Ayendi 720 microgram/actuation Nasal Spray Ayendi 1600 microgram/actuation Nasal Spray

105 Pages·2014·2.37 MB·English

UKPAR; AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY AND AYENDI 1600 MICROGRAM/ACTUATION
NASAL SPRAY, PL 29831/0465-0466

Ayendi 720 microgram/actuation Nasal Spray

Ayendi 1600 microgram/actuation Nasal Spray

(Diamorphine hydrochloride)

PL 29831/0465

PL 29831/0466

UKPAR

TABLE OF CONTENTS

Lay Summary Page 2

Scientific Discussion Page 4

Steps Taken for Assessment Page 97

Summary of Product Characteristics Page 98

Patient Information Leaflet Page 99

Labelling Page 100

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UKPAR; AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY AND AYENDI 1600 MICROGRAM/ACTUATION
NASAL SPRAY, PL 29831/0465-0466

AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY

AYENDI 1600 MICROGRAM/ACTUATION NASAL SPRAY

PL 29831/0465-0466

LAY SUMMARY

This is a summary of the public assessment report (PAR) for Ayendi 720 microgram/actuation Nasal
Spray and Ayendi 1600 microgram/actuation Nasal Spray. It explains how Ayendi Nasal Spray was
assessed and its authorisation recommended, as well as its conditions of use. It is not intended to
provide practical advice on how to use Ayendi Nasal Spray.

For practical information about Ayendi Nasal Spray, patients should read the package leaflet or
contact their doctor or pharmacist.

What is Ayendi Nasal Spray and what is it used for?
Ayendi Nasal Spray contains the active ingredient diamorphine hydrochloride, which belongs to a
group of medicines called the natural opium alkaloids. Ayendi Nasal Spray is used in hospital
emergency departments for the relief of severe pain caused by accidental injury in children and
teenagers between 2 and 15 years of age.

How is Ayendi Nasal Spray used?
The spray should be directed up the nasal side wall. It is recommended that the patient sits at a 45
degree angle when the spray is being administered. Patients are dosed according to their weight;
details of the correct dose to be given are included in the package leaflet

How does Ayendi Nasal Spray work?
Diamorphine works by mimicking the action of naturally-occurring, pain-reducing chemicals called
endorphins. It combines with receptors in the brain and spinal cord, blocking the transmission of pain
signals sent by the nerves to the brain.

How has Ayendi Nasal Spray been studied?
Products containing diamorphine have already been approved for use, however, Ayendi Nasal Spray is
specifically for the relief of severe pain in children and teenagers between 2 and 15 years of age, it
provides a different diamorphine dose to that of other UK approved products and is sprayed up the
patient’s nose. Additional studies were needed to look at the effects of these differences. Therefore, to
demonstrate the efficacy and safety of Ayendi Nasal Spray the Applicant collected data on similar
products and conducted three clinical studies.
In one of these studies 408 children aged 3 to 16 years presenting to an Accident and Emergency
Department with a fracture of a limb were given Ayendi Nasal Spray. In this study Ayendi Nasal
Spray was compared with morphine given by intramuscular injection by asking the children, their
parents/carers and the healthcare professional looking after the child to rate the level of pain that the
child experienced. The Applicant conducted two other studies in support of this application; one study
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NASAL SPRAY, PL 29831/0465-0466

in 56 children aged 1-<16 years looked at how a single dose of Ayendi Nasal Spray is processed by the
body and another study in 226 patients between 2 and <16 years of age investigated the safety of
Ayendi Nasal Spray.

What benefit has Ayendi Nasal Spray shown during studies?
In a study in children aged 3 to 16 years presenting to the Accident and Emergency Department with a
fracture of a limb Ayendi Nasal Spray had significantly better efficacy on pain scores than morphine
delivered by intramuscular injection. In addition, other studies showed that diamorphine in Ayendi
Nasal Spray behaves in a similar way to diamorphine taken by other routes of administration and has
an acceptable level of safety.

What is the risk associated with Ayendi Nasal Spray?
The main side effect that was reported was a sore nose, this side effect is very common and affects
more than 1 in 10 people. Other side effects are dizziness, a change in sense of taste, sneezing, nose
bleeds, laryngitis, feeling or being sick, itching of the skin and pain caused by the use of the nasal
pump; these side effects affect less than one in 10 people but more than one in 100 people. For a full
list of all side effects reported with Ayendi Nasal Spray, please see the package leaflet.

