Naloxone Hydrochloride DBL

Naloxone Hydrochloride DBL (naloxone) 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 DBL (naloxone) is also indicated for diagnosis of suspected or known acute opioid overdosage.

Naloxone Hydrochloride DBL (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 DBL may be used for the complete or partial reversal of opioid depression, including mild to severe respiratory depression induced by natural and synthetic opioids, including dextropropoxyphene, methadone and certain mixed agonist/antagonist analgesics: nalbuphine and pentazocine. It may also be used for the diagnosis of suspected acute opioid overdosage. Naloxone Hydrochloride DBL may also be used to counteract respiratory and other CNS depression in the new-born resulting from the administration of analgesics to the mother during childbirth.

Naloxone may be used for the complete or partial reversal of opioid depression, including mild to severe respiratory depression induced by natural and synthetic opioids, including dextropropoxyphene, methadone and certain mixed agonist/antagonist analgesics: nalbuphine and pentazocine. It may also be used for the diagnosis of suspected acute opioid overdosage. Naloxone may also be used to counteract respiratory and other CNS depression in the new-born resulting from the administration of analgesics to the mother during childbirth.

Naloxone Hydrochloride DBL is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression in adults and pediatric patients.

Naloxone Hydrochloride DBL is intended for immediate administration as emergency therapy in settings where opioids may be present.

Naloxone Hydrochloride DBL is not a substitute for emergency medical care.

NARCAN (naloxone) 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. NARCAN (naloxone) is also indicated for diagnosis of suspected or known acute opioid overdosage.

NARCAN (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 DBL (naloxone) 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 DBL (naloxone) , the patient should be kept under continued surveillance. Repeated doses of Naloxone Hydrochloride DBL (naloxone) should be administered, as necessary.

Intravenous Infusion

Naloxone Hydrochloride DBL (naloxone) may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of Naloxone Hydrochloride DBL (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 DBL (naloxone) 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 DBL (naloxone) 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 DBL (naloxone) 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 DBL (naloxone) 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 DBL (naloxone) are usually sufficient. The dose of Naloxone Hydrochloride DBL (naloxone) should be titrated according to the patient's response. For the initial reversal of respiratory depression, Naloxone Hydrochloride DBL (naloxone) 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 DBL (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 Hydrochloride DBL (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 DBL (naloxone) 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 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 I.V. route of administration is not available, Naloxone Hydrochloride DBL (naloxone) may be administered I.M. or S.C. in divided doses. If necessary, Naloxone Hydrochloride DBL (naloxone) 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 DBL (naloxone) 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 I.V., I.M. or S.C. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

Naloxone Hydrochloride DBL is for intravenous, intramuscular or subcutaneous injection or intravenous infusion.

Intravenous infusion: Naloxone Hydrochloride DBL may be diluted for intravenous infusion in normal saline (0.9%) or 5% dextrose in water or saline: the addition of 2mg (2ml of 1mg/1ml concentration) of Naloxone Hydrochloride DBL in 500ml of either solution provides a concentration of 4 micrograms/ml. Mixtures should be used within 12 hours. After 12 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patient's response to both Naloxone Hydrochloride DBL infusion and to any previous bolus doses administered.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.

Adults:

Opioid overdosage (known or suspected)

An initial dose of 400 to 2000 micrograms of Naloxone Hydrochloride DBL may be administered intravenously. If the desired degree of counteraction and improvement in respiratory function is not obtained it may be repeated at 2 to 3 minute intervals. If no response is observed after 10mg of Naloxone Hydrochloride DBL have been administered the diagnosis of opioid-induced or partial opioid induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if dosing by the intravenous route is not feasible.

N.B. The duration of action of certain opioids can outlast that of an IV bolus of Naloxone Hydrochloride DBL, e.g. dextropropoxyphene (present in commonly prescribed analgesics which in over-dosage have been associated with suicide), dihydrocodeine and methadone. In situations where one of these opioids is known or suspected it is recommended that an infusion of Naloxone Hydrochloride DBL be used to produce sustained antagonism to the opioid without repeated injection.

Post Operative Use

When Naloxone Hydrochloride DBL is used postoperatively, the dose should be titrated for each patient in order to obtain optimum respiratory response while maintaining adequate analgesia. Intravenous doses of 100-200 micrograms (approximately 1.5-3 micrograms/kg body weight) are usually sufficient, but a full two minutes should be allowed between each 100 micrograms increment of Naloxone Hydrochloride DBL administered. Further intramuscular doses may be needed within one to two hours, depending on the interval since the last opioid administration and the amount and type (i.e. long or short-acting) of drug used. Alternatively Naloxone Hydrochloride DBL may be administered as an intravenous infusion (see above).

Children

The usual initial dose in children is 10 micrograms/kg body weight given i.v. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 100 micrograms/kg of bodyweight may be administered. Naloxone Hydrochloride DBL may be required by infusion as described above. If an i.v. route of administration is not feasible, Naloxone Hydrochloride DBL may be administered i.m. or s.c. in divided doses.

