Consumer medicine information

Nyxoid

Naloxone

BRAND INFORMATION

Brand name

Nyxoid

Active ingredient

Naloxone

Schedule

SUMMARY CMI

NYXOID^® nasal spray

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using NYXOID?

NYXOID contains the active ingredient Naloxone. NYXOID is a nasal spray used as part of the emergency treatment of opioid overdose or possible opioid overdose.

For more information, see Section 1. Why am I using NYXOID? in the full CMI.

2. What should I know before I use NYXOID?

Do not use if you have ever had an allergic reaction to Naloxone or any of the ingredients listed at the end of the CMI.

Talk to your doctor or pharmacist if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use NYXOID? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with NYXOID and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use NYXOID?

One spray of NYXOID is given into one nostril.
Each NYXOID nasal spray contains one single dose of naloxone and cannot be reused. Do not prime or test the device before you give it.
Call for an ambulance before giving NYXOID.

More instructions can be found in Section 4. How do I use NYXOID? in the full CMI.

5. What should I know while using NYXOID?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using NYXOID.
Driving or using machines	Do not drive or operate machinery after you have been given NYXOID nasal spray for at least 24 hours (1 day), since the effects of opioids may recur.
Drinking alcohol	If alcohol has been taken in addition to opioids there may be a delay in the action of naloxone.
Looking after your medicine	Store below 30°C. Do not freeze

For more information, see Section 5. What should I know while using NYXOID? in the full CMI.

6. Are there any side effects?

Common side effects include dizziness, headache, nausea and vomiting, or high or low blood pressure. You may experience withdrawal symptoms which include:

restlessness or irritability
change in mood
increased skin sensitivity or goosebumps
vomiting, nausea, stomach or muscle cramps
sleeping difficulty, anxiety
sweating, fast heartbeat, high blood pressure, yawning or fever

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

NYXOID^® nasal spray

Active ingredient: Naloxone Hydrochloride Dihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using NYXOID. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using NYXOID.

Where to find information in this leaflet:

1. Why am I using NYXOID?
2. What should I know before I use NYXOID?
3. What if I am taking other medicines?
4. How do I use NYXOID?
5. What should I know while using NYXOID?
6. Are there any side effects?
7. Product details

1. Why am I using NYXOID?

NYXOID contains the active ingredient naloxone. Naloxone belongs to a group of medicines that cause temporary reversal of the effects of opioids such as methadone or heroin.

NYXOID is a nasal spray used as part of the emergency treatment of opioid overdose or possible opioid overdose.

Signs of overdose include:

breathing problems,
severe sleepiness
not responding to a loud noise or touch.

If you are at risk of an opioid overdose you should always carry your NYXOID with you. It is designed as an emergency rescue treatment only; you must get emergency medical attention as soon as possible after its use.

2. What should I know before I use NYXOID?

Warnings

Do not use NYXOID if:

you are allergic to naloxone hydrochloride dihydrate, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
If it has expired or is damaged, return it to your pharmacist for disposal.

Check with your doctor or pharmacist if you:

Have any other medical conditions, such as
- heart disease
- lung disease
- kidney disease
- liver disease
drug addiction (including an addiction to alcohol)
take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor or pharmacist if you are pregnant or intend to become pregnant.

Talk to your doctor or pharmacist if you are breastfeeding or intend to breastfeed.

If you have received NYXOID close to giving birth or during labour, tell your midwife or doctor. Your baby could suffer from sudden opioid withdrawal syndrome, which could be life-threatening if not treated

If you have not told your doctor about any of the above, tell them before you are given NYXOID.

NYXOID will only be made available after you or your carer have been instructed how to use it

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

These include but are not limited to:

pain killers
cough and cold remedies
alcohol
heart or blood pressure medications.

Some medicines may interfere with NYXOID and affect how it works.

If you take opioids to control chronic pain, you may experience pain when you receive NYXOID.

Talk to your doctor before being given NYXOID if you are physically dependent on opioids or if you have received high doses of opioids (for example methadone or heroin). You may get strong withdrawal symptoms if the effects of this medicine occur too quickly.

Talk to your doctor if you use buprenorphine. NYXOID may not fully reverse breathing problems.

These medicines may be affected by NYXOID nasal spray or may affect how well NYXOID nasal spray works. You may need different amounts of your medicines, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect NYXOID.

4. How do I use NYXOID?

How much to use

One spray of NYXOID is given into one nostril.
Each NYXOID nasal spray contains one single dose of naloxone and cannot be reused.
The signs and symptoms of an opioid overdose can return after this nasal spray is given. If this happens, or there is no response to treatment, another dose after 2 to 3 minutes using a new nasal spray may be administered.

