Naloxone nasal spray (Nyxoid) for opioid overdose

• Naloxone is part of emergency rescue treatment for known or suspected opioid overdose
  It can be administered via nasal spray or intramuscular injection and takes effect 2 to 5 minutes later.
• Naloxone nasal spray (Nyxoid) is PBS-listed as an unrestricted General Schedule listing
  PBS listing is expected to increase use of naloxone in the community.
• Naloxone nasal spray has advantages over naloxone injectables
  Advantages include ease of administration, minimal training requirements and no risk of needle-stick injury.
• Naloxone nasal spray is recommended for patients at increased risk of opioid overdose or people who are likely to witness opioid overdose
  When prescribing opioids for patients with increased overdose risk, incorporate strategies to minimise risk including co-prescribing naloxone.
• Ensure naloxone nasal spray is given for opioid overdose in a timely and effective manner
  Provide education and training about opioid overdose and naloxone nasal spray usage to patients and carers.

Unrestricted benefits

On 1 November 2019, naloxone nasal spray (Nyxoid) was listed on the Pharmaceutical Benefits Scheme (PBS) as an unrestricted General Schedule listing.¹

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended that an unrestricted benefit listing for naloxone nasal spray was appropriate, as this was consistent with naloxone injectables already listed on the PBS.²

Naloxone nasal spray is listed on the PBS, together with naloxone injectables, as an antidote for acute opioid overdose.^1,2

May be prescribed by nurse practitioners

Authorised nurse practitioners may prescribe this medicine on the PBS. See the PBS website for more information on nurse practitioner PBS prescribing.

Naloxone nasal spray is a single-use unit that contains 1.8 mg naloxone in 0.1 mL solution. Each pack of naloxone nasal spray contains two units.^2,3

Naloxone nasal spray is listed on the PBS for a maximum quantity of one pack with no repeat.²

Naloxone

Naloxone is a semi-synthetic morphine derivative that acts competitively at opioid receptors as an opioid antagonist.^3-5 It has a high affinity for opioid receptor sites and rapidly displaces opioid agonists³ such as codeine, fentanyl and methadone.^6,7

As a result, it is able to reverse respiratory/central nervous system depression caused by an overdose of opioids and help prevent fatality and morbidity such as hypoxic brain injury.^3,8

Advantages of intranasal administration

Naloxone may be administered either via injection or intranasally. Naloxone injectables include: ampoules (400 micrograms/1 mL) or prefilled syringes (1 mg/mL injection, 2 mL syringe). ^1,4,9

Naloxone nasal spray offers advantages over naloxone injectables for use in the community, including ease of administration, minimal training requirements and no risk of needle-stick injury.²

Naloxone nasal spray (Nyxoid) is the only naloxone formulation in Australia that can be administered intranasally.⁶

Naloxone nasal spray is intended for use as part of emergency rescue treatment for known or suspected opioid overdose in the community.²

It is recommended that patients who are at increased risk of opioid overdose, or are likely to witness an overdose, carry naloxone nasal spray to use in the event of an opioid overdose emergency.⁶

Increased risk of opioid overdose

Factors associated with an increased risk of opioid overdose can be categorised according to patient history, socio-demographics, current medicines and comorbidities.^10-12

Patient history factors include previous opioid overdose and substance abuse disorder and concurrent alcohol or substance use disorders, or polydrug use (particularly benzodiazepines and opioids).

Socio-demographic factors include older age, pregnancy and recent release from a controlled environment (eg, prison or drug rehabilitation facility).^10-12

Current medicine factors include high opioid doses (> 50 mg oral morphine equivalent daily dose) and slow-release and long acting opioids (eg, transdermal fentanyl or hydromorphone).

Comorbidity factors include complex care, significant respiratory or other illness that increases risk of respiratory depression, sleep-disordered breathing (eg, sleep apnoea), reduced renal or hepatic function and mental health disorders.^10-12

Likely to witness opioid overdose

Many opioid overdoses are witnessed by family members, household members, peers or people whose work brings them into contact with people who use opioids.⁵

It is recommended that people who are likely to witness opioid overdoses should have access to naloxone and know how to use it, so that they are prepared to treat an emergency opioid overdose.⁵

Opioid overdose represents a significant and ongoing problem in Australia. The number of unintentional overdose deaths involving opioids nearly tripled over a 12-year period, increasing from 338 in 2006 to 904 in 2017.¹³

When prescribing opioids for patients at increased risk of overdose, doctors should incorporate strategies to reduce the risk in the patients’ management plans, including offering naloxone.^10,14

