2.1 Important Administration Instructions

• OPVEE is for intranasal use only.
• The device is ready to use. No device assembly is required.
• Do not prime or test prior to administration. OPVEE nasal spray delivers its entire contents automatically, upon activation.
• Do not attempt to reuse OPVEE. Each unit-dose device contains a single dose of nalmefene and cannot be reused.
• No device assembly is required.
• 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 OPVEE nasal spray and the Instructions for Use.
• Instruct the patient or caregiver to read the Instructions for Useat the time they receive a prescription for OPVEE nasal spray. Emphasize the following instructions to the patient or caregiver:
• Administer OPVEE nasal spray as quickly as possiblebecause 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 OPVEE nasal spray in the event of a suspected, potentially life-threatening opioid emergency. Keep the patient under continued surveillance until emergency personnel arrive.
• Additional doses of OPVEE nasal spray may be required until emergency medical assistance becomes available.
• Re-administer OPVEE nasal spray, using a new nasal spray, in the nose, every 2 to 5 minutes if the patient does not respond or responds and then relapses into respiratory depression.
• Administer OPVEE nasal spray according to the printed instructions on the Quick Start Guideand the Instructions for Use.
  • Place the patient in the supine position. Prior to administration, be sure the device nozzle is inserted in the nose of the patient and provide support to the back of the neck to allow the head to tilt back. Do not prime or test the device prior to administration.
  • To administer the dose, press firmly on the device plunger and remove the device nozzle from the nose after use.
  • If the patient responds by waking up to the voice or touch or starts breathing normally, place the patient on their side (recovery position) as shown in the Instructions for Useand call for emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray.

2.2 Dosing in Adults and Pediatric Patients aged 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 OPVEE nasal spray using a new nasal spray device [see Warnings and Precautions (5.2)] .

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 OPVEE nasal spray treatment [See Clinical Pharmacology, Pharmacodynamics (12.3)] . Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray 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 OPVEE nasal spray 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 OPVEE 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 OPVEE 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 OPVEE, 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.

OPVEE 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

OPVEE is unlikely to produce acute withdrawal symptoms in non-opioid dependent patients. The use of OPVEE nasal spray 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 OPVEE nasal spray regardless of withdrawal symptoms.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OPVEE nasal spray is supported by safety and pharmacokinetic studies of OPVEE nasal spray in healthy subjects in a normal state and under steady state opioid agonism. The following adverse reactions were observed.

In a pharmacokinetic study of 66 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril the most common adverse reactions were: nasal discomfort and dizziness.

In a second pharmacokinetic study of 24 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril, two sprays of OPVEE nasal spray in one nostril or one spray of OPVEE nasal spray in each nostril, the most common adverse reactions were: rhinalgia, nasal congestion, nasal discomfort and nausea.

In a pharmacodynamic study of 61 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril, the most common adverse reactions were: headache, nausea, hot flush and dizziness.

Adverse reaction information was obtained following administration of nalmefene injection to 152 normal volunteers and in controlled clinical trials to 1127 patients for the treatment of opioid overdose or for postoperative opioid reversal.

Incidence less than 1%

Cardiovascular: Bradycardia, arrhythmia
Digestive: Diarrhea, dry mouth
Nervous System: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus
Respiratory: Pharyngitis
Skin: Pruritus
Urogenital: Urinary retention

The incidence of adverse events was highest in patients who received more than the recommended dose of nalmefene injection.

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

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 OPVEE nasal spray in pediatric patients.

The safety and effectiveness of OPVEE nasal spray 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 OPVEE nasal spray did not include subjects aged 65 and over. 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 and of concomitant disease 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 OPVEE nasal spray 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 OPVEE nasal spray dosage is not required.

12.1 Mechanism of Action

OPVEE 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 2.7 mg OPVEE on remifentanil-induced respiratory depression in an experimental ventilatory-response to hypercapnia model, assessed by changes in minute ventilation (MV), was evaluated in sixty-one opioid-experienced, non-dependent subjects. In this study subjects started receiving a hypercapnic gas mixture (50% O2, 43% N2, 7% CO2) at -25 minutes. Just prior to initiation of remifentanil infusion at -15 minutes is the baseline MV (marked as 100% in Figure 1 and marked as observed data as liters/minute in Figure 2). Fifteen minutes after initiating remifentanil infusion, nadir in minute ventilation is observed at time zero, at which point OPVEE was administered. The subjects were then monitored for changes in MV over 120 minutes. Following OPVEE 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 the estimated mean increase in minute ventilation was 5.745 L/min (Figure 2). Full recovery of respiratory drive was noted between 5 and 15 minutes after OPVEE administration (Figure 1 and Figure 2).

