Naloxone Hydrochloride Injection, USP, Auto-Injector

1 INDICATIONS AND USAGE NALOXONE HYDROCHLORIDE injection is indicated for use by military personnel and chemical incident responders for: Emergency treatment of patients 12 years of age and older where use of high-potency opioids such as fentanyl analogues as a chemical weapon is suspected. Temporary prophylaxis of respiratory and/or central nervous system depression in military personnel and chemical incident responders entering an area contaminated with high-potency opioids such as fentanyl analogues. NALOXONE HYDROCHLORIDE injection is an opioid antagonist indicated for use by military personnel and chemical incident responders for: Emergency treatment of patients 12 years of age and older where use of high-potency opioids such as fentanyl analogues as a chemical weapon is suspected. ( 1 ) Temporary prophylaxis of respiratory and/or central nervous system depression in military personnel and chemical incident responders entering an area contaminated with high-potency opioids such as fentanyl analogues. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer NALOXONE HYDROCHLORIDE injection according to the INSTRUCTIONS FOR USE. ( 2.1 ) Administer as soon as possible after known or suspected opioid exposure and seek emergency medical assistance immediately after the first dose. ( 2.1 ) Administer into the anterolateral aspect of the thigh, through clothing if necessary. ( 2.2 ) If the patient relapses into respiratory or central nervous system depression after the first dose, administer additional naloxone HCl, as necessary, until emergency medical assistance becomes available. ( 2.2 ) Keep the patient under continued surveillance until medical care is available. ( 2.2 ) 2.1 Important Administration Instructions Read the Instructions for Use at the time of receiving a single-dose, pre-filled NALOXONE HYDROCHLORIDE injection auto-injector. Administer NALOXONE HYDROCHLORIDE injection as soon as possible after known or suspected opioid exposure because prolonged respiratory depression may result in damage to the central nervous system or death. NALOXONE HYDROCHLORIDE injection contains 10 mg/0.4 mL naloxone HCl in a single-dose, pre-filled auto-injector for intramuscular or subcutaneous use only. Do not attempt to reuse the NALOXONE HYDROCHLORIDE injection auto-injector. Periodically visually inspect NALOXONE HYDROCHLORIDE injection through the viewing window for particulate matter. Request a replacement if the solution is cloudy or contains particles, or if the glass container is damaged. Once the red safety guard is removed, NALOXONE HYDROCHLORIDE injection auto-injector must be used immediately or disposed of properly. Do not attempt to replace the red safety guard once it is removed. 2.2 Dosing in Adults and Pediatric Patients at Least 12 Years Old Inject NALOXONE HYDROCHLORIDE injection into the anterolateral aspect of the thigh according to the Instructions for Use and the printed instructions on the device label. In summary, Ensure that the injection site is free of other materials (e.g., equipment or other obstructions), except for clothing. Pull the auto-injector from the outer case. When ready to use, firmly pull off the red safety guard. Do not touch the black base of the auto-injector, which is where the needle comes out. Place the black end of the auto-injector against the anterolateral aspect of the thigh, through clothing, if needed. Press firmly until you hear a click and hiss sound and then hold in place for 5 seconds. Upon actuation, the auto-injector automatically inserts the needle intramuscularly or subcutaneously, delivers the naloxone HCl injection, and retracts the needle into the device. The needle will not be visible before, during, or after the injection. Post-injection, the black base locks in place and a red indicator appears in the drug viewing window. NALOXONE HYDROCHLORIDE injection can be injected through clothing or MOPP4 PPE. NALOXONE HYDROCHLORIDE injection can be self- or buddy-administered. Emergency treatment of patients 12 years of age and older where use of high-potency opioids such as fentanyl analogues as a chemical weapon is suspected. Seek immediate emergency medical assistance immediately after administration of the first dose of NALOXONE HYDROCHLORIDE injection. Keep the patient under continued surveillance until medical care is available. If the patient relapses into respiratory and/or central nervous system depression after the first dose of NALOXONE HYDROCHLORIDE injection, administer additional naloxone HCl, as necessary, until emergency medical assistance becomes available. If the patient does not show some improvement after administering the dose of NALOXONE HYDROCHLORIDE injection, consider if the respiratory depression is due to a non-opioid etiology. Temporary prophylaxis of respiratory and/or central nervous system depression in military personnel and chemical incident responders entering an area contaminated with high-potency opioids such as fentanyl analogues. Administer immediately prior to entering an area believed to be contaminated with high-potency opioids. Each pre-filled NALOXONE HYDROCHLORIDE injection can only be used one time. NALOXONE HYDROCHLORIDE injection provides temporary protection. If exposure to high potency opioids is prolonged, additional doses may be necessary.