Neonatal Use

An adequate airway should be established in the apnoeic infant before Naloxone Hydrochloride DBL is administered. The usual dose is for opioid-induced depression is 10 micrograms/kg body weight administered i.v., i.m., or s.c.. If the desired degree of counteraction and improvement in respiratory function is not obtained it may be repeated at 2-3 minute intervals. Alternatively, a single dose of 200 micrograms, approximately 60 micrograms/kg body weight may be given intramuscularly at birth.

It should, however, be noted that onset of action is slower following i.m. injection. In neonates needing infusion of Naloxone Hydrochloride DBL in saline, care should be taken to avoid excessive sodium intake.

Elderly

There have been no specific studies for use in the elderly.

Naloxone is for intravenous, intramuscular or subcutaneous injection or intravenous infusion.

Intravenous infusion: Naloxone may be diluted for intravenous infusion in normal saline (0.9%) or 5% dextrose in water or saline: the addition of 2mg (2ml of 1mg/1ml concentration) of Naloxone in 500ml of either solution provides a concentration of 4 micrograms/ml. Mixtures should be used within 12 hours. After 12 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patient's response to both Naloxone infusion and to any previous bolus doses administered.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.

Adults:

Opioid overdosage (known or suspected)

An initial dose of 400 to 2000 micrograms of Naloxone may be administered intravenously. If the desired degree of counteraction and improvement in respiratory function is not obtained it may be repeated at 2 to 3 minute intervals. If no response is observed after 10mg of Naloxone have been administered the diagnosis of opioid-induced or partial opioid induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if dosing by the intravenous route is not feasible.

N.B. The duration of action of certain opioids can outlast that of an IV bolus of Naloxone, e.g. dextropropoxyphene (present in commonly prescribed analgesics which in over-dosage have been associated with suicide), dihydrocodeine and methadone. In situations where one of these opioids is known or suspected it is recommended that an infusion of Naloxone be used to produce sustained antagonism to the opioid without repeated injection.

Post Operative Use

When Naloxone is used postoperatively, the dose should be titrated for each patient in order to obtain optimum respiratory response while maintaining adequate analgesia. Intravenous doses of 100-200 micrograms (approximately 1.5-3 micrograms/kg body weight) are usually sufficient, but a full two minutes should be allowed between each 100 micrograms increment of Naloxone administered. Further intramuscular doses may be needed within one to two hours, depending on the interval since the last opioid administration and the amount and type (i.e. long or short-acting) of drug used. Alternatively Naloxone may be administered as an intravenous infusion (see above).

Children

The usual initial dose in children is 10 micrograms/kg body weight given i.v. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 100 micrograms/kg of bodyweight may be administered. Naloxone may be required by infusion as described above. If an i.v. route of administration is not feasible, Naloxone may be administered i.m. or s.c. in divided doses.

Neonatal Use

An adequate airway should be established in the apnoeic infant before Naloxone is administered. The usual dose is for opioid-induced depression is 10 micrograms/kg body weight administered i.v., i.m., or s.c.. If the desired degree of counteraction and improvement in respiratory function is not obtained it may be repeated at 2-3 minute intervals. Alternatively, a single dose of 200 micrograms, approximately 60 micrograms/kg body weight may be given intramuscularly at birth.

It should, however, be noted that onset of action is slower following i.m. injection. In neonates needing infusion of Naloxone in saline, care should be taken to avoid excessive sodium intake.

Elderly

There have been no specific studies for use in the elderly.

Important Administration Instructions

Naloxone Hydrochloride DBL is for intramuscular and subcutaneous use only.

Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of Naloxone Hydrochloride DBL and the Instructions for Use.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for Naloxone Hydrochloride DBL. Emphasize the following instructions to the patient or caregiver:

• Seek emergency medical care immediately after use. Since the duration of action of most opioids exceeds that of naloxone hydrochloride and the suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, keep the patient under continued surveillance until emergency personnel arrive, and administer repeated doses of Naloxone Hydrochloride DBL as necessary. Always seek emergency medical assistance in the event of a suspected, potentially life-threatening opioid emergency after administration of the first dose of Naloxone Hydrochloride DBL.
• Additional doses of Naloxone Hydrochloride DBL may be required until emergency medical assistance becomes available.
• Do not attempt to reuse Naloxone Hydrochloride DBL. Each Naloxone Hydrochloride DBL contains a single dose of naloxone.
• Visually inspect Naloxone Hydrochloride DBL through the viewing window for particulate matter and discoloration prior to administration. Do not administer unless the solution is clear and the glass container is undamaged.
• Naloxone Hydrochloride DBL must be administered according to the printed instructions on the device label or the electronic voice instructions (Naloxone Hydrochloride DBL contains a speaker that provides voice instructions to guide the user through each step of the injection). If the Naloxone Hydrochloride DBL electronic voice instruction system does not operate properly, Naloxone Hydrochloride DBL will still deliver the intended dose of naloxone hydrochloride when used according to the printed instructions on its label.
• Once the red safety guard is removed, Naloxone Hydrochloride DBL must be used immediately or disposed of properly. Do not attempt to replace the red safety guard once it is removed.

