ADVERSE REACTIONS SECTION.

Adverse Reactions. PostoperativeThe following adverse events have been associated with the use of naloxone hydrochloride injection 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 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 DepressionAbrupt 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 DependenceAbrupt 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, and hyperactive reflexes (see WARNINGS).Adverse events associated with the postoperative use of naloxone hydrochloride injection 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, nauseaNervous System Disorders: convulsions, paraesthesia, grand mal convulsionPsychiatric Disorders: agitation, hallucination, tremulousnessRespiratory, Thoracic, and Mediastinal Disorders: dyspnea, respiratory depression, hypoxiaSkin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweatingVascular Disorders: hypertension, hypotension, hot flushes, or flushingSee also PRECAUTIONS and DOSAGE AND ADMINISTRATION: USAGE IN ADULTS, Postoperative Opioid Depression.

CLINICAL PHARMACOLOGY SECTION.

Clinical Pharmacology. Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the agonistic or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone will produce withdrawal symptoms. However, in the presence of opioid dependence, withdrawal symptoms will appear within minutes of naloxone administration and will subside in about hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of dependence.While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor.When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes; the onset of action is slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces more prolonged effect than intravenous administration. Since the duration of action of naloxone may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone dissipate.The requirement for repeat doses of naloxone will also be dependent upon the amount, type and route of administration of the opioid being antagonized.Adjunctive Use in Septic ShockNaloxone has been shown in some cases of septic shock to produce rise in blood pressure that may last up to several hours; however this pressor response has not been demonstrated to improve patient survival. In some studies, treatment with naloxone in the setting of septic shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance.Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established.

DESCRIPTION SECTION.

Description. Naloxone hydrochloride, an opioid antagonist, is 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. It is known chemically as 17-allyl-4,5-epoxy,3-14-dihydroxymorphinan-6-one hydrochloride. It has molecular weight of 363.84, and the following structural formula:Naloxone hydrochloride occurs as white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform.Naloxone hydrochloride injection is available as sterile solution for intravenous, intramuscular, and subcutaneous administration. Each mL contains 0.4 mg of naloxone hydrochloride. Each mL contains 8.9 mg of sodium chloride. The pH is adjusted between 3.0 to 6.5 with hydrochloric acid or sodium hydroxide. The air in the cartridges has been displaced by nitrogen gas.. Formula1.jpg.

DOSAGE & ADMINISTRATION SECTION.

Dosage and Administration. Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration and it 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 InfusionNaloxone hydrochloride injection may be diluted for intravenous infusion in 0.9% sodium chloride or 5% dextrose injection. The addition of mg of naloxone hydrochloride in 500 mL of either solution provides concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patients 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.GeneralParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

HOW SUPPLIED SECTION.

How Supplied. Naloxone hydrochloride injection, USP for intravenous, intramuscular, and subcutaneous administration is available as:Instructions for Use of the Syringe SystemsInstructions for using the Carpuject Syringe are available with the reusable Carpuject Holder, List 2049-02.Protect from light.Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1215-2.0Revised: 4/2019. Image1.jpg.

INDICATIONS & USAGE SECTION.

Indications and 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 the 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).

OVERDOSAGE SECTION.

Overdosage. There is limited clinical experience with naloxone hydrochloride injection overdosage in humans.Adult PatientsIn one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity.In another study, 36 patients with acute stroke received loading dose of mg/kg (10 mg/m2/min) of naloxone hydrochloride injection followed immediately by 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 (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3).At doses of 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 to days.Pediatric PatientsUp 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 2 1/2 year-old child who inadvertently received 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 report of 4 1/2 year-old child who received 11 doses during 12-hour period, with no adverse sequelae.Patient ManagementPatients who experience naloxone overdose should be treated symptomatically in closely supervised environment. Physicians should contact poison control center for the most up-to-date patient management information.

PHARMACOKINETICS SECTION.

Pharmacokinetics. DistributionFollowing parenteral administration, naloxone is rapidly 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.Metabolism and EliminationNaloxone is metabolized in the liver primarily by glucuronide conjugation with naloxone-3-glucuronide as the major metabolite. In one study, the serum half-life in adults ranged from 30 to 81 minutes (mean 64 +- 12 minutes). In neonatal study, the mean plasma half-life was observed to be 3.1 +- 0.5 hours. After an oral or intravenous dose, about 25-40% of the drug is excreted as metabolites in urine within hours, about 50% in 24 hours, and 60-70% in 72 hours.

SPL UNCLASSIFIED SECTION.

USAGE IN ADULTS. Opioid Overdose Known or Suspected. An initial dose of 0.4 mg to 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 patients 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 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).

WARNINGS SECTION.

Warnings. Drug DependenceNaloxone hydrochloride injection should be administered cautiously to persons including newborns of mothers who are known or suspected to be physically dependent on opioids. In such cases, an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome.The signs and symptoms of opioid withdrawal in patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes.Repeat AdministrationThe patient who has satisfactorily responded to naloxone should be kept under continued surveillance and repeated doses of naloxone should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone.Respiratory Depression Due to Other DrugsNaloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.