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

Posology

Opioid overdosage (known or suspected):

Adults

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.

Paediatric population

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.

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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

4.4. Special warnings and precautions for use

Naloxone 400 micrograms/ml must be given with caution to patients who have received large doses of opioids or are physically dependent on opioids. Too rapid reversal of opioid effects can cause an acute withdrawal syndrome in such patients. Hypertension, cardiac arrhythmias, pulmonary oedema and cardiac arrest have been described. This also applies to newborn infants of such patients.

Patients who respond satisfactorily to naloxone hydrochloride must be closely monitored. The effect of opioids can be longer than the effect of naloxone hydrochloride and new injections may be necessary.

Naloxone hydrochloride is not effective in central depression caused by agents other than opioids. Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incomplete response occurs, respiration should be mechanically assisted.

Following the use of opioids during surgery, excessive dosage of naloxone hydrochloride should be avoided, because it may cause excitement, increase in blood pressure and clinically important, reversal of analgesia. A reversal of opioid effects achieved too rapidly may induce nausea, vomiting, sweating or tachycardia.

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.

Naloxone hydrochloride has been reported to induce hypotension, hypertension, ventricular tachycardia, fibrillation and pulmonary oedema. These adverse effects have been observed postoperatively most often in patients who have cardiovascular diseases or who have used medicines with similar cardiovascular adverse effects. Although no direct causative relations have been shown, caution should be used in administering Naloxone 400 micrograms/ml to patients with heart diseases or to patients who are taking relatively cardiotoxic drugs causing ventricular tachycardia, fibrillation and cardiac arrest (e.g. cocaine, methamphetamine, cyclic antidepressants, calcium channel blockers, beta-blockers, digoxin). See section 4.8.

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.

This medicinal product contains 88.2 mg sodium per maximum daily dose of 10mg naloxone hydrochloride, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

The effect of naloxone hydrochloride is due to the interaction with opioids and opioid agonists. When administered to subjects dependent on opioids, in some subjects the administration of naloxone hydrochloride can cause pronounced withdrawal symptoms. Hypertension, cardiac arrhythmias, pulmonary oedema and cardiac arrest have been described.

With a standard naloxone hydrochloride dose there is no interaction with barbiturates and tranquillizers.

Data on interaction with alcohol are not unanimous. In patients with multi-intoxication as a result of opioids and sedatives or alcohol, depending on the cause of the intoxication, one may possibly observe a less rapid result after administration of naloxone hydrochloride.

When administering naloxone hydrochloride to patients who have received buprenorphine as an analgesic complete analgesia may be restored. It is thought that this effect is a result of the arch-shaped dose-response curve of buprenorphine with decreasing analgesia in the event of high doses. However, reversal of respiratory depression caused by buprenorphine is limited.

Severe hypertension has been reported on administration of naloxone hydrochloride in cases of coma due to a clonidine overdose.

4.6. Fertility, pregnancy and lactation

Pregnancy

For naloxone hydrochloride insufficient clinical data on exposed pregnancies are available. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. The medicinal product should not be used during pregnancy unless clearly necessary. Naloxone hydrochloride can cause withdrawal symptoms in new-born infants (see section 4.4).

Breast-feeding

It is not known whether naloxone hydrochloride passes into breast milk and it has not been established whether infants who are breast-fed are affected by naloxone hydrochloride. Therefore, breast-feeding should be avoided for 24 hours after treatment.

Fertility

No clinical data are available. Refer section 5.3 Preclinical safety data for more detail.

4.7. Effects on ability to drive and use machines

Patients who have received naloxone hydrochloride to reverse the effects of opioids should be warned to avoid road traffic, operate machinery or engage in other activities demanding physical or mental exertion for at least 24 hours, since the effect of the opioids may return.

4.8. Undesirable effects

The following frequency terminology is used:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1 000 to < 1/100)

Rare (≥ 1/10 000 to < 1/1 000)

Very rare (< 1/10 000)

Not known (cannot be estimated from the available data)

Immune system disorders

Very rare: Allergic reactions (urticaria, rhinitis, dyspnoea, Quincke's oedema), anaphylactic shock

Nervous system disorders

Common: Dizziness, headache

Uncommon: Tremor, sweating

Rare: Seizures, tension

Seizures have occurred rarely following administration of naloxone hydrochloride; however, a causal relationship to the drug has not been established. Higher than recommended dosage in postoperative use can lead to tension.

Cardiac disorders

Common: Tachycardia

Uncommon: Arrhythmia, bradycardia

Very rare: Fibrillation, cardiac arrest

Vascular disorders

Common: Hypotension, hypertension

Hypotension, hypertension and cardiac arrhythmia (including ventricular tachycardia and fibrillation) have also occurred with the postoperative use of naloxone hydrochloride. Adverse cardiovascular effects have occurred most frequently in postoperative patients with a pre-existing cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects.

Respiratory, thoracic and mediastinal disorders

Very rare: Pulmonary oedema

Pulmonary oedema has also occurred with the postoperative use of naloxone hydrochloride.

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting

Uncommon: Diarrhoea, dry mouth

Nausea and vomiting have been reported in postoperative patients who have received doses higher than recommended. However, a causal relationship has not been established, and the symptoms may be signs of too rapid antagonisation of the opioid effect.

Skin and subcutaneous tissue disorders

Very rare: Erythema multiforme

One case of erythema multiforme cleared promptly after naloxone hydrochloride was discontinued.

General disorders and administration site conditions

Common: Postoperative pain

Uncommon: Hyperventilation, irritation of vessel wall (after i.v. administration); local irritation and inflammation (after i.m. administration)

Higher than recommended dosage in postoperative use can lead to the return of pain.

A fast reversal of opioid effect can induce hyperventilation.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In view of the indication and the broad therapeutic margin overdose is not expected. Single dose of 10mg naloxone hydrochloride i.v. have been tolerated without any adverse effects or changes in laboratory values. Higher than the recommended dosage in postoperative use can lead to the return of pain and tension.