NALOXONE HYDROCHLORIDE injection, solution

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
NALOXONE HYDROCHLORIDE (UNII: F850569PQR) (NALOXONE - UNII:36B82AMQ7N)
Available from:
Medical Purchasing Solutions, LLC
Administration route:
INTRAMUSCULAR
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone hydrochloride injection is also indicated for diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see CLINICAL PHARMACOLOGY; Adjunctive Use in Septic Shock ). Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in the formulation. Naloxone hydrochloride is an opioid antagonist. Physical dependence associated with the use of naloxone hydrochloride has not been reported. Tolerance to the opioid antagonist effect of n
Product summary:
Naloxone hydrochloride injection, USP is a sterile, clear colorless solution for intravenous, intramuscular, or subcutaneous administration and is available as: 0.4 mg per mL 1 mL Single-Dose Vials in a Carton of 10                                                        NDC 55150-327-10 1 mL Single-Dose Vials in a Carton of 25                                                        NDC 55150-327-25 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Store in carton until contents have been used. The vial stopper is not made with natural rubber latex. Distributed by: AuroMedics Pharma LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad - 500038 India Revised: July 2019
Authorization status:
Abbreviated New Drug Application
Authorization number:
71872-7219-1

Read the complete document

NALOXONE HYDROCHLORIDE- naloxone hydrochloride injection, solution

Medical Purchasing Solutions, LLC

----------

Naloxone Hydrochloride Injection, USP

Opioid Antagonist

Rx only

DESCRIPTION

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.

Naloxone hydrochloride, USP 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.

Naloxone hydrochloride injection, USP is available as a sterile, clear colorless solution for

intravenous, intramuscular or subcutaneous administration in the concentration 0.4 mg of naloxone

hydrochloride per mL.

pH is adjusted to 3.0 to 6.5 with hydrochloric acid.

The 0.4 mg/mL vial is available in an unpreserved, paraben-free formulation containing 9 mg/mL of

sodium chloride.

CLINICAL PHARMACOLOGY

Complete or Partial Reversal of Opioid Depression

Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory depression,

sedation and hypotension. Also, naloxone hydrochloride can reverse the psychotomimetic and

dysphoric effects of agonist-antagonists such as pentazocine.

Naloxone hydrochloride is an essentially pure opioid antagonist, i.e., it does not possess the

“agonistic” or morphine-like properties characteristic of other opioid antagonists. When administered

in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits

essentially no pharmacologic activity.

Naloxone hydrochloride has not been shown to produce tolerance or cause physical or psychological

dependence. In the presence of physical dependence on opioids, naloxone hydrochloride will produce

withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms

may appear within minutes of naloxone hydrochloride administration and will subside in about 2 hours.

The severity and duration of the withdrawal syndrome are related to the dose of naloxone

hydrochloride and to the degree and type of opioid dependence. While the mechanism of action of

naloxone hydrochloride is not fully understood, in vitro evidence suggests that naloxone hydrochloride

antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS,

with the greatest affinity for the mu receptor.

Mechanism of Action

When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent

within two minutes. The onset of action is slightly less rapid when it is administered subcutaneously or

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

naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than

intravenous administration. Since the duration of action of naloxone hydrochloride may be shorter than

that of some opiates, the effects of the opiate may return as the effects of naloxone hydrochloride

dissipates. The requirement for repeat doses of naloxone hydrochloride will also be dependent upon

the amount, type and route of administration of the opioid being antagonized.

Adjunctive Use in Septic Shock

Naloxone hydrochloride has been shown in some cases of septic shock to produce a rise in blood

pressure that may last up to several hours; however, this pressor response has not been demonstrated to

improve patient survival. In some studies, treatment with naloxone hydrochloride in the setting of septic

shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary

edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone hydrochloride in

septic shock should be exercised with caution, particularly in patients who may have underlying pain or

have previously received opioid therapy and may have developed opioid tolerance.

Because of the limited number of patients who have been treated, optimal dosage and treatment regimens

have not been established.

PHARMACOKINETICS

Distribution

Following parenteral administration, naloxone hydrochloride is rapidly distributed in the body and

readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the

major binding constituent but significant binding of naloxone also occurs to plasma constituents other

than albumin. It is not known whether naloxone is excreted into human milk.

Metabolism and Elimination

Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with

naloxone-3-glucoronide as the major metabolite. In one study the serum half-life in adults ranged from

30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study the mean plasma half-life was observed to

be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as

metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.

INDICATIONS AND USAGE

Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid

Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid

depression, including respiratory depression, induced by natural and synthetic opioids, including

propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine,

butorphanol, and cyclazocine. Naloxone hydrochloride injection is also indicated for diagnosis of

suspected or known acute opioid overdosage.

Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the

management of septic shock (see CLINICAL PHARMACOLOGY; Adjunctive Use in Septic Shock).

CONTRAINDICATIONS

Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone

hydrochloride or to any of the other ingredients contained in the formulation.

WARNINGS

Drug Dependence

Naloxone hydrochloride should be administered cautiously to persons including newborns of mothers

who are known or suspected to be physically dependent on opioids. In such cases an abrupt and

complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include,

but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing,

piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering

or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid

withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes.

Repeat Administration

The patient who has satisfactorily responded to naloxone hydrochloride should be kept under continued

surveillance and repeated doses of naloxone hydrochloride should be administered, as necessary, since

the duration of action of some opioids may exceed that of naloxone hydrochloride.