Upon actuation, Naloxone Hydrochloride DBL automatically inserts the needle intramuscularly or subcutaneously, delivers the naloxone hydrochloride injection, and retracts the needle fully into its housing. Post injection, the black base locks in place, a red indicator appears in the viewing window, and electronic visual and audible instructions signal that Naloxone Hydrochloride DBL has delivered the intended dose of naloxone hydrochloride and instructs the user to seek emergency medical attention.

Dosing Information

Initial Dosing

Administer the initial dose of Naloxone Hydrochloride DBL to adult or pediatric patients intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary, and seek emergency medical assistance. Administer Naloxone Hydrochloride DBL as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.

Repeat Dosing

The requirement for repeat doses of Naloxone Hydrochloride DBL depends upon the amount, type, and route of administration of the opioid being antagonized.

If the desired response is not obtained after 2 or 3 minutes, an additional dose of Naloxone Hydrochloride DBL may be administered. If there is still no response and additional doses are available, additional doses of Naloxone Hydrochloride DBL may be administered every 2 to 3 minutes until emergency medical assistance arrives. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

If the patient responds to Naloxone Hydrochloride DBL and relapses back into respiratory depression before emergency assistance arrives, an additional dose of Naloxone Hydrochloride DBL may be administered.

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of Naloxone Hydrochloride DBL.

Dosing In Adults And Pediatric Patients Over Age One Year

Instruct patients or their caregivers to administer Naloxone Hydrochloride DBL according to the Instructions for Use, intramuscularly or subcutaneously.

Dosing In Pediatric Patients Under Age One Year

In pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering Naloxone Hydrochloride DBL. Carefully observe the administration site for signs of infection following injection and resolution of the opioid emergency.

There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, consider use of an alternative, naloxone product which can be titrated to effect and, where applicable, dosed according to weight.

NARCAN (naloxone) 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 NARCAN (naloxone) , the patient should be kept under continued surveillance. Repeated doses of NARCAN (naloxone) should be administered, as necessary.

Intravenous Infusion

NARCAN (naloxone) may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of NARCAN (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.

NARCAN (naloxone) 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 NARCAN (naloxone) 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 NARCAN (naloxone) 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 NARCAN (naloxone) 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 NARCAN (naloxone) are usually sufficient. The dose of NARCAN (naloxone) should be titrated according to the patient's response. For the initial reversal of respiratory depression, NARCAN (naloxone) 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 NARCAN (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 NARCAN (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 NARCAN (naloxone) 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 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 I.V. route of administration is not available, NARCAN (naloxone) may be administered I.M. or S.C. in divided doses. If necessary, NARCAN (naloxone) 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, NARCAN (naloxone) 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 I.V., I.M. or S.C. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

Naloxone Hydrochloride DBL (naloxone) is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients in Naloxone Hydrochloride DBL (naloxone).

Naloxone Hydrochloride DBL should not be given to patients who are known to be hypersensitive to the drug.

Naloxone should not be given to patients who are known to be hypersensitive to the drug.

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

NARCAN (naloxone) is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients in NARCAN (naloxone).

WARNINGS

Drug Dependence

Naloxone Hydrochloride DBL (naloxone) 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.

Repeat Administration

The patient who has satisfactorily responded to Naloxone Hydrochloride DBL (naloxone) should be kept under continued surveillance and repeated doses of Naloxone Hydrochloride DBL (naloxone) should be administered, as necessary, since the duration of action of some opioids may exceed that of Naloxone Hydrochloride DBL (naloxone).

Respiratory Depression due to Other Drugs

Naloxone Hydrochloride DBL (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.

PRECAUTIONS

General

In addition to Naloxone Hydrochloride DBL (naloxone) , 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 DBL (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)

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 pre-existing 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 DBL (naloxone) should be used with caution in patients with pre-existing 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 DBL (naloxone) 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals to assess the carcinogenic potential of Naloxone Hydrochloride DBL (naloxone) have not been conducted. Naloxone Hydrochloride DBL (naloxone) was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. 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 DBL (naloxone).

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/m²), demonstrated no embryotoxic or teratogenic effects due to Naloxone Hydrochloride DBL (naloxone). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Naloxone Hydrochloride DBL (naloxone) should be used during pregnancy only if clearly needed.

Non-teratogenic Effects: Risk-benefit must be considered before Naloxone Hydrochloride DBL (naloxone) is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur.

Use in Labor and Delivery

It is not known if Naloxone Hydrochloride DBL (naloxone) 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.

