Ayendi 720microgram/actuation Nasal Spray – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Ayendi 720microgram/actuation Nasal Spray

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each bottle contains diamorphine 72mg (8ml bottle)/144mg (17ml bottle) as diamorphine hydrochloride (equivalent to 720microgram in each 50microlitre spray following reconstitution).

When reconstituted the spray contains 0.02% benzalkonium chloride.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder and diluent for reconstitution for nasal spray, solution

After reconstitution

Nasal spray, solution

A clear, colourless to pale straw coloured solution

Before reconstitution

Nasal spray, powder for solution

A white to off-white, freeze-dried powder.

Diluent for reconstitution

Clear, colourless 0.5%w/v preserved saline solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of acute severe nociceptive pain in children and adolescents 2 to 15 years of age in a hospital setting. Ayendi Nasal Spray should be administered in the emergency setting by practitioners experienced in the administration of opioids in children and with appropriate monitoring.

4.2 Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with diamorphine hydrochloride in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

The 720micrograms/actuation Nasal Spray is only suitable for children weighing between 12kg and less than 30kg. For patients from 30kg to 50kg the 1600micrograms/actuation Nasal Spray should be used.

Posology

The dose should not be repeated.

Patients should be dosed according to weight.

Method of administration

Ayendi Nasal Spray is for nasal use only.

A new tip should be used for any new patient to avoid risk of microbial contamination and soiling of the tip.

Ensure that the dip tube remains in the solution during priming and re-priming to avoid air entering the pump spray and affecting dose uniformity.

For instructions on the reconstitution of the medicinal product before administration, see section 6.6.

The spray should be directed at the nasal side wall (lateral nasal wall) rather than straight up the nose. It is recommended that the patient sits in a semi-recumbent position at about 45 degrees when the nasal spray is being administered.

Ayendi Nasal Spray should be delivered using a total of 2 - 4 actuations of the appropriate product strength directed into alternate nostrils and according to the weight of the child. The maximum total dose for this product strength is 2.88mg diamorphine hydrochloride (four actuations).

The patient should then be monitored for at least 30 minutes following administration.

Special populations

Hepatic impairment

A reduction in dosage should be considered in hepatic impairment.

Renal impairment

A reduction in dosage should be considered in renal impairment.

Elderly

This product is for children and adolescents only.

4.3 Contraindications

Respiratory depression, obstructive airways disease, acute asthma exacerbations (see section 4.4 for information relating to use in controlled asthma).

Known hypersensitivity to diamorphine, morphine or any of the excipients of the nasal spray solution listed in section 6.1.

Phaeochromocytoma (endogenous release of histamine may stimulate catecholamine release).

Biliary colic (see also biliary tract disorders, section 4.4 Special Warnings and Precautions).

Coma. Raised intracranial pressure. Head injuries, as there is an increased risk of respiratory depression that may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient.

Acute alcoholism.

Diamorphine is also contra-indicated where there is a risk of paralytic ileus, or in acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis or diarrhoea caused by poisoning (until the toxic material has been eliminated).

4.4 Special warnings and precautions for use

Ayendi Nasal Spray is only intended for intranasal administration, and must not be administered by any other route.

Morphine-like opioids should either be avoided in patients with biliary tract disorders or they should be given with an antispasmodic (use in biliary colic is a contraindication see section 4.3 Contraindications).

Diamorphine should be given in reduced doses or with caution to patients with asthma or decreased respiratory reserve (including kyphoscoliosis, emphysema, severe obesity, cor pulmonale). Opioids are contraindicated in acute asthma exacerbations. However it has been suggested that they can be used with caution in controlled asthma (see section 4.3 Contraindications).

Use with caution or in reduced doses in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, severe inflammatory or obstructive bowel disorders, hypotension, shock, convulsive disorders or adrenal insufficiency.

Care should be exercised in treating the elderly or children (see section 4.2 Posology for dosage recommendations).

There is a risk of transmission of infectious agents if nasal tips are not changed between patients.

