The following Structured Product Label (SPL) was submitted to the FDA by Indivior Inc. for the product Opvee (NDC 12496-0003). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 important administration instructions, other, 2.3 dosing modifications due to partial agonists or mixed agonists/antagonists, 3 dosage forms and strengths, 4 contraindications, 5.1 risk of recurrent respiratory and central nervous system depression, 5.2 risk of limited efficacy with partial agonists or mixed agonist/antagonists, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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.
Initial Dosing:
The recommended initial dose of OPVEE nasal spray in adults and pediatric patients aged 12 years and older is one spray delivered by intranasal administration, which delivers 2.7 mg of nalmefene.
Repeat Dosing:
Seek emergency medical assistance as soon as possible after intranasal administration of the first dose of OPVEE nasal spray. The requirement for repeat doses of OPVEE nasal spray (2.7 mg) depends upon the amount, type, and route of administration of the opioid being antagonized.
If the patient responds to OPVEE nasal spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of OPVEE in the opposite nostril using a new OPVEE nasal spray and continue surveillance of the patient.
If the desired response is not obtained after 2 to 5 minutes, administer an additional dose of OPVEE using a new OPVEE nasal spray device. If there is still no response and additional doses are available, administer additional doses of OPVEE nasal spray every 2 to 5 minutes using a new OPVEE nasal spray device with each dose until emergency medical assistance arrives.
Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.
Risk Summary
Life-sustaining therapy for opioid overdose should not be withheld (see Clinical Considerations). There are no available data on nalmefene use in pregnant women to evaluate for a drug-associated risk of major birth defects or miscarriage. In animal reproduction studies, no embryotoxic effects on embryo-fetal development were observed in rats and rabbits treated with nalmefene at exposures at least 6 times (rats) and up to 20 times (rabbits) the exposure at two human nasal doses of 5.4 mg (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
An opioid overdose is a medical emergency and can be fatal for the pregnant woman and fetus if left untreated. Treatment with OPVEE for opioid overdose should not be withheld because of potential concerns regarding the effects of OPVEE on the fetus.
Data
Animal Data
Reproduction studies have been performed in rats (up to 1200 mg/m2/day) and rabbits (up to 2400 mg/m2/day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m2/day. No effects on embryo-fetal development were observed at exposures at least 6 times (rats) and up to 20 times (rabbits) the exposure corresponding to a human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis. The treatment in rats did not affect offspring survival.
Risk Summary
There are no data on the presence of nalmefene and its metabolites in human milk, the effects of nalmefene on the breastfed child, or the effects on milk production. Nalmefene and its metabolites are present in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.
Data
Nalmefene and its metabolites were secreted into rat milk, reaching concentrations approximately three times those in plasma at one hour and decreasing to about half the corresponding plasma concentrations by 24 hours following bolus administration. The concentration of nalmefene in animal milk does not necessarily predict the concentration of drug in human milk.
Elimination
After administration of 2.7 mg OPVEE nasal spray to healthy adult subjects, plasma concentrations have a terminal elimination half-life of 11.4 (%CV 20.8) hours. The apparent clearance of nalmefene is 75.7 (%CV 23.8) L/hr.
Metabolism
Nalmefene is metabolized by the liver, primarily by glucuronide conjugation.
Nalmefene is also metabolized to trace amounts of an N-dealkylated metabolite. Nalmefene glucuronide is inactive and the N-dealkylated metabolite has minimal pharmacological activity.
Excretion
Nalmefene and its metabolites are excreted in the urine. Less than 5% of nalmefene is excreted in the urine unchanged. Seventeen percent (17%) of the nalmefene dose is excreted in the feces. The plasma concentration-time profile in some subjects suggests that nalmefene undergoes enterohepatic recycling.
Specific Populations
Geriatric Patients
In previous studies with nalmefene hydrochloride injection, dose proportionality was observed in nalmefene AUC following 0.5 to 2 mg intravenous administration to elderly male subjects. Following a 1 mg intravenous nalmefene dose, there were no significant differences between young (19-32 years) and elderly (62-80 years) adult male subjects with respect to plasma clearance, steady-state volume of distribution, or half-life. There was an apparent age-related decrease in the central volume of distribution (young: 3.9± 1.1 L/kg, elderly: 2.8 ± 1.1 L/kg) that resulted in a greater initial nalmefene concentration in the elderly group. While initial nalmefene plasma concentrations were transiently higher in the elderly, it would not be anticipated that this population would require dosing adjustment. No clinical adverse events were noted in the elderly following the 1 mg intravenous nalmefene dose.