Nursing Mothers

It is not known whether Naloxone Hydrochloride DBL (naloxone) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Naloxone Hydrochloride DBL (naloxone) is administered to a nursing woman.

Pediatric Use

Naloxone Hydrochloride DBL (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 DBL (naloxone) , he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

When Naloxone Hydrochloride DBL (naloxone) 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 DBL (naloxone) directly to the neonate if needed after delivery. Naloxone Hydrochloride DBL (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: The safety and effectiveness of Naloxone Hydrochloride DBL (naloxone) in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures.

Geriatric Use

Clinical studies of Naloxone Hydrochloride DBL (naloxone) 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 DBL (naloxone) in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone Hydrochloride DBL (naloxone) is administered to this patient population

Liver Disease

The safety and effectiveness of Naloxone Hydrochloride DBL (naloxone) in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone Hydrochloride DBL (naloxone) is administered to patients with liver disease.

It should be administered cautiously to patients who have received large doses of opioids or to those physically dependent on opioids since too rapid reversal of opioid effects by Naloxone Hydrochloride DBL may precipitate an acute withdrawal syndrome in such patients. The same caution is needed when giving Naloxone Hydrochloride DBL to neonates delivered of such patients.

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, diarrhoea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea, vomiting, nervousness, restlessness, irritability, shivering, trembling, abdominal cramps, weakness and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying and hyperactive reflexes.

Patients who have responded satisfactorily to Naloxone Hydrochloride DBL should be kept under observation. Repeated doses of Naloxone Hydrochloride DBL may be necessary since the duration of action of some opioids may exceed that of Naloxone Hydrochloride DBL.

Naloxone Hydrochloride DBL is not effective against respiratory depression caused by non-opioid drugs. Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incomplete response occurs, respiration should be mechanically assisted.

Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest which may result in death.

Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest have been reported in postoperative patients. Death, coma and encephalopathy have been reported as sequelae of these events. Although a direct cause and effect relationship has not been established, Naloxone Hydrochloride DBL should be used with caution in patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation and pulmonary oedema.

In addition to Naloxone Hydrochloride DBL, 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 poisoning.

Renal Insufficiency/Failure: The safety and effectiveness of Naloxone Hydrochloride DBL in patients with renal insufficiency/failure have not been established in clinical trials. Caution should be exercised and patients monitored when Naloxone Hydrochloride DBL is administered to this patient population.

Liver disease: The safety and effectiveness of Naloxone Hydrochloride DBL in patients with liver disease have not been established in well-controlled clinical trials. In one small study in patients with liver cirrhosis, plasma Naloxone Hydrochloride DBL concentrations were approximately six times higher than in patients without liver disease. Naloxone Hydrochloride DBL administration had a diuretic effect in these patients with cirrhosis. Caution should be exercised when Naloxone Hydrochloride DBL is administered to a patient with liver disease.

It should be administered cautiously to patients who have received large doses of opioids or to those physically dependent on opioids since too rapid reversal of opioid effects by Naloxone may precipitate an acute withdrawal syndrome in such patients. The same caution is needed when giving Naloxone to neonates delivered of such patients.

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, diarrhoea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea, vomiting, nervousness, restlessness, irritability, shivering, trembling, abdominal cramps, weakness and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying and hyperactive reflexes.

Patients who have responded satisfactorily to Naloxone should be kept under observation. Repeated doses of Naloxone may be necessary since the duration of action of some opioids may exceed that of Naloxone.

Naloxone is not effective against respiratory depression caused by non-opioid drugs. Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incomplete response occurs, respiration should be mechanically assisted.

Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest which may result in death.

Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest have been reported in postoperative patients. Death, coma and encephalopathy have been reported as sequelae of these events. Although a direct cause and effect relationship has not been established, Naloxone should be used with caution in patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation and pulmonary oedema.

In addition to Naloxone, 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 poisoning.

Renal Insufficiency/Failure: The safety and effectiveness of Naloxone in patients with renal insufficiency/failure have not been established in clinical trials. Caution should be exercised and patients monitored when Naloxone is administered to this patient population.

Liver disease: The safety and effectiveness of Naloxone in patients with liver disease have not been established in well-controlled clinical trials. In one small study in patients with liver cirrhosis, plasma naloxone concentrations were approximately six times higher than in patients without liver disease. Naloxone administration had a diuretic effect in these patients with cirrhosis. Caution should be exercised when Naloxone is administered to a patient with liver disease.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Recurrent Respiratory And Central Nervous System Depression

The duration of action of most opioids may exceed that of Naloxone Hydrochloride DBL resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after delivering the first dose of Naloxone Hydrochloride DBL. Keep the patient under continued surveillance, and administer additional doses of Naloxone Hydrochloride DBL as necessary. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

Risk Of Limited Efficacy With Partial Agonists Or Mixed Agonist/Antagonists

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses of naloxone hydrochloride may be required to antagonize buprenorphine because 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.

