REXTOVY

Naloxone hydrochloride is an opioid antagonist. It is chemically identified as 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. Its molecular formula is C 19 H 21 NO 4 • HCl • 2H 2 O and has a molecular weight of 399.87 g/mol. It has the following structural formula: Naloxone hydrochloride dihydrate occurs as a white to slightly off-white powder. It is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform. REXTOVY Nasal Spray is a prefilled unit-dose intranasal spray. Naloxone hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each REXTOVY device delivers a single spray containing 4 mg of naloxone hydrochloride (equivalent to 3.6 mg of naloxone) in 0.25 mL of aqueous solution with a pH of 3.5 to 5.0. Inactive ingredients include sodium chloride, sodium hydroxide to adjust pH, and water for injection USP. structure

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 )

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 )] .

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.

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.

16.2 Storage and Handling Store REXTOVY Nasal Spray in the blister and cartons provided. Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 4°C to 40°C (39°F to 104°F). Do not freeze. Protect from light. Naloxone Hydrochloride freezes at temperatures below -15°C (5°F). If this happens, the device will not spray. If Naloxone Hydrochloride is frozen and is needed in an emergency, do NOT wait for Naloxone Hydrochloride to thaw. Get emergency medical help right away. However, Naloxone Hydrochloride may be thawed by allowing it to sit at room temperature for 15 minutes, and it may still be used if it has been thawed after being previously frozen.