When to use NYXOID

If you or your carer do not understand the instructions on the leaflet, ask your doctor or pharmacist for help.
It is likely that you will be given this medicine by your carer who is trained to do so.
Your carer must call for emergency help immediately before administering the first NYXOID dose.
NYXOID is to be given right away following a suspected overdose and does not take the place of emergency medical care.
Signs of an opioid overdose include breathing problems, severe sleepiness or not being able to respond to a loud noise or touch

How to give NYXOID

1. Call for an ambulance before giving NYXOID.

2. Lay the patient on their back. Support the back of the neck and allow the head to tilt back.

3. It's best to check that the nose is clear before giving NYXOID. Should the nose be blocked, a tissue, or piece of material may be used to clear the obstruction before giving NYXOID.

Peel off the back of the blister from the corner to remove the device from the container.

Hold the nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle. Do not prime or test the device before you give it.

Gently insert the device nozzle in one nostril of the patient. Press firmly on the plunger until it clicks to give the dose. Remove the nozzle from the nostril after giving the dose. Each NYXOID nasal spray contains one single dose of naloxone and cannot be reused.

4. Place the patient into the recovery position on their side with mouth open pointing towards the ground and stay with them until the emergency services arrive. Watch for an improvement in the patient's breathing level, alertness and response to noise and touch.

5. If the patient is no better within 2 - 3 minutes, a second dose can be given. Repeat steps 3 and 4 in the other nostril using a new NYXOID nasal spray. However, the patient does not need to be moved from the recovery position to administer additional doses of NYXOID,
Once the patient is breathing normally, do not administer further does of NYXOID.

6. Further doses may be given every 2 -3 minutes, if needed, until the emergency services arrive.

In patients who are unconscious and not breathing normally, additional life-saving support can be given if possible, e.g. CPR if you are trained to do so.

If you use too much NYXOID

NYXOID is designed as an emergency rescue treatment only, and you should still get medical attention as soon as possible after its use.

Symptoms of a NYXOID overdose are called 'withdrawal symptoms' which may include:

restlessness or irritability
change in mood
increased skin sensitivity or goosebumps
vomiting, nausea, stomach or muscle cramps
sleeping difficulty, anxiety
sweating, fast heartbeat, high blood pressure, yawning or fever

If you think that you have used too much NYXOID, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using NYXOID?

Things you should do

If you are about to be started on any new medicine, advise your doctor and pharmacist that you have been given NYXOID nasal spray.
If you are going to have surgery, tell the surgeon or anaesthetist that you have been given NYXOID nasal spray.
It may affect other medicines used during surgery.
If you become pregnant while being given NYXOID nasal spray medicine, tell your doctor immediately.
If you are about to have any blood tests, tell your doctor that you have been given this medicine.
It may interfere with the results of some tests.

Remind any doctor, dentist or pharmacist you visit that you are using NYXOID.

Things you should not do

Do not use this medicine after the expiry date which is stated on the carton, blister pack and the label after EXP. The expiry date refers to the last day of that month.

Things to be careful of

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from a bed or a chair, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.
Sudden opioid withdrawal syndrome may be life-threatening if not treated properly in children. They should be monitored for at least 24 hours for the signs and symptoms of withdrawal syndrome which include: seizures, crying more than usual and increased reflexes.

Driving or using machines

Do not drive or operate machinery after you have been given NYXOID nasal spray for at least 24 hours (1 day), since the effects of opioids may recur.

Drinking alcohol

Tell your doctor or pharmacist if you drink alcohol.

Alcohol will not stop NYXOID from working. However, if alcohol has been taken in addition to opioids there may be a delay in the action of naloxone. The nasal spray can be used at any time that it is needed.

Looking after your medicine

Keep your unused NYXOID devices in the pack
Keep NYXOID in a place where the temperature stays below 30°C.
Do not freeze

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

People who are dependent on opioids may suffer from withdrawal symptoms caused by NYXOID suddenly blocking the effect the opioids.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions.

Common side effects

Side effects	What to do
dizziness headache nausea and vomiting high blood pressure, low blood pressure	Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Side effects	What to do
sweating tremor increased heart rate nervousness or restlessness irritability or restlessness violent behaviour or agitation	Speak to your doctor as soon as possible.

Very serious side effects

Side effects	What to do
shortness of breath life-threatening irregular heartbeat or heart attack wheezing or difficulty breathing swelling of the face, lips, tongue or other parts of the body build up of fluid in the lungs rash, redness, swelling, severe flaking or peeling, itching or hives on the skin.	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

This medicine is available over-the-counter without a doctor's prescription.