For information regarding the use of this product with other nasally administered medicinal products (see section 4.5 Interactions with other medicinal products and others forms of interaction).

No clinical data are available on the efficacy of this product in children suffering from rhinitis or the common cold.

Opioid use disorder (abuse and dependency)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Ayendi Nasal Spray. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Ayendi Nasal Spray may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the- counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with diamorphine hydrochloride.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Excipients

Ayendi Nasal Spray contains benzalkonium chloride which may cause irritation of the nasal mucosa.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Alcohol may enhance the sedative and hypotensive effects of diamorphine.

Anaesthetics: enhanced depressive effects. Reduced dose may be required.

Anti-arrhythmics: Diamorphine may delay the absorption of mexiletine.

Antidepressants, anxiolytics, hypnotics: Severe CNS excitation or depression (hypertension or hypotension) has been reported with the concomitant use of monoamine oxidase inhibitors (MAOIs) and pethidine. It is therefore possible that a similar interaction may occur with other opioid analgesics - avoid concomitant use and for two weeks after stopping MAOIs.

The depressant effects of diamorphine may be exaggerated and prolonged by tricyclic antidepressants, anxiolytics and hypnotics.

Antivirals: Plasma concentration of opioid analgesics (except methadone) is possibly increased by ritonavir.

Opioids potentiate the effects of CNS depressants including tricyclic antidepressants, anxiolytics and hypnotics.

Antipsychotics: enhanced sedative and hypotensive effect.

Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent use may increase the risk of severe constipation.

Entonox: there is a risk of additive effects when nitrous oxide (contained in

Entonox) is used in combination with drugs having a central depressant action (e.g. opiates, benzodiazepines and other psychotropics). If concomitant central acting agents are used, the risk for pronounced sedation and depression of protecting reflexes should be considered.

Motility stimulants: There may be antagonism of the gastrointestinal effects of domperidone and metoclopramide.

Cimetidine inhibits metabolism of opioid analgesics.

The concomitant use of Ayendi Nasal Spray with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death.

Concomitant administration of Ayendi Nasal Spray with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.

Concomitant use of Ayendi Nasal Spray and other medicinal products administered via the nose has not been evaluated in the clinical trials. It is recommended that alternative administration forms are used for concomitant treatment of conditions requiring nasal administration (see section 4.4, Special warnings and precautions for use).

4.6 Fertility, pregnancy and lactation

Pregnancy

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

Administration to nursing women is not recommended as diamorphine hydrochloride may be secreted in breast milk and may cause respiratory depression in the infant.

4.7 Effects on ability to drive and use machines

Diamorphine causes drowsiness and mental clouding. If affected patients should not drive or use machines.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called ‘statutory offence’) if:

  • The medicine has been prescribed to treat a medical or dental problem and
  • You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
  • It was not affecting your ability to drive safely

4.8 Undesirable effects

The most serious hazard of therapy is respiratory (see section 4.9, Overdose).

The most common side effects of diamorphine are sedation, nausea and vomiting, constipation and sweating. Tolerance generally develops with long-term use, but not to constipation.

The following adverse events have been reported in clinical trials where children age 2 to 16 received Ayendi Nasal Spray:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Psychiatric disorders

Uncommon: anxiety

Nervous system disorders

Common: dizziness, dysguesia

Uncommon: somnolence, paraesthesia mucosal, depressed level of consciousness, nervousness, headache.

Eye disorders

Uncommon: eye pruritis, conjunctivitis.

Vascular disorders

Uncommon: pallor.

Respiratory, thoracic and mediastinal disorders

Very common: nasal discomfort

Common: sneezing, epistaxis, laryngitis

Uncommon: hypoxia, hiccups, nasal mucosa disorder, rhinorrhoea.

Gastrointestinal disorders

Common: vomiting, nausea

Uncommon: abdominal pain, haematemesis.

Skin and subcutaneous tissue disorders

Common: pruritis.

General disorders and administration site conditions Uncommon: pyrexia, feeling hot, dry mouth

Injury, poisoning and procedural complications

Common: procedural pain

Uncommon: narcotic intoxication.

