These Highlights Do Not Include All The Information Needed To Use Zurnai™ Safely And Effectively. See Full Prescribing Information For Zurnai.

Initial Dosing:

The recommended dose of ZURNAI in adults and pediatric patients aged 12 years and older is 1.5 mg delivered by intramuscular or subcutaneous injection into the anterolateral aspect of the thigh, through clothing if necessary.

ZURNAI™ (nalmefene injection) is a sterile, pre-filled, single-dose auto-injector designed to deliver a dose of 1.5 mg nalmefene (provided as nalmefene hydrochloride) in 0.5 mL.

Nalmefene hydrochloride, an opioid antagonist, is a 6-methylene analogue of naltrexone. The molecular structure of nalmefene is presented below:

Molecular Formula: C₂₁H₂₅NO₃∙HCl

Molecular Weight: 375.9, CAS# 58895-64-0

Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt

Nalmefene is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pKa of 7.63.

Each ZURNAI auto-injector delivers 1.5 mg nalmefene (equivalent to 1.7 mg nalmefene hydrochloride) in 0.5 mL solution. The pH range is 3.5 to 4.5.

The inactive ingredients in ZURNAI nalmefene injection include: hydrochloric acid to adjust pH; magnesium chloride, 4.7 mg; and water for injection.

Each single-dose auto-injector delivers 1.5 mg of nalmefene in 0.5 mL. Each carton contains one single-dose ZURNAI (nalmefene injection).

NDC 59011-962-01: One carton containing one single-dose auto-injector.

ZURNAI is not made with natural rubber latex.

The safety and effectiveness of ZURNAI for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, have been established in pediatric patients aged 12 years and older.

Use for this indication in this age group is supported by adult studies and pharmacokinetic simulation [see Clinical Pharmacology (12.3)]. There have been no studies conducted to evaluate the use of ZURNAI in pediatric patients.

The safety and effectiveness of ZURNAI for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, have not been established in pediatric patients younger than 12 years of age.

Clinical studies of nalmefene hydrochloride injection did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function, or other drug therapy. Therefore, the systemic exposure of nalmefene can be higher in these patients.

ZURNAI is contraindicated in patients known to be hypersensitive to nalmefene hydrochloride or to any other ingredients in the product.

The following serious adverse reactions are described elsewhere in the labeling:

• Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions (5.1)]
• Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)]

Renal impairment substantially reduces the clearance of nalmefene [see Clinical Pharmacology (12.3)]. For single episodes of opioid antagonisms, adjustment of ZURNAI dosage is not required.

ZURNAI™ (zur nye)

(nalmefene injection)

The Instructions for Use contains information on how to give ZURNAI in response to a known or suspected opioid overdose in adults and children 12 years of age and older. You and your family members or caregivers should read the Instructions for Use that comes with ZURNAI before using it. Talk to your healthcare provider if you and your family members or caregivers have any questions about the use of ZURNAI.

ZURNAI auto-injector parts:

Important information you need to know before injecting ZURNAI

• The ZURNAI auto-injector is ready to use. Do not test or prime ZURNAI before use.
• Each ZURNAI auto-injector contains 1 dose of medicine and cannot be reused.
• Inject ZURNAI into the muscle (intramuscular) or underneath the skin (subcutaneous) of the outer thigh. Do not inject into any other area of the body.

Preparing to inject ZURNAI

• Check person for signs of a suspected overdose:
  • will not wake to voice or touch
  • very sleepy
  • not breathing well
• Check the auto-injector label to make sure you are injecting ZURNAI.
• Check for any visible damage to the auto-injector before using.
• Check the auto-injector to make sure the safety seal is not broken and the blue cap is secure and not missing.
• Check the liquid through the viewing window before using. It should be clear, colorless to light-yellow and free of particles. You may see air bubbles. This is normal.

Injecting ZURNAI

Nalmefene reverses the effects of natural and synthetic opioids, including respiratory depression, sedation, and hypotension. Pharmacodynamic studies have shown that nalmefene injection has a longer duration of action than naloxone injection at fully reversing doses. Nalmefene has no opioid agonist activity.

