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NARCAN (naloxone hydrochloride injection, USP), 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.
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Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform.
NARCAN injection is available as a sterile solution for intravenous, intramuscular and subcutaneous administration in three concentrations: 0.02 mg, 0.4 mg and 1.0 mg of naloxone hydrochloride per mL. One mL of the 0.02 mg and 0.4 mg strengths contains 8.6 mg of sodium chloride. One mL of the 1.0 mg strength contains 8.35 mg of sodium chloride. In the 10 mL multiple dose vial, one mL of the 0.4 mg and 1.0 mg strengths also contains 2.0 mg of methylparaben and propylparaben as preservatives in a ratio of 9 to 1. pH is adjusted to 3.5 ± 0.5 with hydrochloric acid.
NARCAN injection is also available in a paraben-free formulation in three concentrations: 0.02 mg. 0.4 mg and 1.0 mg of naloxone hydrochloride per mL. One mL of each strength contains 9.0 mg of sodium chloride. pH is adjusted to 3.5 ± 0.5 with hydrochloric acid.
Complete or Partial Reversal of Opioid Depression NARCAN prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.
NARCAN is an essentially pure opioid antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists; NARCAN does not produce respiratory depression, psychotomimetic effects or pupillary constriction. In the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.
NARCAN has not been shown to produce tolerance or cause physical or psychological dependence.
In the presence of physical dependence on opioids NARCAN will produce withdrawal symptoms.
While the mechanism of action of NARCAN is not fully understood, the preponderance of evidence suggests that NARCAN antagonizes opioid effects by competing for the same receptor sites.
When NARCAN is administered intravenously, the onset of action is generally apparent within two minutes; the onset of action is only slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of administration of NARCAN. Intramuscular administration produces a more prolonged effect than intravenous administration. The requirement for repeat doses of NARCAN, however, will also be dependent upon the amount, type and route of administration of the opioid being antagonized.
Following parenteral administration, NARCAN is rapidly distributed in the body. It is metabolized in the liver, primarily by glucuronide conjugation and excreted in urine. In one study the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study the mean plasma half-life was observed to be 3.1 ± 0.5 hours.
Adjunctive Use in Septic Shock Although the mechanism of action is not completely understood, NARCAN appears to block endorphin-mediated hypotension in septic shock patients.
NARCAN 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.
Patients who have responded to NARCAN received the drug early in the course of treatment of septic shock. Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established. Published reports demonstrating a pressor effect have evaluated single bolus injections of 0.4 mg over three (3) to five (5) minutes, which have been repeated for 3-5 doses depending on the response. Bolus infusion doses ranging from 0.03 mg/kg to 0.2 mg/kg over five (5) minutes have also been reported. If a response was elicited, treatment was continued by intravenous infusion of concentrations of 0.03 mg/kg/hour to 0.3 mg/kg/hour for 1-24 hours or more depending upon the clinical response.
NARCAN 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. NARCAN is also indicated for the diagnosis of suspected opioid tolerance or acute opioid overdosage.
NARCAN 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 ).
NARCAN is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients in NARCAN.
NARCAN 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 NARCAN should be kept under continued surveillance and repeated doses of NARCAN should be administered, as necessary, since the duration of action of some opioids may exceed that of NARCAN.
NARCAN is not effective against respiratory depression due to non-opioid drugs. Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incomplete response occurs, respirations should be mechanically assisted.
General In addition to NARCAN, 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.
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 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 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 have not been conducted. NARCAN was weakly positive in the Ames mutagenicity and in vitro human lymphocyte chromosome aberration tests and was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in an in vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses as high as 50 times the usual human dose (10 mg/day) demonstrated no impairment of fertility.
Teratogenic Effects Pregnancy Category B: Reproduction studies performed in mice and rats at doses as high as 50 times the usual human dose (10 mg/day), revealed no evidence of impaired fertility or harm to the fetus due to NARCAN. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NARCAN should be used during pregnancy only if clearly needed.
Non-teratogenic Effects Risk-benefit must be considered before NARCAN 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.
Use in Labor and Delivery It is not known if NARCAN affects the duration of labor and/or delivery.
Nursing Mothers It is not known whether NARCAN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NARCAN is administered to a nursing woman.
Usage in Pediatric Patients and Neonates for Septic Shock The safety and effectiveness of NARCAN in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established.