Other side effects of diamorphine include the following:

Immune system disorder

Rare: anaphylactic reactions following intravenous injection have been reported rarely.

Psychiatric disorders

Not known: Drug dependence (see section 4.4).

Nervous system disorders

Uncommon: dizziness, vertigo, mental clouding, confusion (with large doses), hallucinations, headache, mood changes including dysphoria and euphoria.

Eye disorders

Uncommon: blurred or double vision or other changes in vision, miosis.

Cardiac disorders

Uncommon: palpitations, tachycardia, bradycardia.

Vascular disorders

Uncommon: orthostatic hypotension, facial flushing

Gastrointestinal disorders

Uncommon: dry mouth, biliary spasm.

General disorders and administration site conditions

Uncommon: drug withdrawal syndrome

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, urticaria.

Renal and urinary disorders

Uncommon: urinary retention, difficulty with micturition, ureteric spasm, antidiuretic effect. Tolerance develops to the effects of opioids on the bladder.

Reproductive system and breast disorders

Uncommon: long-term use may lead to a reversible decrease in libido or potency.

Drug dependence

Repeated use of Ayendi Nasal Spray can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse drug 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 via

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: N02AA09

Pharmacotherapeutic group: Natural opium alkaloids

Diamorphine is a narcotic analgesic which acts primarily on the central nervous system and smooth muscle. It is predominantly a central nervous system depressant but it has stimulant actions resulting in nausea, vomiting and miosis.

In a multicentre, randomised, single blind, parallel group, controlled trial to compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers aged between three and 16 years with acute pain due to a clinical fracture, onset of pain relief was faster in the spray group than in the intramuscular group.

The treatment groups were well matched in terms of the nature of the injury (the predominating injury in both groups was fractured radius/ulna), the time since injury and weight and sex distribution, but the nasal diamorphine group were statistically significantly older than the IM morphine group (mean ages 115.3 months vs 107.6 months, respectively, p<0.049). The efficacy populations comprised 405 patients (202 nasal diamorphine; 203 intramuscular morphine).

Pain was evaluated by patient, parent and medical staff using Wong Baker Faces and a Visual Analogue Scale (VAS) pre-treatment (time 0) and at 5, 10, 20 and 30 minutes following treatment administration. A mixed model was used to perform a repeated measures analysis of variance (ANOVA) on the change from baseline in pain scores (both the Wong Baker Face pain scores and the VAS) with baseline scores, treatment, time and treatment time all fitted as fixed effects and patient fitted as a random effect.

The data shows statistically significant differences (at the 5% level) over time between the treatment groups in favour of nasal diamorphine for changes from baseline in:

Wong Baker Faces pain score for patients’ and parents’ assessments (not evaluated by medical staff) (p=0.0069 and p=0.0223, respectively) VAS pain score for all patients’, patients ≥ 8 years old and medical staff assessments (p=0.0108, p=0.0052 and p=0.0015, respectively)

5.2 Pharmacokinetic properties

Diamorphine is a potent opiate analgesic which has a more rapid onset of activity than morphine as the first metabolite, monoacetylmorphine, more readily crosses the blood brain barrier.

Absorption: Diamorphine is essentially a pro-drug for the active metabolites morphine and morphine-6- glucuronide (see metabolism below). Following single dose administration of 0.06mg/kg diamorphine intranasal in children, mean peak plasma concentration of morphine was estimated as 14.0 ng/ml with a median T_max of 22.1 minutes.

Distribution: Diamorphine and the primary metabolite monoacetylmorphine are more readily lipid-soluble than morphine and therefore can more readily cross the blood-brain barrier. The mean central and peripheral volume of distribution of morphine was estimated as 2.2 and 9.9 L/kg respectively following the administration of nasal diamorphine in children.

Metabolism and Excretion: Diamorphine is metabolised into its primary metabolite monoacetylmorphine and then to its secondary metabolite morphine. Morphine forms conjugates with glucuronic acid. The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as unchanged morphine. Alternatively, excretion can occur through the biliary system into the faeces. Following nasal diamorphine administration in children, the terminal half-life of morphine was estimated as 8.4 hours.

