NALOXONE HYDROCHLORIDE- naloxone hydrochloride_injection, solution

PHARMACOKINETICS
Following 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. Naloxone 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 a neonatal study, the mean plasma half-life was observed to be 3. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.
Distribution
Following 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 Elimination
Naloxone 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 a neonatal study, the mean plasma half-life was observed to be 3.1 +/- 0.5 hours. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.">CLINICAL PHARMACOLOGY
Complete or Partial Reversal of Opioid Depression Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, Naloxone can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone is an essentially pure opioid antagonist, i. , it does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and 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, opiate withdrawal symptoms may appear within minutes of naloxone administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of opioid dependence. While the mechanism of action of naloxone is not fully understood, in vitro 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 a 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 dissipates. The requirement for repeat doses of naloxone, however, will also be dependent upon the amount, type and route of administration of the opioid being antagonized. Naloxone has been shown in some cases of septic shock to produce a 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.
PHARMACOKINETICS
Following 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. Naloxone 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 a neonatal study, the mean plasma half-life was observed to be 3. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.
Distribution
Following 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 Elimination
Naloxone 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 a neonatal study, the mean plasma half-life was observed to be 3.1 +/- 0.5 hours. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.

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 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 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 Infusion: 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. Do not administer unless solution is clear and container is undamaged. Usage in Adults: Opioid Overdoseem dashKnown or Suspected: Postoperative Opioid Depression: 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: CLINICAL PHARMACOLOGY Usage in Pediatric Population: Opioid Overdose en dash Known or Suspected: Postoperative Opioid Depression: Adult Postoperative Opioid Depression Opioid-Induced Depression:

ADVERSE REACTIONS
The 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 DOSAGE AND ADMINISTRATION; Usage in Adults; Postoperative 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 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, and 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: Gastrointestinal Disorders: Nervous System Disorders: Psychiatric Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: See PRECAUTIONS DOSAGE AND ADMINISTRATION; Usage in Adults, Postoperative Opioid Depression.
Postoperative
The 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 DOSAGE AND ADMINISTRATION; Usage in Adults; Postoperative Opioid Depression

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

Use in Labor and Delivery
It is not known if naloxone hydrochloride injection affects the duration of labor and/or delivery. However, published reports indicated that the administration of naloxone during labor did not adversely affect maternal or neonatal status.
Nursing Mothers
It is not known whether naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a nursing woman.
Pediatric Use
Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. When naloxone hydrochloride injection is given to the mother shortly before delivery, the duration of its effects lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride injection directly to the neonate if needed after delivery. Naloxone has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia, which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock:
Geriatric Use
Clinical studies of naloxone hydrochloride injection 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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Insufficiency/Failure
The safety and effectiveness of Naloxone hydrochloride injection in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone is administered to this patient population.
Liver Disease
The safety and effectiveness of naloxone hydrochloride injection in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to patients with liver disease.
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 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 2½ 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 4½ year-old child who received 11 doses during a 12-hour period, with no adverse sequelae.

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.

WARNINGS
Naloxone 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 a 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. The 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. Naloxone 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.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Studies in animals to assess the carcinogenic potential of naloxone have not been conducted. Naloxone was weakly positive in the Ames mutagenicity and in the in vitro in vitro in vivo 2 Use in Pregnancy: Teratogenic Effects: Pregnancy Category C Teratology studies conducted in mice and rats at doses 4-times and 8- times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 Non-teratogenic effects:
OVERDOSAGE
There is limited clinical experience with naloxone hydrochloride injection overdosage in humans. 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 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. 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 2½ 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 4½ year-old child who received 11 doses during a 12-hour period, with no adverse sequelae. 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.

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