Pediatric Patients
No pharmacokinetic studies were conducted with OPVEE nasal spray in pediatric patients. Based on population PK simulations, compared to an adult population (mean weight 75.42 kg), 12-year-old subjects with a median weight 50.6 kg, range 27.6 to 126.8 kg are expected to have 7.6% higher mean Cmax and 25.5% higher mean AUC0-∞ [See Pediatric Use (8.4)].
Male and Female Patients
There has not been sufficient pharmacokinetic study to make a definitive statement as to whether the pharmacokinetics of nalmefene differs between the male and female patients.
Patients with Renal Impairment
The pharmacokinetics of OPVEE nasal spray have not been studied in renally impaired subjects. In previous studies with nalmefene hydrochloride injection, there was a statistically significant 27% decrease in plasma clearance of nalmefene in the end-stage renal disease (ESRD) population during interdialysis (0.57± 0.20 L/hr/kg) and a 25% decreased plasma clearance in the ESRD population during intradialysis (0.59 ± 0.18 L/hr/kg) compared to healthy volunteers (0.79±0.24 L/hr/kg). The elimination half-life was prolonged in ESRD patients from 10.2 ± 2.2 hours in healthy volunteers to 26.1 ± 9.9 hours.
Patients with Hepatic Impairment
No pharmacokinetic studies were conducted with OPVEE nasal spray in hepatically impaired subjects. In previous studies with nalmefene hydrochloride injection, subjects with hepatic disease, when compared to matched normal controls, had a 28.3% decrease in plasma clearance of nalmefene (0.56 ± 0.21 L/hr/kg versus 0.78 ± 0.24 L/hr/kg, respectively). Elimination half-life increased from 10.2 ± 2.2 hours to 11.9 ± 2.0 hours in the hepatically impaired. No dosage adjustment is recommended since OPVEE nasal spray will be administered as an acute course of therapy.
Low Body Weight Patients and High Body Weight Patients
The effect of weight on nalmefene PK following a single intranasal 2.7 mg OPVEE administration was assessed using population pharmacokinetic simulations. Compared to the mean PK values across the full population in the PK dataset (median weight 74.70 kg), the 1st quartile of body weight (50.4 to 64.8 kg) had + 5.2% higher Cmax and + 15.7% higher AUC0-∞ whereas the 4th quartile of body weight (91 to 106.8 kg) had – 4.4% lower Cmax and – 11.6% lower AUC0-∞.
Carcinogenesis
The carcinogenic potential of nalmefene has not been evaluated.
Mutagenesis
Nalmefene did not have mutagenic activity in the Ames test with five bacterial strains or the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats. However, nalmefene did exhibit a weak but significant clastogenic activity in the human lymphocyte metaphase assay in the absence but not in the presence of exogenous metabolic activation.
Impairment of Fertility
Oral administration of nalmefene up to 1200 mg/m2/day did not affect fertility in rats at exposures at least 6 times the exposure corresponding to a human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis.
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:
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:
OPVEE® is a registered trademark of Indivior Inc.
©2023 Indivior Inc. All Rights Reserved.
Manufactured for: Indivior Inc., North Chesterfield, VA, 23235, USA
OPVEE®
(nalmefene)
nasal spray
QUICK START GUIDE
Use OPVEE nasal spray for known or suspected opioid overdose in adults and children 12 years of age and older.
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| OPVEE® is a registered trademark of Indivior Inc. | ©2023 Indivior Inc. All Rights Reserved. | Manufactured for: Indivior Inc., North Chesterfield, VA, 23235, USA | |
1. Check for response Image (Opvee 16) |
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2. Prepare Image (Opvee 17) |
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3. Give a dose in the nose Image (Opvee 18) |
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4. Call 911 and place person on their side Image (Opvee 19) |
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5. Watch and give another dose Image (Opvee 20) |
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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)].
Nasal spray: 2.7 mg nalmefene per device. Each unit-dose nasal spray device delivers a single spray containing 2.7 mg of nalmefene.
OPVEE nasal spray is contraindicated in patients known to be hypersensitive to nalmefene or to any of the other ingredients.
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)].
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.
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)].
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.