What NYXOID contains

Active ingredient (main ingredient)	naloxone hydrochloride dihydrate
Other ingredients (inactive ingredients)	sodium citrate dihydrate sodium chloride hydrochloric acid sodium hydroxide purified water

Do not take this medicine if you are allergic to any of these ingredients.

What NYXOID looks like

NYXOID is provided in a pre-filled nasal spray device and contains naloxone in 0.1 mL of a clear, colourless to pale yellow solution.

NYXOID is packed in a box containing 2 nasal sprays individually sealed in blisters. Each nasal spray contains one single dose of naloxone.

Who distributes NYXOID

Mundipharma Pty Limited
ABN 87 081 322 509
10 Carrington Street
SYDNEY NSW 2000

This leaflet was prepared in December 2020.

Revised in May 2022: update to Sponsor address.

® NYXOID is a trade mark of MUNDIPHARMA

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Nyxoid

Active ingredient

Naloxone

Schedule

1 Name of Medicine

Naloxone hydrochloride dihydrate.

2 Qualitative and Quantitative Composition

Each dose of 100 microlitre contains 2.2 mg naloxone hydrochloride dihydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nyxoid nasal spray is a clear, colourless to pale yellow solution in glass vials in a single dose nasal spray device.

4 Clinical Particulars

4.1 Therapeutic Indications

Nyxoid is intended as part of the emergency treatment for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression in:
the home or other non-medical setting;
a health facility setting.
For this reason, Nyxoid should be carried by persons at risk of, or likely to witness such events.
Nyxoid is indicated in adults and children.

4.2 Dose and Method of Administration

Nyxoid is administered as a part of a resuscitation intervention in emergency settings, including the home or other non-medical settings in suspected overdose casualties, where opioids may be involved or suspected.
The prescriber should review in detail, the indications, the instructions and operation of the nasal spray with the patient or any other person who might be in a position to administer this product to a patient experiencing a known or suspected opioid overdose event.
How to identify an opioid overdose (symptoms of respiratory depression):
breathing problems;
severe sleepiness;
not responding to a loud noise or touch.

Dosage.

One spray of Nyxoid into a nostril. Re-administer Nyxoid, using a new Nyxoid container, into the other nostril after 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression. Further doses may be given every 2 to 3 minutes if needed until further assistance is available.

Method of administration.

Nasal use only.
The device is ready for use. No further assembly or priming is required.
If an overdose is suspected, call for emergency medical assistance immediately. Nyxoid is not a substitute for emergency medical care.

How to use Nyxoid.

Nyxoid should be administered as quickly as possible to avoid damage to the central nervous system or death. Nyxoid is a single dose nasal spray. Do not test the device as it cannot be reused. See Table 1.

If no improvement is seen in the patient and the person administering Nyxoid is appropriately trained, CPR can be given as an additional resuscitation measure.

Dosing modifications due to partial agonists or mixed agonist/ antagonists.

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require higher doses of naloxone.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

General.

Instructing patients/ users on the proper use of Nyxoid.

Patients or any other person who might be in a position to administer this product must be instructed in the proper use of Nyxoid.
Nyxoid is not a substitution for emergency medical care and cannot replace intravenous injection. It is administered as a part of a resuscitation intervention in emergency settings, including the home or other non-medical settings in suspected overdose casualties, where opioids may be involved or suspected. The prescriber should describe the symptoms which allow presumptive diagnosis of CNS/respiratory depression, the indication and the instructions for use with the patient and/or person who might be in a position to administer this product to a patient experiencing a known or suspected opioid overdose event. This should be performed in accordance with the educational plan for Nyxoid. Therefore, patients at risk of experiencing an opioid overdose event and/or any other person who might be in a position to administer Nyxoid to a patient experiencing such an event should be carefully instructed in regard to the circumstances under which this potentially life-saving medicinal product should be used.

The importance of seeking medical assistance.

Nyxoid is intended as part of an emergency treatment and the patient/carer should be advised to seek medical help immediately. Therefore patients at risk or likely to witness an opioid overdose should be carefully instructed in regard to the circumstances under which this potentially life-saving medicinal product should be used.
The duration of action of most opioids may exceed that of Nyxoid nasal spray resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms.

Monitoring of the patient for a response.

Patients who respond satisfactorily to naloxone must be closely monitored. The effect of some opioids can be longer than the effect of naloxone which could lead to reoccurrence of respiratory depression and therefore further doses of naloxone may be required.

Opioid withdrawal syndrome.

