Ayendi

Ayendi 720microgram/actuation Nasal Spray

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

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

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.

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.

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).

Ayendi Nasal Spray is only intended for intranasal administration, and must not be administered by any other route.Repeated administration of diamorphine may lead to dependence and tolerance developing. Abrupt withdrawal in patients who have developed dependence may precipitate a withdrawal syndrome. Great caution should be exercised in patients with a known tendency or history of drug abuse.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.

Excipients

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

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.Antimuscarinics: The risk of severe constipation and/or urinary retention is increased by administration of antimuscarinic drugs (e.g. atropine).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.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).

Safety has not been established in pregnancy. Administration during labour may cause respiratory depression in the neonate and gastric stasis during labour, increasing the risk of inhalation pneumonia. Babies born to diamorphine-dependant mothers have been reported to suffer withdrawal symptoms. Diamorphine should not be given to females who are breast-feeding, as there is limited information available on diamorphine in breast milk.

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:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

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, dysguesiaUncommon: 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 discomfortCommon: sneezing, epistaxis, laryngitisUncommon: hypoxia, hiccups, nasal mucosa disorder, rhinorrhoea.

Gastrointestinal disorders

Common: vomiting, nauseaUncommon: 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

Uncommon: The euphoric activity of diamorphine has led to its abuse and physical and psychological dependence may occur (see also 4.4 Special Warnings and Precautions for use).

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.

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.

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

a) SymptomsThe triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops. Pulmonary oedema after overdosage is a common cause of fatalities among diamorphine addicts.Other opioid overdose symptoms include cold, clammy skin, hypotension, bradycardia, circulatory failure, muscle flaccidity, severe weakness, severe nervousness or restlessness, confusion, severe dizziness, severe drowsiness, hallucinations, convulsions (especially in infants and children), rhabdomyolysis progressing to renal failure.b) TreatmentRespiration and circulation should be maintained and the specific opioid antagonist, naloxone is indicated if coma or bradypnoea are present, using one of the recommended dosage regimens. Oxygen and assisted ventilation should be administered if necessary.

ATC Code: N02AA09Pharmacotherapeutic group: Natural opium alkaloidsDiamorphine 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)

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.

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.

Nasal spray, powder for solution

NoneDiluent for reconstitution and Nasal spray, solutionBenzalkonium Chloride Solution (50% w/v)Disodium Edetate Sodium ChlorideHydrochloric Acid (for pH adjustment)Sodium Hydroxide (for pH adjustment)Water for Injections

None

Nasal spray, powder for solution and Diluent for reconstitution:

8ml vial - 36 months

17ml vial - 36 months

Nasal Spray, solution

2 weeks

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.

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 ReconstitutionSqueezable, 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.

Preparation of solution:

1. Flip off the plastic protective cap from the glass bottle.2. Tear off the aluminium seal and pull out the rubber bung.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. 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. 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. 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. 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. 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.

Wockhardt UK LimitedAsh Road NorthWrexham LL13 9UFUnited Kingdom

PL 29831/0465

18/10/2013

21/02/2017