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

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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 00


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AYENDI 720 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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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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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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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: C21H23NO5.HCl.H2O 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.

http://www.pharmacopoeia.co.uk/bp2014/ixbin/bp.cgi?id=1455&a=display&popup=y�




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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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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 (ED50) at 30 and 180 minutes were 1.0 mg/kg and 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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Rats administered 1 mg/kg diamorphine or 10 mg/kg morphine achieved the same maximal level of analgesia in 15 minutes and 45 minutes, respectively.

Effect of gender studies

Gender differences in response to analgesic drugs that act on µ, κ and δ- opioid receptors have been reported in animal and human studies. In a warm-water tail-withdrawal study in rats, the analgesic effect of morphine was more potent in males compared with females but there were no gender-related differences in the antinociceptive potency of diamorphine.

2.2 Secondary pharmacodynamics A range of in vivo secondary pharmacology studies investigating the effect of diamorphine on the ocular, respiratory, gastrointestinal and immune systems were reported in the applicant’s non-clinical overview. Studies investigating the tolerance to diamorphine were also reported; these studies were discussed in the safety pharmacology section of the applicant’s non-clinical overview.

Effect on the ocular system

In rabbits intravenously administered 0.1 to 2 mg/kg diamorphine, a dose-related decrease in intra-ocular pressure and an increase in outflow facility and miosis were observed. Depressed respiration was seen at higher doses.

Effect on the respiratory system

In rats, the ratio of the analgesic to the respiratory depressant potency was the same for diamorphine, morphine, codeine, methadone, dipipanone, piperidylisomethadone, phenadoxone, dextromoramide, and propoxyphene. Fetal rabbits injected with diamorphine showed findings that suggested a reduced alveolar surface tension and increased alveolar surfactant.

Effect on the immune system

Diamorphine has been shown to have inhibitory or stimulating effects on the immune system. In mice subcutaneously administered diamorphine, the production of pro-inflammatory cytokines and nitric oxide were enhanced and allotransplantation reactions were accelerated.

Effect on the gastrointestinal system

Diamorphine was also shown to inhibit contractions and twitches in guinea pig ileum. Tolerance to diamorphine was demonstrated by the lack of inhibition of ileum twitching following further exposure to the drug.

Tolerance studies

In rats, tolerance to diamorphine occurred within 3 to 4 hours of IV infusion. This was prevented by the simultaneous infusion of actinomycin D, a protein synthesis inhibitor.


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The analgesic response to morphine was investigated in mice and rats co-administered morphine and cycloheximide (a protein synthesis inhibitor) for up to 23 days following the IV administration of tolerance-inducing drugs (diamorphine, morphine or methadone). A biphasic pattern of recovery was observed which was independent of the dosing regimen or the drug. In mice, for the second phase of recovery, a mean half time of 17.4 days for morphine-induced tolerance was observed and in rats a mean half time of 13.2 days was seen for all tolerance-inducing treatments.

2.3 Safety pharmacology Effects on the central nervous and respiratory systems In anaethetised cats, administration of 17 to 450 µg diamorphine into the forebrain fourth ventricle or the cisterna magna resulted in a decrease in respiratory minute volume. IV administration of the same dose also produced a decrease in respiratory minute volume. The bilateral application of diamorphine (70 µg/side) to three ventral medullary surface sites resulted in a reduction in respiratory minute volume at only one site (Mitchell’s area), indicating that this site is an area of diamorphine-induced respiratory depression. The bilateral application of naloxone to this site restored normal respiration Effects on the cardiovascular system In cats and rabbits, IV administration of diamorphine, morphine, pethidine and naloxone produced hypotension. 2.4 Pharmacodynamic drug interactions No new pharmacodynamic drug interaction studies with diamorphine have been conducted. However, opioids are known to potentiate the effects of CNS depressants including tricyclic antidepressants, anxiolytics and hypnotics. 2.5 Conclusions on pharmacology No new non-clinical studies have been conducted on the pharmacodynamics of diamorphine, 6-MAM or morphine using the intranasal (IN) or other routes of administration. Literature has been reviewed and is discussed in the applicant’s non-clinical overview. This is acceptable in view of the clinical studies conducted with diamorphine administered via the IV, IN and IM routes which have been discussed in the applicant’s clinical overview. Diamorphine has been shown to produce a range of effects including pain relief, miosis, respiratory depression, hypotension, euphoria and tolerance.

The absence of standard studies on abuse liability and safety pharmacology is acceptable for this application in view of the large amount of published information available from non-clinical and clinical studies that have been conducted with diamorphine, 6-MAM and morphine.


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3 PHARMACOKINETICS No new studies have been conducted on the pharmacokinetics of diamorphine, 6-MAM or morphine. Literature has been reviewed and is discussed in the applicant’s non-clinical overview. Pharmacokinetics are briefly summarised here. 3.1 Methods of analysis Methods of analysis were not discussed. 3.2 Absorption Absorption studies were not discussed. 3.3 Distribution In a positron emission topography study in monkeys intravenously administered radiolabelled diamorphine, morphine, codeine or pethidine, their maximum normalised uptake (with respect to dose per kg body weight) into the brain was 4.6, 0.2, 2.6 and 6.3, respectively, of the calculated activity. For morphine, the maximum brain level was detected at 3 to 45 minutes post dose and the t½ was 2 hours. Maximum brain levels of diamorphine, codeine and pethidine were detected sooner (within 5 minutes) and eliminated at faster rates (t½ was 30 to 50 minutes). High levels of morphine were detected in the pituitary. 3.4 Metabolism In vitro studies In microsomal preparations of liver samples derived from rats administered diamorphine, incubation with morphine resulted in reduced morphine-3-glucuronide (M3G) levels and increased morphine-6-glucuronide (M6G; a potent opioid agonist) levels. These effects were reversed following cessation of diamorphine administration. Ex vivo studies In an isolated perfused rabbit liver preparation study, a single bolus injection of 1.5 mg diamorphine, morphine, methadone or meperidine resulted in single pass hepatic clearances of 59, 25, 86 and 66%, respectively. In vivo studies Studies in various species, including mice and rats, showed that diamorphine is metabolised to 6-MAM and morphine. Morphine was then metabolised to M3G and M6G. In rats, repeated intraperitoneal doses of 2.5 to 10 mg/kg diamorphine (10/day) increased plasma levels of M6G and reduced those of M3G. Repeated morphine administration resulted in slightly reduced M3G formation. Repeated cadmium


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administration resulted in reduced M3G formation and did not induce M6G synthesis. These results indicate that repeated administration of diamorphine can alter morphine glucuronidation and induce formation of the M6G active metabolite. 3.5 Excretion Excretion studies were not discussed. 3.6 Pharmacokinetic drug interactions Pharmacokinetic drug interactions were not addressed. 3.7 Other pharmacokinetic studies Other pharmacokinetics studies were not discussed. 3.8 Conclusions on pharmacokinetics No new studies have been conducted on the pharmacokinetics of diamorphine, 6-MAM or morphine. Literature has been reviewed and is discussed in the applicant’s non-clinical overview. The absence of methods of analysis, absorption and excretion studies is acceptable for this application in view of the large amount of information available from non-clinical and clinical studies conducted with the compounds and also from their clinical use. 4 TOXICOLOGY No new toxicology studies have been conducted with diamorphine, 6-MAM or morphine. Literature has been reviewed in the applicant’s non-clinical overview. Toxicology studies are briefly summarised here. 4.1 Single dose toxicity The following studies were conducted with diamorphine. LD50 values for diamorphine, taken from a register of toxic effects, are provided in Table 1. Table 1. Acute Toxicity of Diamorphine Animal Species Route of Administration LD50 Value (mg/kg) Mouse IV 38 Mouse Intraperitoneal 240 Mouse Subcutaneous >60 Rat IV 21.5 In another study in mice intravenously administered diamorphine at 0.1 mL/min, the lethal dose was 56.7 mg/kg. Diamorphine had no effect on the lung weight. In mice subcutaneously administered diamorphine, the lethal dose was 190 mg/kg. In a further study in mice, the IV lethality of diamorphine, 6-MAM and morphine was determined and the results are presented in Table 2.


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Table 2. IV Lethality of Diamorphine, 6-MAM and Morphine in Mice Drug Slope±SD LD50 (µMol/kg IV

(95% CI) Relative Potency (95% CI)

Diamorphine 8.6±1.9 59 (52-66) 1 6-MAM 11.8±3.2 180 (160-200) 33 (0.28-0.38) Morphine 8.38.3±2.0 560 (500-620) 0.11 (0.09-0.12) Naloxone-sensitive respiratory depressant lethality occurred in mice administered intracerebroventricular doses of 200 µg diamorphine or 6-MAM. In mice administered IV doses of diamorphine, 6-MAM or morphine or intracerebroventricular doses of morphine, convulsions were seen prior to death. 4.2 Repeated Dose toxicity The absence of toxicity studies in animals using the nasal route of administration was justified on the basis of the available clinical data which has suggested that nasal irritation of mild severity will occur at an incidence of approximately 20% with use of Diamorphine HCl Nasal Spray. Nasal irritation is included as an undesirable effect in the product SmPCs. 4.3 Genotoxicity Diamorphine did not show evidence of genotoxic potential. However, at high doses increased levels of chromosome aberrations were seen in monkey white blood cells and a doubling of sister chromosome exchange was observed in pregnant animals. 4.4 Carcinogenicity No carcinogenicity studies have been conducted with diamorphine. 4.5 Reproductive and developmental toxicity 4.5.1 Fertility and early embryonic development Fertility and early embryonic development studies were not discussed. 4.5.2 Embryo-fetal development Teratogenic effects, including cranioschisis and exencephaly, were seen in the fetuses of hamsters subcutaneously administered single or repeated doses of diamorphine and this increased with dose. Teratogenic effects increased by up to six-fold following repeated dosing compared with single dose administration. The teratogenic effects were abolished by pre-treatment with µ- or κ-receptor antagonists or agonists, nalorphine, naloxone, levallorphan or cyclazocine. Reduced birth weights of offspring of diamorphine-treated hamsters and rabbits were also observed.


