OPVEE

1 INDICATIONS AND USAGE OPVEE nasal spray is indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression. OPVEE nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. OPVEE nasal spray is not a substitute for emergency medical care. 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 a substitute for emergency medical care.

2 DOSAGE AND ADMINISTRATION OPVEE nasal spray is for intranasal use only ( 2.1 ) Seek emergency care immediately after use ( 2.1 ) Administer a single spray of OPVEE nasal spray intranasally into nose. ( 2.2 ) Administer additional doses of OPVEE nasal spray, using a 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 2 to 5 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 a single dose of nalmefene and cannot be reused. No device assembly is required. Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of OPVEE nasal spray and the Instructions for Use . Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for OPVEE nasal spray. Emphasize the following instructions to the patient or caregiver: Administer OPVEE nasal spray as quickly as 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 a suspected, potentially life-threatening opioid emergency. Keep the patient under continued surveillance until emergency personnel arrive. Additional doses of OPVEE nasal spray may be required until emergency medical assistance becomes available. Re-administer OPVEE nasal spray, using a new nasal spray, in the nose, every 2 to 5 minutes if the patient does not respond or responds and then relapses into respiratory depression. Administer OPVEE nasal spray according to the printed instructions on the Quick Start 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. 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 a new OPVEE nasal spray and continue surveillance of the patient. If the desired response is not obtained after 2 to 5 minutes, administer an additional dose of OPVEE using a new OPVEE nasal spray device. If there is still no response and additional doses are a…

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, a recurrence of respiratory depression is possible, therefore, keep patient under continued surveillance and administer repeat doses of OPVEE using a 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, a recurrence of respiratory depression is possible, even after an apparently adequate initial response to OPVEE nasal spray treatment [See Clinical Pharmacology, Pharmacodynamics (12.3) ] . Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of OPVEE nasal spray and to keep the patient under continued surveillance. A second dose may be necessary if there is recurrence of symptoms of opioid overdose. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.2) ]. 5.2 Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Repeat doses of OPVEE nasal spray may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [see Dosage and Administration (2.3) ] . Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. 5.3 Precipitation of Severe Opioid Withdrawal The use of OPVEE in patients who are opioid dependent may precipitate opioid withdrawal characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. Abrupt postoperative reversal of opioid depression after using OPVEE may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiova…

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 )

8.1 Pregnancy Risk Summary Life-sustaining therapy for opioid overdose should not be withheld (see Clinical Considerations ). There are no available data on nalmefene use in pregnant women to evaluate for a drug-associated risk of major birth defects or miscarriage. In animal reproduction studies, no embryotoxic effects on embryo-fetal development were observed in rats and rabbits treated with nalmefene at exposures at least 6 times (rats) and up to 20 times (rabbits) the exposure at two human nasal doses of 5.4 mg (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk An opioid overdose is a medical emergency and can be fatal for the pregnant woman and fetus if left untreated. Treatment with OPVEE for opioid overdose should not be withheld because of potential concerns regarding the effects of OPVEE on the fetus. Data Animal Data Reproduction studies have been performed in rats (up to 1200 mg/m 2 /day) and rabbits (up to 2400 mg/m 2 /day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m 2 /day. No effects on embryo-fetal development were observed at exposures at least 6 times (rats) and up to 20 times (rabbits) the exposure corresponding to a human dose of 5.4 mg (two nalmefene nasal sprays) on an AUC basis. The treatment in rats did not affect offspring survival.

