OPVEE

OPVEE (nalmefene) nasal spray is a pre-filled, unit-dose intranasal spray. Nalmefene, an opioid antagonist, is a 6-methylene analogue of naltrexone. The molecular structure of nalmefene is presented below: Molecular Formula: C 21 H 25 NO 3 ∙HCl Molecular Weight: 375.9, CAS # 58895-64-0 Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt. Nalmefene is a white to off-white crystalline powder which is freely soluble in methanol and water, with a pK of 7.63. Each OPVEE nasal spray unit delivers 2.7 mg nalmefene (equivalent to 3mg nalmefene hydrochloride) in 0.1 mL solution. Inactive ingredients include benzalkonium chloride, disodium ethylenediaminetetraacetate, dodecylmaltoside, sodium chloride, and purified water. The pH range is 4.1 to 4.9. Chemical Structure

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.

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 available, administer additional doses of OPVEE nasal spray every 2 to 5 minutes using a new OPVEE nasal spray device with each dose until emergency medical assistance arrives. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. 2.3 Dosing Modifications due to Partial Agonists or Mixed Agonists/Antagonists Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require repeated administration of OPVEE nasal spray using a new nasal spray device [see Warnings and Precautions (5.2) ] .

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 )

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 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 Reaction Nalmefene Placebo N=1127 N=77 Nausea 18% 6% Vomiting 9% 4% Tachycardia 5% - Hypertension 5% - Postoperative Pain 4% N/A Fever 3% - Dizziness 3% 1% Headache 1% 4% Chills 1% - Hypotension 1% - Vasodilatation 1% - Incidence less than 1% Cardiovascular : Bradycardia, arrhythmia Digestive : Diarrhea, dry mouth Nervous System : Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus Respiratory : Pharyngitis Skin : Pruritus Urogenital : Urinary retention The incidence of adverse events was highest in patients who received more than the recommended dose of nalmefene injection. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of nalmefene. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abrupt reversal of opioid depression using nalmefene in both postoperative and emergency department settings has resulted in nausea, vomiting, sweating, tremulousness, seizures, and cardiovascular instability including tachycardia, hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. In persons who were physically dependent on opioids, abrupt reversal of opioid effects has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shiver or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes.

16.2 Storage and Handling Store OPVEE nasal spray in the blister and cartons provided. Store OPVEE nasal spray at controlled room temperature 15°C to 25°C (59°F to 77°F). Short-term excursions permitted between 4°C to 40°C (39°F to 104°F). Do not freeze. Protect from light. Do not open individual blister packs or test nasal spray devices before use. Each unit-dose nasal spray device sprays one (1) time and cannot be re-used.