Naxone is indicated in:

• Post operative opioids central depression including respiratory depression induced by natural or synthetic opioids.
• Known or suspected opioids overdose or dependency.
• The treatment of opiate-induced asphyxia neonatorum, resulting from the administration of opiates to the mother during labor and delivery.
• Naxone is recommended as a screening test (the naloxone challenge test) prior to induction of therapy with naltrexone for opiate cessation in patients formerly dependent on opiates, who have completed detoxification.

(See Section 5.2 Pharmacokinetic Properties-Special patient population)

The drug could be given intravenously (IV), intramuscularly (IM) or subcutaneously (SC). It is preferable to use intravenous (IV) injection in emergency situations, and to use the intramuscular (IM) or subcutaneous (SC) injection when longer duration of action is needed.

For IV infusion preparation, please refer to section 6.6.

Usual dosage

• In post operative opioids depression

Adults: initial dose of 0.4 – 2 mg IV Naxone at 2-3 minute intervals to the desired degree of reversal. Repeated doses may be required within 1 or 2 hours, depending on the amount, type and time interval since the last administration of opioid. Children: inject increments of 0.005 – 0.01 mg IV Naxone at 2-3 minute intervals to desired degree of reversal.

• In opioid overdose

Adults: initial dose of 0.4 – 2 mg IV Naxone, may be repeated at 2-3 minute intervals. If no response is observed after 10 mg have been administered, the diagnosis of opioids overdose must be questioned.

Children: initial dose of 0.01 mg/kg; give subsequent 0.1 mg/kg if needed.

• In asphyxia neonatrum

Initial dose of 0.01 mg administered into the umbilical vein of the neonate at 2-3 minute intervals until the desired response is obtained; if necessary, additional doses may be given at 1-2 hour intervals.

Naloxone 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 and 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 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, 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 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. Although a direct cause and effect relationship has not been established, naloxone should also 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.

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.

Naloxone   prevents   or   reverses   the   effects   of   opioids,   including   respiratory depressive, sedative and hypotensive effects; it reverses the psychotomimetic and dysphoric effects of mixed agonist-antagonist drugs such as pentazocine.

• Pregnancy

Although reproduction studies in animals have not demonstrated any teratogenic or embryo-toxic effects, Naxone should be used with caution, like other drugs, during pregnancy. During the second stage of labor, Naxone may be administered to the mother in order to correct respiratory depression in the newborn due to the use of opioids for obstetrical analgesia.

In  a  pregnant  woman  who  is  known  or  suspected to  be  opioid-dependent, risk benefit must be considered before Naxone is administered, since maternal dependence may be accompanied by fetal dependence. In this time of circumstance, the  neonate  should   be   monitored  for   respiratory  rate  and   signs  of   opioid withdrawal.

• Lactation

It is not known whether naloxone is excreted in human milk. Therefore, caution should be exercised when administering Naxone to a nursing mother.

Following  intravenous administration, there  may be  decreased performances on tests of memory. However, this effect is not clinically relevant since the patients would  already  be  restricted  from  driving  or  using  machines  because  of  the conditions in which the drug is administered.

• Populations

- 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.

- 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, and hyperactive reflexes.

-   Post-operative patients

The following adverse events have been associated with the use of 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 in postoperative patients may result in significant reversal of analgesia and may cause agitation.

The following categories were used for the classification of undesirable effects:

very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, ≤1/100), rare (≥1/10,000, ≤1/1000), very rare (≤1/10,000). Adverse event frequencies have been estimated from spontaneous reports from post-marketing data.

The following are the adverse events associated with the postoperative use of naloxone:

Cardiac Disorders

Frequency unknown   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

Frequency unknown   nausea, vomiting

Nervous System disorders

Frequency unknown   convulsions, paresthesia, grand mal convulsion

Psychiatric disorders

Frequency unknown   agitation, hallucination, tremulousness

Respiratory, thoracic and mediastinal disorders

Frequency unknown   dyspnea, respiratory depression, hypoxia

Skin and subcutaneous tissue disorders

Frequency unknown   nonspecific injection site reactions, sweating

Vascular disorders

Frequency unknown   hypertension, hypotension, hot flushes or flushing

There have been no reports of acute overdosage with naloxone.

Naloxone is a specific semi-senthetic opioid antagonist without agonist morphine- like activity. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity.

While the exact mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the μ, ĸ, and ơ opiate receptor sites in the CNS, with the greatest affinity for the μ receptor.

Naloxone acts within 2 minutes of intravenous administration. The onset of action is slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent on the dose and route of administration and may be 1 to 4 hours or shorter.

ATC code: V03AB15

• Absorption

Although  absorbed  readily  from  the  gastrointestinal  tract  when  taken  orally, naloxone undergoes extensive first-pass metabolism in the liver before reaching the systemic circulation, therefore it must be administered parenterally. It is rapidly absorbed from parenteral sites of injection.

• Distribution

Following parenteral administration, naloxone is rapidly distributed in the body and readily crosses the placenta. Plasma protein binding occurs but it is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin.

• Metabolism

Naloxone is metabolized in the liver, primarily by glucoronide 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.

• Elimination

After an oral or intravenous dose, about 25-40% is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

Preclinical safety data does not add anything of further significance to the prescriber.

- Sodium chloride

- Methyl paraben

- Propyl paraben

- Hydrochloric acid

- Water for injection

Naloxone should not be mixed with preparations containing bisulphite, metabisulphite, long-chain or high molecular weight anions or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone unless its effect on the chemical and physical stability of the solution has first been established.

Store below 25°C. Protect from light. Protect from freezing.

2 mL type I amber ampoule, packed in boxes, 6 ampoules per box.

To prepare IV infusion: the addition of 2 mg Naxone to 500 mL of either normal saline or 5% dextrose solutions, provides a concentration of 0.004 mg/mL.

Titrate the administration rate in accordance with patients within 24 hours, after that, discard the solution.