The effect of ZURNAI was studied in an experimental clinical opioid-induced respiratory depression (OIRD) model in twenty-four opioid-experienced, non-opioid dependent subjects (NAL1004). This model assessed changes in minute ventilation (MV) during administration of a 3-step intravenous fentanyl infusion. In step 1, fentanyl was infused until MV nadir (functional OIRD) was achieved. MV nadir was defined as a 50% reduction in MV from baseline or the MV reduction achieved following the maximum permitted fentanyl titration. Following attainment of MV nadir, the fentanyl infusion rate was decreased (step 2) to maintain the fentanyl concentrations. ZURNAI was administered at 10 minutes following MV nadir. Ten minutes following ZURNAI administration, the fentanyl infusion rate was further decreased (step 3) to maintain constant fentanyl concentrations for the remaining duration of the reversal session.

Following ZURNAI administration the time to onset of effect, that is onset of reversal of respiratory depression, was observed between 2.5 to 5 minutes (Figure 1 and Figure 2). At 5 minutes mean change in MV from nadir was 4.42 L/min (Figure 1). Full recovery of respiratory drive was noted between 5 and 15 minutes after ZURNAI administration (Figure 1 and Figure 2).

Figure 1: Reversal of Fentanyl-Induced Respiratory Depression in adult healthy volunteers treated with ZURNAI (nalmefene)

Figure 2: Percent Recovery of Respiratory Drive after Fentanyl Infusion in Minute Ventilation (Mean SD) in Adult Healthy Volunteers with ZURNAI 1.5 mg

Nalmefene is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when nalmefene was administered in the absence of opioid agonists.

Nalmefene has not been shown to produce tolerance, physical dependence, or abuse potential.

Nalmefene can produce acute withdrawal symptoms in individuals who are opioid dependent.

In a pharmacokinetic study (NAL1005) in 24 healthy adult subjects, the relative bioavailability of one dose of ZURNAI administered intramuscularly was compared to a single dose of nalmefene 1.0 mg administered as an intramuscular injection. The pharmacokinetic parameters obtained in this study are shown in Table 3 and the plasma concentration time profiles of nalmefene are presented in Figure 3.

Figure 3: Mean Plasma Concentration-Time Profiles of Nalmefene (a) 0-12 hours and (b) 0- 60 minutes Following Administration of 1.5 mg ZURNAI Intramuscular (IM), 1.0 mg Nalmefene IM, and 1.0 mg Nalmefene Intravenous (IV)

(a)

(b)

Hepatic impairment substantially reduces the clearance of nalmefene [see Clinical Pharmacology (12.3)]. For single episodes of opioid antagonism, adjustment of ZURNAI dosage is not required.

ZURNAI is indicated for the emergency treatment of known or suspected opioid overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression.

ZURNAI is intended for immediate administration as emergency therapy in settings where opioids may be present.

ZURNAI is not a substitute for emergency medical care.

ZURNAI is an antagonist at opioid receptors.

Store at controlled room temperature 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).

During storage, check ZURNAI through the viewing window of the auto-injector every 30 days. The liquid should be clear, colorless to light yellow. If the ZURNAI liquid is discolored, cloudy, or contains solid particles, replace it with a new ZURNAI.

DO NOT FREEZE OR REFRIGERATE. Store in a clean dry place. Protect from light.

Keep ZURNAI in the carton until use.

Store ZURNAI securely and dispose of properly in a sharps container. For detailed disposal instructions, see the Instructions for Use.

KEEP ZURNAI AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.

Before using, check to make sure the solution in the auto-injector is not discolored. Replace ZURNAI if the solution is discolored or contains a precipitate.

Each ZURNAI can only be used one time and cannot be re-used.

