CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisThe carcinogenic potential of nalmefene has not been evaluated.. MutagenesisNalmefene 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 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 FertilityOral administration of nalmefene up to 1200 mg/m2/day did not affect fertility in rats at exposures at least times the exposure corresponding to human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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 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 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 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 minutes (Figure and Figure 2). At minutes the estimated mean increase in minute ventilation was 5.745 L/min (Figure 2). Full recovery of respiratory drive was noted between and 15 minutes after OPVEE administration (Figure 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 sprayRemifentanil (an initial bolus of 0.5 ug/kg dose followed by an infusion rate of 0.175 ug/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.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 single 2.7 mg administration. The time to reach EC50 was 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.. Figure 1. Figure 2. 12.3 Pharmacokinetics. In 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 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 and the plasma concentration time profiles of nalmefene are presented in Figure 3. Table 3: Geometric Mean (CV%) PK Parameters of Nalmefene after Intranasal (IN) Administration of 2.7 mg OPVEE nasal spray and Intramuscular (IM) Administration of 1.0 mg of Nalmefene ParameterOPVEENalmefene IMNA Not applicableTmax (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)NAT 1/2 (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)(b)In 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 and the plasma concentration time profiles of nalmefene are presented in Figure 4.Table 4: Geometric Mean (CV%) PK Parameters of Nalmefene After Intranasal (IN) Dose 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)ParameterOPVEE 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)T 1/2 (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)(b). AbsorptionAfter administration of one 2.7 mg OPVEE nasal spray to healthy adult subjects, the median Tmax for OPVEE was 0.250 hours, compared to 0.33 hours for the intramuscular nalmefene.After administration of two 2.7 mg OPVEE nasal sprays (total dose 5.4mg) to healthy adult subjects, the median Tmax for OPVEE was 0.250 hours.The dose normalized area under the curve (AUC0-inf) to infinity is similar for one 2.7 mg OPVEE nasal spray in one nostril and one 2.7 mg OPVEE nasal spray in each nostril with geometric mean ratio of 96.23% (90%CI 92.00%-100.65%). The dose normalized AUC0-inf is also similar for one 2.7 mg OPVEE nasal spray in one nostril and two 2.7 mg OPVEE nasal sprays in one nostril with geometric mean ratio of 91.19% (90%CI 87.19%-95.38%).The mean bioavailability (Frel) of OPVEE was 0.806 relative to intramuscular administration of nalmefene.. DistributionFollowing 1 mg parenteral dose, nalmefene was rapidly distributed. In study of brain receptor occupancy, 1 mg dose of nalmefene blocked over 80% of brain opioid receptors within 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 concentration range of 0.1 to 2ug/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.. EliminationAfter administration of 2.7 mg OPVEE nasal spray to healthy adult subjects, plasma concentrations have terminal elimination half-life of 11.4 (%CV 20.8) hours. The apparent clearance of nalmefene is 75.7 (%CV 23.8) L/hr.. MetabolismNalmefene 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.. ExcretionNalmefene 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 PatientsIn previous studies