Receiving naloxone can lead to a rapid reversal of the opioid effect which can cause an acute withdrawal syndrome in such patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients who are receiving opioids for the relief of chronic pain may experience pain and opioid withdrawal symptoms when naloxone is administered.
The use of Nyxoid nasal spray in patients who are opioid-dependent may bring about opioid withdrawal characterised by the following signs and symptoms; body aches, diarrhoea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness and increased blood pressure. If these signs and symptoms occur no further Nyxoid should be given.

Effectiveness of naloxone.

Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incomplete response occurs respiration should be mechanically assisted.
Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine may be incomplete. Larger or repeat doses of naloxone hydrochloride may be required for patients who have taken buprenorphine because it has a long duration of action.
Buprenorphine antagonism is characterised by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

Use in the elderly.

No data available.

Paediatric use.

Absorption of naloxone following intranasal administration in paediatric patients may be erratic or delayed. Monitor the paediatric patients for at least 24 hours for the development of the signs and symptoms of opioid withdrawal syndrome even when the patient responds appropriately to naloxone.
Where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider use of alternative naloxone-containing dosage forms that can be titrated to effect and, where applicable, dosed according to weight.
Opioid withdrawal may be life-threatening in neonates if not recognised and properly treated and may include the following signs and symptoms: convulsions, excessive crying and hyperactive reflexes.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Nyxoid. The effect of naloxone is based on the interaction with opioids and opioid agonists, reversing effects of opioids; rapid reversal may precipitate acute withdrawal syndrome in opioid dependence. At the usual naloxone dose there is no interaction with barbiturates and tranquillisers. Data on the interaction with alcohol are not uniform. In patients with multiple intoxication with opioids and sedatives or alcohol, the result of naloxone administration may be delayed, dependent on the cause of intoxication.
Complete analgesia can be restored following administration of naloxone hydrochloride to patients that had buprenorphine as analgesic. It is assumed that this effect is caused by the arched form of the dose-response curve of buprenorphine with decreasing analgesia at (too) high doses. However, reversal of respiratory depression caused by buprenorphine is limited.
Serious hypertension has been reported following administration of naloxone hydrochloride to patients in a coma caused by clonidine-overdosing.
Naloxone reverses the analgesic and other effects of opioid agonist/ antagonists such as pentazocine, so may precipitate withdrawal symptoms if used concurrently with these medicines in physically dependent patients.
Naloxone reverses the analgesic and other effects of opioid agonist analgesics, and may precipitate withdrawal symptoms if used concurrently with these medicines in physically dependent patients, including patients receiving methadone to treat opioid dependence.
When naloxone is used postoperatively to reverse the central depressive effects of opioid agonists used as anaesthesia adjuncts, the dose of naloxone must be carefully titrated to achieve the desired effect without interfering with control of postoperative pain, or causing other adverse effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No clinical data on effects of naloxone on fertility are available, however data from rat studies indicate no effects.
Naloxone had no effect on fertility and reproduction in the rat or on early embryonic development of the rat. In peri-post natal rat studies, naloxone produced increased pup deaths in the immediate post-partum period at the high doses that also caused significant maternal toxicity in rats (e.g. bodyweight loss, convulsions). Naloxone did not affect development or behaviour of surviving pups. Naloxone is therefore not teratogenic in rats or rabbits.
(Category B1)
Naloxone hydrochloride crosses the placenta and may precipitate withdrawal in the foetus as well as in the opioid-dependent mother. The foetus should be evaluated for signs of distress after Nyxoid nasal spray is used. Careful monitoring is needed until the foetus and mother are stabilised.
There are no adequate data from the use of naloxone in pregnant women. Studies in animals do not show any concerns on reproductive toxicity. The potential risk for humans is unknown. The benefit risk of the medicinal product must be considered before use.
In pregnant women who are opioid dependent, naloxone administration can cause withdrawal symptoms in new-born 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 nursing mother but there is no need to discontinue breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

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.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most common adverse drug reaction (ADR) seen with naloxone administration is nausea (frequency of 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 Nyxoid and/or other naloxone-containing products during clinical studies and post marketing experience. ADRs are listed below by system organ class and frequency. See Table 2.

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.

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 at www.tga.gov.au/reporting-problems via the national reporting system.

Paediatric population.

The frequency, type and severity of adverse reactions in paediatrics are expected to be the same as in adults.
Monitor the paediatric patients for at least 24 hours for the development of the signs and symptoms of opioid withdrawal syndrome even when the patient responds appropriately to naloxone. Opioid withdrawal may be life-threatening in neonates if not recognised and properly treated and may include the following signs and symptoms: convulsions, excessive crying and hyperactive reflexes.

4.9 Overdose

There is limited clinical experience with Nyxoid overdosage in humans. Patients who experience a Nyxoid overdose should be treated symptomatically in a closely-supervised environment.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antidotes, ATC code: V03AB15.

