Naloxone Hydrochloride

Indications and Usage Section Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone hydrochloride injection is also indicated for diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see CLINICAL PHARMACOLOGY; Adjunctive Use in Septic Shock ).

DOSAGE AND ADMINISTRATION Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration, which is recommended in emergency situations. Since the duration of action of some opioids may exceed that of naloxone hydrochloride injection, the patient should be kept under continued surveillance. Repeated doses of naloxone hydrochloride injection should be administered, as necessary. Intravenous Infusion Naloxone hydrochloride injection may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of naloxone hydrochloride injection in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in accordance with the patient’s response. Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the chemical and physical stability of the solution has first been established. General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Usage in Adults Opioid Overdose–Known or Suspected: An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride injection may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions are not obtained, it may be repeated at two- to three-minute intervals. If no response is observed after 10 mg of naloxone hydrochloride injection have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Postoperative Opioid Depression: For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride injection are usually sufficient. The dose of naloxone hydrochloride injection should be titrated according to the patient’s response. For the initial reversal of respiratory depression, naloxone hydrochloride injection should be injected in increments of 0.1 to 0.2 mg intravenously at two- to three-minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone hydrochloride injection may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses of naloxone hydrochloride injection may be required within one- to two-hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride injection or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ). Usage in Pediatric Population Opioid Overdose–Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given intravenously (I.V.). If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an intravenously (I.V.) route of administration is not available, naloxone hydrochloride may be administered intramuscularly (I.M.) or subcutaneously (S.C.) in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection …

CONTRAINDICATIONS Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in the naloxone hydrochloride.

ADVERSE REACTIONS Postoperative The following adverse events have been associated with the use of naloxone hydrochloride in postoperative patients: 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 postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults-Postoperative Opioid Depression ). Opioid Depression Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS ). Opioid Dependence Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but is not limited to, the following signs and symptoms: 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 the neonate, opioid withdrawal may also include: convulsions; excessive crying; hyperactive reflexes (see WARNINGS ). Adverse events associated with the postoperative use of naloxone hydrochloride are listed by organ system and in decreasing order of frequency as follows: Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events. Gastrointestinal Disorders: vomiting, nausea Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion Psychiatric Disorders: agitation, hallucination, tremulousness Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating Vascular Disorders: hypertension, hypotension, hot flushes or flushing. See also PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults; Postoperative Opioid Depression . To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-877-725-2747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Large doses of Naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

USAGE IN ADULTS Opioid Overdose – Known or Suspected. An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions is not obtained, it may be repeated at two to three minute intervals. If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Postoperative Opioid-Induced Depression. For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride are usually sufficient. The dose of naloxone hydrochloride should be titrated according to the patient's response. For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.1 to 0.2 mg intravenously at two to three minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses of naloxone may be required within one to two hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ).

USAGE IN CHILDREN Opioid Overdose – Known or Suspected. The usual initial dose in children is 0.01 mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an intravenous route of administration is not available, naloxone may be administered intramuscularly or subcutaneously in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection. Postoperative Opioid Depression. Follow the recommendations and cautions under Adult Postoperative Opioid Depression. For the initial reversal of respiratory depression naloxone hydrochloride should be injected in increments of 0.005 mg to 0.01 mg intravenously at two to three minute intervals to the desired degree of reversal.

USAGE IN NEONATES Opioid-Induced Depression. The usual initial dose is 0.01 mg/kg body weight administered intravenously, intramuscularly or subcutaneously. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

DESCRIPTION Naloxone Hydrochloride Injection, USP is a sterile, nonpyrogenic solution of naloxone hydrochloride in water for injection. Each milliliter (mL) contains 0.4 mg naloxone hydrochloride and sodium chloride to adjust tonicity in water for injection. May contain hydrochloric acid for pH adjustment; pH 4.0 (3.0 to 6.5). The single-dose solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended for use only as a single-dose injection. When smaller doses are required, the unused portion should be discarded. The multiple-dose solution contains, in addition, 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben added as preservatives. Naloxone Hydrochloride Injection, USP may be administered intravenously, intramuscularly, or subcutaneously. Naloxone, an opioid antagonist, is a synthetic congener of oxymorphone. It differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. Naloxone Hydrochloride, USP is chemically designated 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (C 19 H 21 NO 4 • HCl), a white to slightly off-white powder soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and chloroform. It has a molecular weight of 363.84. It has the following structural formula: structural formula naloxone hydrochloride

OVERDOSAGE There is limited clinical experience with naloxone hydrochloride injection overdosage in humans. Adult Patients In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m 2 /min) of naloxone hydrochloride injection followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (two patients), severe hypertension (one patient), and hypotension and/or bradycardia (three patients). At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2 to 3 days. Pediatric Patients Up to 11 doses of 0.2 mg naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 21⁄2 year-old child who inadvertently received a dose of 20 mg naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae. There is also a report of a 41⁄2 year-old child who received 11 doses during a 12 hour period, with no adverse sequelae. Patient Management Patients who experience a naloxone overdose should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date patient management information.

HOW SUPPLIED Naloxone hydrochloride injection, USP is a sterile, clear colorless solution for intravenous, intramuscular, or subcutaneous administration and is available as: NDC 51662-1544-1 NALOXONE HYDROCHLORIDE INJECTION, USP 0.4mg PER mL 1mL SINGLE-DOSE VIAL NDC 51662-1544-2 NALOXONE HYDROCHLORIDE INJECTION, USP 0.4mg PER mL 1mL SINGLE-DOSE VIAL in 1 Pouch NDC 51662-1544-3 NALOXONE HYDROCHLORIDE INJECTION, USP 0.4mg PER mL 1mL SINGLE-DOSE VIAL in 1 Pouch, 10 Pouches in 1 Case HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Naloxone hydrochloride injection, USP is a sterile, clear colorless solution for intravenous, intramuscular, or subcutaneous administration and is available as: 0.4 mg per mL 1 mL Single-Dose Vials in a Carton of 10 NDC 55150-327-10 1 mL Single-Dose Vials in a Carton of 25 NDC 55150-327-25 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Store in carton until contents have been used. The vial stopper is not made with natural rubber latex. Distributed by: AuroMedics Pharma LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad - 500038 India Revised: July 2019