• Risk of Recurrent Respiratory and CNS Depression: A recurrence of respiratory depression is possible, therefore, keep the patient under continued surveillance and administer repeat doses of ZURNAI using a new auto-injector with each dose while awaiting emergency medical assistance. (5.1)
• Risk of Limited Efficacy with Partial Agonists or Mixed Agonists/Antagonists: Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Repeat doses may be required. (5.2)
• Precipitation of Severe Opioid Withdrawal: The use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. (5.3)
• Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had preexisting CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of nalmefene hydrochloride. (5.3)
• Risk of Opioid Overdose from Attempts to Overcome the Blockade: Attempts to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids may lead to opioid intoxication and death. (5.4)

• ZURNAI is for intramuscular and subcutaneous use only. (2.1)
• Seek emergency medical care immediately after use. (2.1)
• Administer ZURNAI to the outer thigh, through clothing if necessary. (2.1)
• Administer additional doses of ZURNAI using a new ZURNAI auto-injector for each dose. If the patient does not respond or responds and then relapses into respiratory depression, additional doses of ZURNAI may be given every 2 to 5 minutes until emergency medical assistance arrives. (2.2)
• See Full Prescribing Information and Instructions for Use for important information on how to safely administer ZURNAI. (2.1)
• Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. (2.2)

Injection: 1.5 mg nalmefene base/0.5 mL in a prefilled, single-dose auto-injector (3)

The following adverse reactions have been identified during post-approval use of nalmefene. 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.

Abrupt reversal of opioid depression using nalmefene in both postoperative and emergency department settings has resulted in nausea, vomiting, sweating, tremulousness, seizures, and cardiovascular instability including tachycardia, hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects.

In persons who were physically dependent on opioids, abrupt reversal of opioid effects has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shiver or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, and tachycardia. In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes.

Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instruct patients and their family members or caregivers to become familiar with all information contained in the carton as soon as they receive ZURNAI.

• All approved nalmefene products achieve plasma concentrations that have been shown to be efficacious in reversing the effects of opioid overdose. Comparing different products on a nominal mg-for-mg basis may be misleading.
• ZURNAI is for intramuscular and subcutaneous use only.
• The device is ready to use. No device assembly is required.
• Do not prime or test prior to administration. ZURNAI delivers its entire contents automatically, upon injection.
• Inject ZURNAI into the anterolateral aspect of the thigh.
• ZURNAI can be administered through clothing if necessary.
• Do not reuse ZURNAI. Each ZURNAI device contains a single dose of nalmefene and cannot be reused.
• Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of ZURNAI and the Instructions for Use.
• Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for ZURNAI. Emphasize the following instructions to the patient or caregiver:
  • –
    Administer ZURNAI as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.
  • –
    Always seek emergency medical assistance after administration of the first dose of ZURNAI in the event of a suspected, potentially life-threatening opioid emergency. Keep the patient under continued surveillance until emergency personnel arrive.
  • –
    Additional doses of ZURNAI may be required until emergency medical assistance becomes available.
  • –
    If available, re-administer ZURNAI using a new auto-injector, every 2 to 5 minutes if the patient does not respond or responds and then relapses into respiratory depression.
  • –
    Once the safety seal is broken and blue cap is removed, ZURNAI must be used immediately or disposed of properly. Do not attempt to replace the blue cap once it is removed.
  • –
    Visually inspect ZURNAI through the viewing window for particulate matter and discoloration prior to administration. Do not administer unless the solution is clear, free of particulates, and the glass container is undamaged.
  • –
    Administer ZURNAI according to the printed instructions on the device label, carton, and the Instructions for Use.
    • ⮚
      Place the needle guard of ZURNAI against the outer thigh. Press the needle end firmly into the injection site until you hear a click and then hold for 3 seconds. After 3 seconds, the viewing window should turn completely orange, signaling that ZURNAI has delivered the intended dose of nalmefene.
    • ⮚
      Remove ZURNAI from the outer thigh.
    • ⮚
      Call for emergency medical assistance immediately after administration of the first dose of ZURNAI.
    • ⮚
      Move the patient on their side (recovery position). Remain with the patient until emergency medical assistance arrives, even if the patient wakes up.

The use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

Abrupt postoperative reversal of opioid depression after using ZURNAI may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. After use of ZURNAI, monitor patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of pulmonary edema associated with the use of nalmefene is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

ZURNAI is not indicated for use in patients less than 12 years of age. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes. Monitor the patient for the development of the signs and symptoms of opioid withdrawal. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, use an alternative, opioid antagonist product that can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Populations (8.4)].