Ayendi Nasal Spray should not be used in people who are hypersensitive (allergic) to diamorphine
hydrochloride or any of the other ingredients, are having an asthma attack, have a type of tumour
known as a phaeochromocytoma, have severe stomach cramps caused by biliary colic, have increased
pressure on the brain, have just had a head injury or are unconscious, are suffering from acute
alcoholism, are at risk of a blocked intestine or are suffering from acute diarrhoea. Diamorphine
causes drowsiness and mental clouding. If affected, patients should not drive or use machines. Alcohol
may enhance these effects. These products contain the preservative benzalkonium chloride, which may
cause irritation inside the nose.

Why is Ayendi Nasal Spray approved?
It was concluded that the effect of Ayendi Nasal Spray for the relief of severe pain in children and
adolescents 2 to 15 years of age in a hospital setting was better than treatment with other forms of
diamorphine. It was considered that the benefits of using Ayendi Nasal Spray outweigh the risks and
the grant of Marketing Authorisations was recommended.

What measures are being taken to ensure the safe and effective use of Ayendi Nasal Spray?
A risk management plan has been developed to ensure that Ayendi Nasal Spray is used as safely as
possible. Based on this plan, safety information has been included in the summary of product
characteristics and the package leaflet for Ayendi Nasal Spray, including the appropriate precautions
to be followed by healthcare professionals and patients.

Other information about Ayendi Nasal Spray
The MHRA agreed to grant Marketing Authorisations for Ayendi Nasal Spray on 18 October 2013.

For more information about treatment with Ayendi Nasal Spray, read the package leaflet, or contact
your doctor or pharmacist.

This summary was last updated in 12-2013.

The full PAR for Ayendi Nasal Spray follows this summary.

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UKPAR; AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY AND AYENDI 1600 MICROGRAM/ACTUATION
NASAL SPRAY, PL 29831/0465-0466

AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY

AYENDI 1600 MICROGRAM/ACTUATION NASAL SPRAY

PL 29831/0465-0466

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction Page 5

Pharmaceutical assessment Page 6
Non-clinical assessment Page 9
Clinical assessment Page 18

Overall conclusions and risk assessment Page 96

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NASAL SPRAY, PL 29831/0465-0466

INTRODUCTION

The Medicines and Healthcare products Regulatory Agency (MHRA) granted
Marketing Authorisations for the medicinal products Ayendi 720 microgram/actuation
Nasal Spray and Ayendi 1600 microgram/actuation Nasal Spray to Wockhardt UK
Limited on 18 October 2013. These prescription only medicines (POM) are used for
the treatment of acute severe nociceptive pain in children and adolescents 2 to 15
years of age in a hospital setting.

These applications were submitted under Article 10(3) of Directive 2001/83/EC, as
amended, as hybrid applications. The reference medicinal products for these
applications are Diamorphine Hydrochloride 500mg for Injection, Diamorphine
Hydrochloride 100mg for Injection, Diamorphine Hydrochloride 5mg for Injection,
Diamorphine Hydrochloride 30mg for Injection and Diamorphine Hydrochloride
250mg for Injection (PL 29831/0060-0062, PL 29831/0064 and PL 29831/0229,
respectively) which were first granted Marketing Authorisations on 22 March 1993.
On 27 April 2007 the Marketing Authorisations were transferred from CP
Pharmaceuticals Ltd to Wockhardt UK Limited. The Marketing Authorisation for PL
29381/0229 was cancelled on 10 June 2009.

Diamorphine is a narcotic analgesic which acts primarily on the central nervous
system and smooth muscle.

A summary of pharmacovigilance system (PMFS) and a Risk Management Plan have
been submitted and are satisfactory.

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PHARMACEUTICAL ASSESSMENT

ACTIVE SUBSTANCE: Diamorphine hydrochloride

Chemical name: 4,5-Epoxy-17-methylmorphinan-3,6-diyl diacetate
hydrochloride monohydrate
Structure:

Diamorphine hydrochloride contains five chiral centres(*)

Molecular formula: C H NO .HCl.H O
21 23 5 2
Molecular weight: Diamorphine hydrochloride monohydrate - 423.9
Physical form: A white or almost white crystalline powder
Solubility: Freely soluble in water; soluble in ethanol (96%);
practically insoluble in ether.

An Active Substance Master File (ASMF) has been provided by the manufacturer,
covering the manufacture and control of the active substance.

Synthesis of the active substance from the designated starting materials has been
adequately described and appropriate in-process controls and intermediate
specifications are applied. Satisfactory specification tests are in place for all starting
materials and reagents and these are supported by relevant certificates of analysis.

Appropriate proof-of-structure data have been supplied for the active substance. All
potential known impurities have been identified and characterised.

An appropriate specification is provided for the active substance. Analytical methods
have been appropriately validated and are satisfactory for ensuring compliance with
the relevant specifications. Certificates of analysis have been provided for all working
standards. Batch analysis data are provided and comply with the proposed
specification.