Precipitation Of Severe Opioid Withdrawal

The use of Naloxone Hydrochloride DBL in patients who are opioid dependent may precipitate an acute abstinence syndrome characterized by the following signs and symptoms: 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 neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying and hyperactive reflexes. Monitor patients for the development of the signs and symptoms of opioid withdrawal.

Abrupt postoperative reversal of opioid depression after using naloxone hydrochloride may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, monitor patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. 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.

Patient Counseling Information

Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instruct patients and their family members or caregivers to:

• Become familiar with the following information contained in the carton as soon as they receive Naloxone Hydrochloride DBL:
  • Naloxone Hydrochloride DBL Instructions for Use
  • Trainer for Naloxone Hydrochloride DBL Instructions for Use
  • Trainer for Naloxone Hydrochloride DBL
• Become familiar with the device labeling color scheme of Naloxone Hydrochloride DBL and the Trainer for Naloxone Hydrochloride DBL
  • The 2 mg dosage form of Naloxone Hydrochloride DBL is blue and purple.
  • The Trainer for Naloxone Hydrochloride DBL is black and white.
• Practice using the Trainer before Naloxone Hydrochloride DBL is needed.
  • Each Naloxone Hydrochloride DBL can only be used one time; however, Trainer for Naloxone Hydrochloride DBL can be re-used for training purposes and its red safety guard can be removed and replaced.
  • Both Naloxone Hydrochloride DBL and Trainer for Naloxone Hydrochloride DBL incorporate the electronic voice instruction system.
• It is recommended that patients and caregivers become familiar with the Trainer for Naloxone Hydrochloride DBL provided and read the Instructions for Use; however, untrained caregivers or family members should still attempt to use Naloxone Hydrochloride DBL during a suspected opioid overdose while awaiting definitive emergency medical care.

Recognition Of Opioid Overdose

Instruct the patients and their family members or caregivers how to recognize the signs and symptoms of an opioid overdose requiring the use of Naloxone Hydrochloride DBL such as the following:

• Extreme sleepiness -inability to awaken a patient verbally or upon a firm sternal rub.
• Breathing problems -this can range from slow or shallow breathing to no breathing in a patient who cannot be awakened.
• Other signs and symptoms that may accompany sleepiness and breathing problems include the following:
  • Extremely small pupils (the black circle in the center of the colored part of the eye) sometimes called “pinpoint pupils.”
  • Slow heartbeat and/or low blood pressure.

Risk Of Recurrent Respiratory And Central Nervous System Depression

Instruct patients and their family members or caregivers that since the duration of action of most opioids may exceed that of Naloxone Hydrochloride DBL, they must seek immediate emergency medical assistance after the first dose of Naloxone Hydrochloride DBL and keep the patient under continued surveillance.

Limited Efficacy For/With Partial Agonists Or Mixed Agonist/Antagonists

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of Naloxone Hydrochloride DBL.

Precipitation Of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that the use of Naloxone Hydrochloride DBL in patients who are opioid dependent may precipitate an acute abstinence syndrome characterized by the following signs and symptoms: 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 neonates, opioid withdrawal may be life threatening if not recognized and properly treated, and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes.

Administration Instructions

Instruct patients and their family members or caregivers about the following important information:

• Make sure Naloxone Hydrochloride DBL is present whenever persons may be intentionally or accidentally exposed to an opioid to treat serious opioid overdose (i.e., opioid emergencies).
• Administer Naloxone Hydrochloride DBL as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. Naloxone Hydrochloride DBL is not a substitute for emergency medical care.
• Naloxone Hydrochloride DBL is user actuated and may be administered through clothing [e.g., pants, jeans, etc.] if necessary.
• Inject Naloxone Hydrochloride DBL while pressing into the anterolateral aspect of the thigh. In pediatric patients less than 1 year of age, pinch the thigh muscle while administering Naloxone Hydrochloride DBL.
• Upon actuation, Naloxone Hydrochloride DBL automatically inserts the needle intramuscularly or subcutaneously, delivers the naloxone, and retracts the needle fully into its housing. The needle is not visible before, during, or after injection.
• Each Naloxone Hydrochloride DBL can only be used one time.
• If the electronic voice instruction system on Naloxone Hydrochloride DBL does not work properly, Naloxone Hydrochloride DBL will still deliver the intended dose of naloxone hydrochloride when used according to the printed instructions on its label.
• The electronic voice instructions are independent of activating Naloxone Hydrochloride DBL and it is not necessary to wait for the voice instructions to be completed prior to moving to the next step in the injection process.
• Post-injection, the black base locks in place, a red indicator appears in the viewing window and electronic visual and audible instructions signal that Naloxone Hydrochloride DBL has delivered the intended dose of naloxone hydrochloride.
• Naloxone Hydrochloride DBL’s red safety guard should not be replaced under any circumstances. However, the Trainer is designed for re-use and its red safety guard can be removed and replaced.
• Periodically visually inspect the naloxone solution through the viewing window. If the solution is discolored, cloudy, or contains solid particles, replace it with a new Naloxone Hydrochloride DBL.
• Replace Naloxone Hydrochloride DBL before its expiration date.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.