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4.5.3 Prenatal and postnatal development, including maternal function In rats subcutaneously administered 2.5 and 10 mg/kg diamorphine, mortalities occurred during the gestation period. An extended gestation period was observed in the 2.5 and 10 mg/kg dose groups and smaller litter sizes were produced in the 5 and 10 mg/kg dose groups. The number of stillborn rats and deaths within 3 days of birth were increased in the 2.5, 5 and 10 mg/kg dose groups and the birth weight of all pups exposed to diamorphine was reduced by up to 24%. On Days 6 and 10, reduced body weight (by up to 36%) was observed in rat offspring exposed to up to 10 mg/kg diamorphine. Female rats intraperitoneally administered 3 to 20 mg/kg diamorphine also produced smaller litter sizes when compared with controls In a study where rats were subcutaneously administered 2 to 4 mg/kg diamorphine, 7 mg/kg methadone or 3 mg/kg buprenorphine once or twice daily during Days 3 to 20 of the gestation period, a reduced body weight gain was observed in the dams of all dose groups. The highest number of mortalities was seen in the buprenorphine dose group. 4.5.4 Studies in juvenile animals Studies in juvenile animals were not discussed. 4.6 Local tolerance As discussed previously, toxicity studies have not been conducted with diamorphine using the IN route of administration on the basis that documented clinical data on nasal irritation following use of the proposed product in children were provided. 4.7 Other toxicity studies 4.7.1 Dependence It has been shown that long term potentiation (LPT) in the rat hippocampal CA1 region is significantly reduced during withdrawal following chronic opiate treatment, and the reduced LTP can be restored by re-exposure of animals to corresponding drugs. It has also been shown that during opiate withdrawal, the re-exposure to morphine either systemically (subcutaneously) or locally (intracerebroventricularly) could restore the reduced LTP in diamorphine-dependent rats, indicating differential modulations of hippocampal functions by those two opiates. 4.8 Ecotoxicity/environmental risk assessment In accordance with the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP4447/00), a justification for the absence of an environmental risk assessment (ERA) has been provided. Fpen and PEC values have not been provided for the Ayendi Nasal Spray. The applicant states that the inhalation product would replace the currently marketed parenteral products and, hence, the exposure of the environment to diamorphine is not likely to increase. This is acceptable.


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4.9 Overall conclusions on toxicology No new studies have been conducted on the toxicology of diamorphine, 6-MAM or morphine. Literature has been reviewed and is discussed in the applicant’s non-clinical overview. This is acceptable for this application in view of the large amount of information available from non-clinical and clinical studies conducted with the compounds and also from their clinical use. The non-clinical studies showed that following IV, intraperitoneal and subcutaneous administration of diamorphine, acute toxicity was detected at doses higher than those approved or proposed for human use. In reproductive and developmental toxicity studies, teratogenic effects and reduced pup weights were observed following subcutaneous administration of diamorphine. Diamorphine was not considered to be genotoxic overall, although it has been shown to induce some chromosome abnormalities at high doses. The safety of the impurity profile of the diamorphine hydrochloride nasal spray formulation and any potential degradants was not discussed by the applicant. As this is a new formulation and contains different excipients from the marketed injection formulation, the impurity limits and potential degradants should have been addressed. The Quality dossier provides adequate information showing that these impurities are appropriately controlled. The applicant has justified the absence of toxicity studies. 5 ASSESSOR’S OVERALL CONCLUSIONS No new studies have been conducted on the pharmacology, pharmacokinetics and toxicology of diamorphine, 6-MAM or morphine. Literature has been reviewed and is discussed in the applicant’s non-clinical overview. An adequate justification for the absence of an ERA has been provided for Ayendi 720 microgram/actuation Nasal Spray. The non-clinical sections of the SmPCs are in line with the approved SmPCs for diamorphine injections. The grant of Marketing Authorisations is recommended.


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CLINICAL ASSESSMENT

1 INTRODUCTION 1.1 Type of Application The MAAs are for a new dosage form (nasal spray) specifically developed for a new route of administration (nasal) and indication (relief of acute pain). The therapeutic indications, strength, pharmaceutical form and route of administration for Ayendi 720 microgram/actuation Nasal Spray and Ayendi 1600 microgram/actuation Nasal Spray differ from those of the reference products Diamorphine 5mg, 10mg, 30mg, 100mg, 250mg, and 500mg for Injection (PL 29831/0062-64, 0061, 0229 and 0060) in the following respects: - The indication for the proposed products is for the relief of acute, severe

nociceptive pain in children and adolescents, whereas the reference products are indicated in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema.

- The active ingredient used in the proposed products is the same qualitatively but not quantitatively as in the reference products.

- The proposed pharmaceutical form is nasal spray. The reference products are solutions for injection.

- The route of administration is nasal compared to the reference products, which is parenteral.

1.2 Clinical Background Diamorphine is a narcotic analgesic, a semisynthetic derivative of morphine. It 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.

The major metabolites of diacetylmorphine (6-MAM (6-monoacetylmorphine), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)), may be measured in blood, plasma or urine. Diamorphine has been used as a parenterally administered analgesic for acute pain since 1898, when it was first marketed by Bayer. It is a pro-drug of morphine but has a faster onset of action due to its ability to cross the blood-brain barrier more rapidly. It is reported to have a potency of approximately twice that of morphine salts and has a similar onset (circa 10 minutes) and duration of action. Administration of drugs via the nasal mucosa is well described and is attractive for a number of reasons: - The nasal mucosa is richly vascularised and the subepithelial cells are lined by a

fenestrated epithelium - Vascular drainage is via the facial and sphenopalatine veins and thus nasal

administration avoids first pass drug metabolism in the gut and liver


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- Patient acceptability may be higher when compared with the rectal and IM/IV routes of administration

The nasal spray is designed as a multi-use product with replacement of the paediatric tip and priming between patients. It is provided in two strengths: 144mg and 320mg, providing 720μg and 1600μg diamorphine hydrochloride per actuation (50μl), respectively, following reconstitution. It is proposed that the diamorphine will be delivered at a single dose of 0.1mg/kg, using a total of 2-4 actuations of the appropriate product strength, according to the weight of the child and thus the quantity required, directed into alternate nostrils. The maximum volume administered per nostril will be 100μL and the maximum total dose will be 4.8mg diamorphine hydrochloride (equivalent to three sprays of the 1600μg/actuation product). 1.3 Indications The indication for these products is as follows:

“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.” It is considered that this indication is justified based on the results of the studies conducted by the Applicant and documented evidence of clinical use of IN diamorphine to treat acute severe pain with a range of causes. These are discussed later in this report. 1.4 Dose and Dose Regimen The posology and method of administration for the 720 micrograms/actuation Nasal Spray is as follows:

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

Posology The dose should not be repeated. Patients should be dosed according to weight.

Child Weight (kg)

Approx Age (years)

No of Sprays Dose administered

12 – <18 2-5 2 1.44mg 18 – <24 5-8 3 2.16mg 24 - <30 8-10 4 2.88mg

Method of administration Ayendi Nasal Spray is for nasal use only.


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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.” The posology and method of administration for the 1600 micrograms/actuation Nasal Spray is as follows:

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

Posology

The dose should not be repeated.

Patients should be dosed according to weight.

Child Weight (kg)

Approx Age (years)

No of Sprays Dose administered

30 - <40 10-14 2 3.20mg 40 - 50 14-15 3 4.80mg

Method of administration Ayendi Nasal Spray is for nasal use only.


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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 4.8mg diamorphine hydrochloride (three 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.” It is considered that the proposed dose of 0.1mg/kg IN diamorphine has been sufficiently justified from both an efficacy and safety perspective based on studies conducted by the Applicant and by supportive published data. These are discussed later in this report. 1.5 GCP Aspects The data package consists of three main studies sponsored by the applicant for which a Clinical Study Report (CSR) are available. These CSR contain a statement establishing that the studies were conducted according to GCP and WHO guidelines. The applicant also refers to a number of published studies. Most of the publications submitted do not state whether these studies were GCP compliant, hence no assumption can be made for these. 1.6 Paediatric Development Programme A Paediatric Investigation Plan (PIP) has not been included. Since the applications were submitted under Article 10 this is acceptable.