with nalmefene hydrochloride injection, dose proportionality was observed in nalmefene AUC following 0.5 to mg intravenous administration to elderly male subjects. Following 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 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 mg intravenous nalmefene dose.. Pediatric PatientsNo 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 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 PatientsThere has not been sufficient pharmacokinetic study to make definitive statement as to whether the pharmacokinetics of nalmefene differs between the male and female patients.. Patients with Renal ImpairmentThe pharmacokinetics of OPVEE nasal spray have not been studied in renally impaired subjects. In previous studies with nalmefene hydrochloride injection, there was 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 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 ImpairmentNo 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 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 PatientsThe effect of weight on nalmefene PK following 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-.. Figure (a). Figure (b). Figure (a). Figure (b).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 normal state and under steady state opioid agonism. The following adverse reactions were observed.In 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 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 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.Table 1: Relative Frequencies of Treatment-Related Common Adverse Events That Occurred in Greater Than 1% of Healthy Adult VolunteersNalmefene 2.7 mgNalmefene 5.4 mgSystem Organ Class Preferred TermTotal 2.7 mgN=150n (%)PD StudyN=61n (%)PK StudiesN=89n (%)PK Study(1 spray in each nostril)N=23n (%)PK Study(2 sprays in one nostril)N=24n (%)PK Studies OPNT003-PK-001 OPNT003-PK-002 and PD Study OPNT003-OOD-001Respiratory, thoracic and mediastinal disorders Nasal discomfort43 (28.7%)5 (8.2%)38 (42.7%)3 (13.0%)3 (12.5%) Nasal congestion6 (4.0%)2 (3.3%)4 (4.5%)1 (4.3%)4 (16.7%) Throat irritation6 (4.0%)3 (4.9%)3 (3.4%)00 Rhinalgia4 (2.7%)1 (1.6%)3 (3.4%)2 (8.7%)6 (25.0%) Dyspnea2 (1.3%)2 (3.3%)000 Oropharyngeal pain2 (1.3%)2 (3.3%)01 (4.3%)1 (4.2%)Nervous system disorders Headache40 (26.7%)34 (55.7%)6 (6.7%)1 (4.3%)0 Dizziness14 (9.3%)9 (14.8%)5 (5.6%)01 (4.2%) Dysgeusia3 (2.0%)2 (3.3%)1 (1.1%)00 Paresthesia2 (1.3%)2 (3.3%)01 (4.3%)1 (4.2%) Presyncope0001 (4.3%)0Gastrointestinal disorders Nausea25 (16.7%)22 (36.1%)3 (3.4%)5 (21.7%)1 (4.2%) Vomiting9 (6.0%)7 (11.5%)2 (2.2%)1 (4.3%)0 Abdominal pain2 (1.3%)1 (1.6%)1 (1.1%)00 Dry mouth1 (0.7%)1 (1.6%)01 (4.3%)0 Constipation00001 (4.2%)Vascular disorders Hot flush12 (8.0%)12 (19.7%)000Psychiatric disorders Anxiety7 (4.7%)7 (11.5%)000 Agitation2 (1.3%)2 (3.3%)000 Claustrophobia2 (1.3%)2 (3.3%)000 Insomnia1 (0.7%)01 (1.1%)1 (4.3%)0General disorders and administration site conditions Fatigue6 (4.0%)3 (4.9%)3 (3.4%)00 Chills2 (1.3%)2 (3.3%)000 Chest discomfort0001 (4.3%)0Skin and subcutaneous tissue disorders Erythema3 (2.0%)03 (3.4%)1 (4.3%)1 (4.2%) Hyperhidrosis3 (2.0%)3 (6.6%)001 (4.2%) Urticaria00001 (4.2%)Metabolism and nutrition disorders Decreased appetite3 (2.0%)2 (3.3%)1 (1.1%)00Infections and infestations Rhinitis1 (0.7%)01 (1.1%)1 (4.3%)0Eye disorders Dry eye0001 (4.3%)0Cardiac disorders Tachycardia0001 (4.3%)0Adverse 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. Table 2. Relative Frequencies of Common Adverse Reactions with an Incidence Greater than 1% (all patients, all clinical settings)Adverse ReactionNalmefenePlaceboN=1127N=77Nausea18%6%Vomiting9%4%Tachycardia5%-Hypertension5%-Postoperative Pain4%N/AFever3%-Dizziness3%1%Headache1%4%Chills1%-Hypotension1%-Vasodilatation1%-Incidence less than 1%Cardiovascular: Bradycardia, arrhythmiaDigestive: Diarrhea, dry mouthNervous System: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonusRespiratory: PharyngitisSkin: PruritusUrogenital: Urinary retentionThe incidence of adverse events was highest in patients who received more than the recommended dose of nalmefene injection.