Naloxone

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.

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.

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).

Naloxone must be given with caution to patients who have received high doses of opioids or are physically dependent on opioids. Too rapid reversal of the opioid effect 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.

There are no adequate data from the use of naloxone in pregnant women. Studies in animals have shown reproductive toxicity only at maternally toxic doses. The potential risk for humans is unknown. Naloxone should not be used during pregnancy unless the clinical condition of the woman requires treatment with naloxone.

In pregnant women who have been treated with naloxone, the fetus should be monitored for signs of distress.

In opioid dependent pregnant women, naloxone administration can cause withdrawal symptoms in newborn infants.

It is unknown whether naloxone is excreted in human breast milk and it has not been established whether infants who are breast-fed are affected by naloxone. However, as naloxone is practically not orally bioavailable its potential to affect a breast-fed infant is negligible. Caution should be exercised when naloxone is administered to a breast-feeding mother but there is no need to discontinue breast-feeding. Breast-fed babies from mothers who have been treated with naloxone should be monitored to check for sedation or irritability.

Patients who have received naloxone to reverse the effects of opioids should be warned not to drive, to operate machinery or to engage in other activities demanding physical or mental exertion for at least 24 hours, since the effect of the opioids may return.

Summary of the safety profile

The most common adverse reaction (AR) seen with naloxone administration is nausea (frequency very common). Typical opioid withdrawal syndrome is expected with naloxone which may be caused by the abrupt withdrawal of opioid in persons physically dependent on them.

Tabulated list of adverse reactions

The following adverse reactions have been reported with naloxone-containing medicinal products during clinical studies and post marketing experience. ARs are listed below by system organ class and frequency.

Frequency categories are assigned to those adverse reactions considered to be at least possibly causally related to naloxone and are defined as very common: (≥1/10); common: (≥1/100, <1/10); uncommon: (≥1/1,000, <1/100); rare: (≥1/10,000, <1/1,000) very rare: (<1/10,000); not known (cannot be estimated from the available data).

Immune system disorders

Very rare: Hypersensitivity, Anaphylactic shock

Nervous system disorders

Common: Dizziness, Headache

Uncommon: Tremor

Cardiac disorders

Common: Tachycardia

Uncommon: Arrhythmia, Bradycardia

Very rare: Cardiac fibrillation, Cardiac arrest

Vascular disorders

Common: Hypotension, Hypertension

Respiratory, thoracic and mediastinal disorders

Uncommon: Hyperventilation

Very rare: Pulmonary oedema

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting

Uncommon: Diarrhoea, Dry mouth

Skin and subcutaneous tissue disorders

Uncommon: Hyperhidrosis

Very rare: Erythema multiforme

General disorders and administration site conditions

Uncommon: Drug withdrawal syndrome (in patients dependent on opioids)

Description of selected adverse reactions

Drug withdrawal syndrome

Signs and symptoms of drug withdrawal syndrome include restlessness, irritability, hyperaesthesia, nausea, vomiting, gastrointestinal pain, muscle spasms, dysphoria, insomnia, anxiety, hyperhidrosis, piloerection, tachycardia, increased blood pressure, yawning, pyrexia. Behavioural changes including violent behaviour, nervousness and excitement may also be observed.

Vascular disorders

In reports on intravenous/intramuscular naloxone: hypotension, hypertension, cardiac arrhythmia (including ventricular tachycardia and fibrillation) and pulmonary oedema have occurred with the postoperative use of naloxone. Adverse cardiovascular effects have occurred more frequently in postoperative patients with a pre-existing cardiovascular disease or in those receiving other medicines that produce similar adverse cardiovascular effects.

Paediatric population

Intranasal naloxone is intended for use in adolescents 14 years and over. Frequency, type and severity of adverse reactions in adolescents are expected to be the same as in adults.