Naloxone Hydrochloride

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

2 DOSAGE AND ADMINISTRATION Naloxone hydrochloride nasal spray is for intranasal use only. ( 2.1 ) Seek emergency medical care immediately after use. ( 2.1 ) Administration of a single spray of naloxone hydrochloride nasal spray intranasally into one nostril. ( 2.2 ) Administer additional doses of naloxone hydrochloride nasal spray, using a new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses of naloxone hydrochloride 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 Naloxone hydrochloride 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 hydrochloride 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 hydrochloride nasal spray. Emphasize the following instructions to the patient or caregiver: Administer naloxone hydrochloride 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 hydrochloride 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 hydrochloride nasal spray. Additional doses of naloxone hydrochloride nasal spray may be required until emergency medical assistance becomes available. Do not attempt to reuse naloxone hydrochloride nasal spray. Each naloxone hydrochloride nasal spray contains a single dose of naloxone and cannot be reused. Re-administer naloxone hydrochloride 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. Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose. Administer naloxone hydrochloride nasal spray according to the printed instructions on the device label 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 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 naloxone hydrochloride nasal spray. 2.2 Dosing in Adults and Pediatric Patients Initial Dosing The recommended initial dose of naloxone hydrochloride nasal spray in adults and pediatric patients is one spray delivered by intranasal administration into one nostril. Repeat Dosing Seek emergency medical assistance as soon as possible after administering the first dose of naloxone hydrochloride nasal spray. The requirement for repeat doses of naloxone hydrochloride nasal spray depends upon the amount, type, and route of administration of the opioid being antagonized. Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose. If the patient responds to naloxo…

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 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 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 naloxone hydrochloride 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 hydrochloride nasal spray and to keep the patient under continued surveillance. Administer additional doses of naloxone hydrochloride 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 hydrochloride 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 simila…

4 CONTRAINDICATIONS Naloxone hydrochloride 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 )

8.1 Pregnancy Risk Summary The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations] . 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 naloxone hydrochloride 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 Fetal/Neonatal adverse reactions Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother [see Warnings and Precautions ( 5.3 )] . The fetus should be evaluated for signs of distress after naloxone hydrochloride nasal spray is used. Careful monitoring is needed until the fetus and mother are stabilized. Data Animal Data Naloxone hydrochloride was administered during organogenesis to mice and rats at subcutaneous doses up to 10 mg/kg/day (equivalent to 6-times and 12-times, respectively, a human dose of 8 mg (two naloxone hydrochloride nasal sprays) (based on body surface area comparison). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Pregnant female rats were administered 2 or 10 mg/kg naloxone subcutaneously from Gestation Day 15 to Postnatal day 21. There were no adverse effects on the offspring (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison).

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 naloxone hydrochloride nasal spray clinical study. In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of naloxone hydrochloride nasal spray in one nostril or two sprays of naloxone hydrochloride nasal spray, one in each nostril, the most common adverse reactions were: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma. 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 naloxone hydrochloride nasal spray clinical study: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.