NYXOID 1.8mg nasal spray, solution medication leaflet

Nyxoid 1.8 mg nasal spray, solution in single-dose container

Each nasal spray container delivers 1.8 mg of naloxone (as hydrochloride dihydrate).

For the full list of excipients, see section 6.1.

Nasal spray, solution in single-dose container (nasal spray)

Clear, colourless to pale yellow solution

Nyxoid is intended for immediate administration as emergency therapy for known or suspected opioidoverdose as manifested by respiratory and/or central nervous system depression in both non-medicaland healthcare settings.

Nyxoid is indicated in adults and adolescents aged 14 years and over.

Nyxoid is not a substitute for emergency medical care.

Adults and adolescents aged 14 years and over

The recommended dose is 1.8 mg administered into one nostril (one nasal spray).

In some cases, further doses may be necessary. The appropriate maximum dose of Nyxoid is situationspecific. If the patient does not respond, the second dose should be administered after 2-3 minutes. Ifthe patient responds to the first administration but then relapses again into respiratory depression, thesecond dose should be administered immediately. Further doses (if available) should be administeredin alternate nostrils and the patient should be monitored whilst awaiting arrival of the emergencyservices. Emergency services may administer further doses according to local guidelines.

The safety and efficacy of Nyxoid in children below 14 years has not been established. No data areavailable.

Nasal use.

Nyxoid should be administered as soon as possible to avoid damage to the central nervous system ordeath.

Nyxoid contains only one dose and therefore it must not be primed or tested prior to administration.

Detailed instructions on how to use Nyxoid are provided in the Package Leaflet and a Quick Start

Guide is printed on the back of each blister. In addition, training is provided via a video and a Patient

Information Card.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Instructing patients/users on the proper use of Nyxoid

Nyxoid should only be made available once the suitability and competence of an individual toadminister naloxone in the appropriate circumstances has been established. Patients or any otherperson who might be in a position to administer Nyxoid must be instructed in its proper use and theimportance of seeking medical assistance.

Nyxoid is not a substitute for emergency medical care and may be used instead of intravenousinjection, when intravenous access is not immediately available.

Nyxoid is intended to be administered as a part of a resuscitation intervention in suspected overdosecasualties, where opioid drugs may be involved or suspected, likely in a non-medical setting.

Therefore, the prescriber should take appropriate steps to ensure that the patient and/or any otherperson who might be in a position to administer Nyxoid thoroughly understands the indications anduse of Nyxoid.

The prescriber should describe the symptoms which allow presumptive diagnosis of central nervoussystem (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 orsuspected opioid overdose event. This should be performed in accordance with the educationalguidance for Nyxoid.

Monitoring of the patient for a response

Patients who respond satisfactorily to Nyxoid must be closely monitored. The effect of some opioidscan be longer than the effect of naloxone, which could lead to reoccurrence of respiratory depressionand therefore further doses of naloxone may be required.

Opioid withdrawal syndrome

Receiving Nyxoid can lead to a rapid reversal of the opioid effect which can cause an acutewithdrawal syndrome (see section 4.8). Patients who are receiving opioids for the relief of chronicpain may experience pain and opioid withdrawal symptoms when Nyxoid is administered.

Effectiveness of naloxone

Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incompleteresponse occurs, respiration should be mechanically assisted.

Intranasal absorption and efficacy of naloxone can be altered in patients with damaged nasal mucosaand septal defects.

Opioid withdrawal may be life-threatening in neonates if not recognised and properly treated and mayinclude the following signs and symptoms: convulsions, excessive crying and hyperactive reflexes.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Naloxone elicits a pharmacological response due to the interaction with opioids and opioid agonists.

When administered to opioid dependent subjects, naloxone can cause acute withdrawal symptoms insome individuals. Hypertension, cardiac arrhythmias, pulmonary oedema and cardiac arrest have beendescribed, more typically when naloxone is used post-operatively (see sections 4.4 and 4.8).

Administration of Nyxoid may decrease the analgesic effects of opioids used primarily to provide painrelief, due to its antagonist properties (see section 4.4).

When administering naloxone to patients who have received buprenorphine as an analgesic, completeanalgesia may be restored. It is thought that this effect is a result of the arch-shaped dose-responsecurve of buprenorphine with decreasing analgesia in the event of high doses. However, reversal ofrespiratory depression caused by buprenorphine is limited.

There are no adequate data from the use of naloxone in pregnant women. Studies in animals haveshown reproductive toxicity only at maternally toxic doses (see section 5.3). The potential risk forhumans is unknown. Nyxoid should not be used during pregnancy unless the clinical condition of thewoman requires treatment with naloxone.

In pregnant women who have been treated with Nyxoid, the fetus should be monitored for signs ofdistress.

In opioid dependent pregnant women, naloxone administration can cause withdrawal symptoms innewborn infants (see section 4.4).