Suitable specifications have been provided for all packaging used. The primary
packaging has been shown to comply with current guidelines concerning contact with
food.

Appropriate stability data have been generated to support a suitable retest period when
stored in the proposed packaging.

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UKPAR; AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY AND AYENDI 1600 MICROGRAM/ACTUATION
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MEDICINAL PRODUCTS: AYENDI 720 AND 1600 MICROGRAM/
ACTUATION NASAL SPRAY

Description and composition
Ayendi 720 microgram/actuation Nasal Spray and Ayendi 1600 microgram/actuation
Nasal Spray for marketing are presented in bottles containing white to off-white,
freeze-dried powders. The products are also marketed with bottles containing clear,
colourless 0.5% w/v preserved saline solution for reconstitution. After reconstitution
the nasal sprays are clear, colourless to pale straw coloured solutions.

Each bottle of Ayendi 720microgram/actuation Nasal Spray and Ayendi 1600
microgram/actuation Nasal Spray contains 144mg and 320mg diamorphine,
respectively, as diamorphine hydrochloride (equivalent to 720 microgram and 1600
microgram, respectively, in each 50 microlitre spray following reconstitution). Each
bottle of nasal spray, solution, contains 160 metered dose sprays.

The diluent for reconstitution contains the excipients benzalkonium chloride,
disodium edetate, sodium chloride, hydrochloric acid, sodium hydroxide and Water
for Injections. When reconstituted the nasal spray solution contains 0.02%
benzalkonium chloride.

All excipients comply with their European Pharmacopoeia monographs.

None of the excipients contain materials of animal or human origin.

Pharmaceutical development
The development of Ayendi Nasal Spray has been carried out in line with the
requirements for nasal liquid to be delivered in a non-pressurised, multiple use
metered dose spray, which is acceptable. Suitable pharmaceutical development
data have been provided for these applications.

Manufacture
Satisfactory batch formulae have been provided for the manufacture of both strengths
of the products, along with an appropriate account of the manufacturing process. The
manufacturing process has been validated and has shown satisfactory results.

Control of medicinal products
The finished product specifications proposed for both strengths of the products are
acceptable. Test methods have been described and have been adequately validated, as
appropriate. Batch data have been provided and comply with the release
specifications. Certificates of analysis have been provided for any working standards
used.

Container closure system
The powder for solution is stored in a clear, Type 1, neutral glass bottle (17ml) with a
dark grey rubber (bromobutyl) stopper and an aluminium overseal with a flip off-tear
off seal. The diluent for reconstitution is stored in a squeezable, medium density
polyethylene tube with a high density polyethylene neck and a twist-off top,
containing 10ml of diluent.

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The reconstituted nasal spray, solution is stored in a clear, Type 1, neutral glass bottle
(17ml) fitted with a nasal spray pump. Each pack includes nine disposable white
polypropylene nasal tips and a spray pump attachment. The replacement tips are
provided in individual tamper evident packs. Unopened packed nasal tips should be
used to avoid microbial cross-contamination.
Satisfactory specifications and Certificates of analysis have been provided for all
packaging components. All primary packaging complies with the relevant regulations
concerning use of materials in contact with food.

Stability
Stability studies were performed on batches of both strengths of finished product in
the packaging proposed for marketing and in accordance with current guidelines.
These data support a shelf-life of 36 months for the individual components (nasal
spray powder for solution and diluent) prior to reconstitution and 2 weeks for the
nasal spray following reconstitution, when stored below 25°C, in the original carton
protected from light.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL)
and labelling
The SmPCs, PIL and labelling are satisfactory from a pharmaceutical perspective.

A package leaflet has been submitted to the MHRA along with results of consultations
with target patient groups ("user testing"), in accordance with Article 59 of Council
Directive 2001/83/EC. The results indicate that the package leaflet is well-structured
and organised, easy to understand and written in a comprehensive manner. The test
shows that the patients/users are able to act upon the information that it contains.

Marketing Authorisation Application (MAA) forms
The MAA forms are satisfactory from a pharmaceutical perspective.

Quality Overall Summary
The quality overall summary is written by an appropriately qualified person and is a
suitable summary of the pharmaceutical aspects of the dossier.

Conclusion
The grant of Marketing Authorisations is recommended.
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UKPAR; AYENDI 720 MICROGRAM/ACTUATION NASAL SPRAY AND AYENDI 1600 MICROGRAM/ACTUATION
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NON-CLINICAL ASSESSMENT

1 INTRODUCTION

1.1 Type of application and aspects on development

Diamorphine hydrochloride is currently authorised in the UK as an injection for
intravenous (IV), intramuscular (IM) or subcutaneous use. However, no Marketing
Authorisations exist in the UK for the nasal spray formulation. This application
therefore represents a new pharmaceutical form and route of administration.