Mutagenesis

Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study.

Impairment Of Fertility

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 adverse effect of naloxone hydrochloride on fertility.

Use In Specific Populations

Pregnancy

Risk Summary

The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are risks to the fetus of the opioid-dependent mother with use of naloxone. In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus as well as in the opioid-dependent mother. The fetus should be evaluated for signs of distress after Naloxone Hydrochloride DBL is used. Careful monitoring is needed until the fetus and mother are stabilized.

Data

Animal Data

Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 4-times and 8times, respectively, the dose of 10 mg/day given to a 50 kg human (when based on body surface area or mg/m²). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.

Lactation

Risk Summary

There is no information regarding the presence of naloxone in human milk, or the effects of naloxone on the breastfed infant or on milk production. Studies in nursing mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Naloxone Hydrochloride DBL and any potential adverse effects on the breastfed infant from Naloxone Hydrochloride DBL or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Naloxone Hydrochloride DBL (for intramuscular and subcutaneous use) have been established in pediatric patients of all ages for the emergency treatment of known or suspected opioid overdose. Use of naloxone hydrochloride in all pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of another naloxone hydrochloride injectable product. No pediatric studies were conducted for Naloxone Hydrochloride DBL.

Absorption of naloxone hydrochloride following subcutaneous or intramuscular administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. Unlike acute opioid withdrawal in adults, acute opioid withdrawal in neonates manifesting as seizures may be life-threatening if not recognized and properly treated. Other signs and symptoms in neonates may include excessive crying and hyperactive reflexes. In these settings where it may be preferable to avoid the abrupt precipitation of acute opioid withdrawal symptoms, consider use of an alternative, naloxone hydrochloride product that can dosed according to weight and titrated to effect..

In pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering Naloxone Hydrochloride DBL. Carefully observe the administration site for evidence of residual needle parts, signs of infection, or both..

Geriatric Use

Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone can be higher in these patients.

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.

WARNINGS

Drug Dependence

NARCAN (naloxone) 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.

Repeat Administration

The patient who has satisfactorily responded to NARCAN (naloxone) should be kept under continued surveillance and repeated doses of NARCAN (naloxone) should be administered, as necessary, since the duration of action of some opioids may exceed that of NARCAN (naloxone).

Respiratory Depression due to Other Drugs

NARCAN (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.

PRECAUTIONS

General

In addition to NARCAN (naloxone) , 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 NARCAN (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)

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 pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, NARCAN (naloxone) should be used with caution in patients with pre-existing 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 NARCAN (naloxone) 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals to assess the carcinogenic potential of NARCAN (naloxone) have not been conducted. NARCAN (naloxone) was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. 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 NARCAN (naloxone).

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/m²), demonstrated no embryotoxic or teratogenic effects due to NARCAN (naloxone). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NARCAN (naloxone) should be used during pregnancy only if clearly needed.

Non-teratogenic Effects: Risk-benefit must be considered before NARCAN (naloxone) is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur.

Use in Labor and Delivery

It is not known if NARCAN (naloxone) 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.

Nursing Mothers

It is not known whether NARCAN (naloxone) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NARCAN (naloxone) is administered to a nursing woman.

Pediatric Use

NARCAN (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 NARCAN (naloxone) , he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

When NARCAN (naloxone) 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 NARCAN (naloxone) directly to the neonate if needed after delivery. NARCAN (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: The safety and effectiveness of NARCAN (naloxone) in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures.

Geriatric Use

Clinical studies of NARCAN (naloxone) 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 NARCAN (naloxone) in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when NARCAN (naloxone) is administered to this patient population

Liver Disease

The safety and effectiveness of NARCAN (naloxone) in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when NARCAN (naloxone) is administered to patients with liver disease.

Postoperative

The following adverse events have been associated with the use of Naloxone Hydrochloride DBL (naloxone) 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 DBL (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 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 DBL (naloxone) 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, paresthesia, 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.

Drug Abuse And Dependence

Naloxone Hydrochloride DBL (naloxone) is an opioid antagonist. Physical dependence associated with the use of Naloxone Hydrochloride DBL (naloxone) has not been reported. Tolerance to the opioid antagonist effect of Naloxone Hydrochloride DBL (naloxone) is not known to occur.

Postoperative: The following adverse effects have been associated with the use of Naloxone Hydrochloride DBL in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnoea, pulmonary oedema, and cardiac arrest. Death, coma and encephalopathy have been reported as sequelae of these events. Excessive doses of Naloxone Hydrochloride DBL in postoperative patients may result in significant reversal of analgesia and may cause agitation.

