fentanyl analogues. ( 1 )

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.

e 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.

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) ] .

he 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. 8.2 lactation risk summary naloxone is minimally orally available and is unlikely to affect the breastfed infant. there is no information regarding the presence of naloxone in human milk, or the effects of naloxone on the breastfed infant or on milk production. published studies in lactating women have shown that naloxone does not affect prolactin or oxytocin hormone levels. 8.4 pediatric use the safety and effectiveness of naloxone hydrochloride injection, 10 mg, in an auto-injector have been established in pediatric patients 12 years of age and older for emergency treatment where use of high-potency opioids such as fentanyl analogues as a chemical weapon is suspected. use of naloxone hydrochloride injection in this age group is supported by evidence from adult bioavailability studies, adult pk/pd modeling and simulation analysis supporting an effective dose, along with additional evidence from the reported safe and effective use of other naloxone hcl products [ see clinical pharmacology (12.2) ]. no pediatric studies were conducted for naloxone hydrochloride injection. the safety and effectiveness of naloxone hydrochloride injection for intramuscular and subcutaneous use have not been established for pediatric patients less than 12 years old. absorption of naloxone hcl following subcutaneous or intramuscular administration in pediatric patients may be erratic or delayed. even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hcl injection, the patient must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. in opioid-dependent pediatric patients, administration of naloxone hcl may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. in these settings where it may be preferable to avoid the abrupt precipitation of acute opioid withdrawal symptoms, consider use of an alternative naloxone hcl product that can be dosed according to weight and titrated to effect [see warnings and precautions (5.1) ] . 8.5 geriatric use clinical studies of naloxone hcl 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. 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 can be higher in these patients.

e 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.

ratic or delayed. even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hcl injection, the patient must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. in opioid-dependent pediatric patients, administration of naloxone hcl may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. in these settings where it may be preferable to avoid the abrupt precipitation of acute opioid withdrawal symptoms, consider use of an alternative naloxone hcl product that can be dosed according to weight and titrated to effect [see warnings and precautions (5.1) ] .

l treatment was dependent on the administered opioid, amount of opioid, amount of naloxone, and timing of naloxone hcl administration relative to opioid exposure. 12.3 pharmacokinetics a pharmacokinetic study using a crossover design was conducted in 24 fasted healthy subjects to evaluate a single 2 mg naloxone hydrochloride injection (0.4 ml of 5 mg/ml naloxone hcl solution) and a single 10 mg naloxone hydrochloride injection (0.4 ml of 25 mg/ml naloxone hcl solution) administered to the anterolateral aspect of the thigh. plasma samples were analyzed for naloxone 12-hours post dose. the pharmacokinetic parameters obtained in this study are shown in table 1 and the plasma concentration time profiles of naloxone are presented in figure 1 . a slightly greater than 5-fold increase was observed for 10 mg naloxone hydrochloride injection compared to 2 mg naloxone hydrochloride injection for the mean pharmacokinetic parameters of c max , auc 0-t , and auc 0-inf . table 1 mean pharmacokinetic parameters (%cv) for naloxone following naloxone hydrochloride injection intramuscular/subcutaneous administration to healthy subjects † t max reported as median (minimum, maximum) parameter 2 mg naloxone hydrochloride injection (n=24) 10 mg naloxone hydrochloride injection (n=24) t max (h)† 0.17 (0.08, 0.67) 0.26 (0.09, 0.67) c max (ng/ml) 6.95 (44.8) 42.0 (49.9) auc 0-t (ng.h/ml) 9.22 (14.6) 51.1 (17.9) auc 0-inf (ng.h/ml) 9.25 (14.6) 51.3 (17.8) t 1/2 (h) 1.46 (11.1) 1.46 (14.1) figure 1 mean ± sd plasma concentration of naloxone, (a) 0-8 h and (b) 0-3 h following intramuscular/subcutaneous administration using naloxone hydrochloride injection (a) (b) absorption the median t max for naloxone hydrochloride injection is 15.6 minutes (range 5.4 to 40.2 minutes). 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 the mean plasma half-life of naloxone in healthy adults was 1.46 hours (14.1%cv) following a single administration of naloxone hydrochloride injection. metabolism naloxone hcl 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. figure1a figure1b

dian (minimum, maximum) parameter 2 mg naloxone hydrochloride injection (n=24) 10 mg naloxone hydrochloride injection (n=24) t max (h)† 0.17 (0.08, 0.67) 0.26 (0.09, 0.67) c max (ng/ml) 6.95 (44.8) 42.0 (49.9) auc 0-t (ng.h/ml) 9.22 (14.6) 51.1 (17.9) auc 0-inf (ng.h/ml) 9.25 (14.6) 51.3 (17.8) t 1/2 (h) 1.46 (11.1) 1.46 (14.1) figure 1 mean ± sd plasma concentration of naloxone, (a) 0-8 h and (b) 0-3 h following intramuscular/subcutaneous administration using naloxone hydrochloride injection (a) (b) absorption the median t max for naloxone hydrochloride injection is 15.6 minutes (range 5.4 to 40.2 minutes). 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 the mean plasma half-life of naloxone in healthy adults was 1.46 hours (14.1%cv) following a single administration of naloxone hydrochloride injection. metabolism naloxone hcl 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. figure1a figure1b