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:

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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.

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Additional doses of REZENOPY nasal spray may be required before emergency medical assistance becomes available.

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Do not attempt to reuse REZENOPY nasal spray. Each REZENOPY nasal spray contains a single dose of naloxone.

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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.

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Administer REZENOPY nasal spray in alternate nostrils with each dose.

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Administer REZENOPY nasal spray according to the printed instructions on the device label and the Instructions for Use.

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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.

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To administer the dose firmly press the bottom of the device plunger.

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Remove the device nozzle from the nostril after use.

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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)].

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)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of REZENOPY for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression have been established in pediatric patients Use of naloxone hydrochloride in pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of other naloxone hydrochloride drug products. No pediatric studies were conducted for REZENOPY nasal spray.

Absorption of naloxone hydrochloride following intranasal administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours, as a relapse may occur as naloxone hydrochloride is metabolized.

In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized, and should be treated according to protocols developed by neonatology experts [see Warnings and Precautions (5.3)].

In settings such as in neonates with known or suspected exposure to maternal opioid use, where it may be preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider use of an alternate naloxone-containing product that can be dosed according to weight and titrated to effect.

Also, in situations where the primary concern is for infants at risk for opioid overdose, consider whether the availability of alternate naloxone-containing products may be better suited than REZENOPY nasal spray.

8.5 Geriatric Use

Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone hydrochloride can be higher in these patients.

Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

12.1 Mechanism of Action

Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.

Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2 Pharmacodynamics

When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.

12.3 Pharmacokinetics

In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one nasal spray of a 10 mg total dose (0.11 mL of 91 mg/mL naloxone hydrochloride solution) was compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular injection and a single dose of 2 mg naloxone hydrochloride intravenous injection. For intranasal administration, the subjects were instructed not to breathe through the nose during administration of the nasal spray and remained fully supine for approximately one-hour post-dose. For intramuscular administration, naloxone was administered as a single injection in the gluteus maximus muscle. For intravenous administration, naloxone was administered as an intravenous bolus. The pharmacokinetic parameters obtained in the study are shown in Table 1.

Figure 1 Mean ± SD Plasma Concentration of Naloxone 0-30 minutes Following Intranasal, Intramuscular and Intravenous Administration.

Figure 2 Mean ± SD Plasma Concentration of Naloxone 0-8 hours Following Intranasal, Intramuscular and Intravenous Administration.

Absorption

REZENOPY nasal spray showed median Tmax 0.75 hour. The median Tmax for the 0.4 mg naloxone hydrochloride intramuscular injection was 0.5 hour. The dose normalized absolute bioavailability of one dose (10 mg) of REZENOPY nasal spray and 0.4 mg of naloxone HCl intramuscular injection compared to 2 mg of naloxone HCl intravenous injection was 34% and 84% respectively.

Distribution

Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.

Elimination

Following a single intranasal administration of REZENOPY nasal spray (10 mg dose of naloxone hydrochloride), the mean plasma half-life of naloxone in healthy adults was approximately 1.33 hours (16.09% CV) hours. Following the administrations of a 0.4 mg naloxone hydrochloride intramuscular injection and a 2 mg naloxone hydrochloride intravenous injection, the half-life was 1.22 hours (18.48% CV) and 1.18 hours (11.59% CV), respectively. In a neonatal study of naloxone hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.

Metabolism

Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite.

Excretion

After an oral or intravenous dose, about 25-40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.

Mutagenesis

Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study.

Impairment of Fertility

Reproductive studies conducted in mice and rats at doses 2-times and 4-times, respectively, a human dose of 20 mg/day (from two nasal sprays of REZENOPY) based on body surface area comparison, demonstrated no adverse effects on fertility of naloxone hydrochloride.

16.1 How Supplied

REZENOPY nasal spray 10 mg is supplied as a carton containing two (2) blister packages (NDC 43674-004-02) each with a single spray device.

REZENOPY nasal spray is not made with natural rubber latex.

16.2 Storage and Handling

Store REZENOPY nasal spray in the blister and cartons provided.

Store between 2°C to 25°C (36°F to 77°F). Excursions permitted up to 40°C (104°F). Do not freeze or expose to excessive heat above 40°C (104°F). Protect from light.

REZENOPY nasal spray may freeze at cold temperatures. If this happens, the device will not spray. If REZENOPY nasal spray is frozen and is needed in an emergency, do NOT wait for REZENOPY nasal spray to thaw. Get emergency medical help right away.