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. OPVEE nasal spray is contraindicated in patients known to be hypersensitive to nalmefene or to any of the other ingredients.. Hypersensitivity to nalmefene or to any of the other ingredients. (4).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions (5.1)] Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)] Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions (5.1)] Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)] Most common adverse reactions (incidence at least 2%) are nasal discomfort, headache, nausea, dizziness, hot flush, vomiting, anxiety, fatigue, nasal congestion, throat irritation, rhinalgia, decreased appetite, dysgeusia, erythema, and hyperhidrosis. (6)To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 normal state and under steady state opioid agonism. The following adverse reactions were observed.In 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 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 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.Table 1: Relative Frequencies of Treatment-Related Common Adverse Events That Occurred in Greater Than 1% of Healthy Adult VolunteersNalmefene 2.7 mgNalmefene 5.4 mgSystem Organ Class Preferred TermTotal 2.7 mgN=150n (%)PD StudyN=61n (%)PK StudiesN=89n (%)PK Study(1 spray in each nostril)N=23n (%)PK Study(2 sprays in one nostril)N=24n (%)PK Studies OPNT003-PK-001 OPNT003-PK-002 and PD Study OPNT003-OOD-001Respiratory, thoracic and mediastinal disorders Nasal discomfort43 (28.7%)5 (8.2%)38 (42.7%)3 (13.0%)3 (12.5%) Nasal congestion6 (4.0%)2 (3.3%)4 (4.5%)1 (4.3%)4 (16.7%) Throat irritation6 (4.0%)3 (4.9%)3 (3.4%)00 Rhinalgia4 (2.7%)1 (1.6%)3 (3.4%)2 (8.7%)6 (25.0%) Dyspnea2 (1.3%)2 (3.3%)000 Oropharyngeal pain2 (1.3%)2 (3.3%)01 (4.3%)1 (4.2%)Nervous system disorders Headache40 (26.7%)34 (55.7%)6 (6.7%)1 (4.3%)0 Dizziness14 (9.3%)9 (14.8%)5 (5.6%)01 (4.2%) Dysgeusia3 (2.0%)2 (3.3%)1 (1.1%)00 Paresthesia2 (1.3%)2 (3.3%)01 (4.3%)1 (4.2%) Presyncope0001 (4.3%)0Gastrointestinal disorders Nausea25 (16.7%)22 (36.1%)3 (3.4%)5 (21.7%)1 (4.2%) Vomiting9 (6.0%)7 (11.5%)2 (2.2%)1 (4.3%)0 Abdominal pain2 (1.3%)1 (1.6%)1 (1.1%)00 Dry mouth1 (0.7%)1 (1.6%)01 (4.3%)0 Constipation00001 (4.2%)Vascular disorders Hot flush12 (8.0%)12 (19.7%)000Psychiatric disorders Anxiety7 (4.7%)7 (11.5%)000 Agitation2 (1.3%)2 (3.3%)000 Claustrophobia2 (1.3%)2 (3.3%)000 Insomnia1 (0.7%)01 (1.1%)1 (4.3%)0General disorders and administration site conditions Fatigue6 (4.0%)3 (4.9%)3 (3.4%)00 Chills2 (1.3%)2 (3.3%)000 Chest discomfort0001 (4.3%)0Skin and subcutaneous tissue disorders Erythema3 (2.0%)03 (3.4%)1 (4.3%)1 (4.2%) Hyperhidrosis3 (2.0%)3 (6.6%)001 (4.2%) Urticaria00001 (4.2%)Metabolism and nutrition disorders Decreased appetite3 (2.0%)2 (3.3%)1 (1.1%)00Infections and infestations Rhinitis1 (0.7%)01 (1.1%)1 (4.3%)0Eye disorders Dry eye0001 (4.3%)0Cardiac disorders Tachycardia0001 (4.3%)0Adverse 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. Table 2. Relative Frequencies of Common Adverse Reactions with an Incidence Greater than 1% (all patients, all clinical settings)Adverse ReactionNalmefenePlaceboN=1127N=77Nausea18%6%Vomiting9%4%Tachycardia5%-Hypertension5%-Postoperative Pain4%N/AFever3%-Dizziness3%1%Headache1%4%Chills1%-Hypotension1%-Vasodilatation1%-Incidence less than 1%Cardiovascular: Bradycardia, arrhythmiaDigestive: Diarrhea, dry mouthNervous System: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonusRespiratory: PharyngitisSkin: PruritusUrogenital: Urinary retentionThe 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