Mechanism of action.

Naloxone, a semisynthetic morphine derivative (N-allyl-nor-oxymorphone), 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. Naloxone does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. In the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or mental dependence. In the presence of physical dependence on opioids Nyxoid may produce withdrawal symptoms.
The fastest onset of action (apparent within 2 minutes) is provided by intravenous administration. Administration via subcutaneous (SC) and intramuscular route result in a slightly slower onset of action, although it was found that for SC administration, the slower onset of action was offset by not having to gain intravenous access first.
As the duration of action of some opioid agonists may be longer than that of naloxone, the effects of the opioid agonist may return as the effects of naloxone disappear. This may necessitate repeat doses of naloxone - though the need for repeat naloxone doses is dependent on the quantity, type and route of administration of the opioid agonist that is being treated.
A study demonstrated mean absolute bioavailability of 47% and mean half-lives of 1.4 h from the intranasal (IN) doses of 2 mg.

Clinical trials.

No clinical trials have been conducted with Nyxoid. Efficacy has been inferred based on pharmacokinetic studies.

5.2 Pharmacokinetic Properties

Absorption.

Intranasal administration of naloxone has demonstrated naloxone to be rapidly absorbed, as evidenced by very early appearance (as early as 1 minute after administration) of the active substance in systemic circulation, with peak plasma concentrations being attained as early as 8 minutes (median 30 minutes) after dosing.
A study investigating intranasal naloxone at doses of 1, 2, 4 mg (MR903-1501) shows that the median t_max associated with intranasal administration of naloxone is between 15-30 minutes, with individuals attaining peak concentrations as early as 8 minutes. Onset of action following intranasal administration can reasonably be expected to occur in each individual before the t_max is reached.
The half value duration (HVD) values for IN administration were longer than for IM administration (IN, 2 mg, 1.27 h, IM, 0.4 mg 1.09 h) from which we can infer a longer duration of action of naloxone given by the IN rather than the IM route. If the duration of action of the opioid agonist exceeds that of IN naloxone, the effects of the opioid agonist may return, necessitating a second IN naloxone administration.

Distribution.

Distribution following administration via the nasal spray has not been studied. Following parenteral administration, naloxone is rapidly distributed in the body. It is metabolised in the liver primarily by glucuronide conjugation and the metabolites are excreted in the urine. It is 50% protein bound. The elimination half-life in adults is 60-90 minutes and 180 minutes in neonates.

Metabolism.

Naloxone is rapidly metabolized in the liver and excreted in the urine. It undergoes extensive hepatic metabolism mainly by glucuronide conjugation. The principal metabolites are naloxone-3-glucuronide, 6-beta-naloxol and its glucuronide.

Excretion.

There are no data available on the excretion of naloxone following IN administration, however, the disposition of labelled naloxone following IV administration was studied in healthy volunteers and opioid-dependent patients. Following an IV dose of 125 microgram, 38% of the dose was recovered in the urine within 6 hours in healthy volunteers compared with 25% of the dose being recovered in opioid-dependent patients in the same time period. After a period of 72 hours, 65% of the injected dose was recovered in urine in the healthy volunteers compared with 68% of the dose in opiate-dependent patients.

5.3 Preclinical Safety Data

Genotoxicity.

Naloxone was not mutagenic in the bacterial reverse mutation assay, but was positive in mouse lymphoma assay and was clastogenic in vitro, however, naloxone was not clastogenic in vivo.

Carcinogenicity.

Naloxone was not carcinogenic following oral administration in a rat 2-year study or in a 26-week study in Tg-rasH2 mice.
Overall, the weight of evidence indicates that naloxone poses minimal, if any, risk for human genotoxicity and carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium citrate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide, purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Do not store above 30°C. Do not freeze.

6.5 Nature and Contents of Container

The container consists of a type I Ph.Eur. glass vial with chlorobutyl stopper and polypropylene applicator. Nyxoid nasal spray: unit dose spray device containing 0.1 mL solution. Each pack contains two single dose nasal sprays.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Naloxone hydrochloride is an off-white powder soluble in water. The chemical name is 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. It is a synthetic congener of oxymorphone, with molecular formula C₁₉H₂₁NO₄.HCl.2H₂O and molecular weight 399.87. The pKa is 7.9 and the Partition Coefficient Log P is 1.5. The structural formula for naloxone hydrochloride is:

Chemical structure.

CAS number.

51481-60-8.

7 Medicine Schedule (Poisons Standard)

S3 Pharmacist Only Medicine.

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Nyxoid

Naloxone

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