Zurnai_™

(nalmefene injection)

for intramuscular or subcutaneous use

1.5 mg/0.5 mL Auto-Injector

Do not use if solution is discolored or cloudy or contains particles.

Rx Only

Single-dose Auto-Injector.

Zurnai_™

(nalmefene injection)

for intramuscular or subcutaneous use

1.5 mg/0.5 mL Auto-Injector

Dosage: see Full Prescribing Information

Use for known or suspected opioid overdose in adults and children 12 years of

age and older.

Each single-dose auto-injector device delivers 1.5 mg of nalmefene in 0.5 mL.

Each Zurnai Auto-Injector has only one dose and cannot be re-used.

NDC 59011-962-01

Rx Only

Each carton contains:

• One single-dose Zurnai Auto-Injector
• Full Prescribing Information, including detailed
  
  Patient Information with Instructions for Use

Manufactured for:

Purdue Pharma L.P. Stamford, CT 06901-3431

306452-0B

ZURNAI is unlikely to produce acute withdrawal symptoms in non-opioid dependent patients. The use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal. Attempting to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids could lead to opioid intoxication and death.

Inform patients of the potential consequences of trying to overcome the opioid blockade. Get emergency medical assistance as soon as possible after use of ZURNAI regardless of withdrawal symptoms.

Respiratory depression in the community overdose setting may be complex and involve the effects of multiple or unknown drugs, some of which may be long-acting opioids. While the duration of action of nalmefene is as long as most opioids, a recurrence of respiratory depression is possible, even after an apparently adequate initial response to ZURNAI treatment [see Clinical Pharmacology (12.3)]. Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of ZURNAI and to keep the patient under continued surveillance. A second dose may be necessary if there is recurrence of symptoms of opioid overdose. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.2)].

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require repeated administration of ZURNAI using a new auto-injector [see Warnings and Precautions (5.2)].

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Repeat doses of ZURNAI may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [see Dosage and Administration (2.3)]. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

Initial Dosing:

The recommended dose of ZURNAI in adults and pediatric patients aged 12 years and older is 1.5 mg delivered by intramuscular or subcutaneous injection into the anterolateral aspect of the thigh, through clothing if necessary.

ZURNAI™ (nalmefene injection) is a sterile, pre-filled, single-dose auto-injector designed to deliver a dose of 1.5 mg nalmefene (provided as nalmefene hydrochloride) in 0.5 mL.

Nalmefene hydrochloride, an opioid antagonist, is a 6-methylene analogue of naltrexone. The molecular structure of nalmefene is presented below:

Molecular Formula: C₂₁H₂₅NO₃∙HCl

Molecular Weight: 375.9, CAS# 58895-64-0

Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt

Nalmefene is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pKa of 7.63.

Each ZURNAI auto-injector delivers 1.5 mg nalmefene (equivalent to 1.7 mg nalmefene hydrochloride) in 0.5 mL solution. The pH range is 3.5 to 4.5.

The inactive ingredients in ZURNAI nalmefene injection include: hydrochloric acid to adjust pH; magnesium chloride, 4.7 mg; and water for injection.

Each single-dose auto-injector delivers 1.5 mg of nalmefene in 0.5 mL. Each carton contains one single-dose ZURNAI (nalmefene injection).

NDC 59011-962-01: One carton containing one single-dose auto-injector.

ZURNAI is not made with natural rubber latex.

The safety and effectiveness of ZURNAI for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, have been established in pediatric patients aged 12 years and older.

Use for this indication in this age group is supported by adult studies and pharmacokinetic simulation [see Clinical Pharmacology (12.3)]. There have been no studies conducted to evaluate the use of ZURNAI in pediatric patients.

The safety and effectiveness of ZURNAI for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, have not been established in pediatric patients younger than 12 years of age.

Clinical studies of nalmefene hydrochloride injection did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function, or other drug therapy. Therefore, the systemic exposure of nalmefene can be higher in these patients.