DESCRIPTION SECTION.

11 DESCRIPTION. OPVEE (nalmefene) nasal spray is pre-filled, unit-dose intranasal spray.Nalmefene, an opioid antagonist, is 6-methylene analogue of naltrexone. The molecular structure of nalmefene is presented below:Molecular Formula: C21H25NO3HClMolecular Weight: 375.9, CAS 58895-64-0Chemical Name: 17-(Cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt.Nalmefene is white to off-white crystalline powder which is freely soluble in methanol and water, with 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.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. OPVEE nasal spray is for intranasal use only (2.1)Seek emergency care immediately after use (2.1)Administer single spray of OPVEE nasal spray intranasally into nose. (2.2)Administer additional doses of OPVEE nasal spray, using new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses of OPVEE nasal spray may be given every to minutes until emergency medical assistance arrives. (2.2)Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. (2.2). OPVEE nasal spray is for intranasal use only (2.1). Seek emergency care immediately after use (2.1). Administer single spray of OPVEE nasal spray intranasally into nose. (2.2). Administer additional doses of OPVEE nasal spray, using new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses of OPVEE nasal spray may be given every to minutes until emergency medical assistance arrives. (2.2). Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. (2.2). 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 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 Use at the time they receive prescription for OPVEE nasal spray. Emphasize the following instructions to the patient or caregiver:Administer OPVEE nasal spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Always seek emergency medical assistance after administration of the first dose of OPVEE nasal spray in the event of 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 new nasal spray, in the nose, every to 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 Guide and 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 Use and call for emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray. 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 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 Use at the time they receive prescription for OPVEE nasal spray. Emphasize the following instructions to the patient or caregiver:. Administer OPVEE nasal spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Always seek emergency medical assistance after administration of the first dose of OPVEE nasal spray in the event of 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 new nasal spray, in the nose, every to 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 Guide and 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 Use and call for emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray. -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 Use and 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. 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 new OPVEE nasal spray and continue surveillance of the patient.If the desired response is not obtained after to minutes, administer an additional dose of OPVEE using new OPVEE nasal spray device. If there is still no response and additional doses are available, administer additional doses of OPVEE nasal spray every to minutes using 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.. 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 new nasal spray device [see Warnings and Precautions (5.2)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Nasal spray: 2.7 mg nalmefene per device. Each unit-dose nasal spray device delivers single spray containing 2.7 mg of nalmefene.. Nasal spray: 2.7 mg of nalmefene in 0.1 mL (3).

