REZENOPY

1 INDICATIONS AND USAGE REZENOPY nasal spray is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression in adult and pediatric patients. REZENOPY nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. REZENOPY nasal spray is not a substitute for emergency medical care. REZENOPY nasal spray is an opioid antagonist for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression in adult and pediatric patients. ( 1 ) REZENOPY nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. ( 1 ) REZENOPY nasal spray is not a substitute for emergency medical care. ( 1 )

2 DOSAGE AND ADMINISTRATION REZENOPY nasal spray is for intranasal use only. ( 2.1 ) Seek emergency medical care immediately after use. ( 2.1 ) Administration of a single spray of REZENOPY nasal spray intranasally into one nostril in adult and pediatric patients. ( 2.2 ) If the patient does not respond within 2 to 3 minutes or responds and then relapses into respiratory depression, an additional dose of REZENOPY nasal spray may be given into the other nostril with a new device. ( 2.2 ) Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. ( 2.2 ) 2.1 Important Administration Instructions REZENOPY nasal spray is for intranasal use only. All approved naloxone hydrochloride 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 [see Clinical Pharmacology (12.3) ] . 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 REZENOPY 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 REZENOPY nasal spray. Emphasize the following instructions to the patient or caregiver: Seek medical care immediately after use. Since the duration of action of most opioids exceeds that of naloxone hydrochloride and the suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, keep the patient under continued surveillance until emergency personnel arrive, and administer additional doses of REZENOPY nasal spray, as necessary. Always seek emergency medical assistance in the event of a suspected, potentially life-threatening opioid emergency after administration of the first dose of REZENOPY nasal spray. Additional doses of REZENOPY nasal spray may be required before emergency medical assistance becomes available. Do not attempt to reuse REZENOPY nasal spray. Each REZENOPY nasal spray contains a single dose of naloxone. Re-administer REZENOPY nasal spray, using a new nasal spray, if the patient does not respond within 2 to 3 minutes or responds and then relapses into respiratory depression. Administer REZENOPY nasal spray in alternate nostrils with each dose. Administer REZENOPY nasal spray according to the printed instructions on the device label and the Instructions for Use . Place the patient in the supine position on their back. Prior to administration, be sure the device nozzle is inserted in either nostril of the patient, support the back of the neck and tilt the patient’s head back. Do not prime or test the device prior to administration . To administer the dose firmly press the bottom of the device plunger. Remove the device nozzle from the nostril after use. Turn patient on their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of REZENOPY nasal spray. 2.2 Dosing in Adult and Pediatric Patients Initial Dosing The recommended initial dose of REZENOPY nasal spray in adults and pediatric patients is one spray delivered by intranasal administration. Administer REZENOPY nasal spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Repeat Dosing Seek emergency medical assistance as soon as possible after administering the first dose of REZENOPY nasal spray. The requirement for repeat doses of REZENOPY nasal spray depends upon the amount, type, and route of administration of the opioid being antagonized. Administer REZENOPY nasal spray in alternate nostrils with each dose. If the desired response is not obtained after 2 to 3 minutes, administer a second dose of REZENOPY nasal spray using a new REZENOPY nasal spray device. If there is still no response and additional doses are available, administer additional doses of REZENOPY every 2 to 3 minutes, alternating nostrils and using a new REZENOPY, until emergency medical assistance arrives. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. If the patient responds to REZENOPY nasal spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of REZENOPY nasal spray using a new REZENOPY nasal spray device and continue surveillance of the patient. 2.3 Dosing Modifications due to 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 and require higher doses of naloxone hydrochloride or repeat administration of REZENOPY nasal spray using a new nasal spray device [see Warnings and Precautions (5.2) ].

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

5 WARNINGS AND PRECAUTIONS Risk of Recurrent Respiratory and CNS Depression : Due to the duration of action of naloxone relative to the opioid, keep patient under continued surveillance and administer additional doses of REZENOPY nasal spray, as necessary, using a new nasal spray device while awaiting emergency medical assistance. ( 5.1 ) Risk of Limited Efficacy with Partial Agonists or Mixed Agonists/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 Withdrawa l: 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 pre-existing 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 naloxone hydrochloride. ( 5.3 ) 5.1 Risk of Recurrent Respiratory and Central Nervous System Depression The duration of action of most opioids may exceed that of REZENOPY nasal spray resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of REZENOPY nasal spray and to keep the patient under continued surveillance. Administer additional doses of REZENOPY nasal spray if the patient does not adequately respond or responds and then relapses back into respiratory depression, as necessary [see Dosage and Administration (2.2) ] . Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. 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. Larger or repeat doses of naloxone hydrochloride 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 (2.2) ]. 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 REZENOPY nasal spray 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. 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. Abrupt postoperative reversal of opioid depression after using naloxone hydrochloride 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. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, 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 naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. 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, consider use of an alternative, naloxone containing product that can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Population (8.4) ].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3) ]. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. The following adverse reactions were observed in a REZENOPY nasal spray clinical study. In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of REZENOPY nasal spray, adverse reactions of abdominal pain upper, nasopharyngitis and dysgeusia were observed. The following adverse reactions have been identified primarily during post-approval use of naloxone hydrochloride in the post-operative setting. 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: Hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone hydrochloride in post-operative patients have resulted in significant reversal of analgesia, and have caused agitation. Abrupt reversal of opioid effects in persons who were physically dependent on opioids has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering 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 signs and symptoms also included convulsions, excessive crying, and hyperactive reflexes. The following adverse reactions were observed in a REZENOPY nasal spray clinical study: abdominal pain upper, nasopharyngitis, and dysgeusia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Scienture, LLC at 1-833-754-4917 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

8.1 Pregnancy Risk Summary Life-sustaining therapy for opioid overdose should not be withheld (see Clinical Considerations). Available data from retrospective cohort studies on naloxone use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats administered naloxone hydrochloride during organogenesis at doses equivalent to 2-times and 4-times, respectively, a human dose of 20 mg/day (2 sprays of Rezenopy) (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 Rezenopy for opioid overdose should not be withheld because of potential concerns regarding the effects of Rezenopy on the fetus. Data Animal Data Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 2-times and 4-times, respectively, a human dose of 20 mg (two REZENOPY nasal sprays) based on body surface area comparison. These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.