ZURNAI is contraindicated in patients known to be hypersensitive to nalmefene hydrochloride or to any other ingredients in the product.

The following serious adverse reactions are described elsewhere in the labeling:

• Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions (5.1)]
• Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)]

Renal impairment substantially reduces the clearance of nalmefene [see Clinical Pharmacology (12.3)]. For single episodes of opioid antagonisms, adjustment of ZURNAI dosage is not required.

ZURNAI™ (zur nye)

(nalmefene injection)

The Instructions for Use contains information on how to give ZURNAI in response to a known or suspected opioid overdose in adults and children 12 years of age and older. You and your family members or caregivers should read the Instructions for Use that comes with ZURNAI before using it. Talk to your healthcare provider if you and your family members or caregivers have any questions about the use of ZURNAI.

ZURNAI auto-injector parts:

Important information you need to know before injecting ZURNAI

• The ZURNAI auto-injector is ready to use. Do not test or prime ZURNAI before use.
• Each ZURNAI auto-injector contains 1 dose of medicine and cannot be reused.
• Inject ZURNAI into the muscle (intramuscular) or underneath the skin (subcutaneous) of the outer thigh. Do not inject into any other area of the body.

Preparing to inject ZURNAI

• Check person for signs of a suspected overdose:
  • will not wake to voice or touch
  • very sleepy
  • not breathing well
• Check the auto-injector label to make sure you are injecting ZURNAI.
• Check for any visible damage to the auto-injector before using.
• Check the auto-injector to make sure the safety seal is not broken and the blue cap is secure and not missing.
• Check the liquid through the viewing window before using. It should be clear, colorless to light-yellow and free of particles. You may see air bubbles. This is normal.

Injecting ZURNAI

Nalmefene reverses the effects of natural and synthetic opioids, including respiratory depression, sedation, and hypotension. Pharmacodynamic studies have shown that nalmefene injection has a longer duration of action than naloxone injection at fully reversing doses. Nalmefene has no opioid agonist activity.

The effect of ZURNAI was studied in an experimental clinical opioid-induced respiratory depression (OIRD) model in twenty-four opioid-experienced, non-opioid dependent subjects (NAL1004). This model assessed changes in minute ventilation (MV) during administration of a 3-step intravenous fentanyl infusion. In step 1, fentanyl was infused until MV nadir (functional OIRD) was achieved. MV nadir was defined as a 50% reduction in MV from baseline or the MV reduction achieved following the maximum permitted fentanyl titration. Following attainment of MV nadir, the fentanyl infusion rate was decreased (step 2) to maintain the fentanyl concentrations. ZURNAI was administered at 10 minutes following MV nadir. Ten minutes following ZURNAI administration, the fentanyl infusion rate was further decreased (step 3) to maintain constant fentanyl concentrations for the remaining duration of the reversal session.

Following ZURNAI administration the time to onset of effect, that is onset of reversal of respiratory depression, was observed between 2.5 to 5 minutes (Figure 1 and Figure 2). At 5 minutes mean change in MV from nadir was 4.42 L/min (Figure 1). Full recovery of respiratory drive was noted between 5 and 15 minutes after ZURNAI administration (Figure 1 and Figure 2).

Figure 1: Reversal of Fentanyl-Induced Respiratory Depression in adult healthy volunteers treated with ZURNAI (nalmefene)

Figure 2: Percent Recovery of Respiratory Drive after Fentanyl Infusion in Minute Ventilation (Mean SD) in Adult Healthy Volunteers with ZURNAI 1.5 mg

Nalmefene is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when nalmefene was administered in the absence of opioid agonists.

Nalmefene has not been shown to produce tolerance, physical dependence, or abuse potential.

Nalmefene can produce acute withdrawal symptoms in individuals who are opioid dependent.

In a pharmacokinetic study (NAL1005) in 24 healthy adult subjects, the relative bioavailability of one dose of ZURNAI administered intramuscularly was compared to a single dose of nalmefene 1.0 mg administered as an intramuscular injection. The pharmacokinetic parameters obtained in this study are shown in Table 3 and the plasma concentration time profiles of nalmefene are presented in Figure 3.