The following serious adverse reactions are discussed elsewhere in the labeling:
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.
| Nalmefene 2.7 mg | Nalmefene 5.4 mg | ||||
|---|---|---|---|---|---|
| System Organ Class Preferred Term | Total 2.7 mg N=150 n (%) | PD Study N=61 n (%) | PK Studies N=89 n (%) | PK Study (1 spray in each nostril) N=23 n (%) | PK Study (2 sprays in one nostril) N=24 n (%) |
| PK Studies OPNT003-PK-001 + OPNT003-PK-002 and PD Study OPNT003-OOD-001 | |||||
| Respiratory, thoracic and mediastinal disorders | |||||
| Nasal discomfort | 43 (28.7%) | 5 (8.2%) | 38 (42.7%) | 3 (13.0%) | 3 (12.5%) |
| Nasal congestion | 6 (4.0%) | 2 (3.3%) | 4 (4.5%) | 1 (4.3%) | 4 (16.7%) |
| Throat irritation | 6 (4.0%) | 3 (4.9%) | 3 (3.4%) | 0 | 0 |
| Rhinalgia | 4 (2.7%) | 1 (1.6%) | 3 (3.4%) | 2 (8.7%) | 6 (25.0%) |
| Dyspnea | 2 (1.3%) | 2 (3.3%) | 0 | 0 | 0 |
| Oropharyngeal pain | 2 (1.3%) | 2 (3.3%) | 0 | 1 (4.3%) | 1 (4.2%) |
| Nervous system disorders | |||||
| Headache | 40 (26.7%) | 34 (55.7%) | 6 (6.7%) | 1 (4.3%) | 0 |
| Dizziness | 14 (9.3%) | 9 (14.8%) | 5 (5.6%) | 0 | 1 (4.2%) |
| Dysgeusia | 3 (2.0%) | 2 (3.3%) | 1 (1.1%) | 0 | 0 |
| Paresthesia | 2 (1.3%) | 2 (3.3%) | 0 | 1 (4.3%) | 1 (4.2%) |
| Presyncope | 0 | 0 | 0 | 1 (4.3%) | 0 |
| Gastrointestinal disorders | |||||
| Nausea | 25 (16.7%) | 22 (36.1%) | 3 (3.4%) | 5 (21.7%) | 1 (4.2%) |
| Vomiting | 9 (6.0%) | 7 (11.5%) | 2 (2.2%) | 1 (4.3%) | 0 |
| Abdominal pain | 2 (1.3%) | 1 (1.6%) | 1 (1.1%) | 0 | 0 |
| Dry mouth | 1 (0.7%) | 1 (1.6%) | 0 | 1 (4.3%) | 0 |
| Constipation | 0 | 0 | 0 | 0 | 1 (4.2%) |
| Vascular disorders | |||||
| Hot flush | 12 (8.0%) | 12 (19.7%) | 0 | 0 | 0 |
| Psychiatric disorders | |||||
| Anxiety | 7 (4.7%) | 7 (11.5%) | 0 | 0 | 0 |
| Agitation | 2 (1.3%) | 2 (3.3%) | 0 | 0 | 0 |
| Claustrophobia | 2 (1.3%) | 2 (3.3%) | 0 | 0 | 0 |
| Insomnia | 1 (0.7%) | 0 | 1 (1.1%) | 1 (4.3%) | 0 |
| General disorders and administration site conditions | |||||
| Fatigue | 6 (4.0%) | 3 (4.9%) | 3 (3.4%) | 0 | 0 |
| Chills | 2 (1.3%) | 2 (3.3%) | 0 | 0 | 0 |
| Chest discomfort | 0 | 0 | 0 | 1 (4.3%) | 0 |
| Skin and subcutaneous tissue disorders | |||||
| Erythema | 3 (2.0%) | 0 | 3 (3.4%) | 1 (4.3%) | 1 (4.2%) |
| Hyperhidrosis | 3 (2.0%) | 3 (6.6%) | 0 | 0 | 1 (4.2%) |
| Urticaria | 0 | 0 | 0 | 0 | 1 (4.2%) |
| Metabolism and nutrition disorders | |||||
| Decreased appetite | 3 (2.0%) | 2 (3.3%) | 1 (1.1%) | 0 | 0 |
| Infections and infestations | |||||
| Rhinitis | 1 (0.7%) | 0 | 1 (1.1%) | 1 (4.3%) | 0 |
| Eye disorders | |||||
| Dry eye | 0 | 0 | 0 | 1 (4.3%) | 0 |
| Cardiac disorders | |||||
| Tachycardia | 0 | 0 | 0 | 1 (4.3%) | 0 |
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.