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1.7 Legal Status The products are subject to medical prescription, and are products on restricted prescription. 1.8 Summary of Clinical Data The clinical data package comprises three clinical studies sponsored by the applicant and a number of published articles/abstracts or personal communications. The three studies performed by the applicant are: - DIA001 - CP9703 - DIA002 Study CP9703 was conducted in the period 1997-1999. Diamorphine as a dry powder was reconstituted with preserved saline and administered into one nostril as a fixed dose of 100 µl via the same proposed nasal spray device. It is considered that any effect of the difference in the product delivery will be minimal and of no clinical significance with respect to absorption, efficacy and safety of the proposed product. Thus, the Applicant is justified in extrapolating the results from pivotal study CP9703 to use of the current product. Studies DIA001 and DIA002 are more recent and are the only studies that used the product in exactly the same way as proposed for these applications. Listing of Clinical Studies


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2 CLINICAL PHARMACOLOGY 2.1 INTRODUCTION The pharmacological profile of diamorphine is known and has been studied mainly in adults. The SmPCs for Ayendi Nasal Spray contain the following information: 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


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administration of 0.06mg/kg diamorphine IN in children, mean peak plasma concentration of morphine was estimated as 14.0 ng/ml with a median Tmax 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. 2.2 Pharmacokinetics 2.2.1 Pharmacokinetics in Children 2.2.1.1 Study DIA001 – Clinical Study Report Title of study An open label single dose pharmacokinetic (PK) study of diamorphine hydrochloride nasal spray (0.06 mg/kg) in children Objectives Primary objective: To determine the single dose PK profile of intranasally administered diamorphine in children aged 1–<16 years. Secondary objectives: To obtain pharmacodynamic endpoints (post-operative pain scores, respiratory rate, pulse rate, oxygen saturation and temperature). Methodology

An open label, single dose, sparse sampling PK modelling study in children aged from 1–<16 years attending hospital clinics for minor day surgery or laser treatment and requiring IV cannulation and opiate analgesia for their routine clinical management.

Design

The cannulation site on the child’s arm was numbed with local anaesthetic cream, and a cannula was inserted. The child was then anaesthetised and a baseline blood sample taken. The child received 1–3 sprays of IN diamorphine, depending on their weight, and another blood sample was taken as soon as possible (from 0–10 minutes) post- dose. Up to four further PK blood samples were taken from the cannula for the

Blood sampling


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purposes of the study spaced out over the following time windows: 10–20 minutes, 20–30 minutes, 30–45 minutes, 45–60 minutes, 60–120 minutes and between 120 minutes post-dose and following removal of the cannula. The protocol was written such that sampling time points could be amended following the interim study analyses; however total blood volume and numbers of samples were to remain constant. There was no reason to amend sampling times at the interim review and the study proceeded unmodified. Adverse events (AEs), vital signs, nasal tolerance and pain scores were also monitored.

At least 50 patients were planned to complete the study. 57 patients (male and female) were screened, and entered. One subject withdrew prior to treatment; 56 patients completed the study (53 aged 1–11 years, three aged 12–< 16 years).

Number of patients (planned and analysed)

Safety population: 56; PK population: 50

Ayendi Nasal Spray, comprising diamorphine hydrochloride (144mg or 320mg), freeze dried powder reconstituted with 0.5% preserved saline solution (10ml) and administered using an IN spray device as a single dose of 0.06mg/kg.

Test product, dose and mode of administration, batch number

Note: The first ten patients who entered the original study received the dose 0.1mg/kg. Two of these patients experienced a prolongation of sedation. The exact reason for this prolongation of sedation is not known, however it is considered likely to be due to an interaction between the concomitant medication (or procedures) used during the anaesthesia of the patients. As would be the case in standard clinical practice, the dose of the diamorphine was reduced. In the case of this study protocol the dose was reduced to a target of 0.06mg/kg. This is a dose that was practical and achievable for this trial whilst maintaining the safety of the trial patients, the integrity of the PK investigation and the presentation of the investigational medicinal product as proposed for the target marketing indication. The protocol amendment was written such that if the lower dose of 0.06mg/kg did not give adequate pain relief, additional analgesics could be administered. If the additional analgesic agent was known to interact with diamorphine or if it was unclear whether it could interact with diamorphine, then the final blood sample for PK evaluation of diamorphine would be taken prior to the administration of the analgesic agent (as the primary objective of the study is to determine the PK profile of IN diamorphine). In any event, no child required additional pain relief that would interfere with the PK evaluation as a result of this reduced dose.

Primary – PK (metabolites: acetylmorphine, morphine, M3G, M6G) Criteria for evaluation

Primary parameters Systemic input function (Ka/Rin/Dn); clearance (CL/Fm); volume of distribution (V/Fm)

Secondary parameters Half-life (t1/2); time to maximum concentration (Tmax); maximum plasma concentration (Cmax); area under plasma concentration time curve (AUC)


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Secondary and Safety Assessments Post-operative pain scores; respiratory rate; pulse rate; oxygen saturation; temperature; AE monitoring; local (nasal) tolerability

The bioanalytical method employed has been validated. The method was demonstrated to be sufficiently accurate and precise, and to have sufficient selectivity to reliably allow the determination of each metabolite in human plasma samples over the examined range. The analysis was not significantly affected by the presence of potential concomitant drugs.

Bioanalytical method

Approximately 50–75 (but at least 50 unique) patients, both male and female, aged 1–<16 years of age were to be recruited. The sample size chosen for the study was considered appropriate based on previous experience. No formal sample size calculations were performed. In order to develop a robust population PK model (i.e. precisely estimated parameters) data from a minimum of 150–200 blood samples would be required. It was hoped that the required number of samples could be obtained from 50 children. However, if problems were encountered in obtaining samples further children would be included in the study.

Sample size

To ensure that the cohort was appropriately represented by age, consecutively enrolled patients were allocated to the following stratifications. Recruitment was to continue until the required number was achieved in each stratification:

• Age 1–11 years : 40–60 patients • Age 12–<16 years : 10–15 patients

Statistical methods A planned single, simple, interim analysis was conducted after the inclusion of 25 patients. These data were reviewed by the PK expert who recommended that the trial could continue without modification. A sparse sampling approach was employed in the study. Therefore, a population-PK approach was applied in which all data from different individuals were fitted simultaneously using a non-linear, mixed effects modelling approach and post hoc individual kinetic parameters could be calculated with as few samples as one per individual. Results The final model assumed zero order systemic input (accounting for absorption and systemic conversion of diamorphine to acetylmorphine), two compartment disposition for acetylmorphine and morphine, a metabolic compartment to allow for the lag in appearance of M3G and M6G and one compartment with fixed parameters to describe their disposition. The population estimates of central volume of distribution for acetylmorphine were shown to increase non-linearly with age. For morphine, the population estimates of central volume of distribution were linearly related to weight, whereas the formation clearance of M3G was shown to increase non-linearly with weight.


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Baseline characteristics of the PK population

Histogram of distribution of categorical and continuous covariates explored in the model (age=years; weight=kg)


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Primary parameters Population PK parameters of the metabolites from the final model

Final Full Covariate Model (Age on VAM, Weight on VM, CL2M3G) None of the children recruited was below the weight of 10 kg, therefore the clearance for children below 10 kg of weight is extrapolated. Also there is little data for children above 50 kg. Bouwmeester at al. estimate that total morphine clearance was 80% of that of adults by 6 months and 96% of that predicted in adults by 1 year. Following adjustment of systemic exposure parameters to the proposed posology dose of 0.1mg/kg, a weak


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correlation of age with morphine AUC is apparent, but there is considerable overlap and these results do not suggest that the proposed posology dose needs to be modified by age. Systemic exposure parameters following a single dose of IN diamorphine suggest significant between-subject variability in morphine Cmax and AUC and since it is assumed that virtually all of the acetylmorphine is converted to morphine, variability in exposure reflects underlying bioavailability of IN diamorphine. Secondary parameters Summary of secondary PK parameters determined from the final covariate model

Plots of acetylmorphine AUC and Cmax versus age and bodyweight do not reveal any relationship. Plots of morphine AUC versus age and bodyweight suggest a weak relationship (r2= 0.28 and 0.19, respectively). This is explained by the effect of bodyweight on CL2M3G in the model, as identified during the covariate analysis. However, no relationship between Cmax and age or bodyweight was identified. These changes in the morphine PK caused by statistically significant covariates, age and bodyweight, identified above in the population PK analysis do not appear to be clinically significant.


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Although literature reports suggest that perhaps up to 10% of morphine is cleared via non-glucuronide (predominantly renal) pathways (Rook et al., 2006b), the inclusion of a third clearance route for morphine resulted in a very small estimate and model instability (rounding errors suggesting that the model was over parameterised) and hence was not included in further model development. Major protocol deviations/exclusions There were two major protocol deviations which resulted in data from patients being excluded from the PK analyses. Storage Conditions Blood plasma samples for three patients were not stored at the correct temperature. The data from these children were excluded from the PK analyses, but their safety data are included in the safety analyses. Repeat treatment Three patients were included twice in the study, repeating their treatment visit at the request of the parents and children. The protocol requires data from 50 to 75 unique individuals. Blood samples from the patients repeat visit were analysed and the results presented in the listings but not included in the PK analyses. Concomitant medication Some concomitant medications were administered which were not specifically allowed by the protocol. None of these drugs are known to specifically interact with diamorphine or any of its metabolites. However: - some children received diclofenac, this could affect renal elimination of M3G and

M6G - a number of children were induced using propofol, which undergoes

glucuronidation and could be competing for the same metabolic route as morphine.

