NALOXONE HYDROCHLORIDE

Naloxone hydrochloride, an opioid antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. NALOXONE HYDROCHLORIDE (-)-17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride Naloxone hydrochloride dihydrate occurs as a white to almost white powder, and is freely soluble in water, soluble in ethanol (96%); practically insoluble in toluene. Naloxone hydrochloride injection, USP is available as a sterile solution for intravenous, intramuscular and subcutaneous administration in 1 mg/mL concentration. pH is adjusted to 3.5 ± 0.5 with hydrochloric acid. Each mL also contains 9 mg of sodium chloride. Naloxone hydrochloride injection, USP is preservative-free. STRUCTURE

INDICATIONS & USAGE 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 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).

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, the patient should be kept under continued surveillance. Repeated doses of naloxone 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 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 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 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 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 an 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 intravenous. 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 intramuscular or subcutaneous 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 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 intravenous, intramuscular, or subcutaneous. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

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

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.