Naloxone Hydrochloride Injection, USP, Auto-Injector

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) ] .