The interaction of diclofenac and propofol with the metabolites is, however, theoretical and not proven and, therefore, no patient was excluded as a result. The use of these two medications by patients (in relation to the diamorphine and the blood sampling times) was included in the PK analysis to explore possible interactions. Thus diclofenac and propofol were included in the PK modelling dataset as covariates.


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A number of children received non-permitted medications known to interact with the PK of diamorphine (e.g. codeine), however, in all of these cases the medication was administered to the children after the last PK sample had been obtained. Outlier During the development of the base structural model, one patient was identified as an outlier. The plasma levels of all four metabolites for this subject suggested unconventional results with a PK profile that was difficult to explain physiologically or clinically. This child was therefore excluded from further model development. Safety results The safety population included all 56 patients who completed the study (i.e. including all protocol deviators excluded from PK population). This population included the three patients who were re-treated (i.e. 53 unique patients). The incidence of treatment-emergent adverse events (TEAEs) was 41% of all patients; events were unremarkable, except for two serious AEs of prolonged sedation. There were 42 TEAEs reported by 23 patients. 41% of all patients reported at least one event; 40% of the younger children (1–11 years), and 67% of the older children (12–<16). None of these events led to death or withdrawal of a patient. The most commonly reported body system for AEs was gastrointestinal disorders with six patients reporting 16 events, in all cases post-operatively: - vomiting (six patients; definite (one), probably (two) and possibly (three) related

to the nasal spray) - nausea (three patients; possibly related (three)) - haematemesis (one patient; possibly related to the test product). All were considered mild except the haematemesis (severity moderate; the child had most likely swallowed blood during the dental procedure). The vast majority of gastrointestinal AEs were seen with dental surgery and although the events were rated as possibly related to the nasal spray, it is it is also possible that other factors surrounding day case dental surgery contributed to the increased incidence at this site.


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The incidence of related TEAEs was anticipated (26 out of 42 events; 62% of events). All were known effects of the drug or route of administration, with the exception of mild procedural pain (in two patients). Two of the reported events were considered to be serious TEAEs; both were as a result of narcotic intoxication, and resulted in a prolongation of sedation. However, all the contributing events were expected as a result of diamorphine intoxication. There was no apparent relationship between incidence of AEs and age. Respiratory depression: There was no respiratory depression (in terms of clinically notable changes in vital signs) seen during the study that resulted in reporting as AEs. Local tolerability: There were five TEAEs relating to nasal irritation (preferred term, nasal discomfort) reported by five patients; all reported as ‘itchy/itching’ and all considered mild. None of these events were serious or considered to be of clinical relevance to the study. No further nasal irritation events were reported to the research site for any patient in the 7 days following treatment. Relationship between PK and safety: There were no safety concerns (other than the two SAEs that resulted in the dose reduction) raised during the conduct of the study. Thus, there was no relationship between PK of IN diamorphine and safety. This study recruited children who were due for surgery and who received the study drug as a post-operative measure. Therefore, the drug was given concomitantly with other products such as NSAIDs and anaesthetic drugs. The dosing was reduced from 0.1mg/kg to 0.06mg/kg after two of the first 10 patients recruited suffered narcotic intoxication. Potential drug interaction was used as a covariate in the final model. The safety data are difficult to assess considering the concomitant use of analgesic and anti-emetics. The PK sampling schedule appears to capture well the appearance and disappearance of acetylmorphine and morphine in plasma, but not those of morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). For morphine-6-glucuronide concentrations continue to increase throughout individual profiles for all subjects, precluding characterisation of its Cmax and AUC in this study. The incomplete plasma concentration-time profiles precluded estimation of the clearance of the two glucuronide metabolites and fixed values from the literature were used instead. The applicant has followed the analysis plan for the population PK analysis. However, there are some discrepancies between what is reported in the literature for the impact of size and maturation on morphine and metabolite PK and the applicant’s findings. Also, some relationships are difficult to reconcile with biological expectations. In general, it is anticipated over the age range studied here that drug clearance will be proportional to body weight raised to the power of 3/4 (allometric scaling factor) and volumes of distribution will be proportional to body weight. Publications cited by the applicant have taken different approaches (allometric scaling or allometric scaling with maturation) to describe morphine and metabolites in the paediatric population (term neonates up to children aged 3 years). In both cases, however, the same approach for scaling is used for all clearance and volume terms. In the current analysis there are clearance terms that are treated as independent of


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weight: acetylmorphine clearance to morphine (CLM/F) and formation clearance of morphine-6-glucuronide (CL2M6G/F), while an allometric scaling factor of 1.08 was estimated for the formation clearance of morphine-3-glucuronide (CL2M3G). Literature values for elimination clearance of the glucuronide metabolites are assumed to be proportional to weight, although the reference from which the values are taken uses an allometric scaling factor of 3/4. While it is normally expected for children over 1 year that volume of distribution will be proportional to weight, with no impact of age, the V/F for acetylmorphine was found to be independent of weight, but related to age raised to the power of 0.27 (approximately 1/3). Despite these discrepancies, the model describes individual concentration-time profiles for acetylmorphine and morphine well. Thus, the AUC, Cmax, tmax and t1/2 estimates for these analytes are viewed as representative of the data collected in this study. The model is not endorsed, however, for prediction of the two glucuronide metabolites or for extrapolation of acetylmorphine and morphine beyond the context of this study. 2.2.1.2 Kidd S et al. – Arch Dis Child 2009; 84:974-78 Objective: To compare plasma morphine concentration–time profiles following IN and IV diamorphine administration. Design: Observational. Setting: Emergency department in a city-centre paediatric teaching hospital. Patients: 24 Children, aged 3–13 years, with deformed fractured long bone. Interventions: An IV catheter was sited and baseline blood taken. The first 12 children received IV diamorphine (0.1 mg/kg), and the subsequent 12 IN diamorphine (0.1 mg/kg) in 0.2 ml sterile water drops. Subsequent samples were taken at intervals up to 60 min. the IN dose was administered in 0.2 mL of sterile water dropped into both nostrils over a period of 1 minute. Measurements: Plasma morphine radioimmunoassay. Results: Peak plasma morphine concentrations were higher (median 109 vs. 36 nmol/l), and occurred earlier (median 2 vs. 10 min), with greater area under the curve (3761 vs. 1794) following IV compared to IN diamorphine (all p<0.001, Mann–Whitney U test). Higher plasma concentrations at 60 min (47 vs. 32 nmol/l) were also observed following IV diamorphine (p=0.01, Mann–Whitney U test). Plasma concentrations were higher at 60 minutes with IV than with IN (47 vs. 32 nmol/L, p=0.01). No AE was detected. The number of patients was insufficient for the analysis of parallel pain scores).


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This study only gives measurements for morphine, but none for monoacetylmorphine or the glucuronide metabolites. The bioanalytical method used, i.e. radioimmunoassay, does not seem to be the best method for diamorphine and the fact that the values obtained are given in nmol/l and not in the usual ng/l makes it difficult to compare with other data. This study shows a three times higher Cmax for IV morphine than with IN diamorphine, with a Tmax five times shorter. 2.2.2 Pharmacokinetics in Adults – Published articles Population Methodology Dosing Results Published Article Cone EJ, 1993

Adults – Drug free heroin users

Prospective, DB, double-dummy, placebo controlled, cross-over

Single dose - 6mg INDa, b + IM placebo, - 12mg INDa, c + IM placebo, - 6mg IMb + IN placebo. - IN placebo + IM

The relative potency of IN heroin was estimated to be approximately one-half that of the IM administration.


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placebo Doses separated by a week

Skopp G et al., 1997

Adults – Drug free heroin users

Prospective, DB, double-dummy, placebo controlled, cross over

Single dose - 6mg INDa, b + IM placebo, - 12mg INDa, c + IM placebo, - 6mg IMb + IN placebo. - IN placebo + IM placebo Doses separated by a week

AUC values of M3G depended on dose, not on route of administration. The apparent terminal half-lives of M3Gs ranged from 2.2 to 5.2 for intranasally administered heroin and were 3.0 and 1.7 h for the intramuscularly applied drug. A mean M3G-heroin:AUC ratio of 93 for the IN route as compared with 38 for the IM route demonstrated that circulating amounts of heroin were about half the size after IN administration of the same dose.

Mitchell TB, 2006

Adults heroin addicts

Prospective, Single Dose, Comparator-controlled, cross over

Single dose 40mg IV (~0.6mg/kg)a in 0.9% normal saline > 1 week later: -Single dose 40mg IND (~0.6mg/kg)a (400mg/ml in 0.9% normal saline, administered as spray of 50μl [20mg] to each nostril)

Significant greater speed and magnitude of peak plasma morphine and 6MAM concentrations for IV versus IN diamorphine. Beyond this initial peak, mean ratings suggested that withdrawal suppression and positive effects were at least as strong for IN compared to IV administration. All subjects gave favourable appraisals of the IN diamorphine spray, citing advantages including ease of use, the avoidance of needle hazards, and reduced stigma.

