ZURNAI

ZURNAI™ (nalmefene injection) is a sterile, pre-filled, single-dose auto-injector designed to deliver a dose of 1.5 mg nalmefene (provided as nalmefene hydrochloride) in 0.5 mL. Nalmefene hydrochloride, 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 water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pKa of 7.63. Each ZURNAI auto-injector delivers 1.5 mg nalmefene (equivalent to 1.7 mg nalmefene hydrochloride) in 0.5 mL solution. The pH range is 3.5 to 4.5. The inactive ingredients in ZURNAI nalmefene injection include: hydrochloric acid to adjust pH; magnesium chloride, 4.7 mg; and water for injection. Chemical Structure

ZURNAI is indicated for the emergency treatment of known or suspected opioid 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. ZURNAI is intended for immediate administration as emergency therapy in settings where opioids may be present. ZURNAI is not a substitute for emergency medical care. ZURNAI is an opioid antagonist indicated for the emergency treatment of known or suspected opioid 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. ( 1 ) ZURNAI is intended for immediate administration as emergency therapy in settings where opioids may be present. ( 1 ) ZURNAI is not a substitute for emergency medical care. ( 1 )

ZURNAI is for intramuscular and subcutaneous use only. ( 2.1 ) Seek emergency medical care immediately after use. ( 2.1 ) Administer ZURNAI to the outer thigh, through clothing if necessary. ( 2.1 ) Administer additional doses of ZURNAI using a new ZURNAI auto-injector for each dose. If the patient does not respond or responds and then relapses into respiratory depression, additional doses of ZURNAI may be given every 2 to 5 minutes until emergency medical assistance arrives. ( 2.2 ) See Full Prescribing Information and Instructions for Use for important information on how to safely administer ZURNAI. ( 2.1 ) Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. ( 2.2 ) 2.1 Important Administration Instructions All approved nalmefene products achieve plasma concentrations that have been shown to be efficacious in reversing the effects of opioid overdose. Comparing different products on a nominal mg-for-mg basis may be misleading. ZURNAI is for intramuscular and subcutaneous use only. The device is ready to use. No device assembly is required. Do not prime or test prior to administration. ZURNAI delivers its entire contents automatically, upon injection. Inject ZURNAI into the anterolateral aspect of the thigh. ZURNAI can be administered through clothing if necessary. Do not reuse ZURNAI. Each ZURNAI device contains a single dose of nalmefene and cannot be reused. 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 ZURNAI and the Instructions for Use . Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for ZURNAI. Emphasize the following instructions to the patient or caregiver: – Administer ZURNAI 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 ZURNAI in the event of a suspected, potentially life-threatening opioid emergency. Keep the patient under continued surveillance until emergency personnel arrive. – Additional doses of ZURNAI may be required until emergency medical assistance becomes available. – If available, re-administer ZURNAI using a new auto-injector, every 2 to 5 minutes if the patient does not respond or responds and then relapses into respiratory depression. – Once the safety seal is broken and blue cap is removed, ZURNAI must be used immediately or disposed of properly. Do not attempt to replace the blue cap once it is removed. – Visually inspect ZURNAI through the viewing window for particulate matter and discoloration prior to administration. Do not administer unless the solution is clear, free of particulates, and the glass container is undamaged. – Administer ZURNAI according to the printed instructions on the device label, carton, and the Instructions for Use. ⮚ Place the needle guard of ZURNAI against the outer thigh. Press the needle end firmly into the injection site until you hear a click and then hold for 3 seconds. After 3 seconds, the viewing window should turn completely orange, signaling that ZURNAI has delivered the intended dose of nalmefene. ⮚ Remove ZURNAI from the outer thigh. ⮚ Call for emergency medical assistance immediately after administration of the first dose of ZURNAI. ⮚ Move the patient on their side (recovery position). Remain with the patient until emergency medical assistance arrives, even if the patient wakes up. 2.2 Dosing in Adults and Pediatric Patients 12 Years and Older Initial Dosing : The recommended dose of ZURNAI in adults and pediatric patients aged 12 years and older is 1.5 mg delivered by intramuscular or subcutaneous injection into the anterolateral aspect of the thigh, through clothing if necessary. Repeat Dosing : Seek emergency medical assistance as soon as possible after administration of the first dose of ZURNAI. The requirement for repeat doses of ZURNAI depends upon the amount, type, and route of administration of the opioid being antagonized. If the patient responds to ZURNAI and subsequently relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of ZURNAI using a new auto-injector and continue surveillance of the patient. If the desired response is not obtained after 2 to 5 minutes, administer an additional dose of ZURNAI using a new auto-injector. If there is still no response and additional doses are available, administer additional doses of ZURNAI every 2 to 5 minutes using a new ZURNAI auto-injector for 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 ZURNAI using a new auto-injector [see Warnings and Precautions (5.2) ] .

