PRENOXAD Solution for injection/infusion Ref.[27751] Active ingredients: Naloxone

Patients must be instructed in the proper use of Prenoxad Injection . See Section 4.2.

Prenoxad Injection is intended as an emergency treatment and the patient should be advised to seek medical help immediately. Therefore patients at risk of experiencing an opioid overdose event and/or any other person who might be in a position to administer Prenoxad Injection to a patient experiencing such an event should be carefully instructed in regard to the circumstances under which this potentially life-saving medication should be used.

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 Prenoxad Injection may precipitate an acute withdrawal syndrome in such patients. The same caution is needed when giving Prenoxad to neonates delivered to such patients.

Hypertension, cardiac arrhythmias, pulmonary oedema and cardiac arrest have been described.

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 Prenoxad Injection should be placed under medical supervision and kept under observation for at least 2 hours. Repeated doses of Prenoxad Injection may be necessary since the duration of action of some opioids may exceed that of Prenoxad Injection.

Prenoxad Injection 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 sequel of these events. Although a direct cause and effect relationship has not been established, Prenoxad Injection 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 Prenoxad Injection 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 Prenoxad Injection in patients with renal insufficiency/failure have not been established in clinical trials. Caution should be exercised and patients monitored when Prenoxad Injection is administered to this patient population.

Liver disease: The safety and effectiveness of Prenoxad Injection 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 Prenoxad Injection is administered to a patient with liver disease.

1 ml of naloxone hydrochloride contains 3.497 mg of sodium which is less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

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.

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established.

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.In a pregnant woman who is known or suspected to be opioid-dependent, risk benefit must be considered before Prenoxad Injection 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.

Use in Labour and Delivery

Prenoxad injection may be administered to mothers during the second stage of labour to correct respiratory depression caused by opioids used to provide obstetrical analgesia.

It is not known if Naloxone affects the duration of labour and/or delivery. Breast-feeding

It is not known whether Naloxone is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when Prenoxad Injection is administered to a nursing mother. Therefore, breast-feeding should be avoided in the first 24 hours after treatment.

Patients who have received Prenoxad 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.

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

It is recommended that infusions of Naloxone Hydrochloride should not be mixed with preparations containing bisulphite, metabisulphite, long-chain or high molecular weight anions, or solutions with an alkaline pH.