DB: double-blind; DD: double-dummy; PCA: patient controlled analgesia IN: Intranasal (snorted); IND: Intranasal diamorphine; IM: Intramuscular; IMD: Intramuscular diamorphine; PD: Pharmacodynamic. a three parts diamorphine as the dry powder was mixed with 97 parts lactose to a total weight of 100 mg, divided into 2 equal portions and inhaled through a short straw (“snorted”) into both nostrils. b ~0.09mg/kg using mean weight of 70kg; c ~0.18mg/kg using mean weight of 70kg; *four volunteers discussed in the publication but some data from one of these volunteers was included in the Cone study (Cone EJ et al 1993), i.e. only three ‘new’ volunteers treated. 2.2.2.1 Cone EJ et al. - J Ana Tox 1993; 17: 327-30 Methodology Six healthy, male volunteers were administered single doses of IN heroin hydrochloride (6 and 12 mg), IM diamorphone hydrochloride (6mg), and placebo (doses separated by a week): - 6mg IND + IM placebo - 12mg IND + IM placebo - 6mg IM + IN placebo. - IN placebo + IM placebo Blood levels of heroin, 6-acetylmorphine (6-AM), and morphine were measured by gas chromatography/mass spectrometry. Simultaneous physiological, behavioural, and performance measures were obtained.


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Results Peak heroin concentrations were attained in blood within 5 minutes after IN and IM administration of heroin. Concentrations declined thereafter in a first-order logarithmic manner (see figure below). Mean elimination half-lives (in hours, SD) were estimated to be 0.09 ± 0.05, 0.07 ± 0.02, and 0.13 ± 0.07, respectively, following IN administration of 6 and 12 mg of heroin, and IM administration of 6mg of heroin.

Peak 6-AM concentrations were attained 5-10 min after heroin administration. Thereafter, the decline in concentration of 6-AM was somewhat slower than that observed for heroin. Mean elimination half-lives (in hours) plus or minus SD for 6-AM were estimated to be 0.18 ± 0.14, 0.22 ± 0.14, and 0.19 ± 0.09, respectively following IN administration of 6 and 12 mg of heroin, and IM administration of 6mg of heroin. Morphine concentrations peaked within the first hour after heroin administration, with the single exception of one subject whose morphine peak after 12mg IN heroin did not occur until 1.5h. Morphine concentrations declined more slowly than heroin or 6-AM. Mean elimination half-lives (in hours) plus or minus SD for morphine were estimated to be 1.5±1.6, 2.8±3.6 and 1.1±.2, respectively, following IN administration of 6 and 12 mg of heroin, and IM administration of 6 mg heroin.


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Generally, the PK profile of IN heroin was equivalent to that for the IM route. Physiological, behavioural, and performance effects following IN administration were similar to the effects following IM administration. The relative potency of IN heroin was estimated to be approximately one half that of the IM administration. The IN diamorphine was snorted which might not give as good an administration as with a pulverised spray. The authors note that the IN route was half as potent as with the IM route. 2.2.2.2 Skopp G et al. - J Analytical Toxicology; 1997, 21:105 Methods: Four healthy male volunteers following IN administration of 6 and 12 mg heroin hydrochloride. In addition, two doses of 6 mg heroin hydrochloride were injected intramuscularly for comparison of PK parameters. Serum samples were analysed for heroin, 6-AM, and morphine by solid-phase extraction, gas-chromatography-mass spectrometry. The concentration of morphine glucuronides was determined by high performance liquid chromatography based on the native fluorescence of the conjugates. Results: Heroin concentrations peaked in blood within 5 minutes of dosing independently of the route of administration. The Cmax and AUC for heroin 6mg were significantly higher with the IM than the IND route.

Major findings were rapidly rising and declining terminal phases for heroin and 6-AM and slowly declining phases of morphine and metabolites after both routes of administration. The AUC values of morphine-3-glucuronide depended on dose but not on route of administration. The apparent terminal half-lives of morphine-3-glucuronides ranged from 2.2 to 5.2 for intranasally administered heroin and were 3.0 and 1.7 h for the intramuscularly applied drug.


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A mean morphine-3-glucuronide/heroin AUC ratio of 93 for the IN route as compared with 38 for the IM route demonstrated that circulating amounts of heroin were about half the size after IN administration of the same dose. When the amount of IN applied heroin was doubled, so did the AUC, which is generally the case for IV administered drugs. 2.2.2.3 Mitchell TB et al. – Eur Addict Res. 2006; 12(2):91-95 Open-label crossover study: 40 mg IND (spray in 0.9% normal saline) vs. 40 mg IV diamorphine in four patients receiving injectable diamorphine. One week between sessions. Analytical: Plasma morphine and 6-monoacetylmorphine (6MAM) concentrations and pharmacodynamic responses were measured for 4 h following IV and IND administration using LC/MS. Results: Cmax for morphine was 335 ng/ml ± 158 and 225 ± 128 ng/ml following IV morphine and IND, respectively, with Tmax of 2 and 15 minutes. Cmax for 6MAM was 1,860 ± 1,372 and 525 ± 654 following IV morphine and IND. All subjects gave favourable appraisals of the IN diamorphine spray, citing advantages including ease of use, the avoidance of needle hazards, and reduced stigma. IN administration may be an alternative or supplementary form of diamorphine maintenance and deserves further investigation. Patients complained of a bitter taste but noted that the IN route was more convenient. This study was done in patients taking maintenance diamorphine ± methadone, therefore it is not clear whether recent use of methadone would have impacted on the PK results. 2.2.3 Assessor’s overall conclusions on pharmacokinetics The note for guidance on clinical investigation of medicinal products in the paediatric population (ICH Topic E11) states that: ‘When a medicinal product is to be used in the paediatric population for the same indication(s) as those studied and approved in adults, the disease process is similar in adults and paediatric patients, and the outcome of therapy is likely to be comparable, extrapolation from adult efficacy data may be appropriate. In such cases, pharmacokinetic studies in all the age ranges of paediatric patients likely to receive the medicinal product, together with safety studies, may provide adequate information for use by allowing selection of paediatric doses that will produce blood levels similar to those observed in adults. If this approach is taken, adult pharmacokinetic data should be available to plan the paediatric studies’. Diamorphine is currently indicated for the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema. Therefore, the proposed indication is new and PK data alone are not sufficient. Because the product is a new route of administration, the PK profile of diamorphine when given intranasally was characterised. The applicant performed a PK study in children having surgery. The studies by Cone EJ and Skopp G seem to indicate that the morphine concentrations following IM injection are twice as much as when given intranasally.


40

Other parameters like terminal half-life do not coincide with the data from study DIA001, in which the terminal half-life for morphine was found to be about 8.4 hours, compared to about 1.5-2.8 hours in the study by Cone et al. However, there are many differences between the Cone et al. study and DIA001. Apart from the significant differences in study population (adults versus children), sample size (six versus 50), study design (traditional versus population PK), setting (addiction centre versus hospital day surgery), PK analysis method (individual subject fits versus pooled analysis applying non-linear mixed effects models), the differences in half-life probably largely reflect the different models used to derive the estimates i.e. in the Cone study, they have assumed that morphine displays 1-compartment disposition, whereas in the DIA001, a 2-compartment model was applied. That is to say, the two half-lives are describing different processes. A more sophisticated approach was possible with DIA001 because of the substantially greater number of subjects and observations available. A comparison of DIA001 primary PK estimates with other reports in the literature was conducted. In DIA001, data on plasma concentration profiles of diamorphine metabolites from 49 children following a single intranasal dose of 0.1mg/kg (n=10) or 0.06mg/kg (n=39) diamorphine hydrochloride was modelled simultaneously using a single, integral multi-compartmental model. The final model assumed zero order systemic input (accounting for absorption and systemic conversion of diamorphine to acetylmorphine), 2 compartment disposition for acetylmorphine and morphine, a metabolic compartment to allow for the lag in appearance of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) and 1 compartment with fixed parameters to describe their disposition. The population estimates of central volume of distribution for acetylmorphine was shown to increase non-linearly with age. For morphine, the population estimates of central volume of distribution was linearly related to weight whereas the formation clearance of M3G was shown to increase non-linearly with weight. The metabolite PK estimates derived from the population in this study are similar to previous reports in the literature for children. Since diamorphine itself was not measured in this study the zero order duration of drug input was 1.3 minutes and reflects rapid diamorphine absorption and conversion to acetylmorphine. Acetylmorphine itself undergoes rapid esterase hydrolysis and the clearance of 1.93 L/min (115.8 L/hr) exceeds liver blood flow and suggests extra-liver tissue hydrolysis. This estimate is similar to that reported by Rook et al. (2006a; 55.9 L/hr) . The mean (SD) distribution and elimination half-lives of acetylmorphine reported in this study (11.9 and 86.2 minutes, respectively) are longer than that reported by Rook (3.9 and 21.8 min, respectively). However, this may reflect the different routes of administration (in the Rook study, the diamorphine was administered by inhalation of diamorphine vapour via a straw in the mouth) as well as differences in sensitivity of bioanalytical techniques and hence definition of the terminal phase. The LLOQ in this study was 1ng/ml whilst in the study by Rook it was 5ng/ml. Parameters to describe systemic exposure, Cmax and AUC, show considerable between-subject variability and probably reflect the variability in bioavailability following intranasal administration. In DIA001, the formation of morphine occurred reasonably rapidly, with a mean (SD) Tmax of 23.7 (10.4) minutes. The steady state volume of distribution (central and peripheral combined) of morphine estimated in this study (258 L in a 21.8 kg child) is