The products are indicated for the relief of acute pain in children. The maximum total
dose would be 4.8 mg diamorphine hydrochloride (equivalent to three sprays of
Ayendi 1600 microgram/actuation Nasal Spray).

Literature searches for the pharmacology, pharmacokinetics and safety and toxicology
of diamorphime were conducted by the applicant. The non-clinical overview has been
written by an appropriately qualified author. The report, dated December 2011, refers
to 55 publications up to the year 2011.

1.2 GLP aspects

Since a literature review has been presented, it cannot be verified whether the studies
cited were conducted in compliance with the Good Laboratory Practice (GLP)
regulations; however, it is assumed that the studies conducted by the originator would
have been conducted in compliance with the standards prevailing at the time.

2 PHARMACOLOGY

2.1 Primary pharmacodynamics
The pharmacology of the active ingredient diamorphine and its metabolites,
6-monoacetylmorphine (6-MAM) and morphine, used intravenously, intramuscularly
and subcutaneously in humans is well known. No new studies have been conducted
on the pharmacology of diamorphine, 6-MAM or morphine. This is acceptable as the
active substance is known. The pharmacology studies discussed in the non-clinical
overview are summarised here.
The pharmacology of diamorphine has been investigated in vitro and in vivo.
Receptor binding studies have been conducted with diamorphine, 6-MAM and
morphine and their analgesic activities were evaluated in animals using tests that
measure pain intensity). The effect of gender on diamorphine activity was also
investigated.
Effects on opioid receptors
In vitro studies: In a study conducted to determine the relative affinity to opioid
receptors, diamorphine showed minimal binding to these receptors in the rat brain and
6-MAM was shown to bind predominantly to the µ-receptors with some binding at the
κ-receptors.
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In vivo studies: In a study in mice, subcutaneous administration of diamorphine and
6-MAM exhibited almost identical dose response curves and time-pharmacological
action curves for antinociceptive, excitory, antidiarrhoeal and antidiuretic activity.
The results suggested that these pharmacological actions were mediated by 6-MAM
and morphine.
In Swiss-Webster mice, diamorphine and morphine were shown to activate the brain
δ- and µ-receptors, respectively, to produce antinociception. In Swiss-Webster mice,
intracerebroventricularly administered 6-MAM was shown to act on δ-receptors.
Following intrathecal administration, 6-MAM was shown to act on δ-receptors and
diamorphine on µ-receptors. However, in imprinting control region (ICR) mice,
6-MAM given by intracerebroventricular or intrathecal administration was shown to
act on supraspinal µ-receptors.
In a series of tail flick studies in mice, the response to the intracerebroventricular
administration of diamorphine and 6-MAM was altered from a µ-receptor-mediated
action to a δ-receptor-mediated action by IV pre-treatment with 200 mg/kg
streptozotocin (a drug used in cancer and diabetes treatments) or when administered
to diabetic animals. These studies suggested that both extrinsic and genetic factors
can influence opioid receptor activity. In additional studies using five different strains
of mice, the opioid receptor selectivity of diamorphine varied and was shown to be
genotype-dependent.
Studies in mice also showed that the antinociceptive tail flick responses to
diamorphine, 6-MAM and methadone, mediated by the µ-receptor, were changed to a
δ-receptor activity following the brain implantation of morphine or methadone pellets.
Morphine-induced antinociceptive tail flick responses were unaffected by these
pellets.
Studies in exon 1 µ-opioid receptor (MOR-1) knockout mice that do not respond to
morphine, and exon 11 knockout mice provided evidence of receptors that were
selectively involved with diamorphine and morphine-6β-glucuronide-(M6G; a major
active metabolite of morphine) induced analgesia.
Effects on neurones
Neurones of the raphe nucleus, which sends axons to the CNS, particularly the
hypothalamus, synthesis serotonin. Diamorphine was shown to selectively increase
the metabolic activity in neurones involved in serotonin metabolism.
Analgesic activity studies
A series of studies was conducted to evaluate the analgesic activities of diamorphine,
6-MAM and morphine. In mice and rats subcutaneously administered diamorphine,
analgesia was shown to increase with dose. Using the tail clip technique, the
calculated mean effective dose (ED ) at 30 and 180 minutes were 1.0 mg/kg and
50
27.5 mg/kg, respectively. Similar results were obtained using the hot-plate method.
Morphine was up to three times more potent as a naloxone (a known opioid
antagonist)-reversible analgesic than either diamorphine or 6-MAM.
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