Zurnai: Package Insert / Prescribing Info

2.1 Important Administration Instructions

• 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:

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  Administer ZURNAI as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.

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  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.

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  Additional doses of ZURNAI may be required until emergency medical assistance becomes available.

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  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.

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  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.

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  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.

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  Administer ZURNAI according to the printed instructions on the device label, carton, and the Instructions for Use.

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  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.

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  Remove ZURNAI from the outer thigh.

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  Call for emergency medical assistance immediately after administration of the first dose of ZURNAI.

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  Move the patient on their side (recovery position). Remain with the patient until emergency medical assistance arrives, even if the patient wakes up.

2.2 Dosing in Adults and Pediatric Patients 12 Years and Older

2.3 Dosing Modifications Due to 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 and require repeated administration of ZURNAI using a new auto-injector [see Warnings and Precautions (5.2)].

Injection: 1.5 mg/0.5 mL nalmefene (base), clear, colorless to light yellow solution in a pre-filled, single-dose auto-injector. Each ZURNAI auto-injector delivers 1.5 mg nalmefene (base) injection (0.5 mL).

5.1 Risk of Recurrent Respiratory and Central Nervous System Depression

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)].

5.2 Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists

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.

5.3 Precipitation of Severe Opioid Withdrawal

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)].

5.4 Risk of Opioid Overdose from Attempts to Overcome the Blockade

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.

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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.

8.5 Geriatric Use

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.

8.6 Hepatic Impairment

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.

8.7 Renal Impairment

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.

12.1 Mechanism of Action

ZURNAI is an antagonist at opioid receptors.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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)

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

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.

16.2 Storage and Handling

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.

Recognition of Opioid Overdose

Instruct patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose, such as the following:

• Extreme somnolence – inability to awaken a patient verbally or upon a firm sternal rub
• Respiratory depression – this can range from slow or shallow respiration to no respiration in a patient who is unarousable
• Other signs and symptoms that may accompany somnolence and respiratory depression include the following:
  • Miosis
  • Bradycardia and/or hypotension

Risk of Recurrent Respiratory and Central Nervous System Depression

While the duration of action of nalmefene is as long as most opioids, instruct patients and their family members or caregivers that they must seek immediate emergency medical assistance after administration of the first dose of ZURNAI, and keep the patient under continued surveillance even after an apparently adequate initial response to ZURNAI. A second dose may be necessary if there is recurrence of symptoms of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require repeated administration of ZURNAI, using a new ZURNAI auto-injector each time [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Precipitation of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that the use of ZURNAI in patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and Precautions (5.3), Adverse Reactions (6)].

Administration Instructions

Instruct patients and their family member or caregivers to:

• Ensure ZURNAI is readily available in locations where persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies).
• Use ZURNAI one time only. DO NOT test or prime prior to use [see Dosage and Administration (2.1)].
• Carefully read the Instructions for Use that comes with ZURNAI.
• Administer ZURNAI as quickly as possible if a person is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. ZURNAI is not a substitute for emergency medical care [see Dosage and Administration (2.1)].
• Administer ZURNAI directly into the outer thigh. Press the needle end firmly into the injection site (through clothing, if necessary) and hold for 3 seconds [see Dosage and Administration (2.1)]. 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 911 immediately after injecting the first dose of ZURNAI.
• Move the person to the recovery position by turning them to their side. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.1)].
• Watch the person carefully. Wait 2 to 5 minutes to see if the person wakes up.
• If the person is not responding or responds and then relapses back into respiratory depression, administer additional doses of ZURNAI every 2 to 5 minutes using a new ZURNAI auto-injector [see Dosage and Administration (2.1)].
• Remain with the person until emergency medical help arrives, even if they wake up.
• Visually inspect the nalmefene solution through the viewing window every 30 days. If the solution is discolored, cloudy, or contains solid particles, replace it with a new ZURNAI.
• Replace ZURNAI before its expiration date.

Healthcare professionals can telephone Purdue Pharma's Medical Information Department (1-888-726-7535) for information on this product.

Manufactured for:
Purdue Pharma L.P.
Stamford, CT 06901-3431

©2024, Purdue Pharma L.P., Stamford, CT 06901-3431