4 CONTRAINDICATIONS NALOXONE HYDROCHLORIDE injection is contraindicated in individuals known to be hypersensitive to naloxone HCl or to any of the other ingredients. Hypersensitivity to naloxone hydrochloride or to any of the other ingredients in NALOXONE HYDROCHLORIDE injection. ( 4 )

5 WARNINGS AND PRECAUTIONS Precipitation of Severe Opioid Withdrawal: Use in patients who are opioid dependent may cause abrupt opioid withdrawal. Monitor for the development of opioid withdrawal. Use of a product that delivers a dose lower than 10 mg of naloxone HCl may be preferable in treatment of a patient with known opioid dependence. ( 5.1 ) Risk of Recurrent Respiratory and Central Nervous System Depression: Due to the duration of action of naloxone HCl relative to the opioid, keep the patient under continued surveillance and administer additional naloxone HCl, as necessary, while awaiting emergency medical assistance. ( 5.2 ) 5.1 Precipitation of Severe Opioid Withdrawal The safety of NALOXONE HYDROCHLORIDE injection, 10 mg, in an auto-injector has not been established in opioid-dependent adults. Because NALOXONE HYDROCHLORIDE injection is expected to cause abrupt opioid withdrawal in opioid-dependent individuals, use NALOXONE HYDROCHLORIDE injection when the potential benefits are expected to outweigh the risks. Use of a product that delivers a dose lower than 10 mg naloxone HCl may be preferable in treatment of a patient with known opioid dependence. Abrupt reversal of opioid depression after using naloxone HCl 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. Although a direct cause and effect relationship has not been established, after use of naloxone HCl, monitor individuals with opioid-dependence 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 HCl 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. 5.2 Risk of Recurrent Respiratory and Central Nervous System Depression The duration of action of most opioids may exceed that of naloxone HCl 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 delivering the first dose of NALOXONE HYDROCHLORIDE injection. Keep the patient under continued surveillance and administer additional naloxone HCl as necessary [ see Dosage and Administration (2.2) ]. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.1) ] Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions (5.2) ] The following adverse reactions were observed in more than one subject in clinical studies evaluating NALOXONE HYDROCHLORIDE injection: dizziness, feeling hot, headache, and injection site erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact kaleo, Inc. at 1-877-341-5330 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 three pharmacokinetic studies with a total of 78 healthy adult subjects exposed to NALOXONE HYDROCHLORIDE injection 0.4 mg auto-injector, two NALOXONE HYDROCHLORIDE injection 0.4 mg (0.8 mg naloxone HCl total) auto-injectors, NALOXONE HYDROCHLORIDE injection 2 mg auto-injector, or NALOXONE HYDROCHLORIDE injection 10 mg auto-injector, adverse reactions occurring in more than one subject were dizziness, feeling hot, headache, and injection site erythema. 6.2 Postmarketing Experience The following adverse reactions have been identified during the use of naloxone HCl to reverse the effects of opioids. 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: aggression, anger, anxiety, back pain, bradycardia, cardiac arrest, confusion, depression, disorientation, dyspnea, hypertension, hypotension, loss of consciousness, malaise, miosis, pain, pulmonary edema, somnolence, unresponsiveness to stimuli, and ventricular tachycardia and fibrillation. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone HCl have resulted in significant reversal of analgesia and have caused agitation [see Warnings and Precautions (5.1) ] .

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 HCl 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 HCl during the period of organogenesis at doses equivalent to 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg naloxone HCl [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 NALOXONE HYDROCHLORIDE injection for opioid overdose should not be withheld because of potential concerns regarding the effects of NALOXONE HYDROCHLORIDE injection on the fetus. Data Animal Data Naloxone HCl was administered during organogenesis to mice and rats at doses 4-times and 8-times, respectively, the dose of 10 mg/day given to a 50 kg human (when based on body surface area or mg/m 2 ). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone HCl.