There is limited clinical experience with Naloxone Hci 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 Hci 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 Hci (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 Hci 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 Hci 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
Naloxone Hci should not be given to patients who are known to be hypersensitive to the drug.
Naloxone Hci is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients.
It is recommended that infusions of Naloxone Hci 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).
Postoperative: The following adverse effects have been associated with the use of Naloxone Hci 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 Hci 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 Hci.
The following serious adverse reactions are discussed elsewhere in the labeling:
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 Hci clinical studies. In two pharmacokinetic studies with a total of 54 healthy adult subjects exposed to 0.4 mg Naloxone Hci, 0.8 mg Naloxone Hci (two 0.4 mg Naloxone Hcis) or 2 mg Naloxone Hci, 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 Hci 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.
There is no pre-clinical data of relevance to the prescriber which is additional to that already included in other sections of the SPC.
Naloxone Hci 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 Hci 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 Hci 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 Hci is intended for immediate administration as emergency therapy in settings where opioids may be present.
Naloxone Hci is not a substitute for emergency medical care.
Naloxone Hci is a competitive antagonist of µ, δ and κ-opioid receptors. Naloxone Hci is most potent at the µ-receptor. Naloxone Hci, 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 Hci has little effect on the pain threshold in normal conditions, but causes hyperalgesia in stressful conditions where endogenous opioids are produced. Naloxone Hci also inhibits acupuncture analgesia, which is associated with the release of opioid peptides. Naloxone Hci also prevents analgesia produced by PAG (periaqueductal grey matter) stimulation. PAG is one site of action in pain transmission. Naloxone Hci 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 Hci is rapidly absorbed following oral administration but high presystemic metabolism makes this route unreliable. Naloxone Hci 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 Hci 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 Hci is bound to plasma proteins, principally albumin. The plasma half-life is 1-2 hours. When Naloxone Hci 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 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 Hci may precipitate an acute withdrawal syndrome in such patients. The same caution is needed when giving Naloxone Hci 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 Hci should be kept under observation. Repeated doses of Naloxone Hci may be necessary since the duration of action of some opioids may exceed that of Naloxone Hci.
Naloxone Hci 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 Hci 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 Hci, 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 Hci in patients with renal insufficiency/failure have not been established in clinical trials. Caution should be exercised and patients monitored when Naloxone Hci is administered to this patient population.
Liver disease: The safety and effectiveness of Naloxone Hci 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 Hci concentrations were approximately six times higher than in patients without liver disease. Naloxone Hci administration had a diuretic effect in these patients with cirrhosis. Caution should be exercised when Naloxone Hci is administered to a patient with liver disease.
WARNINGSIncluded as part of the "PRECAUTIONS" Section
PRECAUTIONS Risk Of Recurrent Respiratory And Central Nervous System DepressionThe duration of action of most opioids may exceed that of Naloxone Hci 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 Hci. Keep the patient under continued surveillance, and administer additional doses of Naloxone Hci 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/AntagonistsReversal 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 WithdrawalThe use of Naloxone Hci 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 InformationAdvise 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:
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 Hci such as the following:
Instruct patients and their family members or caregivers that since the duration of action of most opioids may exceed that of Naloxone Hci, they must seek immediate emergency medical assistance after the first dose of Naloxone Hci and keep the patient under continued surveillance.
Limited Efficacy For/With Partial Agonists Or Mixed Agonist/AntagonistsInstruct 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 Hci.
Precipitation Of Severe Opioid WithdrawalInstruct patients and their family members or caregivers that the use of Naloxone Hci 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 InstructionsInstruct patients and their family members or caregivers about the following important information:
Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.
MutagenesisNaloxone 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 FertilityReproduction 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 SummaryThe 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 ConsiderationsFetal/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 Hci is used. Careful monitoring is needed until the fetus and mother are stabilized.
DataAnimal 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 SummaryThere 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 Hci and any potential adverse effects on the breastfed infant from Naloxone Hci or from the underlying maternal condition.
Pediatric UseThe safety and effectiveness of Naloxone Hci (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 Hci.
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 Hci. Carefully observe the administration site for evidence of residual needle parts, signs of infection, or both..
Geriatric UseGeriatric 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.
Naloxone Hci is for intravenous, intramuscular or subcutaneous injection or intravenous infusion.
Intravenous infusion: Naloxone Hci 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 Hci 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 Hci 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 Hci 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 Hci 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 Hci, 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 Hci be used to produce sustained antagonism to the opioid without repeated injection.
Post Operative Use
When Naloxone Hci 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 Hci 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 Hci 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 Hci may be required by infusion as described above. If an i.v. route of administration is not feasible, Naloxone Hci 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 Hci 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 Hci 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 InstructionsNaloxone Hci 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 Hci 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 Hci. Emphasize the following instructions to the patient or caregiver:
Upon actuation, Naloxone Hci 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 Hci has delivered the intended dose of naloxone hydrochloride and instructs the user to seek emergency medical attention.
Dosing Information Initial DosingAdminister the initial dose of Naloxone Hci 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 Hci as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.
Repeat DosingThe requirement for repeat doses of Naloxone Hci 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 Hci may be administered. If there is still no response and additional doses are available, additional doses of Naloxone Hci 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 Hci and relapses back into respiratory depression before emergency assistance arrives, an additional dose of Naloxone Hci 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 Hci.
Dosing In Adults And Pediatric Patients Over Age One YearInstruct patients or their caregivers to administer Naloxone Hci according to the Instructions for Use, intramuscularly or subcutaneously.
Dosing In Pediatric Patients Under Age One YearIn pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering Naloxone Hci. 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.
Use once and discard any remaining solution.
