REXTOVY

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

2 DOSAGE AND ADMINISTRATION REXTOVY Nasal Spray is for intranasal use only. ( 2.1 ) Seek emergency medical care immediately after use. ( 2.1 ) Administer one spray of REXTOVY Nasal Spray to adults or pediatric patients intranasally into one nostril. ( 2.2 ) Administer additional doses of REXTOVY Nasal Spray using a new nasal spray device with each dose if the patient does not respond or responds and then relapses into respiratory depression. Additional doses of REXTOVY Nasal Spray may be given every 2 to 3 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 REXTOVY Nasal Spray is for intranasal use only. The device is ready to use. Do not prime or test prior to administration. Do not attempt to reuse REXTOVY Nasal Spray. Each unit-dose device contains a single dose of naloxone and cannot be reused. Figure 1 REXTOVY Nasal Spray Device 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 REXTOVY Nasal Spray and the Instructions for Use . Instruct the users or caregiver to read the Instructions for Use at the time they receive a prescription for REXTOVY Nasal Spray. Emphasize the following instructions to the patient or caregiver: Administer REXTOVY Nasal Spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Always seek immediate emergency medical assistance after the first dose of REXTOVY Nasal Spray has been administered in the event of a suspected, potentially life-threatening opioid emergency because the duration of action of most opioids exceeds that of naloxone hydrochloride. Keep the patient under continued surveillance and administer repeated doses of REXTOVY Nasal Spray, as necessary, until emergency personnel arrive [see Warnings and Precautions ( 5.1 )] . Administer REXTOVY Nasal Spray according to the printed instructions on the carton and the Instructions for Use . ◦ Place the patient in the supine position. Prior to administration, be sure the device nozzle is inserted in either nostril 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 green plunger of the device and remove the REXTOVY Nasal Spray nozzle from the nostril after use. ◦If the patient responds by waking up to the voice or touch or starts breathing normally, place the person on their side (recovery position) as shown in the Instructions for Use and call for emergency medical assistance immediately after the first dose of REXTOVY Nasal Spray. ◦Administer additional doses of REXTOVY Nasal Spray, using a new REXTOVY Nasal Spray, every 2 to 3 minutes as needed if the patient does not respond or responds and then relapses into respiratory depression. Administer REXTOVY Nasal Spray in alternate nostrils with each dose [see Dosing and Administration ( 2.2 )] . figure1 2.2 Dosing in Adults and Pediatric Patients Initial Dosing The recommended initial dose of REXTOVY Nasal Spray in adults and pediatric patients is one spray delivered by intranasal administration, which delivers 4 mg of naloxone hydrochloride. Repeat Dosing Seek emergency medical assistance as soon as possible after administering the REXTOVY Nasal Spray. The requirement for repeat doses of REXTOVY Nasal Spray depends upon the amount, type, and route of administration of the opioid being antagonized. Administer REXTOVY Nasal Spray in alternate nostrils with each dose. If the patient responds to REXTOVY Nasal Spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of REXTOVY Nasal Spray in opposite nostril using a new REXTOVY Nasal Spray device and continue surveillance of the patient. If the desired response is not obtained after 2 minutes, administer an additional dose of REXTOVY Nasal Spray using a new REXTOVY Nasal Spray device. If there is still no response and additional doses are available, administer additional doses of REXTOVY Nasal Spray every 2 to 3 minutes using a new REXTOVY 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 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 repeated administration of REXTOVY Nasal Spray using a new REXTOVY Nasal Spray [see Warnings and Precautions ( 5.2 )] .

4 CONTRAINDICATIONS REXTOVY Nasal Spray is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients. Hypersensitivity to naloxone hydrochloride or to any of the other ingredients.

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 repeat doses of naloxone using a new nasal spray device with each dose, as necessary, 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 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 REXTOVY Nasal Spray. ( 5.3 ) 5.1 Risk of Recurrent Respiratory and Central Nervous System Depression The duration of action of most opioids may exceed that of REXTOVY 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 REXTOVY Nasal Spray and to keep the patient under continued surveillance. Administer additional doses of REXTOVY Nasal Spray if the patient is not adequately responding 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 ( 2.3 )] . 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 REXTOVY 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. 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 Populations ( 8.4 )] .

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 )] The following adverse reactions were observed in a REXTOVY Nasal Spray clinical study: oral paraesthesia (3.7%), headache (3.7%) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. In two clinical studies, N002-CL-A3 (Study A3) and N002-CL-A4 (Study A4), which comprised a total of 141 study treatments from 60 subjects, including 55 treatments using 4 mg and 10 mg of REXTOVY nasal spray (IN), the following adverse reactions were observed: oral paraesthesia (3.7%), headache (3.7%). The following adverse reactions have been observed with other naloxone products: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, xeroderma, abdominal pain, asthenia, dizziness, nasal discomfort, and presyncope. 6.2 Postmarketing Experience The following adverse events have been identified during the post-approval use of naloxone hydrochloride injection in the postoperative 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 postoperative 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 was 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 [see Warnings and Precautions ( 5.3 )] . The following most frequently reported events (in decreasing frequency) have been identified primarily during postapproval use of naloxone hydrochloride (all routes of administration): withdrawal syndrome, vomiting, nonresponsiveness to stimuli, drug ineffective, agitation, somnolence, and loss of consciousness.

8.1 Pregnancy Risk Summary Life-sustaining therapy for opioid overdose should not be withheld (see Clinical Considerations) . There is an absence of data on naloxone hydrochloride administered for known or suspected opioid overdose in pregnant patients. Available data from retrospective cohort studies on oral naloxone use in pregnant women for opioid use disorder 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 treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 6-times and 12-times, respectively, a human dose of 8 mg/day (two REXTOVY Nasal Sprays) based on body surface area comparison ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 REXTOVY Nasal Spray for opioid overdose should not be withheld because of potential concerns regarding the effects of REXTOVY Nasal Spray on the fetus. Data Animal Data Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 6-times and 12-times, respectively, a human dose of 8 mg (two REXTOVY Nasal Sprays) based on body surface area comparison. These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.