| Adverse Reaction | Nalmefene | Placebo |
|---|---|---|
| N=1127 | N=77 | |
| Nausea | 18% | 6% |
| Vomiting | 9% | 4% |
| Tachycardia | 5% | - |
| Hypertension | 5% | - |
| Postoperative Pain | 4% | N/A |
| Fever | 3% | - |
| Dizziness | 3% | 1% |
| Headache | 1% | 4% |
| Chills | 1% | - |
| Hypotension | 1% | - |
| Vasodilatation | 1% | - |
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.
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.
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.
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.
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.
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.
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:
Chemical Structure (Opvee 01)
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 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.
OPVEE is an antagonist at opioid receptors.
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 1 (Opvee 02)
Figure 2: Reversal of Remifentanil-Induced Respiratory Depression (Mean Minute Ventilation +/- Standard Deviation) by OPVEE (nalmefene) nasal spray
| Remifentanil (an initial bolus of 0.5 µg/kg dose followed by an infusion rate of 0.175 µg/kg/min) was administered for 15 min prior to test agents and continued for the duration of the study. The dashed line represents the mean minute ventilation (MV) prior to remifentanil administration. |
 Figure 2 (Opvee 03) |
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.
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.
| Parameter | OPVEE | Nalmefene IM |
|---|---|---|
| NA Not applicable | ||
| Tmax (h) Tmax presented as median (range) | 0.250 (0.0833-2.00) | 0.33 (0.117-18.0) |
| Cmax (ng/mL) Arithmetic mean | 10.4 (62.6) | 1.50 (59.4) |
| AUC0-2.5min (ng-hr/mL) | 0.00763 (233) | 0.00168 (186) |
| AUC0-5min (ng-hr/mL) | 0.0599 (201) | 0.0102 (142) |
| AUC0-10min (ng-hr/mL) | 0.523 (124) | 0.0639 (118) |
| AUC0-15min (ng-hr/mL) | 1.20 (94.2) | 0.142 (98.6) |
| AUC0-20min (ng-hr/mL) | 1.89 (77.2) | 0.228 (84.5) |
| AUC0-30min (ng-hr/mL) | 3.07 (60.4) | 0.405 (69.2) |
| AUC0-inf (ng-hr/mL) | 40.6 (22.0) | 16.8 (18.7) |
| Frel | 0.806 (10.9) | NA |
| T½ (h) | 11.4 (20.8) | 10.6 (18.5) |
| 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) |
 Figure 3 (a) (Opvee 04) |
| (b) |
 Figure 3 (b) (Opvee 05) |
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.
| Parameter | OPVEE 2.7mg (one spray) | OPVEE 5.4mg (one spray in each nostril) | OPVEE 5.4mg (two sprays in one nostril) |
|---|---|---|---|
| Tmax (h) Tmax presented as median (range) | 0.267 (0.167-2.03) | 0.250 (0.117-3.00) | 0.250 (0.117-2.03) |
| Cmax (ng/mL) | 9.75 (49.4) | 18.9 (88.0) | 16.1 (62.9) |
| AUC0-2.5min (ng-hr/mL) | 0.00594 (134) | 0.0163 (217) | 0.0172 (117) |
| AUC0-5min (ng-hr/mL) | 0.0446 (99.6) | 0.110 (161) | 0.108 (92.9) |
| AUC0-10min (ng-hr/mL) | 0.388 (72.1) | 0.828 (102) | 0.717 (93.2) |
| AUC0-15min (ng-hr/mL) | 0.999 (65.9) | 2.08 (81.8) | 1.73 (83.0) |
| AUC0-20min (ng-hr/mL) | 1.66 (61.3) | 3.42 (69.9) | 2.85(74.3) |
| AUC0-30min (ng-hr/mL) | 2.83 (56.0) | 5.63 (57.7) | 4.78 (60.8) |
| AUC0-inf (ng-hr/mL) | 45.8 (21.7) | 88.1 (18.3) | 83.8 (22.0) |
| T½ (h) Arithmetic mean | 11.4 (22.0) | 11.3 (16.6) | 11.3 (16.5) |
| Values represent the mean and standard deviation (n=24) |
| Figure 4: Mean Plasma Concentration of Nalmefene, (a) 0-12 hours and (b) 0-60 minutes Following Intranasal (IN) Administration of 2.7 mg Nalmefene (One OPVEE nasal spray in One Nostril), IN Dose of 5.4 mg Nalmefene (One OPVEE nasal spray in Each Nostril) and IN Dose of 5.4 mg Nalmefene (Two OPVEE nasal sprays in One Nostril) |
| (a) |
 Figure 4 (a) (Opvee 06) |
| (b) |
 Figure 4 (b) (Opvee 07) |
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.