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

No clinical data on effects of naloxone on fertility are available, however data from rat studies (seesection 5.3) indicate no effects.

Patients who have received naloxone to reverse the effects of opioids should be warned not to drive, tooperate machinery or to engage in other activities demanding physical or mental exertion for at least24 hours, since the effect of the opioids may return.

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

The following adverse reactions have been reported with Nyxoid and/or other naloxone-containingmedicinal products during clinical studies and post marketing experience. ARs are listed below bysystem organ class and frequency.

Frequency categories are assigned to those adverse reactions considered to be at least possibly causallyrelated 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).

Very rare: Hypersensitivity, Anaphylactic shock

Common Dizziness, Headache

Uncommon Tremor

Common Tachycardia

Uncommon Arrhythmia, Bradycardia

Very rare Cardiac fibrillation, Cardiac arrest

Common Hypotension, Hypertension

Uncommon Hyperventilation

Very rare Pulmonary oedema

Very common Nausea

Common Vomiting

Uncommon Diarrhoea, Dry mouth

Uncommon Hyperhidrosis

Very rare Erythema multiforme

Uncommon Drug withdrawal syndrome (in patients dependent on opioids)

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 includingviolent behaviour, nervousness and excitement may also be observed.

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In view of the indication and the broad therapeutic margin, overdose is not to be expected.

Pharmacotherapeutic group: Antidotes, ATC code: V03AB15

Mechanism of action and pharmacodynamic effects

Naloxone, a semisynthetic morphine derivative (N-allyl-nor-oxymorphone), is a specific opioidantagonist that acts competitively at opioid receptors. It reveals very high affinity for the opioidreceptor sites and therefore displaces both opioid agonists and partial antagonists. Naloxone does notpossess the 'agonistic' or morphine-like properties characteristic of other opioid antagonists. In theabsence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially nopharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical ormental dependence.

As the duration of action of some opioid agonists may be longer than that of naloxone, the effects ofthe opioid agonist may return as the effects of naloxone disappear. This may necessitate repeat dosesof naloxone - though the need for repeat naloxone doses is dependent on the quantity, type and routeof administration of the opioid agonist that is being treated.

No data are available.

Intranasal administration of naloxone has demonstrated naloxone to be rapidly absorbed, as evidencedby very early appearance (as early as 1 minute after administration) of the active substance in systemiccirculation.

A study investigating intranasal naloxone at doses of 1, 2, 4 mg (MR903-1501) shows that themedian (range) tmax associated with intranasal administration of naloxone was 15 (10, 60) minutes for1 mg, 30 (8, 60) minutes for 2 mg and 15 (10, 60) minutes for 4 mg intranasal doses. Onset of actionfollowing intranasal administration can reasonably be expected to occur in each individual before thetmax is reached.

The half value duration (HVD) values for intranasal administration were longer than for intramuscularadministration (intranasal, 2 mg, 1.27h, intramuscular, 0.4 mg 1.09h) from which we can infer a longerduration of action of naloxone given by the intranasal rather than the intramuscular route. If theduration of action of the opioid agonist exceeds that of intranasal naloxone, the effects of the opioidagonist may return, necessitating a second intranasal naloxone administration.

A study demonstrated mean absolute bioavailability of 47% and mean half-lives of 1.4 h fromintranasal doses of 2 mg.

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

There are no data available on the excretion of naloxone following intranasal administration, however,the disposition of labelled naloxone following intravenous administration was studied in healthyvolunteers and opioid-dependent patients. Following an intravenous dose of 125 µg, 38% of the dosewas recovered in the urine within 6 hours in healthy volunteers compared with 25% of the dose beingrecovered in opioid-dependent patients in the same time period. After a period of 72 hours, 65% ofthe injected dose was recovered in urine in the healthy volunteers compared with 68% of the dose inopiate-dependent patients.

No data are available.

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

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

Naloxone had no effect on fertility and reproduction in the rat or on early embryonic development ofthe rat and rabbit. In peri-post natal rat studies, naloxone produced increased pup deaths in theimmediate 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 survivingpups. Naloxone is therefore not teratogenic in rats or rabbits.

Trisodium citrate dihydrate (E331)

Sodium chloride

Hydrochloric acid (E507)

Sodium hydroxide (E524)

Purified water

Not applicable.

3 years

Do not freeze.

The immediate container consists of a type I glass vial with siliconised chlorobutyl stopper containing0.1 ml solution. The secondary packaging (actuator) is comprised of polypropylene and stainlesssteel.

Each pack contains two single-dose nasal sprays.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Mundipharma Corporation (Ireland) Limited

United Drug House Magna Drive

Magna Business Park

Citywest Road

Dublin 24

Ireland

EU/1/17/1238/001

Date of first authorisation: 10 November 2017

Date of latest renewal: 15 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.