Figure 3: Mean Plasma Concentration-Time Profiles of Nalmefene (a) 0-12 hours and (b) 0- 60 minutes Following Administration of 1.5 mg ZURNAI Intramuscular (IM), 1.0 mg Nalmefene IM, and 1.0 mg Nalmefene Intravenous (IV)

(a)

(b)

Hepatic impairment substantially reduces the clearance of nalmefene [see Clinical Pharmacology (12.3)]. For single episodes of opioid antagonism, adjustment of ZURNAI dosage is not required.

ZURNAI is indicated for the emergency treatment of known or suspected opioid overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression.

ZURNAI is intended for immediate administration as emergency therapy in settings where opioids may be present.

ZURNAI is not a substitute for emergency medical care.

ZURNAI is an antagonist at opioid receptors.

Store at controlled room temperature 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).

During storage, check ZURNAI through the viewing window of the auto-injector every 30 days. The liquid should be clear, colorless to light yellow. If the ZURNAI liquid is discolored, cloudy, or contains solid particles, replace it with a new ZURNAI.

DO NOT FREEZE OR REFRIGERATE. Store in a clean dry place. Protect from light.

Keep ZURNAI in the carton until use.

Store ZURNAI securely and dispose of properly in a sharps container. For detailed disposal instructions, see the Instructions for Use.

KEEP ZURNAI AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.

Before using, check to make sure the solution in the auto-injector is not discolored. Replace ZURNAI if the solution is discolored or contains a precipitate.

Each ZURNAI can only be used one time and cannot be re-used.

• Risk of Recurrent Respiratory and CNS Depression: A recurrence of respiratory depression is possible, therefore, keep the patient under continued surveillance and administer repeat doses of ZURNAI using a new auto-injector with each dose while awaiting emergency medical assistance. (5.1)
• Risk of Limited Efficacy with Partial Agonists or Mixed Agonists/Antagonists: Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Repeat doses may be required. (5.2)
• Precipitation of Severe Opioid Withdrawal: The use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. (5.3)
• Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had preexisting CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of nalmefene hydrochloride. (5.3)
• Risk of Opioid Overdose from Attempts to Overcome the Blockade: Attempts to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids may lead to opioid intoxication and death. (5.4)

• ZURNAI is for intramuscular and subcutaneous use only. (2.1)
• Seek emergency medical care immediately after use. (2.1)
• Administer ZURNAI to the outer thigh, through clothing if necessary. (2.1)
• Administer additional doses of ZURNAI using a new ZURNAI auto-injector for each dose. If the patient does not respond or responds and then relapses into respiratory depression, additional doses of ZURNAI may be given every 2 to 5 minutes until emergency medical assistance arrives. (2.2)
• See Full Prescribing Information and Instructions for Use for important information on how to safely administer ZURNAI. (2.1)
• Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. (2.2)

Injection: 1.5 mg nalmefene base/0.5 mL in a prefilled, single-dose auto-injector (3)

The following adverse reactions have been identified during post-approval use of nalmefene. 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.

Abrupt reversal of opioid depression using nalmefene in both postoperative and emergency department settings has resulted in nausea, vomiting, sweating, tremulousness, seizures, and cardiovascular instability including tachycardia, hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects.

In persons who were physically dependent on opioids, abrupt reversal of opioid effects has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shiver or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, and tachycardia. In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes.

Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instruct patients and their family members or caregivers to become familiar with all information contained in the carton as soon as they receive ZURNAI.