Figure 1: Percentage recovery of respiratory drive after infusion of remifentanil in CO2 stimulated minute ventilation (mean +/- standard deviation) in adult healthy volunteers treated with OPVEE (nalmefene) nasal spray

Figure 2: Reversal of Remifentanil-Induced Respiratory Depression (Mean Minute Ventilation +/- Standard Deviation) by OPVEE (nalmefene) nasal spray

Based on population pharmacokinetic/pharmacodynamic model simulations, the EC50 (drug concentration at which pharmacological effect is half maximum change in response) was 1.50 ng/mL for OPVEE following a single 2.7 mg administration. The time to reach EC50 was 4 minutes for OPVEE. The plasma concentrations remained above the EC50 for 5.94 hours for OPVEE.

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 (OPNT003-PK-001) in 68 healthy adult subjects, the relative bioavailability of one 2.7 mg OPVEE nasal spray in one nostril (0.1 mL of 27 mg/mL nalmefene), was compared to a single dose of nalmefene 1.0 mg administered as an intramuscular injection. Subjects remained fully supine and were instructed to hold their breath during the intranasal spray administration. 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.

Values represent the mean and standard deviation (n=68)

Figure 3: Mean Plasma Concentration-Time Profiles of Nalmefene (a) 0-12 hours and (b) 0-60 minutes Following Intranasal (IN) Administration of OPVEE nasal spray (2.7 mg) and Intramuscular (IM) Injection of Nalmefene (1.0 mg)

(a)

(b)

In a second pharmacokinetic study (OPNT003-PK-002) in 24 healthy adult subjects, one 2.7 mg OPVEE nasal spray in one nostril was compared with two 2.7 mg OPVEE nasal sprays in one nostril and one 2.7 mg OPVEE nasal spray in each nostril. Subjects remained fully supine and were instructed to hold their breath during the intranasal spray administration. The pharmacokinetic parameters obtained in this study are shown in Table 4 and the plasma concentration time profiles of nalmefene are presented in Figure 4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

Each unit-dose nasal spray device delivers 2.7 mg of nalmefene (equivalent to 3 mg of nalmefene hydrochloride) in 0.1 mL. Each carton contains two unit-dose nasal spray devices.

NDC # 12496-0003-2

OPVEE is not made with natural rubber latex.

16.2 Storage and Handling

Store OPVEE nasal spray in the blister and cartons provided.

Store OPVEE nasal spray at controlled room temperature 15°C to 25°C (59°F to 77°F). Short-term excursions permitted between 4°C to 40°C (39°F to 104°F). Do not freeze. Protect from light.

Do not open individual blister packs or test nasal spray devices before use.

Each unit-dose nasal spray device sprays one (1) time and cannot be re-used.

Recognition of Opioid Overdose

Inform 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 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 OPVEE and keep the patient under continued surveillance, even after an apparently adequate initial response to OPVEE nasal spray treatment. A second dose may be necessary if there is recurrence of symptoms of opioid overdose [see Dosage and Administration (2.1), 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 OPVEE nasal spray, using a new nasal spray device each time [see Dosage and Administration (2.3), Warnings and Precautions (5.2)] .

Precipitation of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that the use of OPVEE nasal spray 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 members or caregivers to:

• Ensure OPVEE is readily available in locations where persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies).
• Use each OPVEE device only one time. Do not test or prime prior to use [see Dosage and Administration (2.1)] .
• Administer OPVEE as quickly as possible if a patient 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. OPVEE is not a substitute for emergency medical care [see Dosage and Administration (2.1)] .
• Lay the patient on their back and administer OPVEE into one nostril while providing support to the back of the neck to allow the head to tilt back [see Dosage and Administration (2.1)].
• Hold the OPVEE nasal spray device with your fingers on either side of the nozzle and thumb on the white plunger.
• Insert the nozzle into the nose.
• Press the plunger firmly to give a dose in the nose.
• The dose has been delivered when the white plunger has been pushed all the way down until it stops.
• Remove the OPVEE nasal spray from the nose after the dose has been given.
• Call 911 after giving the first dose of OPVEE nasal spray.
• Put the person on their side in the recovery position.
• Watch the person carefully. Wait 2 to 5 minutes to see if the person wakes up.
• If the patient responds by waking up to the voice or touch or starts breathing normally, place them in the recovery position by turning them to their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of OPVEE. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.1)] .
• Monitor the patient and re-administer additional doses of OPVEE every 2 to 5 minutes, using a new OPVEE device. If the patient is not responding or responds and then relapses back into respiratory depression, administer OPVEE in alternate nostrils with each dose [see Dosage and Administration (2.1)] .
• Remain with the person until emergency medical help arrives.
• Replace OPVEE before its expiration date.