Opioid Depression: Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest which may result in death (see Special Warnings).

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, trembling, nervousness, restlessness, irritability, diarrhoea, nausea, vomiting, abdominal cramps, increased blood pressure and tachycardia. In the neonate, opioid withdrawal may also include convulsions, excessive crying and hyperactive reflexes (see Special Warnings).

Agitation and paraesthesias have been infrequently reported with the use of Naloxone Hydrochloride DBL.

Postoperative: The following adverse effects have been associated with the use of Naloxone in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnoea, pulmonary oedema, 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.

Opioid Depression: Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary oedema and cardiac arrest which may result in death (see Special Warnings).

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, trembling, nervousness, restlessness, irritability, diarrhoea, nausea, vomiting, abdominal cramps, increased blood pressure and tachycardia. In the neonate, opioid withdrawal may also include convulsions, excessive crying and hyperactive reflexes (see Special Warnings).

Agitation and paraesthesias have been infrequently reported with the use of Naloxone.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Precipitation of Severe Opioid Withdrawal

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The following adverse reactions were observed in Naloxone Hydrochloride DBL clinical studies. In two pharmacokinetic studies with a total of 54 healthy adult subjects exposed to 0.4 mg Naloxone Hydrochloride DBL, 0.8 mg Naloxone Hydrochloride DBL (two 0.4 mg Naloxone Hydrochloride DBLs) or 2 mg Naloxone Hydrochloride DBL, adverse reactions occurring in more than one subject were dizziness and injection site erythema.

The following adverse reactions have been identified during post-approval use of naloxone hydrochloride in the post-operative setting. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: 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 post-operative patients have resulted in significant reversal of analgesia and have caused agitation.

Other events that have been reported in post-marketing use of Naloxone Hydrochloride DBL include agitation, disorientation, confusion, and anger.

Abrupt reversal of opioid effects in persons who were physically dependent on opioids has precipitated an acute withdrawal syndrome. Signs and symptoms have included: 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 signs and symptoms also included: convulsions, excessive crying, hyperactive reflexes.

Postoperative

The following adverse events have been associated with the use of NARCAN (naloxone) 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 NARCAN (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 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 NARCAN (naloxone) 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, paresthesia, 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.

Drug Abuse And Dependence

NARCAN (naloxone) is an opioid antagonist. Physical dependence associated with the use of NARCAN (naloxone) has not been reported. Tolerance to the opioid antagonist effect of NARCAN (naloxone) is not known to occur.

There is limited clinical experience with Naloxone Hydrochloride DBL (naloxone) 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/m²/min) of Naloxone Hydrochloride DBL (naloxone) 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 (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3).

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 2-3 days.

Pediatric Patients

Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2-1/2 year-old child who inadvertently received a dose of 20 mg of 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 4-1/2 year-old child who received 11 doses during a 12-hour period, with no adverse sequelae.

Patient Management

Patients who experience a Naloxone Hydrochloride DBL (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.

There is limited clinical experience with Naloxone Hydrochloride DBL overdosage in humans.

Adult Patients: In one study, volunteers and morphine-dependent subjects who received a single subcutaneous dose of 24mg/70kg did not demonstrate toxicity.

In another study, 36 patients with acute stroke received a loading dose of 4mg/kg (10mg/m²/min) of Naloxone Hydrochloride DBL followed immediately by 2mg/kg/hr for 24 hours. There were a few reports of serious adverse events: seizures (2 patients), severe hypertension (1) and hypotension and/or bradycardia (3).

At doses of 2 mg/kg in normal subjects, memory impairment has been reported.

Paediatric Patients: Up to 11 doses of 0.2mg of Naloxone Hydrochloride DBL (2.2mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulphate. Paediatric reports include a 2½ year old child who inadvertently received a dose of 20mg of Naloxone Hydrochloride DBL and a 4½ year old child who received 11 doses during a 12-hour period, both of whom had no adverse sequelae.

Patient Management: Patients who experience a Naloxone Hydrochloride DBL overdose should be treated symptomatically in a closely-supervised environment. Physicians should contact a poison control centre for the most up-to-date patient management information.

There is limited clinical experience with Naloxone overdosage in humans.

Adult Patients: In one study, volunteers and morphine-dependent subjects who received a single subcutaneous dose of 24mg/70kg did not demonstrate toxicity.

In another study, 36 patients with acute stroke received a loading dose of 4mg/kg (10mg/m²/min) of Naloxone followed immediately by 2mg/kg/hr for 24 hours. There were a few reports of serious adverse events: seizures (2 patients), severe hypertension (1) and hypotension and/or bradycardia (3).

At doses of 2 mg/kg in normal subjects, memory impairment has been reported.

