.

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.

Gafacom

DSUVIA (sufentanil) sublingual tablet, CII

DSUVIA (sufentanil) sublingual tablet, CII