Renal Insufficiency/Failure The safety and effectiveness of NARCAN in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when NARCAN is administered to this patient population.
Liver Disease The safety and effectiveness of NARCAN 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. NARCAN was well tolerated and no adverse events were reported. Caution should be exercised when NARCAN is administered to patients with liver disease.
Postoperative The following adverse events have been associated with the use of NARCAN 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 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 ).
Agitation and paresthesias have been infrequently reported with the use of NARCAN (naloxone hydrochloride injection, USP).
NARCAN is an opioid antagonist. Physical dependence associated with the use of NARCAN has not been reported. Tolerance to the opioid antagonist effect of NARCAN is not known to occur.
There is limited clinical experience with NARCAN overdosage in humans.
Adult Patients In one study, volunteers and morphine-dependent subjects who received 24 mg/70 kg did not demonstrate toxicity.
In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m 2 /min) of NARCAN followed immediately by 2 mg/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.
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 and a 4-1/2 year-old who received 11 doses during a 12-hour period, both of whom had no adverse sequelae.
Patient Management Patients who experience a NARCAN 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.
Animal Data The intravenous single-dose LD 50 (95% confidence limits) in rats and mice is 150 (135-165) mg/kg and 109 (97-121) mg/kg, respectively. In newborn rats, the subcutaneous single-dose LD 50 (95% confidence limits) is 260 (228-296) mg/kg. Subcutaneous injection in rats at 100 mg/kg/day for three weeks produced only transiently increased salivation and partial ptosis; no drug-related effects were seen at 10 mg/kg/day for three weeks.
Some chemical impurities in naloxone, i.e., noroxymorphone and bisnaloxone, have been shown to produce emesis in dogs when administered alone at i.v. doses equivalent to impurity levels present in naloxone at 60 times the usual human dose (10 mg/day).
NARCAN 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, the patient should be kept under continued surveillance. Repeated doses of NARCAN should be administered, as necessary.
Intravenous Infusion NARCAN may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of NARCAN 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' response.
NARCAN 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 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.
Opioid Overdose - Known or Suspected An initial dose of 0.4 mg to 2 mg of NARCAN 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 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 are usually sufficient. The dose of NARCAN should be titrated according to the patient' response. For the initial reversal of respiratory depression, NARCAN 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 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 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.
NARCAN Challenge Test Used for the diagnosis of suspected opioid tolerance or acute opioid overdosage. The NARCAN challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal, or in a patient whose urine contains opioids. The NARCAN challenge test may be administered by either the intravenous or subcutaneous routes.
Inject 0.2 mg NARCAN.
Observe for 30 seconds for signs or symptoms of withdrawal.
If no evidence of withdrawal, inject 0.6 mg NARCAN.
Observe for an additional 20 minutes.
Administer 0.8 mg NARCAN.
Observe for 20 minutes for signs or symptoms of withdrawal.
Note: Individual patients, especially those with opioid dependence, may respond to lower doses of NARCAN. In some cases, 0.1 mg I.V. NARCAN has produced a diagnostic response.
Interpretation of the Challenge Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal. These may include, but are not limited to: nausea, vomiting, dysphoria, yawning, sweating, tearing, rhinorrhea, stuffy nose, craving for opioid, poor appetite, abdominal cramps, sense of fear, skin erythema, disrupted sleep patterns, fidgeting, uneasiness, poor ability to focus, mental lapses, muscle aches or cramps, pupillary dilation, piloerection, fever, changes in blood pressure, pulse or temperature, anxiety, depression, irritability, back ache, bone or joint pains, tremors, sensations of skin crawling or fasciculations. If signs or symptoms of withdrawal appear, the test is positive and no additional NARCAN should be administered.
Septic Shock The optimal dosage of NARCAN or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ).
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 may be administered I.M. or S.C. in divided doses. If necessary, NARCAN 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 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.
NARCAN (naloxone hydrochloride injection, USP) for intravenous, intramuscular and subcutaneous administration is available as:
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Store at controlled room temperature 15°-30°C (59°-86°F).
Protect from excessive light.
Store in carton until contents have been used.
CAUTION: Federal (USA) law prohibits dispensing without prescription.
NARCAN® is a Registered Trademark of Endo Pharmaceuticals Inc.
Copyright © Endo Pharmaceuticals Inc. 1998
6487-00/January, 1998