Increasing access and availability

A key response to the increase in opioid overdose deaths has been to increase access to and availability of naloxone in the community.⁸

An important step was the 2016 rescheduling of naloxone formulations from Schedule 4 (Prescription Only Medicine) to Schedule 3 (Pharmacist Only Medicine) under the Therapeutic Good Administration (TGA) Poisons Standard.^2,8

In its March 2019 meeting the PBAC found that there had been a relatively low uptake of PBS-listed naloxone injectables from 2016 to 2018.²

The PBAC considered that there was a public health need to increase the use of naloxone. It advised that naloxone nasal spray was likely to be easier to administer than injectables in some scenarios, did not carry any risk of needle-stick injury and might contribute to improved uptake in an emergency because it does not require specific training.²

The PBAC considered that the PBS-listing of naloxone nasal spray was likely to result in the increased uptake of naloxone in the community setting and to contribute to reducing the current high rates of harm from opioid overdose.²

Free take-home naloxone pilot schemes

When purchasing naloxone nasal spray over the counter, patients can expect to pay $48.42 (the current PBS-listed Dispensed Price for Maximum Quantity [DPMQ]), although the retail price can vary between pharmacies depending on individual pharmacy mark-up.^1,8

With a prescription as a PBS-listed medicine, patients without a concession card can expect to pay a maximum of $41.00 for naloxone nasal spray, while concessional patients pay $6.60.^1,15

Cost can be a barrier, even for concessional patients, and could make the difference between accessing and not accessing naloxone. The process of obtaining naloxone, including attending a prescriber and pharmacy, may also act as a barrier.⁸

Access points for free take-home naloxone distributed to people at high risk of harm from opioids are increasing across Australia and include drug and alcohol services and needle syringe programs.^8,16 From 1 December 2019 to February 2021, New South Wales, South Australia and Western Australia are participating in a PBS-subsidised take-home naloxone pilot. Under the pilot, naloxone will be provided free for people at risk of opioid overdose, and for those who are likely to witness an opioid overdose. Naloxone nasal spray and pre-filled injectable naloxone are available without a prescription as part of the pilot.^17-20

The PBAC considered that naloxone 1 mg/mL prefilled syringe was an appropriate comparator to naloxone nasal spray, as this formulation was intended for bystander administration and therefore most likely to be replaced in practice.²

The PBAC included one pharmacokinetic study and a 2014 meta-analysis by the World Health Organization in its consideration of the evidence.² The data from the pharmacokinetic study were used to establish effective doses and routes of administration of naloxone for overdose reversal in the absence of head-to-head, comparative efficacy studies.²¹

The PBAC was satisfied that, despite slight pharmacokinetic differences, the clinical benefit of naloxone nasal spray was comparable to the clinical benefit of injectable naloxone. It also considered that while superior safety wasn’t quantifiable, there were likely to be safety benefits of naloxone nasal spray, including a reduction in needle-stick injury and potential reduction in withdrawal-related harms.²

Naloxone has a very low abuse potential.² In the absence of opioids or agonistic effects of opioid antagonists, it generally has no pharmacological activity and does not produce tolerance or cause physical or psychological dependence.³

The only contraindication to naloxone nasal spray is hypersensitivity to the active substance or to any of the excipients.³

However, there are some precautions for the use of naloxone nasal spray. These include incomplete/slow reversal of respiratory depression, recurrence of opioid overdose and acute opioid withdrawal.^3,4

Incomplete or slow reversal of respiratory depression in response to the usual dose of naloxone nasal spray can happen if the overdose is caused by opioids that are partial agonists (eg, buprenorphine), longer-acting opioids (eg, buprenorphine, methadone, extended-release formulations), or opioids with active metabolites (eg, methadone, diphenoxylate, codeine).^3,4,22,23

Recurrence of opioid overdose can also happen because naloxone stays in the body for a shorter period of time (30–90 minutes) than some longer-acting opioids.^22,24,25 Recurrence is also more likely if the person has taken other depressant drugs such as alcohol or benzodiazepines.²⁵

If incomplete or slow reversal or recurrence happens, higher or repeat doses of naloxone may be required (see Dosing issues for more information) and/or respiration of the patient should be mechanically assisted.^3,4,22

It should be noted that the PBAC considered two doses of naloxone nasal spray to be sufficient in the community, and therefore it is listed on the PBS for a maximum quantity of one pack (two doses) with no repeats.²

Acute withdrawal can occur

Acute opioid withdrawal is a common adverse effect that can occur when the patient has a physical dependence on opioids.^3,4

