Composition:
Each 1ml solution contains 400µg Naloxone hydrochloride (as Naloxone hydrochloride dehydrate), it contains 3.54ng sodium.
Mechanism of action:
Pharmacotherapeutic group: antidotes.
Xonidan is a specific opioid-antagonist that acts competitively at opioid receptors. It reveals very high affinity for the opioid receptor sites and therefore displaces both opioid agonists and partial antagonists.
Xonidan does not counteract central depression caused by hypnotics or other non-opioids and does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists.
Xonidan has not been shown to produce tolerance or cause physical or mental dependence. In case of opioid dependence, administration of Xonidan will enhance the symptoms of physical dependence.
When administered intravenously, the pharmacological effect will usually be visible within 2 minutes. The duration of the antagonistic effect depends on the dose, but in general is in the range of 45 minutes to 4 hours. The need of repeated doses depends on the quantity, type and route of administration of the opioid that must be antagonized.
Pharmacokinetic properties:
Absorption:
Xonidan is rapidly absorbed from the gastrointestinal tract but it is subject to considerable first-pass metabolism and is rapidly inactivated following oral administration. Although the drug is effective orally, doses much larger than those required for parenteral administration are required for complete opioid antagonism (the bioavailability is about 1/50 compared to parenteral administration). Therefore, Xonidan is administered parenterally.
Distribution:
Following parenteral administration, Xonidan is rapidly distributed into body tissues and fluids, especially into the brain, because the drug is highly lipophilic. At maximal serum concentration (15 minutes after injection) the cerebral concentration is 1.5 times higher than the plasma concentration. Xonidan readily crosses the placenta; however, it is not known whether it is distributed into breast milk.
Biotransformation:
Xonidan is rapidly metabolised in the liver. Xonidan and its metabolites are excreted into urine (70 % in 72 hours).
Elimination:
Xonidan has a short plasma half-life of approximately 1-1.5 hours after parenteral administration. The plasma half-life for neonates is approximately 3 hours. The total body clearance amounts to 22ml/min/kg.
Indications:
Contraindications:
Hypersensitivity to the active substance or to any of the excipients.
Posology:
Adults:
Dosage is determined for each patient in order to obtain optimum respiratory response while maintaining adequate
analgesia. An IV injection of 100 to 200µg Xonidan is usually sufficient. If necessary, additional IV injections of 100µg can be administered at 2 – 3 minutes intervals until satisfactory respiration and consciousness are obtained. An additional injection can again be necessary within 1 to 2 hours, depending on the type of active substance to be antagonised (short-term effect or slow release), the amount administered and time and mode of administration.
Xonidan 400µg/ml can alternatively be administered as an IV infusion, if the duration of action for some opioids is longer than that of the Xonidan IV bolus.
The infusion rate is determined according to the individual patient, depending on the response of the patient to the IV bolus and on the reaction of the patient to the IV infusion.
Children and adolescents:
Initially, 10-20µg/kg of Xonidan IV at intervals of 2-3 minutes until satisfactory respiration and
consciousness are obtained. Additional doses may be necessary at 1- to 2-hours intervals depending on the response of the patient and the dosage and duration of action of the opiate administered.
The dose in children and adolescents can be different due to local recommendations.
Elderly:
In elderly patients with pre-existing cardiovascular disease or in those receiving potentially cardiotoxic drugs, Xonidan should be used with caution since serious adverse cardiovascular effects such as ventricular tachycardia and fibrillation have occurred in postoperative patients following administration of naloxone hydrochloride.
Diagnosis and treatment of suspected acute opioid overdose or intoxication:
Adults:
The usual starting dose for adults is 400-2000µg Xonidan, administered intravenously. If the desired degree of reversal and improvement of the respiratory function are not attained directly after the IV injection, the injection can be repeated intravenously at 2-3 minutes intervals. Xonidan can also be injected intramuscularly, if IV administration is not possible.
If 10mg Xonidan does not produce a significant improvement, this suggests that the depression is wholly or partially caused by other pathological conditions or active substances than opioids.