41

higher than previous reports of 1.9-3.6 L/kg (Bouwmeester et al., 2006; Knibbe et al., 2009). However, this is probably explained by the differences in sampling schedule, study design as well as sensitivity of the bioanalytical techniques. For example, the LLOQ of morphine in DIA001 was 1ng/ml, whereas in both literature reports the LLOQ was reported as 5ng/ml (van der Marel et al. 2007). Based on the assumed values of metabolite volume of distribution, the predominant morphine elimination pathway is formation of M3G. Formation clearances to M3G and M6G and total morphine clearance were estimated for the population to be 1.06 L/min/70kg, 0.132 L/min and 1.19 L/min/70kg, respectively, and are similar to previous estimates in paediatric studies of morphine. Bouwmeester et al. estimated the formation clearances of M3G and M6G and the total morphine clearance in a mature 3 year old to be1.07L/min/70kg, 0.06 L/min/70kg and 1.18 L/min/kg. Knibbe et al. estimated formation clearance to M3G to be very similar at 0.92 L/min/70kg, however their estimate of M6G was considerably higher at 0.48 L/min/70kg. Both literature reports are of population pharmacokinetic studies of multiple morphine doses and involved children aged 0-3 years including neonates. In study DIA001 formation clearance to M3G accounts for 67.2% of total morphine clearance in a 10 kg child and 88% in a 60kg child. Bouwmeester et al. estimated the formation clearance to M3G in a 3 year old infant to account for 90% of morphine elimination. Although routes other than glucuronidation are known to clear morphine in humans, accounting for approximately 10% of clearance in older children and adults, it was not possible to quantify this route in DIA001 (Rook et al., 2006b). Indeed Knibbe et al. also failed to quantify this route in their study and Bouwmeester et al. reported a less than 5% contribution in their study. The formation clearance to M3G was non-linearly related to weight. However the total morphine clearance between the weight range 10-60 kg does not change a great deal. Bouwmeester et al. estimate that total morphine clearance was 80% of that of adults by 6 months and 96% of that predicted in adults by 1 year. Following adjustment of systemic exposure parameters to the proposed posology dose of 0.1mg/kg, a weak correlation of age with morphine AUC is apparent, but there is considerable overlap and does not suggest that the proposed posology dose needs to be modified by age. Systemic exposure parameters following a single dose of intranasal diamorphine suggest significant between subject variability in morphine Cmax and AUC and since it is assumed that virtually all of the acetylmorphine is converted to morphine, variability in exposure reflects underlying bioavailability of intranasal diamorphine. The delay in the appearance of M3G and M6G was modelled by the introduction of a 'metabolic' compartment with a first order rate constant and a typical transit time of 6 and 46 minutes, respectively. Such a delay in morphine glucuronidation has been previously reported and was explained by a trapping effect that prolonged the transit time of the generated glucuronide metabolite across the site of metabolism i.e. by a long intracellular residence time of the more hydrophillic metabolite caused by the lower permeability of the cell membrane (Lotsch et al., 2002). As in the model developed by Bouwmeester et al. (2004) the M3G and M6G metabolite volumes of distribution were fixed to previously reported values of 23 L/70kg and 30 L/kg in adults, respectively. Volume of distribution for M6G is believed to be greater than M3G because of higher lipophilicity at physiological pH. Since sampling was limited


42

to predominantly the accumulation phase, it was not possible to estimate the elimination clearances of M3G and M6G and hence they were fixed at 0.29 and 0.097 L/min/70kg, derived from the Bouwmeester et al. (2004) report of clearances in a 3 year old. These estimates provided a reasonable fit of the metabolite data, although there was substantial variability in the observed exposures. The metabolites M3G and M6G are water soluble compounds, enabling renal excretion, although the clearance of the metabolites is greater than the glomerular filtration rate (GFR) and suggests that active renal tubular secretion and non-renal elimination contribute. Rhodin et al. (2009) report that at 1 year postnatal age, the GFR is predicted to be 90% of the adult GFR. Hence, in those children with normal renal function, the elimination clearance of M3G and M6G is unlikely to be age-dependent. In conclusion, an integral pharmacokinetic model developed for the metabolites of diamorphine following a single intranasal dose in children aged 1-<16 years, describes the pharmacokinetics of all analytes satisfactorily. The parameter estimates are similar to previous reports in children of morphine metabolism. Apart from morphine, there were no age-dependent changes in parameters of systemic exposure for the metabolites. A weak correlation of age and weight with morphine AUC was identified, but there is considerable between subject variability and does not suggest that the proposed posology needs to be modified by age. Final Covariate Model (mod37) predicted change in population clearance of morphine* (L/kg/min) versus bodyweight.

Total clearance of morphine = CL2M3G + CL2M6G

0.12

0.13

0.14

0.15

0.16

0.17

0.18

0.19

0 10 20 30 40 50 60

Tota

l Mor

phin

e C

lear

ance

(L/k

g/m

in)

Bodyweight (kg)


43

The applicant submitted an article by Bouwmeester et al. that describes the PK data of morphine and its metabolites in children 0-3 years old. The article concludes that morphine-3-glucuronide is the main metabolite in young children and total morphine clearance is 80% that of adult values by 6 months, and similar to that of adults within 6 to 12 months. It is, therefore, assumed that clearance in the targeted population (2/3 years and older) will be similar to that of adults. The article also mentions that altered renal function has little impact on the renal excretion of metabolites but hepatic clearance may be reduced if hepatic function is impaired. The impact of hepatic impairment has, therefore, been discussed by the applicant and appropriate warnings are included in the SmPC. As no local drug interaction study has been performed, section 4.5 of the SmPC includes information regarding the concomitant use of other nasally administered drugs. The absence of data in children suffering from rhinitis has been stated in Section 4.4 of the SmPC. 2.3 Bioequivalence The pivotal IM-morphine-controlled efficacy/safety study of IN diamorphine in children (CP9703) which has been submitted to support the proposed indication used the same product (formulation, diluent, delivery container, delivery device) as that proposed except for strength (which is comparable to the range studied) and used the same proposed maximum volume per nostril (100µl). Thus, a bridging PK study to demonstrate relative bioavailability or bioequivalence of the proposed formulation to that used in the pivotal study was not required. 2.4 Pharmacodynamics No specific data have been presented.


44

3 CLINICAL EFFICACY 3.1 Introduction From the total defined clinical dataset, the clinical data package to support the efficacy (and safety) of IN administration of diamorphine in paediatric patients is provided from six studies conducted in a total of >417 children at the proposed IN dose (0.1mg/kg) and for the proposed indication (relief of acute pain). There are six published studies in children; four were comparator-controlled (versus IM morphine or oral morphine, of which one was double dummy) studies conducted in a total of 375 IN diamorphine-treated children. One of these four studies is a publication of the pivotal clinical study conducted by the applicant and for which data from the full clinical study report are presented (CP9703). This dataset was considered to be robust and sufficient to support the efficacy of the proposed products for the proposed indication and route of administration for the MAAs. Therefore, no additional efficacy studies have been conducted (the pivotal study CP9703 had already been conducted prior to this review). 3.2 Dose-response studies None were submitted. 3.3 Main studies in children

Age N Methodology Dose Diagnosis CSR CP9703, 2001

3-16 407 (204 / 203)

Multicentre, prospective, randomised, single blind, parallel group, controlled

Single dose of IND (0.1mg/kg in 0.1ml proposed diluent using proposed nasal spray device) OR IM (0.2mg/kg)

Upper or lower limb fracture

Published Wilson JA, 1997

3-16 43 (20 / 23 (oral))

Single centre, prospective, non blinded, randomised, controlled

Single dose of IND (0.1mg/kg in saline, 0.2ml administered as drops via syringe into ONE nostril) OR IM (0.2mg/kg)

Limb fracture

Marzouk O, 2008

4-16 244 (124 / 120 (oral))

Single centre, single blind, randomised, double dummy, controlled

Single dose of IND (0.1mg/kg in 0.2ml normal saline delivered with nasal atomiser into ONE nostril) + oral placebo OR oral M (0.4mg/kg [Oramorph]) + IN placebo

Traumatic injury

Communication Sajjanhar T, 2007

3-16 43 (20 / 23 (oral))

Randomised, controlled

Single dose of IND (0.1mg/kg delivered with nasal spray into ONE nostril) OR oral M (0.25mg/kg [Oramorph])

Suspected fracture and moderate/severe pain

Davies F 42 Audit of IND use in children. Uncontrolled.