GERIATRIC USE SECTION.

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 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 SUBSECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Each unit-dose nasal spray device delivers 2.7 mg of nalmefene (equivalent to mg of nalmefene hydrochloride) in 0.1 mL. Each carton contains two unit-dose nasal spray devices.NDC 12496-0003-2OPVEE 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 15C to 25C (59F to 77F). Short-term excursions permitted between 4C to 40C (39F to 104F). 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.

INDICATIONS & USAGE SECTION.

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 substitute for emergency medical care.. OPVEE nasal spray is an opioid antagonist 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 substitute for emergency medical care.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use). 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 patient verbally or upon firm sternal rub. Respiratory depression -this can range from slow or shallow respiration to no respiration in patient who is unarousable. Other signs and symptoms that may accompany somnolence and respiratory depression include the following: -Miosis-Bradycardia and/or hypotension. Extreme somnolence -inability to awaken patient verbally or upon firm sternal rub. Respiratory depression -this can range from slow or shallow respiration to no respiration in patient who is unarousable. Other signs and symptoms that may accompany somnolence and respiratory depression include the following: -Miosis-Bradycardia and/or hypotension. -Miosis. -Bradycardia and/or hypotension. Risk of Recurrent Respiratory DepressionWhile 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. 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/AntagonistsInstruct 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 new nasal spray device each time [see Dosage and Administration (2.3), Warnings and Precautions (5.2)].. Precipitation of Severe Opioid WithdrawalInstruct 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 InstructionsInstruct 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 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 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 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 to 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 to minutes, using 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.. 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 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 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 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 to 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 to minutes, using 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.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEOPVEE (op vee)(nalmefene)nasal spray. The Instructions for Use contains information on how to give OPVEE nasal spray in response to 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.Important Information You Need to Know Before Giving OPVEE nasal sprayFor use in the nose only.Do not remove or test the OPVEE nasal spray before use.Each OPVEE nasal spray has dose and cannot be reused.You do not need to prime OPVEE nasal spray.Check for responseStep 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 APrepare to give OPVEE nasal sprayStep 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 BFigure CGive OPVEE nasal sprayStep 4. Provide support behind the neck with your hand and tilt the persons 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 persons 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 DAfter giving OPVEE nasal sprayStep 8. Call 911 or get emergency medical help right away (Figure E). Step 9. Move the person on their side (recovery position) (Figure F):Hand is supporting their head. Bend their knee. Turn their face to the side. Step 10. Wait for to minutes to see if the person wakes up. If the person does not respond by waking up, to voice or touch, or start breathing normally, another dose may be given (Figure G).Get new OPVEE nasal spray from the box. Repeat Steps through to give another dose of OPVEE in the other nostril.If more OPVEE nasal sprays are available, repeat Steps through every to minutes, alternating nostrils, until the person wakes up or medical help arrives.Stay with the person until medical help arrives. 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 place that is away from children. Figure EFigure FFigure GStoring OPVEE nasal sprayStore OPVEE nasal spray at room temperature between 59F to 77F (15C to 25C).Do not freeze OPVEE nasal spray.Keep OPVEE nasal spray in its box until ready to use. Protect from light. Replace OPVEE nasal spray before the expiration date on the box.Keep OPVEE nasal spray and all medicines out of the reach of children.For more information about OPVEE nasal spray, go to www.OPVEE.com or call 1-877-782-6966.OPVEE(R) is registered trademark of Indivior Inc. (C)2023 Indivior Inc. All Rights Reserved. Manufactured for: Indivior Inc., North Chesterfield, VA, 23235, USAThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 06/2023 For use in the nose only.. Do not remove or test the OPVEE nasal spray before use.. Each OPVEE nasal spray has dose and cannot be reused.. You do not need to prime OPVEE nasal spray.. Hand is supporting their head. Bend their knee. Turn their face to the side.. Get new OPVEE nasal spray from the box. Repeat Steps through to give another dose of OPVEE in the other nostril.. If more OPVEE nasal sprays are available, repeat Steps through every to minutes, alternating nostrils, until the person wakes up or medical help arrives.. Store OPVEE nasal spray at room temperature between 59F to 77F (15C to 25C).. Do not freeze OPVEE nasal spray.. Keep OPVEE nasal spray in its box until ready to use. Protect from light. Replace OPVEE nasal spray before the expiration date on the box.. Figure. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 drug is present in animal milk, it is likely that the drug will be present in human milk.. DataNalmefene 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. OPVEE is an antagonist at opioid receptors.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisThe carcinogenic potential of nalmefene has not been evaluated.. MutagenesisNalmefene 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 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 FertilityOral administration of nalmefene up to 1200 mg/m2/day did not affect fertility in rats at exposures at least times the exposure corresponding to human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 2.7 mg Bottle Carton. NDC 12496-0003-2Rx onlyOPVEE(R) (nalmefene)NASAL SPRAY2.7 mgFOR USE IN THE NOSE ONLY DO NOT TEST BEFORE USEUse for known or suspected opioid overdose in adults and children 12 years of age and older.Two Unit-Dose Nasal Spray DevicesEach 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 1-877-782-6966Check product expiration date before use.. Principal Display Panel 2.7 mg Bottle Carton.

PEDIATRIC USE SECTION.

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.

PHARMACODYNAMICS SECTION.