Paediatric Patients: Up to 11 doses of 0.2mg of naloxone (2.2mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulphate. Paediatric reports include a 2½ year old child who inadvertently received a dose of 20mg of naloxone and a 4½ year old child who received 11 doses during a 12-hour period, both of whom had 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 centre for the most up-to-date patient management information.

No Information Provided

There is limited clinical experience with NARCAN (naloxone) 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/m²/min) of NARCAN (naloxone) 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 (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3).

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 2-3 days.

Pediatric Patients

Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2-1/2 year-old child who inadvertently received a dose of 20 mg of 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 4-1/2 year-old child who received 11 doses during a 12-hour period, with no adverse sequelae.

Patient Management

Patients who experience a NARCAN (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.

Naloxone Hydrochloride DBL is a competitive antagonist of µ, δ and κ-opioid receptors. Naloxone Hydrochloride DBL is most potent at the µ-receptor. Naloxone Hydrochloride DBL, given on its own, produces very little effect. However, if it is given in higher doses it rapidly reverses the effect of morphine and other opioids, including pentazocine and nalorphine. Naloxone Hydrochloride DBL has little effect on the pain threshold in normal conditions, but causes hyperalgesia in stressful conditions where endogenous opioids are produced. Naloxone Hydrochloride DBL also inhibits acupuncture analgesia, which is associated with the release of opioid peptides. Naloxone Hydrochloride DBL also prevents analgesia produced by PAG (periaqueductal grey matter) stimulation. PAG is one site of action in pain transmission. Naloxone Hydrochloride DBL is given intravenously and its effects are produced immediately. It is rapidly metabolised by the liver, and its effect lasts only 1-2 hours, which is a lot shorter than that of most morphine-like drugs. Thus it may have to be given repeatedly.

Naloxone is a competitive antagonist of µ, δ and κ-opioid receptors. Naloxone is most potent at the µ-receptor. Naloxone, given on its own, produces very little effect. However, if it is given in higher doses it rapidly reverses the effect of morphine and other opioids, including pentazocine and nalorphine. Naloxone has little effect on the pain threshold in normal conditions, but causes hyperalgesia in stressful conditions where endogenous opioids are produced. Naloxone also inhibits acupuncture analgesia, which is associated with the release of opioid peptides. Naloxone also prevents analgesia produced by PAG (periaqueductal grey matter) stimulation. PAG is one site of action in pain transmission. Naloxone is given intravenously and its effects are produced immediately. It is rapidly metabolised by the liver, and its effect lasts only 1-2 hours, which is a lot shorter than that of most morphine-like drugs. Thus it may have to be given repeatedly.

When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration.

The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.

Naloxone Hydrochloride DBL is rapidly absorbed following oral administration but high presystemic metabolism makes this route unreliable. Naloxone Hydrochloride DBL is highly lipid soluble and is thus rapidly distributed throughout the body, with a volume of distribution of 5.1kg ^-1. High concentrations occur in brain, kidney, lung, heart and skeletal muscle. The brain/serum ratio has been estimated to be 1.5-4.6, approximately 15 times that of morphine. Levels of Naloxone Hydrochloride DBL in the central nervous system are short-lived as rapid redistribution occurs and this could account for the short duration of action. About 50% of Naloxone Hydrochloride DBL is bound to plasma proteins, principally albumin. The plasma half-life is 1-2 hours. When Naloxone Hydrochloride DBL reaches the liver it undergoes extensive biotransformation, almost none of the drug excreted being unchanged. Metabolites are excreted largely in the urine, 70% of the dose being recoverable over 72 hours. In the neonate the elimination half-life is prolonged because of reduced hepatic metabolism.

Naloxone is rapidly absorbed following oral administration but high presystemic metabolism makes this route unreliable. Naloxone is highly lipid soluble and is thus rapidly distributed throughout the body, with a volume of distribution of 5.1kg ^-1. High concentrations occur in brain, kidney, lung, heart and skeletal muscle. The brain/serum ratio has been estimated to be 1.5-4.6, approximately 15 times that of morphine. Levels of naloxone in the central nervous system are short-lived as rapid redistribution occurs and this could account for the short duration of action. About 50% of naloxone is bound to plasma proteins, principally albumin. The plasma half-life is 1-2 hours. When naloxone reaches the liver it undergoes extensive biotransformation, almost none of the drug excreted being unchanged. Metabolites are excreted largely in the urine, 70% of the dose being recoverable over 72 hours. In the neonate the elimination half-life is prolonged because of reduced hepatic metabolism.

It is recommended that infusions of Naloxone Hydrochloride DBL Hydrochloride should not be mixed with preparations containing bisulphite, metabisulphite, long-chain or high molecular weight anions, or solutions with an alkaline pH (Martindale, 1996).

It is recommended that infusions of Naloxone Hydrochloride DBL should not be mixed with preparations containing bisulphite, metabisulphite, long-chain or high molecular weight anions, or solutions with an alkaline pH (Martindale, 1996).