• All approved nalmefene products achieve plasma concentrations that have been shown to be efficacious in reversing the effects of opioid overdose. Comparing different products on a nominal mg-for-mg basis may be misleading.
• ZURNAI is for intramuscular and subcutaneous use only.
• The device is ready to use. No device assembly is required.
• Do not prime or test prior to administration. ZURNAI delivers its entire contents automatically, upon injection.
• Inject ZURNAI into the anterolateral aspect of the thigh.
• ZURNAI can be administered through clothing if necessary.
• Do not reuse ZURNAI. Each ZURNAI device contains a single dose of nalmefene and cannot be reused.
• Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of ZURNAI and the Instructions for Use.
• Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for ZURNAI. Emphasize the following instructions to the patient or caregiver:
  • –
    Administer ZURNAI as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.
  • –
    Always seek emergency medical assistance after administration of the first dose of ZURNAI in the event of a suspected, potentially life-threatening opioid emergency. Keep the patient under continued surveillance until emergency personnel arrive.
  • –
    Additional doses of ZURNAI may be required until emergency medical assistance becomes available.
  • –
    If available, re-administer ZURNAI using a new auto-injector, every 2 to 5 minutes if the patient does not respond or responds and then relapses into respiratory depression.
  • –
    Once the safety seal is broken and blue cap is removed, ZURNAI must be used immediately or disposed of properly. Do not attempt to replace the blue cap once it is removed.
  • –
    Visually inspect ZURNAI through the viewing window for particulate matter and discoloration prior to administration. Do not administer unless the solution is clear, free of particulates, and the glass container is undamaged.
  • –
    Administer ZURNAI according to the printed instructions on the device label, carton, and the Instructions for Use.
    • ⮚
      Place the needle guard of ZURNAI against the outer thigh. Press the needle end firmly into the injection site until you hear a click and then hold for 3 seconds. After 3 seconds, the viewing window should turn completely orange, signaling that ZURNAI has delivered the intended dose of nalmefene.
    • ⮚
      Remove ZURNAI from the outer thigh.
    • ⮚
      Call for emergency medical assistance immediately after administration of the first dose of ZURNAI.
    • ⮚
      Move the patient on their side (recovery position). Remain with the patient until emergency medical assistance arrives, even if the patient wakes up.

The use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.

Abrupt postoperative reversal of opioid depression after using ZURNAI may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. After use of ZURNAI, monitor patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of pulmonary edema associated with the use of nalmefene is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

ZURNAI is not indicated for use in patients less than 12 years of age. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes. Monitor the patient for the development of the signs and symptoms of opioid withdrawal. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, use an alternative, opioid antagonist product that can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Populations (8.4)].

Zurnai_™

(nalmefene injection)

for intramuscular or subcutaneous use

1.5 mg/0.5 mL Auto-Injector

Do not use if solution is discolored or cloudy or contains particles.

Rx Only

Single-dose Auto-Injector.

Zurnai_™

(nalmefene injection)

for intramuscular or subcutaneous use

1.5 mg/0.5 mL Auto-Injector

Dosage: see Full Prescribing Information

Use for known or suspected opioid overdose in adults and children 12 years of

age and older.

Each single-dose auto-injector device delivers 1.5 mg of nalmefene in 0.5 mL.

Each Zurnai Auto-Injector has only one dose and cannot be re-used.

NDC 59011-962-01

Rx Only

Each carton contains:

• One single-dose Zurnai Auto-Injector
• Full Prescribing Information, including detailed
  
  Patient Information with Instructions for Use

Manufactured for:

Purdue Pharma L.P. Stamford, CT 06901-3431

306452-0B

ZURNAI is unlikely to produce acute withdrawal symptoms in non-opioid dependent patients. The use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal. Attempting to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids could lead to opioid intoxication and death.

Inform patients of the potential consequences of trying to overcome the opioid blockade. Get emergency medical assistance as soon as possible after use of ZURNAI regardless of withdrawal symptoms.

Respiratory depression in the community overdose setting may be complex and involve the effects of multiple or unknown drugs, some of which may be long-acting opioids. While the duration of action of nalmefene is as long as most opioids, a recurrence of respiratory depression is possible, even after an apparently adequate initial response to ZURNAI treatment [see Clinical Pharmacology (12.3)]. Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of ZURNAI and to keep the patient under continued surveillance. A second dose may be necessary if there is recurrence of symptoms of opioid overdose. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.2)].

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require repeated administration of ZURNAI using a new auto-injector [see Warnings and Precautions (5.2)].

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Repeat doses of ZURNAI may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [see Dosage and Administration (2.3)]. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.