2.1 Important Administration Instructions

Naloxone HCl Nasal Spray is for intranasal use only.

No additional device assembly is required.

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 Naloxone HCl 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 Naloxone HCl Nasal Spray. Emphasize the following instructions to the patient or caregiver:

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Administer Naloxone HCl Nasal Spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. 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 repeated doses of Naloxone HCl 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 Naloxone HCl Nasal Spray.

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Additional doses of Naloxone HCl Nasal Spray may be required until emergency medical assistance becomes available.

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Do not attempt to reuse Naloxone HCl Nasal Spray. Each Naloxone HCl Nasal Spray contains a single dose of naloxone and cannot be reused.

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Re-administer Naloxone HCl Nasal Spray, using a new nasal spray, every 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression.

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Administer Naloxone HCl Nasal Spray in alternate nostrils with each dose.

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Administer Naloxone HCl 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. 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.

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To administer the dose press firmly on 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 Naloxone HCl Nasal Spray.

2.2 Dosing in Adults and Pediatric Patients

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 Naloxone HCl Nasal Spray using a new nasal spray [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 Naloxone HCl 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 Naloxone HCl Nasal Spray and to keep the patient under continued surveillance. Administer additional doses of Naloxone HCl 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 Naloxone HCl 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.

There are limited data to inform if the 2 mg dose of Naloxone HCl Nasal Spray will avoid precipitation of severe opioid withdrawal in the setting of opioid dependence. However, the 2 mg dose may not provide an adequate and timely reversal in persons who may be exposed to an overdose of a potent or very high dose of opioids.

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 Populations (8.4)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Naloxone HCl Nasal Spray have been established in pediatric patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression. Use of naloxone hydrochloride in all 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 Naloxone HCl 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 Naloxone HCl 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 in one nostril, consisting of a 2 mg total dose (0.1 mL of 20 mg/mL naloxone hydrochloride solution) and a 4 mg total dose (0.1 mL of 40 mg/mL naloxone hydrochloride solution), and two nasal sprays administered as one nasal spray in each nostril, consisting of a 4 mg total dose (0.1 mL of 20 mg/mL naloxone hydrochloride solution in each nostril) and an 8 mg total dose (0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril), were compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular 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. The pharmacokinetic parameters obtained in the study are shown in Table 1.

Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection

(a) Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection

(b) Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection

The median naloxone tmax after intranasal administration of Naloxone HCl Nasal Spray (one nasal spray in one nostril (2 mg or 4 mg) or two nasal sprays as one spray in each nostril (4 mg or 8 mg) was not significantly different compared to the 0.4 mg dose of naloxone hydrochloride intramuscular injection (Table 1).

The dose normalized relative bioavailability of one dose (2 mg or 4 mg) or two doses (4 mg or 8 mg) of Naloxone HCl Nasal Spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by intramuscular injection was 52%, 44%, 54%, and 43%, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

Naloxone HCl Nasal Spray 4 mg is supplied as Carton containing two (2) blister packages (NDC 0781-7176-12) each with a single spray device.

Naloxone HCl Nasal Spray is not made with natural rubber latex.

16.2 Storage and Handling

Store Naloxone HCl Nasal Spray in the blister and cartons provided.

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

Naloxone HCl Nasal Spray freezes at temperatures below 5°F (-15°C). If this happens, the device will not spray. If Naloxone HCl Nasal Spray is frozen and is needed in an emergency, do NOT wait for Naloxone HCl Nasal Spray to thaw. Get emergency medical help right away. However, Naloxone HCl Nasal Spray 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.

Recognition of Opioid Overdose

Inform patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose such as the following:

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Extreme somnolence - inability to awaken a patient verbally or upon a firm sternal rub.

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Respiratory depression - this can range from slow or shallow respiration to no respiration in a patient who is unarousable.

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Other signs and symptoms that may accompany somnolence and respiratory depression include the following:

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Miosis.

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Bradycardia and/or hypotension.

Risk of Recurrent Respiratory and Central Nervous System Depression

Instruct patients and their family members or caregivers that, since the duration of action of most opioids may exceed that of Naloxone HCl Nasal Spray, they must seek immediate emergency medical assistance after the first dose of Naloxone HCl Nasal Spray and keep the patient under continued surveillance [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of Naloxone HCl Nasal Spray, using a new nasal spray each time [see Dosage and Administration (2.3), Warnings and Precautions (5.2)].

Precipitation of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that the use of Naloxone HCl Nasal Spray in patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and Precautions (5.3), Adverse Reactions (6)].

Administration Instructions

Instruct patients and their family members or caregivers to:

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Ensure Naloxone HCl Nasal Spray is present whenever persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies).

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Administer Naloxone HCl Nasal Spray as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. Naloxone HCl Nasal Spray is not a substitute for emergency medical care [see Dosage and Administration (2.1)].

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Lay the patient on their back and administer Naloxone HCl Nasal Spray into one nostril while providing support to the back of the neck to allow the head to tilt back [see Dosage and Administration (2.1)].

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Use each nasal spray only one time [see Dosage and Administration (2.1)].

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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 Naloxone HCl Nasal Spray. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.1)].

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Monitor patients and re-administer Naloxone HCl Nasal Spray using a new Naloxone HCl Nasal Spray every 2 to 3 minutes, if the patient is not responding or responds and then relapses back into respiratory depression. Administer Naloxone HCl Nasal Spray in alternate nostrils with each dose [see Dosage and Administration (2.1)].

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Replace Naloxone HCl Nasal Spray before its expiration date.