Naloxone Hydrochloride Injection USP 40 micrograms / 2ml

1. Name Of The Medicinal Product

Naloxone Hydrochloride Injection USP 40 micrograms/2ml (0.02mg/ml, 2ml)

2. Qualitative And Quantitative Composition

Each 2ml of solution contains 40 micrograms (0.04mg) of Naloxone Hydrochloride USP

3. Pharmaceutical Form

Clear, colourless, sterile solution.

4. Clinical Particulars

4.1 Therapeutic Indications

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, the agonists/antagonists nalbuphine and pentazocine, or dextropropoxyphene.

It may also be used for the diagnosis of suspected acute opioid overdosage. Naloxone may be used to counteract respiratory and other CNS depression in the newborn resulting from the administration of analgesics to the mother during childbirth.

4.2 Posology And Method Of Administration

Naloxone is for intravenous, intramuscular or subcutaneous injection. It may also be administered by intravenous infusion.

Intravenous infusion:

Addition of 2mg of naloxone to 500ml of normal saline (0.9%) or to 500ml of 5% dextrose in water or in saline will provide a concentration of 4 micrograms/ml (0.004mg/ml). After 24 hours, any unused solution should be discarded. The rate of infusion should be titrated according to the patient's response to the infused naloxone and to any previously administered bolus doses.

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. Before administration, parenteral drugs should be inspected visually for particulate matter and discolouration whenever the solution and container permit.

Adults:

Opioid overdosage (known or suspected):

An initial dose of 400 to 2000 micrograms (0.4mg to 2mg) of naloxone may be given intravenously and may, if required, be repeated at 2 to 3 minute intervals. The diagnosis of opioid-related toxicity should be reconsidered if there is still failure to respond after a total of 10mg of naloxone has been administered. If intravenous administration is impracticable, naloxone may be administered by the intramuscular or subcutaneous route. The duration of action of some opioids (including dextropropoxyphene, dihydrocodeine and methadone) may exceed that of naloxone. In these circumstances, an intravenous infusion of naloxone will provide sustained antagonism of the opioid and obviate the need for repeated injections.

Post-operative use: Intravenous doses of 100 to 200 micrograms (0.1 to 0.2mg), corresponding to 1.5 to 3 micrograms (0.0015 to 0.003mg) per kg body weight, may be used. The dose should be titrated according to the individual patient's response and a full 2 minutes should be allowed between each 100 micrograms (0.1mg) increment of naloxone administered.

Depending on the type of opioid, the dose and the time interval from its last administration, repeat doses of naloxone may be required within one to two hours and may be administered by intramuscular injection or by intravenous infusion in order to produce a more sustained effect.

Children:

The usual initial dose is 10 micrograms (0.01mg) per kg body weight, intravenously. A subsequent dose of 100 micrograms (0.1mg) per kg body weight may be used if required. Naloxone may be administered by intravenous infusion, if appropriate. Alternatively, it may be given I.M. or S.C. in divided doses.

Neonatal Use:

For opioid-related depression, the usual initial dose is 10 micrograms (0.01mg) per kg body weight, I.V., I.M. or S.C., and this may be repeated, if required, at 2 to 3 minute intervals. Alternatively, a single dose of 200 micrograms (0.2mg), approximately 60 micrograms (0.06mg) per kg body weight, may be administered intramuscularly at birth.

An adequate airway should be established prior to administering naloxone to the apnoeic infant.

4.3 Contraindications

Naloxone should not be given to patients who are known to be hypersensitive to the drug, or any of the excipients (see section 6.1)

4.4 Special Warnings And Precautions For Use

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 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 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 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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.

4.6 Pregnancy And Lactation

Although reproduction studies in animals have not demonstrated any teratogenic or embryotoxic effects, naloxone should be used with caution, like other drugs, during pregnancy. During the second stage of labour, Naloxone 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 Naloxone is administered, since maternal dependence may be accompanied by foetal dependence. In this type 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. Because many drugs are excreted in human milk, caution should be exercised when Naloxone is administered to a nursing mother.

4.7 Effects On Ability To Drive And Use Machines

Following I.V. 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.

4.8 Undesirable Effects

Nausea and vomiting have been reported in some post-operative patients who received naloxone in doses higher than those recommended; a direct relationship has not been established.

Abrupt reversal of narcotic depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures and cardiac arrest. In postoperative patients, larger than necessary dosage of naloxone may result in significant reversal of analgesia and excitement.

Hypotension, hypertension, ventricular tachycardia and fibrillation and pulmonary oedema have been associated with the use of naloxone postoperatively.

4.9 Overdose

There have been no reports of acute overdosage with naloxone.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Naloxone is a specific opioid antagonist without agonist morphine-like activity. It acts within two minutes of administration. The duration of action is dependent on the dose and route of administration and may be one to four hours or shorter.

5.2 Pharmacokinetic Properties

Although absorbed readily from the gastrointestinal tract, 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 and is metabolised in the liver, mainly by glucuronide conjugation, and excreted in urine. Naloxone has a short plasma half-life of approximately 1 to 1.5 hours after parenteral administration. In neonates, a plasma half-life of 3 hours was reported.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injections

Dilute Hydrochloric Acid

6.2 Incompatibilities

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.

6.3 Shelf Life

4 years.

6.4 Special Precautions For Storage

Store below 25°C.

Protect from light.

6.5 Nature And Contents Of Container

2ml, clear glass ampoules, glass type 1 Ph. Eur. borosilicate glass, packed in cardboard cartons to contain 10 x 2ml ampoules; 3 x 2ml ampoules and 5 x 2ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Antigen International Ltd.

Roscrea

Co. Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 02848/0134

9. Date Of First Authorisation/Renewal Of The Authorisation

5/9/90

10. Date Of Revision Of The Text

25/06/2007