Naloxone Hydrochloride
Naloxone Hydrochloride Prescribing Information
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 and 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
Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory depression, sedation, and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonist such as pentazocine.
Naloxone hydrochloride 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 and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.
Naloxone hydrochloride has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone hydrochloride will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone hydrochloride administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone hydrochloride and to the degree and type of opioid dependence.
While the mechanism of action of naloxone hydrochloride is not fully understood,
When naloxone hydrochloride is administered intravenously (I.V.), the onset of action is generally apparent within two minutes. The onset of action is slightly less rapid when it is administered subcutaneously (S.C.) or intramuscularly (I.M.). 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 hydrochloride may be shorter than that of some opiates, the effect of the opiate may return as the effects of naloxone hydrochloride dissipates. The requirement for repeat doses of naloxone hydrochloride will also be dependent upon the amount, type and route of administration of the opioid being antagonized.
Naloxone hydrochloride 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 hydrochloride 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 hydrochloride 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.
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.
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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
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.
Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory depression, sedation, and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonist such as pentazocine.
Naloxone hydrochloride 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 and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.
Naloxone hydrochloride has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone hydrochloride will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone hydrochloride administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone hydrochloride and to the degree and type of opioid dependence.
While the mechanism of action of naloxone hydrochloride is not fully understood,
When naloxone hydrochloride is administered intravenously (I.V.), the onset of action is generally apparent within two minutes. The onset of action is slightly less rapid when it is administered subcutaneously (S.C.) or intramuscularly (I.M.). 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 hydrochloride may be shorter than that of some opiates, the effect of the opiate may return as the effects of naloxone hydrochloride dissipates. The requirement for repeat doses of naloxone hydrochloride will also be dependent upon the amount, type and route of administration of the opioid being antagonized.
Naloxone hydrochloride 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 hydrochloride 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 hydrochloride 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.
Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to it or to any of the other ingredients in naloxone hydrochloride.
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
In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning.
Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONSand DOSAGE AND ADMINISTRATION;
Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride 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.
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.
Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the
Reproduction 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/m2), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.
It is not known if naloxone hydrochloride affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status.
Naloxone hydrochloride injection, USP 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, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.
When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride directly to the neonate if needed after delivery. Naloxone hydrochloride 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.
Clinical studies of naloxone hydrochloride 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.
The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population.
The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to patients with liver disease.
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.
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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
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.
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
In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning.
Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONSand DOSAGE AND ADMINISTRATION;
Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride 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.
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.
Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the
Reproduction 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/m2), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.
It is not known if naloxone hydrochloride affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status.
Naloxone hydrochloride injection, USP 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, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.
When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride directly to the neonate if needed after delivery. Naloxone hydrochloride 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.
Clinical studies of naloxone hydrochloride 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.
The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population.
The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to patients with liver disease.
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
Naloxone hydrochloride 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 hydrochloride should be kept under continued surveillance and repeated doses of naloxone hydrochloride should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone hydrochloride.
Naloxone hydrochloride 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.
Adverse events associated with the postoperative use of naloxone hydrochloride are listed by organ system and in decreasing order of frequency as follows:
See also
In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning.
Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONSand DOSAGE AND ADMINISTRATION;
Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride 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.
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.
Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the
Reproduction 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/m2), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.
It is not known if naloxone hydrochloride affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status.
Naloxone hydrochloride injection, USP 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, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.
When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride directly to the neonate if needed after delivery. Naloxone hydrochloride 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.
Clinical studies of naloxone hydrochloride 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.
The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population.
The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to patients with liver disease.
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.
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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
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.
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.
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 Injection 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 8.35 mg of sodium chloride. Naloxone Hydrochloride Injection is preservative-free.