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 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 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 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 minutes (Figure and Figure 2). At minutes the estimated mean increase in minute ventilation was 5.745 L/min (Figure 2). Full recovery of respiratory drive was noted between and 15 minutes after OPVEE administration (Figure 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 sprayRemifentanil (an initial bolus of 0.5 ug/kg dose followed by an infusion rate of 0.175 ug/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.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 single 2.7 mg administration. The time to reach EC50 was 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.. Figure 1. Figure 2.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. In 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 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 and the plasma concentration time profiles of nalmefene are presented in Figure 3. Table 3: Geometric Mean (CV%) PK Parameters of Nalmefene after Intranasal (IN) Administration of 2.7 mg OPVEE nasal spray and Intramuscular (IM) Administration of 1.0 mg of Nalmefene ParameterOPVEENalmefene IMNA Not applicableTmax (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)NAT 1/2 (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)(b)In 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 and the plasma concentration time profiles of nalmefene are presented in Figure 4.Table 4: Geometric Mean (CV%) PK Parameters of Nalmefene After Intranasal (IN) Dose 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)ParameterOPVEE 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)T 1/2 (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)(b). AbsorptionAfter administration of one 2.7 mg OPVEE nasal spray to healthy adult subjects, the median Tmax for OPVEE was 0.250 hours, compared to 0.33 hours for the intramuscular nalmefene.After administration of two 2.7 mg OPVEE nasal sprays (total dose 5.4mg) to healthy adult subjects, the median Tmax for OPVEE was 0.250 hours.The dose normalized area under the curve (AUC0-inf) to infinity is similar for one 2.7 mg OPVEE nasal spray in one nostril and one 2.7 mg OPVEE nasal spray in each nostril with geometric mean ratio of 96.23% (90%CI 92.00%-100.65%). The dose normalized AUC0-inf is also similar for one 2.7 mg OPVEE nasal spray in one nostril and two 2.7 mg OPVEE nasal sprays in one nostril with geometric mean ratio of 91.19% (90%CI 87.19%-95.38%).The mean bioavailability (Frel) of OPVEE was 0.806 relative to intramuscular administration of nalmefene.. DistributionFollowing 1 mg parenteral dose, nalmefene was rapidly distributed. In study of brain receptor occupancy, 1 mg dose of nalmefene blocked over 80% of brain opioid receptors within 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 concentration range of 0.1 to 2ug/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.. EliminationAfter administration of 2.7 mg OPVEE nasal spray to healthy adult subjects, plasma concentrations have terminal elimination half-life of 11.4 (%CV 20.8) hours. The apparent clearance of nalmefene is 75.7 (%CV 23.8) L/hr.. MetabolismNalmefene 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.. ExcretionNalmefene 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 PatientsIn previous studies with nalmefene hydrochloride injection, dose proportionality was observed in nalmefene AUC following 0.5 to mg intravenous administration to elderly male subjects. Following 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 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 mg intravenous nalmefene dose.. Pediatric PatientsNo 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 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 PatientsThere has not been sufficient pharmacokinetic study to make definitive statement as to whether the pharmacokinetics of nalmefene differs between the male and female patients.. Patients with Renal ImpairmentThe pharmacokinetics of OPVEE nasal spray have not been studied in renally impaired subjects. In previous studies with nalmefene hydrochloride injection, there was 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 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 ImpairmentNo 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 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 PatientsThe effect of weight on nalmefene PK following 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-.. Figure (a). Figure (b). Figure (a). Figure (b).

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of nalmefene. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLife-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 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 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 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 riskAn opioid overdose is 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 DataReproduction 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 times (rats) and up to 20 times (rabbits) the exposure corresponding to human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis. The treatment in rats did not affect offspring survival.

RENAL IMPAIRMENT SUBSECTION.