Children and adolescent:
The usual starting dose of Xonidan is 10µg/kg body weight IV. If a satisfactory clinical response is not achieved, an increased additional dose of 100µg/kg can be administered. Depending on the individual patient, IV infusion may also be necessary. If IV administration is not possible, Xonidan 400µg/ml can also be injected IM (initial dose 10µg/kg), divided into several doses.
The dose in children and adolescents can be different due to local recommendations.
Neonates whose mothers have received opioids:
The usual dosage of Xonidan is 10µg/kg IV. If the respiratory function is not reversed to a satisfactory level with this dosage, the injection can be repeated at 2 to 3 minutes intervals. If IV administration is not possible, Xonidan 400µg/ml can also be injected IM. (Initial dose 10µg/kg).
The dose in neonates can be different due to local recommendations.
Method of administration:
The medicinal product can be injected intravenously IV, intramuscularly IM or can be given via intravenous infusion.
IM administration of Xonidan should only be used in cases where an IV administration is not possible.
The most rapid effect is obtained by means of IV administration, which is why this method of administration is
recommended in acute cases.
When Xonidan is administered IM, it is necessary to remember that the onset of action is slower than following IV injection; however, IM administration has a longer action than IV administration. The duration of action is dependent upon the dose and route of administration of Naloxone hydrochloride, varying between 45 minutes and 4 hours.
As it is possible that the duration of action of some opioids is longer than that of naloxone hydrochloride, the patient must be constantly monitored and repeated doses must be administered, if necessary.
Naloxone hydrochloride is for single use only. Discard any unused solution, and inspect it visually prior to use.
Use only clear and colourless solutions free from particles.
For IV infusion Xonidan 400µg/ml is diluted with sodium chloride 0.9% or glucose 5%.
Warnings and precautions:
Undesirable effects:
Nervous system disorders: Common: dizziness, headache. Uncommon: tremor, sweating. Rare: seizures, tension.
Higher than recommended dosage in postoperative use can lead to tension.
Cardiac disorders: Common: tachycardia. Uncommon: arrhythmia, bradycardia.
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:
Pulmonary oedema has 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 antagonization of the opioid effect.
General disorders and administration site conditions: Common: postoperative pain. Uncommon: Hyperventilation, irritation of vessel wall (after IV administration).
Higher than recommended dosage in postoperative use can lead to the return of pain. A fast reversal of opioid effect can induce hyperventilation.
Drug Interactions:
The effect of Xonidan is based on the interaction with opioids and opioid agonists.
At the usual dose there is no interaction with barbiturates and tranquillizers.
Data on the interaction with alcohol are not uniform. In patients with multiple intoxication with opioids and sedatives or alcohol, the result of administration may be delayed, dependent on the cause of intoxication.
In administration of naloxone to patients that had buprenorphine as analgesic, complete analgesia can be restored. However, reversal of respiratory depression caused by buprenorphine is limited. In administration in coma caused by clonidine-overdosing, serious hypertension has been reported.
Incompatibilities:
This medicinal product must not be mixed with other medicinal products except: sodium chloride 0.9% or glucose 5%.
Overdose:
Regarding the indication and the wide therapeutic index, overdosing is not to be expected.
Single doses of 10mg naloxone hydrochloride intravenously and cumulative doses up to 90 mg/day subcutaneously have been tolerated without undesirable effects or changes in laboratory parameters. Thus far no cases of intoxication are known.
Pregnancy:
There are no adequate data available on the use of naloxone hydrochloride in pregnant women.
Animal studies have shown reproductive toxicity but the potential risk for humans is unknown. Naloxone hydrochloride should not be used during pregnancy unless clearly necessary.
Naloxone hydrochloride can cause withdrawal symptoms in the new-born infant.
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.
Effects on ability to drive and use machines:
No studies on the effects on the ability to drive and use machines have been performed.
Patients who have received Naloxone hydrochloride to reverse the effect of opioids should be warned not to take part in road traffic, to operate machinery or to engage in other activities demanding physical or mental exertation for at least 24 hours, since the effect of the opioids may return.