Single dose of IND (0.1 mg/kg in 0.2ml water delivered with 1mL syringe into ONE nostril)

Painful conditions requiring rapidly acting opiate

Gahir KK Not stated

Audit of IND use in children.

BAEM guidelines specified. Assume single dose of IND

Not stated


45

Uncontrolled 0.1mg/kg in 0.2ml sterile water with 1ml syringe into ONE nostril

DB: double-blind; DD: double-dummy; PCA: patient controlled analgesia 3.3.1 CP9703 – Clinical Study Report Study title: Randomised, controlled, one-way blinded multicentre study comparing nasal diamorphine hydrochloride with IM morphine sulphate for emergency analgesia in children presenting to the Accident and Emergency department for clinical fractures. Methodology Study design Prospective, multicentre, randomised, controlled, observer blinded, outpatient, parallel group study. Study population Otherwise healthy and conscious patients of both sexes aged 3-16 years presenting at participating accident and emergency departments in the South West of England between 2 July 1997 and 16 September 1999 with clinically diagnosed limb fractures. The majority of the exclusion criteria used in the clinical development programme were not contraindications, rather they were exclusion criteria for the clinical study. The exclusion criteria and, where applicable, justification for their exclusion from the SmPC, are listed below:

i) patients with head injuries – this is included in the SmPC ii) patients who require immediate IV access – this exclusion criterion was

only included on ethical basis, as patients arriving in an emergency room and requiring IV access would be given diamorphine or morphine via this route rather than intranasally. There is no pharmacological reason to include this exclusion criteria as a contraindication

iii) patients with a blocked nose – this is included in the SmPC iv) patients with upper respiratory tract infections - other than the possible

interference with absorption occasioned by having a blocked nose (see above) there is no pharmacological reason to include this exclusion criteria as a contraindication

v) patients with learning difficulties – this exclusion criteria was included as patient consent was required for the trial. It is not a contraindication.

vi) blind patients or those with impaired sight – again, there is no pharmacological reason to include this exclusion criteria as a contraindication

vii) patients who had taken opioid analgesia in the last 2 days – this exclusion criterion was included to ensure that clean data were obtained in the pharmacokinetic study. There is no pharmacological reason to include this exclusion criteria as a contraindication

viii) patients who had already participated in the study (see vii).


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Randomisation/blinding The randomisation was stratified by centre using random number blocks of 18 with an initial expectation of 80 patients for each of the major centres and 40 patients at the Royal Hospital for Sick Children. Stratification was employed to increase the likelihood of equal numbers of patients in each group within each centre. The trial was single-blind. Once the nurse administered the analgesia, the patient was handed over to another nurse so that assessments could be made without the nurse knowing which treatment has been given. However, while the nurse making the assessment was blinded, the patient and parents knew whether they had received IN or IM treatment. To assess the success of the single blinding, staff were asked which treatment they believed the patient was taking.

There was no measurement of pain at randomisation as this was not an inclusion criterion; a clinical fracture of the upper or lower limb was the requirement in this respect only. This is not in accordance with the original guidelines of the British Association for Emergency Medicine (BAEM) (now incorporated and updated (2010) into the College of Emergency Medicine Guideline) since these guidelines were only published in 2004, after this study had been conducted and published (Kendall et al., 2001). Thus, children were entered into the study and their baseline pain score recorded immediately prior to administration of study treatment. Generally, children with these types of injuries would be expected to be in severe pain. The study data indicate that the majority of children had high pain scores (5–6) at baseline although some had lower scores. However, none of the baseline pain score distributions, whether assessed by patients, parents or staff, showed a significant difference between the treatment groups. Thus, the fact that some patients had low pain scores at baseline did not impact the study outcome and conclusions. Table 59 Baseline pain Scores from study CP9703: percentage of patients scoring 5–6 Baseline median pain score (95% CI)

Percentage of Patients Scoring 5-6 IN Diamorphine IM Morphine

Patient – Wong Baker faces 62% 66% Patient – VAS 53% 46% Parent – Wong Baker faces 62% 66% Parent – VAS 42% 42% Nurse – Wong Baker faces 58% 65% Nurse – VAS 46% 48%

Identification of Study Treatment by Staff In each group, approximately 89% of patients were assessed by a different observer from the one who had administered treatment.


47

The majority (89%) of assessments in both treatment groups were carried out by a different nurse from the one who had administered the analgesia. These assessors correctly guessed the medication at 30 minutes in 42% of patients given IM morphine but in only 10% of patients given IN diamorphine. The study was meant to be single blinded with the observer not being the same as the one who gave the study medication. This was true in 89% of cases. Taken at face value there is no evidence from questioning staff that the single blind was not generally maintained. In the IM morphine group there was a close to 50:50 split in the staff questioned as to what the treatment was – this is what would be hoped for if the blind has held. In the nasal diamorphine group the vast majority of patients actually guessed the allocation incorrectly – again not consistent with the single blind being broken. So if there was any inclination amongst staff to favour nasal treatment, there is no evidence here to suggest that this will have biased the trial in favour of the nasal formulation in any way. Study treatment/method of administration Single dose of either: - 0.1mg/kg IN diamorphine HCl, reconstituted in concentrations of 15.8-52.6 mg/ml - or 0.2 mg/kg IM morphine sulphate Rescue analgesia (0.2 mg/kg IM morphine) was offered at 20 or 30 minutes, if required.

The dose of diamorphine was 0.1 mg/kg. The diamorphine hydrochloride was reconstituted with diluent using the correct volume for the weight of child using a 5 ml syringe fitted with a green needle. The diamorphine hydrochloride solution was withdrawn from the ampoule and put into the nasal dosing bottle using the syringe. The nasal dosing device was fixed tightly onto the bottle. Immediately before dosing,


48

the dosing mechanism was depressed several times to prime the system. The dose of 0.1 ml was then delivered with a single complete depression of the mechanism. The bottle was held upright during priming and dosing.

Morphine sulphate injection was obtained from the accident and emergency department and was prepared according to the manufacturer’s instructions. Both diamorphine hydrochloride and morphine sulphate are controlled drugs and so their storage, dispensing and disposal were in accordance with Misuse of Drugs regulations 1995, as amended. The administration of the 0.1mg/kg nasal diamorphine dose in the pivotal study CP9703 differed from that proposed for marketing and used in the PK (DIA001) and safety (DIA002) studies in the following respects: Administration of 0.1mg nasal diamorphine across studies conducted by the applicant IN Diamorphine CP9703 DIA001*, DIA002 and Proposed for

Marketing Concentration of solution (mg/ml)

Bodyweight Concentration Bodyweight Concentration 14.00-18.49 15.8 12-<30kg 14.4 18.50-24.99 21.3 25.00-33.49 28.6 33.50-44.00 38.5 30-50kg 32.0 45.00-62.00 52.6

Spray tip Paediatric Paediatric Spray volume 100μl 50μl Number of sprays 1 in 1 nostril Minimum of 1 in each nostril;

Maximum 2 per nostril (Total 2-4 sprays of 14.4mg/ml; Total 2-3 sprays of 32.0mg/ml)

Total dose volume 100μl in 1 nostril Minimum of 50μl in each nostril; Maximum 100μl per nostril (Total 100μl - 200μl of 14.4mg/ml; Total 100μl - 150μl of 32.0mg/ml)

* Data presented relate to administration of 0.1mg/kg (10 children prior to dose reduction to 0.06mg/kg). After dose reduction the equivalent data are presented below: IN Diamorphine DIA001 after dose reduction to

0.06mg/kg Concentration of solution (mg/ml)

Bodyweight Concentration 10-<45kg 14.4


49

45 – 70kg 32.0

Spray volume 50μl Number of sprays Minimum of 1 in ONE nostril;

Maximum 2 in ONE nostril (Total 1-3 sprays of 14.4mg/ml; Total 2 sprays of 32.0mg/ml)

Total dose volume Minimum of 50μl in ONE nostril; Maximum 100μl in ONE nostril (Total 100μl - 150μl of 14.4mg/ml; Total 100μl of 32.0mg/ml)

The nasal spray tip used in CP9703 was a paediatric tip of the same size as that proposed and used in DIA001 and DIA002 but delivered a volume of 100μl rather than the proposed 50μl. Thus, in CP9703 the total dose was administered to one nostril in a volume of 100μl. In DIA001 (prior to dose reduction), DIA002 and the SmPC instruction, the dose is administered in a spray volume of 50μl but to both nostrils and up to two sprays per nostril (100μl) can be administered dependent upon bodyweight.