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) ] 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in clinical trials of another drug and may not reflect the rates observed in practice. The safety of OPVEE nasal spray is supported by safety and pharmacokinetic studies of OPVEE nasal spray in healthy subjects in a normal state and under steady state opioid agonism. The following adverse reactions were observed. In a pharmacokinetic study of 66 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril the most common adverse reactions were: nasal discomfort and dizziness. In a second pharmacokinetic study of 24 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril, two sprays of OPVEE nasal spray in one nostril or one spray of OPVEE nasal spray in each nostril, the most common adverse reactions were: rhinalgia, nasal congestion, nasal discomfort and nausea. In a pharmacodynamic study of 61 healthy adult volunteers exposed to one spray of OPVEE nasal spray in one nostril, the most common adverse reactions were: headache, nausea, hot flush and dizziness. Table 1: Relative Frequencies of Treatment-Related Common Adverse Events That Occurred in Greater Than 1% of Healthy Adult Volunteers Nalmefene 2.7 mg Nalmefene 5.4 mg System Organ Class Preferred Term Total 2.7 mg N=150 n (%) PD Study N=61 n (%) PK Studies N=89 n (%) PK Study (1 spray in each nostril) N=23 n (%) PK Study (2 sprays in one nostril) N=24 n (%) PK Studies OPNT003-PK-001 + OPNT003-PK-002 and PD Study OPNT003-OOD-001 Respiratory, thoracic and mediastinal disorders Nasal discomfort 43 (28.7%) 5 (8.2%) 38 (42.7%) 3 (13.0%) 3 (12.5%) Nasal congestion 6 (4.0%) 2 (3.3%) 4 (4.5%) 1 (4.3%) 4 (16.7%) Throat irritation 6 (4.0%) 3 (4.9%) 3 (3.4%) 0 0 Rhinalgia 4 (2.7%) 1 (1.6%) 3 (3.4%) 2 (8.7%) 6 (25.0%) Dyspnea 2 (1.3%) 2 (3.3%) 0 0 0 Oropharyngeal pain 2 (1.3%) 2 (3.3%) 0 1 (4.3%) 1 (4.2%) Nervous system disorders Headache 40 (26.7%) 34 (55.7%) 6 (6.7%) 1 (4.3%) 0 Dizziness 14 (9.3%) 9 (14.8%) 5 (5.6%) 0 1 (4.2%) Dysgeusia 3 (2.0%) 2 (3.3%) 1 (1.1%) 0 0 Paresthesia 2 (1.3%) 2 (3.3%) 0 1 (4.3%) 1 (4.2%) Presyncope 0 0 0 1 (4.3%) 0 Gastrointestinal disorders Nausea 25 (16.7%) 22 (36.1%) 3 (3.4%) 5 (21.7%) 1 (4.2%) Vomiting 9 (6.0%) 7 (11.5%) 2 (2.2%) 1 (4.3%) 0 Abdominal pain 2 (1.3%) 1 (1.6%) 1 (1.1%) 0 0 Dry mouth 1 (0.7%) 1 (1.6%) 0 1 (4.3%) 0 Constipation 0 0 0 0 1 (4.2%) Vascular disorders Hot flush 12 (8.0%) 12 (19.7%) 0 0 0 Psychiatric disorders Anxiety 7 (4.7%) 7 (11.5%) 0 0 0 Agitation 2 (1.3%) 2 (3.3%) 0 0 0 Claustrophobia 2 (1.3%) 2 (3.3%) 0 0 0 Insomnia 1 (0.7%) 0 1 (1.1%) 1 (4.3%) 0 General disorders and administration site conditions Fatigue 6 (4.0%) 3 (4.9%) 3 (3.4%) 0 0 Chills 2 (1.3%) 2 (3.3%) 0 0 0 Chest discomfort 0 0 0 1 (4.3%) 0 Skin and subcutaneous tissue disorders Erythema 3 (2.0%) 0 3 (3.4%) 1 (4.3%) 1 (4.2%) Hyperhidrosis 3 (2.0%) 3 (6.6%) 0 0 1 (4.2%) Urticaria 0 0 0 0 1 (4.2%) Metabolism and nutrition disorders Decreased appetite 3 (2.0%) 2 (3.3%) 1 (1.1%) 0 0 Infections and infestations Rhinitis 1 (0.7%) 0 1 (1.1%) 1 (4.3%) 0 Eye disorders Dry eye 0 0 0 1 (4.3%) 0 Cardiac disorders Tachycardia 0 0 0 1 (4.3%) 0 Adverse reaction information…