^
Distribution
Following a 1 mg parenteral dose, nalmefene was rapidly distributed. In a study of brain receptor occupancy, a 1 mg dose of nalmefene blocked over 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally (Vd) and at steady-state (Vss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. Ultrafiltration studies of nalmefene have demonstrated that 45% (CV 4.1%) is bound to plasma proteins over a concentration range of 0.1 to 2μg/mL. An in vitro determination of the distribution of nalmefene in human blood demonstrated that nalmefene distributed 67% (CV 8.7%) into red blood cells and 39% (CV 6.4%) into plasma. The whole blood to plasma ratio was 1.3 (CV 6.6%) over the nominal concentration range in whole blood from 0.376 to 30 ng/mL.
^ 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.
^ Patient Counseling Information
Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
^ Description
OPVEE (nalmefene) nasal spray is a pre-filled, unit-dose intranasal spray.
Nalmefene, an opioid antagonist, is a 6-methylene analogue of naltrexone. The molecular structure of nalmefene is presented below:
Molecular Formula: C 21H 25NO 3∙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 methanol and water, with a pK of 7.63.
Each OPVEE nasal spray unit delivers 2.7 mg nalmefene (equivalent to 3mg nalmefene hydrochloride) in 0.1 mL solution.
Inactive ingredients include benzalkonium chloride, disodium ethylenediaminetetraacetate, dodecylmaltoside, sodium chloride, and purified water. The pH range is 4.1 to 4.9.
^ 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)].
^ 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)] .
^ 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.
^ 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.
^3 Dosage Forms And Strengths
Nasal spray: 2.7 mg nalmefene per device. Each unit-dose nasal spray device delivers a single spray containing 2.7 mg of nalmefene.
^ Important Administration Instructions
^ 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.
^ 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.
^ 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.
^ 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.
^4 Contraindications
OPVEE nasal spray is contraindicated in patients known to be hypersensitive to nalmefene or to any of the other ingredients.
^ 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.
^ 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.
^ 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.
^ 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.
^Instructions For Use Opvee (op Vee) (nalmefene) Nasal Spray
The Instructions for Use contains information on how to give OPVEE nasal spray 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 OPVEE nasal spray before using it. Talk to your healthcare provider if you and your family members or caregivers have any questions about the use of OPVEE nasal spray.
For more information about OPVEE nasal spray, go to www.OPVEE.com or call 1-877-782-6966.
OPVEE ®is a registered trademark of Indivior Inc. ©2023 Indivior Inc. All Rights Reserved. Manufactured for: Indivior Inc., North Chesterfield, VA, 23235, USA
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 06/2023
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
^ 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)] .
^6 Adverse Reactions
The following serious adverse reactions are discussed elsewhere in the labeling:
^ 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.
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.
^Principal Display Panel - Mg Bottle Carton
NDC 12496-0003-2 Rx only
OPVEE ® (nalmefene) NASAL SPRAY 2.7 mg
FOR USE IN THE NOSE ONLY DO NOT TEST BEFORE USE
Use for known or suspected opioid overdose in adults and children 12 years of age and older.
Two Unit-Dose Nasal Spray Devices
Each unit-dose nasal spray device delivers 2.7 mg nalmefene in 0.1 mL solution.
EACH DEVICE SPRAYS ONCE ONLY.
For more information about OPVEE Nasal Spray, go to www.OPVEE.com or 1-877-782-6966
Check product expiration date before use.
1
^1 Indications And Usage
OPVEE nasal spray is indicated for the emergency treatment of known or suspected 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.
OPVEE nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present.
OPVEE nasal spray is not a substitute for emergency medical care.
^ Mechanism Of Action
OPVEE is an antagonist at opioid receptors.