Respiratory Depression due to Other Drugs

Naloxone hydrochloride is not effective against respiratory depression due to non-opioid drugs and in

the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by

partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete

or require higher doses of naloxone. If an incomplete response occurs, respirations should be

mechanically assisted as clinically indicated.

PRECAUTIONS

General

In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free

airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed

when necessary to counteract acute opioid poisoning.

Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating,

tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation,

pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone

hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause

agitation (see 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 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 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.

Drug Interactions

Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration

of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor.

Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased

duration of action of the normally prolonged respiratory depression. The barbiturate methohexital

appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been

conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the 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/m

), demonstrated no embryotoxic

or teratogenic effects due to naloxone hydrochloride.

Use in Pregnancy

Teratogenic Effects:

Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a

50 kg human given 10 mg/day (when based on surface area or mg/m

), demonstrated no embryotoxic or

teratogenic effects due to naloxone hydrochloride. 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 should be used during pregnancy only if clearly needed.

Non-teratogenic Effects:

Risk-benefit must be considered before naloxone hydrochloride 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 injection 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 is excreted in human milk. Because many drugs are

excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a

nursing woman.

Pediatric Use

Naloxone hydrochloride injection may be administered intravenously, intramuscularly or

subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of

Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate

intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds

dramatically to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours as a

relapse may occur as naloxone is metabolized.

When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect

lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride

directly to the neonate if needed after delivery. Naloxone hydrochloride has no apparent benefit as an

additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not

related to opioid use.

Usage in Pediatric Patients and Neonates for Septic Shock:

The safety and effectiveness of naloxone hydrochloride 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 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 in patients with renal insufficiency/failure have

not been established in well-controlled clinical trials. Caution should be exercised when naloxone

hydrochloride is administered to this patient population.

Liver Disease

The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been

established in well-controlled clinical trials. Caution should be exercised when naloxone

hydrochloride is administered to patients with liver disease.

ADVERSE REACTIONS

Postoperative

The following adverse events have been associated with the use of naloxone hydrochloride in

postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea,

pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae

of these events. Excessive doses of naloxone hydrochloride in postoperative patients may result in

significant reversal of analgesia and may cause agitation (see 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 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, paraesthesia, 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 flashes, or flushing.

See also PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults;

Postoperative Opioid Depression.

DRUG ABUSE AND DEPENDENCE

Naloxone hydrochloride is an opioid antagonist. Physical dependence associated with the use of

naloxone hydrochloride has not been reported. Tolerance to the opioid antagonist effect of naloxone

hydrochloride is not known to occur.

OVERDOSAGE

There is limited clinical experience with naloxone hydrochloride 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/m

/min) of naloxone

hydrochloride 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 to 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 2½ 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 4½ year-old child who received 11

doses during a 12-hour period, with no adverse sequelae.

Patient Management

Patients who experience a naloxone hydrochloride 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.

DOSAGE AND ADMINISTRATION

Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or

subcutaneously. The most rapid onset of action is achieved by intravenous administration, which is

recommended in emergency situations.

Since the duration of action of some opioids may exceed that of naloxone hydrochloride injection, the

patient should be kept under continued surveillance. Repeated doses of naloxone hydrochloride

injection should be administered, as necessary.

Intravenous Infusion

Naloxone hydrochloride injection may be diluted for intravenous infusion in normal saline or 5%

dextrose solutions. The addition of 2 mg of naloxone hydrochloride injection in 500 mL of either

solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24

hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in

accordance with the patient’s response.

Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite,

metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No

drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the

chemical and physical stability of the solution has first been established.

Usage in Adults

Opioid Overdose–Known or Suspected:

An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride injection 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 injection 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 injection are usually sufficient. The dose of naloxone hydrochloride

injection should be titrated according to the patient’s response. For the initial reversal of respiratory

depression, naloxone hydrochloride injection 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 injection 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 injection 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 injection or duration of therapy for the treatment of

hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY).

Usage in Pediatric Population

Opioid Overdose–Known or Suspected:

The usual initial dose in pediatric patients is 0.01 mg/kg body weight given intravenously. 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 intravenous route of administration is not available, naloxone

hydrochloride injection may be administered intramuscularly or subcutaneously in divided doses. If

necessary, naloxone hydrochloride injection 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 injection 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 intravenously, intramuscularly or

subcutaneously. This dose may be repeated in accordance with adult administration guidelines for

postoperative opioid depression.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to

administration whenever solution and container permit.

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

HOW SUPPLIED

Naloxone hydrochloride injection, USP is a sterile, clear colorless solution for intravenous,

intramuscular, or subcutaneous administration and is available as:

0.4 mg per mL

1 mL Single-Dose Vials

in a Carton of 10 NDC 55150-327-10

1 mL Single-Dose Vials

in a Carton of 25 NDC 55150-327-25

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light.

Store in carton until contents have been used.

The vial stopper is not made with natural rubber latex.

Distributed by:

AuroMedics Pharma LLC

279 Princeton-Hightstown Rd.

E. Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad - 500038

India

Revised: July 2019

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL- VIAL LABEL

Rx only

Naloxone

Hydrochloride

Injection, USP

0.4 mg per mL

1 mL Single-Dose Vial

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL- OUTER PACKAGE

NDC 71872-7219-1

1 x 1 mL Single-Dose Vial

0.4 mg per mL

Rx only

Naloxone

Hydrochloride

Injection, USP

For Intravenous, Intramuscular or Subcutaneous Use.

Protect from light.

Sterile, nonpyrogenic

Similar products

Search alerts related to this product

View documents history

Share this information