Diamorphine does not bind to protein. However, morphine is about 35% bound to human plasma proteins, mainly to albumin. The analgesic effect lasts approximately three to four hours.

5.3 Preclinical safety data

In reproductive and developmental toxicity studies in rats, hamsters and rabbits, repeated administration of ≥2.5 mg/kg/day diamorphine was shown to cause increased maternal, fetal and newborn mortalities. Increased gestation period and birth weight were also observed.

6.1 List of excipients

Nasal spray, powder for solution

None

Diluent for reconstitution and Nasal spray, solution

Benzalkonium Chloride Solution (50% w/v)

Disodium Edetate

Sodium Chloride

Hydrochloric Acid (for pH adjustment)

Sodium Hydroxide (for pH adjustment)

Purified water

6.2 Incompatibilities

None

6.3 Shelf life

Nasal spray, powder for solution and Diluent for reconstitution:

8ml vial – 36 months

17ml vial - 36 months

Nasal Spray, solution

2 weeks

6.4 Special precautions for storage

Nasal spray, powder for solution and Diluent for reconstitution: Store below 25°C. Store in the original carton to protect from light.

Nasal Spray, solution

Store below 25°C. Store in the original carton to protect from light.

6.5 Nature and contents of container

Nasal spray, powder for solution

Clear Type 1 neutral glass bottle (8ml or 17ml) with a dark grey rubber (bromobutyl) stopper and an aluminium overseal with a white flip off-tear off seal.

Diluent for Reconstitution

Squeezable, medium density polyethylene (MDPE) tube with a high density polyethylene (HDPE) neck and a twist-off top, containing 5ml of diluent (8ml vial) or 10ml of diluent (17ml vial).

Nasal Spray, solution

Clear Type 1 neutral glass bottle (8ml or 17ml) with a nasal spray pump. Pack includes 9 disposable white polypropylene nasal tips. The replacement tips are provided in individual tamper evident packs. Unopened packed nasal tips should be used to avoid microbial cross-contamination.

Each 8ml bottle of Nasal Spray, solution, contains 68 metered doses and each 17ml bottle of Nasal Spray, Solution, contains 160 metered dose sprays. Each metered spray is 50 microlitres.

6.6 Special precautions for disposal

Preparation of solution:

1. 1. Flip off the plastic protective cap from the glass bottle.
2. 2. Tear off the aluminium seal and pull out the rubber bung.
3. 3. Twist off the seal from the plastic tube containing the diluent and squeeze the contents into the glass bottle. Not all of the diluents can be squeezed from the tube. This is to be expected and calculations have been made to allow for the amount of solution left in the tube.
4. 4. Push the nasal pump with the paediatric nasal tip attached onto the glass bottle so that it snaps into place and remove the green safety clip. Unopened packed nasal tips should be used to avoid microbial cross-contamination.
5. 5. Swirl gently until all the diamorphine powder is dissolved, this should take approximately one minute with gentle movement of the bottle. To avoid excessive foaming, do not vigorously shake the bottle.
6. 6. Prime the nasal spray by holding it upright and actuating eight times in order to achieve the optimum spray before the first use. Following this, each time the disposable paediatric tip is changed (e.g. for each child) the pump must be primed a further two times to ensure the correct dose is delivered. The product should be primed into a sink. Replace the green safety clip before applying a new tip to prevent accidental actuation.
7. 7. Ensure that the dip tube remains in the solution during priming and re-priming to avoid air entering the pump spray and affecting dose uniformity. The bottle contains an excess volume of solution to ensure that the dip tube remains covered during priming and administration to ensure correct functioning of the spray.
8. 8. Write the date of reconstitution and the date for discarding on the label of the bottle.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements and in a manner appropriate for controlled drugs.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited

Ash Road North

Wrexham LL13 9UF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 29831/0465

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

20/01/2025

10 DATE OF REVISION OF THE TEXT

04/12/2025