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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 06/2023PATIENT INFORMATIONOPVEE (op vee)(nalmefene)nasal sprayYou 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 should know about OPVEE nasal sprayOPVEE 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.Use OPVEE nasal spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:unusual sleepiness and you are not able to awaken the person with loud voice or rubbing firmly on the middle of their chest (sternum)breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathingthe black circle in the center of the colored part of the eye (pupil) is very small, sometimes called pinpoint pupils in someone difficult to awaken Family members, caregivers, or other people who may have to use OPVEE nasal spray in an opioid emergency should know where OPVEE nasal spray is stored and how to give it before an opioid emergency happens.Call 911 or get emergency medical help right away after giving the first dose of OPVEE nasal spray. Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help.The signs and symptoms of an opioid emergency can return after OPVEE nasal spray is given. If this happens, give another dose every to minutes using new OPVEE nasal spray and watch the person closely until emergency help is received.What is OPVEE nasal sprayOPVEE nasal spray is prescription medicine used in adults and children 12 years of age and older for the treatment of an opioid emergency such as an overdose or possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond.OPVEE nasal spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right way after giving the first dose of OPVEE nasal spray, even if the person wakes up.It is not known if OPVEE nasal spray is safe and effective in children younger than 12 years of age.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 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:have heart problems are pregnant or plan to become pregnant. Use of OPVEE nasal spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by healthcare provider right away after you use OPVEE nasal spray. are breastfeeding or plan to breastfeed. It is not known if OPVEE nasal spray passes into your breast milk. Tell your healthcare provider about the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements.How should use OPVEE nasal sprayRead the Instructions for Use at the end of this Patient Information leaflet for detailed information about how to use OPVEE nasal spray.Use OPVEE nasal spray exactly as prescribed by your healthcare provider.Each OPVEE nasal spray only contains dose of medicine and cannot be reused. Do not test or prime OPVEE nasal spray before use.Lay the person on their back. Use your hand to support behind their neck and allow the head to tilt back before giving OPVEE nasal spray.OPVEE nasal spray should be given into one nostril.If additional doses are needed, give OPVEE nasal spray in the other nostril.What are the possible side effects of OPVEE nasal sprayOPVEE nasal spray may cause serious side effects, including:Sudden opioid withdrawal symptoms. In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving OPVEE nasal spray and may include:body achesdiarrheaincreased heart ratefeverrunny nosesneezinggoose bumpssweatingyawningnausea or vomitingnervousnessrestlessness or irritabilityshivering or tremblingstomach crampingweaknessincreased blood pressureRisk of opioid overdose. OPVEE nasal spray blocks the effects of opioids and may cause opioid withdrawal in someone who has been using opioids regularly. Do not take large amounts of opioids to try to overcome the opioid-blocking effects of OPVEE nasal spray. This could lead to an opioid overdose and death. Call 911 or get emergency medical help right away after using OPVEE nasal spray. The most common side effects of OPVEE nasal spray include:nose (nasal) discomfortheadachenauseadizzinesshot flushvomitinganxietytirednessnasal congestionthroat irritationpain in the nose decreased appetitechanges in the sense of tasteskin rednessincreased sweatingThese 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 store OPVEE nasal sprayStore OPVEE nasal spray at room temperature between 59F to 77F (15C to 25C).Do not freeze OPVEE nasal spray. Keep OPVEE nasal spray in its box until ready to use.Protect from light. Replace OPVEE nasal spray before the expiration date on the box. Keep OPVEE nasal spray and all medicines out of the reach of children.General information about the safe and effective use of OPVEE nasal spray.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use OPVEE nasal spray for 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 sprayActive 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(R) is registered trademark of Indivior Inc. (C)2023 Indivior Inc. All Rights Reserved.Manufactured for: Indivior Inc., North Chesterfield, VA, 23235, USAFor more information, visit www.OPVEE.com or call 1-877-782-6966 Use OPVEE nasal spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:unusual sleepiness and you are not able to awaken the person with loud voice or rubbing firmly on the middle of their chest (sternum)breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathingthe black circle in the center of the colored part of the eye (pupil) is very small, sometimes called pinpoint pupils in someone difficult to awaken unusual sleepiness and you are not able to awaken the person with loud voice or rubbing firmly on the middle of their chest (sternum). breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathing. the black circle in the center of the colored part of the eye (pupil) is very small, sometimes called pinpoint pupils in someone difficult to awaken. Family members, caregivers, or other people who may have to use OPVEE nasal spray in an opioid emergency should know where OPVEE nasal spray is stored and how to give it before an opioid emergency happens.. Call 911 or get emergency medical help right away after giving the first dose of OPVEE nasal spray. Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help.. The signs and symptoms of an opioid emergency can return after OPVEE nasal spray is given. If this happens, give another dose every to minutes using new OPVEE nasal spray and watch the person closely until emergency help is received.. OPVEE nasal spray is prescription medicine used in adults and children 12 years of age and older for the treatment of an opioid emergency such as an overdose or possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond.. OPVEE nasal spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right way after giving the first dose of OPVEE nasal spray, even if the person wakes up.. have heart problems are pregnant or plan to become pregnant. Use of OPVEE nasal spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by healthcare provider right away after you use OPVEE nasal spray. are breastfeeding or plan to breastfeed. It is not known if OPVEE nasal spray passes into your breast milk. Use OPVEE nasal spray exactly as prescribed by your healthcare provider.. Each OPVEE nasal spray only contains dose of medicine and cannot be reused. Do not test or prime OPVEE nasal spray before use.. Lay the person on their back. Use your hand to support behind their neck and allow the head to tilt back before giving OPVEE nasal spray.. OPVEE nasal spray should be given into one nostril.. If additional doses are needed, give OPVEE nasal spray in the other nostril.. Sudden opioid withdrawal symptoms. In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving OPVEE nasal spray and may include:. body aches. diarrhea. increased heart rate. fever. runny nose. sneezing. goose bumps. sweating. yawning. nausea or vomiting. nervousness. restlessness or irritability. shivering or trembling. stomach cramping. weakness. increased blood pressure. Risk of opioid overdose. OPVEE nasal spray blocks the effects of opioids and may cause opioid withdrawal in someone who has been using opioids regularly. Do not take large amounts of opioids to try to overcome the opioid-blocking effects of OPVEE nasal spray. This could lead to an opioid overdose and death. Call 911 or get emergency medical help right away after using OPVEE nasal spray. nose (nasal) discomfort. headache. nausea. dizziness. hot flush. vomiting. anxiety. tiredness. nasal congestion. throat irritation. pain in the nose decreased appetite. changes in the sense of taste. skin redness. increased sweating. Store OPVEE nasal spray at room temperature between 59F to 77F (15C to 25C).. Do not freeze OPVEE nasal spray. Keep OPVEE nasal spray in its box until ready to use.. Protect from light. Replace OPVEE nasal spray before the expiration date on the box.