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.
Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Issued: 06/2023 | |||
| PATIENT INFORMATION OPVEE (op vee) (nalmefene) nasal spray | ||||
| You and your family members or caregivers should read this Patient Information leaflet before an opioid emergency happens. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. | ||||
| What is the most important information I should know about OPVEE nasal spray? OPVEE nasal spray is used to temporarily reverse the effects of opioid medicines. The medicine in OPVEE nasal spray is not expected to have an effect in people who are not taking opioid medicines. Always carry OPVEE nasal spray with you in case of an opioid emergency.
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What is OPVEE nasal spray?
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| Do not use OPVEE nasal spray if you are allergic to nalmefene or any of the ingredients in OPVEE nasal spray. See the end of this leaflet for a complete list of ingredients in OPVEE nasal spray. | ||||
Before using OPVEE nasal spray, tell your healthcare provider about all of your medical conditions, including if you:
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| How should I use OPVEE nasal spray? Read the "Instructions for Use" at the end of this Patient Information leaflet for detailed information about how to use OPVEE nasal spray.
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| What are the possible side effects of OPVEE nasal spray? OPVEE nasal spray may cause serious side effects, including:
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| These are not all of the possible side effects of OPVEE nasal spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||||
How should I store OPVEE nasal spray?
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| General information about the safe and effective use of OPVEE nasal spray. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use OPVEE nasal spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about OPVEE nasal spray that is written for health professionals. | ||||
| What are the ingredients in OPVEE nasal spray? Active ingredient: nalmefene Inactive ingredients: benzalkonium chloride, disodium ethylenediaminetetraacetate, dodecyl maltoside, sodium chloride, and purified water. OPVEE nasal spray is not made with natural rubber latex. OPVEE® is a registered trademark of Indivior Inc. ©2023 Indivior Inc. All Rights Reserved. Manufactured for: Indivior Inc., North Chesterfield, VA, 23235, USA For more information, visit www.OPVEE.com or call 1-877-782-6966 | ||||
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.
 Figure (Opvee 08) | Important Information You Need to Know Before Giving OPVEE nasal spray
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| Check for response Step 1. Shout "wake up" and shake the person gently. If there is no response, slow breathing, or no breathing, lay the person flat on their back (Figure A). |  Figure A (Opvee 09) | |
| Prepare to give OPVEE nasal spray Step 2. Remove OPVEE nasal spray from the box. Peel off the back from the top corner to open the OPVEE nasal spray blister (Figure B). Step 3. Hold the OPVEE nasal spray with your fingers on both sides of the nozzle and your thumb on the white plunger (Figure C). Do not press the plunger yet. |  Figure B (Opvee 10)  Figure C (Opvee 11) | |
| Give OPVEE nasal spray Step 4. Provide support behind the neck with your hand and tilt the person's head back (Figure D). Step 5. Gently insert the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person's nose. (Figure D). Step 6. Press the plunger firmly to give the dose of OPVEE nasal spray in the nose. The dose has been delivered when the white plunger has been pushed all the way down until it stops. Step 7. Remove the OPVEE nasal spray from the nostril after the dose has been given. |  Figure D (Opvee 12) | |
| After giving OPVEE nasal spray Step 8. Call 911 or get emergency medical help right away (Figure E). Step 9. Move the person on their side (recovery position) (Figure F):
Step 11. After OPVEE nasal spray has been used, put it back into its box. Throw away (dispose of) the used OPVEE nasal spray in a place that is away from children. |  Figure E (Opvee 13)  Figure F (Opvee 14)  Figure G (Opvee 15) | |
Storing OPVEE nasal spray
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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
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.
Principal Display Panel (2.7 mg Bottle Carton)
* Please review the disclaimer below.