Symptoms of acute opioid withdrawal include, restlessness, nausea, vomiting, gastrointestinal pain, yawning, muscle spasms, dysphoria, anxiety, agitation, tachycardia, increased blood pressure and confusion. If these symptoms occur, then no further naloxone nasal spray should be given to the patient.^3,4

Precautions are required for pregnant women, neonates and paediatric patients. Naloxone crosses the placenta and can cause acute opioid withdrawal in the foetus as well as the mother if they have opioid dependency. A balance of the risks and benefits should be considered before using naloxone nasal spray for pregnant women. If used, the foetus should be monitored for signs of distress.^3,4

In neonates, acute opioid withdrawal can be life-threatening if not recognised and properly treated. Signs of withdrawal include convulsions, excessive crying and hyperactive reflexes.³

In paediatric patients, absorption of naloxone nasal spray may be erratic or slow. Children should be monitored for at least 24 hours for symptoms of withdrawal, which may occur even after a patient has responded appropriately to naloxone.³

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Naloxone nasal spray is supplied in one pack containing two single use units. When an opioid overdose is known or suspected, an initial dose is given with one unit.^2,3

If there are no signs of overdose reversal after 2–3 minutes, a second dose is given in the other nostril with the second unit.³

After another 2–3 minutes, if there are still no signs of opioids overdose reversal (see Safety issues for more information) further doses may be given every 2–3 minutes if additional nasal spray units or naloxone are available.³

Once the patient is breathing normally, do not give any further doses of naloxone.³

If the patient starts to show signs of acute opioid withdrawal, do not give any further doses.³

Patients at increased risk of opioid overdose or likely to witness an opioid overdose should receive education and training about opioid overdose and correct naloxone nasal spray usage to ensure it is given in a timely and effective manner.^5,10

General information about naloxone nasal spray and opioids

Naloxone nasal spray can be used in the case of a known or suspected opioid overdose where the person is unresponsive, not breathing or unconscious.³

• Opioids include methadone, morphine, oxycodone, oxycontin, fentanyl, hydromorphone, buprenorphine and heroin.⁷
• Naloxone nasal spray temporarily blocks the action of opioids and reverses opioid overdose allowing the person to breathe again.⁹
• Naloxone nasal spray is not a substitute for emergency medical care.³
• Naloxone nasal spray comes in a pack containing two single use units.³
• It is legal for a non-medical person to give naloxone nasal spray to someone else to treat a potentially fatal opioid overdose.⁹

Recognising opioid overdose

Someone experiencing an opioid overdose may:²⁵

• be unresponsive to touch or sounds
• have irregular/shallow breathing or no breathing at all
• make snoring/gurgling noises
• have blue lips, if pale-skinned, or look grey or ashen, if dark-skinned
• go limp and floppy
• possibly vomit.

What to do if opioid overdose is known or suspected

It is recommended that first responders (people who may witness an overdose such as family, friends, community members, health professionals or emergency medical personnel) focus on calling emergency assistance, providing ventilation support (rescue breathing), airway management (clearing/maintaining the airway) and administering naloxone.⁵

Specific instructions include:

• If you know or suspect a person is having an overdose, call 000 for emergency assistance.³
• Lay the person on their back and clear anything you see blocking their nose.²⁵
• Give a dose of naloxone by inserting the nasal spray unit into one nostril and pressing the plunger until it clicks.³
• Do not press, prime or test the plunger before use.³
• Place the person in the recovery position, checking that their airway is clear.³
• Check for signs of reversal of opioid overdose. See Recognising reversal of opioid overdose for more information.
• If there is no breathing or pulse, commence rescue breaths or cardiopulmonary resuscitation (CPR), if trained and comfortable to do so.²⁵
• If the person begins breathing normally, do not give further doses of naloxone.³
• If there are no signs of opioid overdose reversal after 2–3 minutes, give a second dose of naloxone nasal spray, using the second unit in the other nostril.³
• Second doses can be given while the person is lying in the recovery position.³
• Monitor the person closely until medical help arrives.^3,25
• If the person begins to lose consciousness or their breathing becomes shallow or irregular again and you have further units of naloxone nasal spray available, continue to give every 2–3 minutes until the person begins breathing normally.³
• People who have been revived with naloxone may experience a strong urge to take more opioids, especially if they have an opioid dependency.²⁴
• Discourage the person from taking opioids for at least 2 hours after being given naloxone.²⁵

Recognising reversal of opioid overdose

Reversal of overdose is best indicated by:^3,5

• improvement in the person’s breathing level
• increased level of consciousness
• walking and talking normally.

Discuss the Nyxoid Consumer Medicine Information (CMI) leaflet with the patient.

Information about the Department of Health take-home naloxone pilot