SPL UNCLASSIFIED SECTION.

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 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 Use at the time they receive prescription for OPVEE nasal spray. Emphasize the following instructions to the patient or caregiver:Administer OPVEE nasal spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Always seek emergency medical assistance after administration of the first dose of OPVEE nasal spray in the event of 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 new nasal spray, in the nose, every to 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 Guide and 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 Use and call for emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray. 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 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 Use at the time they receive prescription for OPVEE nasal spray. Emphasize the following instructions to the patient or caregiver:. Administer OPVEE nasal spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Always seek emergency medical assistance after administration of the first dose of OPVEE nasal spray in the event of 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 new nasal spray, in the nose, every to 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 Guide and 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 Use and call for emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray. -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 Use and call for emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store OPVEE nasal spray in the blister and cartons provided.Store OPVEE nasal spray at controlled room temperature 15C to 25C (59F to 77F). Short-term excursions permitted between 4C to 40C (39F to 104F). 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLife-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 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 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 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 riskAn opioid overdose is 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 DataReproduction 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 times (rats) and up to 20 times (rabbits) the exposure corresponding to human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis. The treatment in rats did not affect offspring survival.. 8.2 Lactation. Risk SummaryThere 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 drug is present in animal milk, it is likely that the drug will be present in human milk.. DataNalmefene 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.. 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk of Recurrent Respiratory and Central Nervous System Depression: While the duration of action of nalmefene is as long as most opioids, recurrence of respiratory depression is possible, therefore, keep patient under continued surveillance and administer repeat doses of OPVEE using new nasal spray with each dose, as necessary, while awaiting emergency medical assistance (5.1)Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists: Reversal of respiratory depression caused by partial agonists or mixed agonists/antagonists, such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses may be required. (5.2)Precipitation of Severe Opioid Withdrawal: Use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. (5.3)Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had preexisting CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of nalmefene hydrochloride. (5.3)Risk of Opioid Overdose from Attempts to Overcome the Blockade: Attempts to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids may lead to opioid intoxication and death (5.4). Risk of Recurrent Respiratory and Central Nervous System Depression: While the duration of action of nalmefene is as long as most opioids, recurrence of respiratory depression is possible, therefore, keep patient under continued surveillance and administer repeat doses of OPVEE using new nasal spray with each dose, as necessary, while awaiting emergency medical assistance (5.1). Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists: Reversal of respiratory depression caused by partial agonists or mixed agonists/antagonists, such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses may be required. (5.2). Precipitation of Severe Opioid Withdrawal: Use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. (5.3). Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had preexisting CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of nalmefene hydrochloride. (5.3). Risk of Opioid Overdose from Attempts to Overcome the Blockade: Attempts to overcome opioid withdrawal symptoms caused by opioid antagonists with high or repeated doses of exogenous opioids may lead to opioid intoxication and death (5.4). 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, 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. 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 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 gradual onset of the reversal effects and 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., centrally mediated massive catecholamine response leading to 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.