ZURNAI is contraindicated in patients known to be hypersensitive to nalmefene hydrochloride or to any other ingredients in the product. Hypersensitivity to nalmefene hydrochloride or to any other ingredients in ZURNAI. ( 4 )

The following serious adverse reactions are described 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 > 5%) are feeling hot, nausea, headache, dizziness, chills, vomiting, allodynia, palpitations, tinnitus, ear discomfort, feeling abnormal, burning sensation, hot flush, and irritability. ( 6 ) To report Suspected Adverse Reactions, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Adult Clinical Trial 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZURNAI is supported by pharmacokinetic and pharmacodynamic studies of ZURNAI in healthy subjects in a normal state and under steady state opioid agonism. The following adverse reactions were observed. In a pharmacokinetic study (NAL1005) of 21 healthy adult volunteers exposed to one dose of ZURNAI the most common adverse reactions were: dizziness and headache. In a pharmacodynamic study (NAL1004) of 23 healthy adult volunteers exposed to one dose of ZURNAI, the most common adverse reactions were: feeling hot, chills, nausea, allodynia, and headache. Table 1: Relative Frequencies of Most Common Adverse Reactions that Occurred in Greater than 5% of Subjects in Study NAL1004 and Study NAL1005 (pooled dataset) Nalmefene Auto-Injector 1.5 mg IM System Organ Class Preferred Term Pooled NAL1004 and NAL1005 N=44 n (%) Study NAL1004 N=23 n (%) Study NAL1005 N=21 n (%) Any AR 28 (63.6) 21 (91.3) 7 (33.3) Cardiac disorders Palpitations 4 (9.1) 4 (17.4) 0 Ear and labyrinth disorders Tinnitus 4 (9.1) 4 (17.4) 0 Ear discomfort 3 (6.8) 3 (13.0) 0 Gastrointestinal disorders Nausea 8 (18.2) 6 (26.1) 2 (9.5) Vomiting 5 (11.4) 3 (13.0) 2 (9.5) General disorders and administration site conditions Feeling hot 11 (25.0) 11 (47.8) 0 Chills 6 (13.6) 6 (26.1) 0 Feeling abnormal 3 (6.8) 3 (13.0) 0 Nervous system disorders Dizziness 7 (15.9) 4 (17.4) 3 (14.3) Headache 8 (18.2) 5 (21.7) 3 (14.3) Allodynia 5 (11.4) 5 (21.7) 0 Burning sensation 3 (6.8) 3 (13.0) 0 Psychiatric disorders Irritability 3 (6.8) 3 (13.0) 0 Vascular disorders Hot flush 3 (6.8) 3 (13.0) 0 Adverse reaction information was obtained following administration of nalmefene hydrochloride injection to 152 healthy volunteers and to 1127 patients in controlled clinical trials 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 N=1127 Placebo 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 hydrochloride 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, and 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 at controlled room temperature 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F). During storage, check ZURNAI through the viewing window of the auto-injector every 30 days. The liquid should be clear, colorless to light yellow. If the ZURNAI liquid is discolored, cloudy, or contains solid particles, replace it with a new ZURNAI. DO NOT FREEZE OR REFRIGERATE. Store in a clean dry place. Protect from light. Keep ZURNAI in the carton until use. Store ZURNAI securely and dispose of properly in a sharps container. For detailed disposal instructions, see the Instructions for Use . KEEP ZURNAI AND ALL MEDICINES OUT OF THE REACH OF CHILDREN. Before using, check to make sure the solution in the auto-injector is not discolored. Replace ZURNAI if the solution is discolored or contains a precipitate. Each ZURNAI can only be used one time and cannot be re-used.