It can be seen that the concentrations of the solutions used for CP9703 and Ayendi Nasal Spray are not dissimilar. The proposed concentrations per bodyweight are slightly lower than those used in CP9703. Thus, from a theoretical basis and applying Fick’s Law, the rate of nasal absorption might be slightly lower for Ayendi Nasal Spray compared to the slightly higher concentration solution used in CP9703 resulting in a lower Cmax of the parent diamorphine. However, given the variability in peak exposures observed with the subsequent metabolites, this potential difference is not likely to be of any significance. Moreover, any potential difference in the rate of absorption may be balanced to some extent, as the proposed solution is administered to each nostril (rather than just one in CP9703), thus providing a larger surface area for nasal absorption of the dose. The heavier children would require up to two sprays per nostril of the proposed solution such that the volume administered per nostril is in fact 100μl. Thus, any issues regarding swallowing of the dose would apply equally to both administration methods in this case. A dose volume of 100μl was selected as the maximum per nostril as it is a small enough volume that it should be readily absorbed by the nasal cavity without loss down the back of the throat. Indeed the PK data obtained in study DIA001 which used the proposed administration method with up to two sprays (100μl) in one nostril for some children, did not show any evidence of late phase (gastro-intestinal) absorption. Additionally, the droplet size distribution, spray pattern and coverage do not differ significantly between the administration method used in study CP9703 (100μl pumps) and the proposed product (50μl pumps and both product strengths). It is considered that any effect of the difference in the product delivery will be minimal and of no clinical significance with respect to absorption, efficacy and safety of the proposed product. The results from Study CP9703 can be extrapolated to Ayendi Nasal Spray.


50

Intramuscular morphine was used as a comparator because the objective of the pivotal study was to demonstrate that IN diamorphine is as effective and safe as IM morphine, which was accepted as the standard at the time of these studies. Children requiring immediate IV access were excluded from both the pilot and pivotal studies as these children would be administered IV morphine, the gold standard for pain relief, in accordance with standard practice. Thus, it would have been considered unethical in this situation to include them in the study and administer the study treatments rather than IV morphine. However, the pain and distress involved in IV administration result in this method of administration not being used in children below the age of 16 years old generally, unless they require immediate IV access for other reasons. IV access can be difficult and painful in children and although topical analgesia can be used this takes time (30-50 minutes) to become effective, and is considered to be too long a time period for use in the treatment of acute pain. Study parameters Assessments were made immediately before dosing and at 5, 10, 20 and 30 minutes after dosing of: - Pain assessed by all patients, parents and nurses using Wong Baker faces and a

Visual Analogue Scale (VAS), without reference to previous assessments or assessments by others. Nurse assessments were to be by a different nurse from the one administering drug, if possible, to retain blindness.

- Level of consciousness, using the Glasgow coma score - Peripheral oxygen saturation, measured by continuous pulse oximetry - Respiration rate - Pulse Tolerability to treatment administration was assessed by the nurse on a 5-point scale at the time of administration. Acceptability assessed on a 3-point scale by a nurse at administration and at 30 minutes by the parent/carer, and by asking the patient at 30 minutes if they would be prepared to have the same treatment again. Unwanted side effects were recorded, particularly irritation at the site of administration, which was elicited by a specific question. Patients and parents assessed pain using the Wong Baker face pain tool at all assessment times. The staff also assessed pain using this tool at baseline only. The VAS was also used at all assessment times by nurses, parents and patients. Each assessor made his/her assessment without seeing the assessment made by someone else and without seeing his/her previous assessment. Wherever possible there was a change of nurse between treatment and subsequent assessments so that the observing nurse did not know which treatment had been given. The Wong Baker face pain tool employs six drawings of faces (1-6); the first face (1) is happy and smiling and the last (6) is sad and crying. The most applicable face is selected. The 12 cm graduated VAS had extremes of no pain (=0) and extreme pain (6). The scale was marked with an X at the appropriate point. The results were recorded to the nearest whole number to give a score of 0, 1, 2, 3, 4, 5 or 6.


51

One of the primary endpoints of the study was the reduction in pain from baseline measured by patient, parent and staff over 30 minutes. Children had to be 3 years and above as the pain scales used are not validated for younger children. Pain scores were measured using the Wong Baker Faces pain rating scale, in the children aged between 3 and 8, and VAS, in the children aged between 8 and 16. Statistical methods For both Wong Baker pain faces and VAS scores, the change from pre-treatment was calculated and summarised as “improved”, “no-change” or “deteriorated”. Also all data were summarised with frequency distributions. The treatment groups were compared at each time-point with the Wilcoxon signed rank test. There were issues relating to multiplicity because of the lack of definition of a primary endpoint – just stating pain scores with no more detail There were two scales (faces, VAS), three groups of raters (child, parent, staff), four time-points (5, 10, 20, 30 mins), and two methods of analysis (change from baseline, frequency distribution of scores) – meaning 40 endpoints with no defined order of priority. It was not clear what the success criteria were for these new analyses. Clinical interpretation of the data was difficult as the Wilcoxon signed rank test does not provide confidence intervals. Given the vast number of unranked endpoints it would have been valuable to see confidence intervals to determine if any general conclusions can be drawn that are consistent across endpoints. Results Patient accountability Nasal IM Entered study 207 206 Received study drug 204 204 Safety population 204 203 Efficacy population 202 203 Completed study 195 199 There were 408 patients who received study medication. One patient was never assessed for efficacy or safety and a further two were not assessed for efficacy. These were all excluded from the efficacy population. This is not ideal, but the small number of patients involved means it could not have a major impact on the results. However, the efficacy tables will show that there were no assessments where the entire efficacy population was included in the analysis. The analysis did not account for the missing patients. Mitigating this concern is the fact that the number of missing patients at each assessment is not large and is not consistently different in one treatment group compared to the other. The most notable is the assessment from the child using VAS. It might be expected that younger children would struggle to use the


52

VAS so the low patient number of patients included here is to be expected and does not represent a large loss from baseline, simply a consistently low number throughout. Patients’ characteristics Children randomised in this study were mainly males (67%) and on average 3 years of age. Fractures involved mainly the arm, and mainly below the elbow.

Nasal diamorphine group (n=207) IM morphine group (n=206) Mean (SD) age (months)* 115.3 (41.0) 107.6 (38.8) Mean (SD) weight (kg) 33.9 (13.2) 32.0 (13.1) Male 136 (66) 140 (68) Injury site †: Radius or ulna 131 (64) 143 (70) Supracondylar 43 (21) 34 (17) Tibia or fibula 11 (5) 10 (5) Other 19 (9) 17 (8) Hospital: A 74 (36) 74 (37) B 23 (11) 25 (12) C 42 (20) 43 (21) D 13 (6) 13 (6) E 35 (17) 36 (17) F 11 (5) 7 (3) G 2 (1) 2 (1) H 7 (3) 6 (3)

• ↵* Age not recorded for one patient given IM morphine. • † Site of injury not recorded for three patients given spray and two given IM morphine.

The children in the IN diamorphine group were significantly older than in the IM morphine group. Efficacy results The distribution of patient’s pain scores on the Wong Baker Faces was statistically significantly different between groups at 5 (p=0.047), 10 (p=0.0072) and 20 (p=0.0037) minutes but not at 30 minutes post-dosing (p=0.3), in favour of nasal diamorphine.


53

Child’s pain score

The figure below shows the patient’s mean pain scores (using Wong Baker Faces) which were estimated for the two groups at each time point.


54

There was also a highly significant reduction in patients’ pain score at every time point in both treatment groups (p<0.001), with a significantly greater improvement in the IN diamorphine group at 10 (p<0.01) and 20 (p=0.036) minutes. The distribution of patients’ pain scores on the VAS did not differ significantly at baseline or at any time points, other than at 20 minutes when they were significantly lower on IN diamorphine (p=0.032). However, there was a significant reduction in pain from baseline in both treatment groups at every time point (p<0.001), with significantly greater improvement in the IN diamorphine group at 10 (p=0.0066) and 20 (p=0.016) minutes. Change in child’s pain score (Wong Baker Faces) IN diamorphine IM morphine P Value

N % N % 5 min Improved No Change Deteriorated

124 62 8

63.9 32.0 4.1

114 66 13

59.1 34.2 6.7

0.10

10 min Improved No change Deteriorated

160 27 6

82.9 14.0 3.1

145 40 11

74.0 20.4 5.6

0.010


165 18 4

88.2 9.6 2.1

156 27 11

80.4 13.9 5.7

0.036


166 17 5

88.3 9.0 2.7

166 18 9

86.0 9.3 4.7

0.68


55

Child’s VAS pain score


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Change in child’s VAS IN diamorphine IM morphine P Value


106 43 10

66.7 27.0 6.3

94 40 15

63.1 26.8 10.1

0.091


136 20 4

85.0 12.5 2.5

110 26 20

75.3 17.8 6.8

0.0066


142 11 1

92.2 7.1 0.6

120 18 7

82.8 12.4 4.8

0.016


142 10 3

91.6 6.5 1.9

130 10 6

89.0 6.8 4.1

0.13

Parent’s pain scores Changes from in parent’s scores using the Wong Baker Faces or VAS scores did not show significant differences between IND and IM morphine, although the distribution of scores at each visit showed differences at 5, 10 and 20 minutes for the Wong Baker Faces and at 20 minutes for the VAS.


57


58


59


60

Staff’s pain scores For the staff’s ratings statistically significant differences in favour of nasal diamorphine were seen at 10 and 20 minutes for both the distribution of scores and change from baseline. A difference was also seen at 5 minutes when looking at distribution of scores.


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62

Change in staff’s VAS score IN diamorphine IM morphine P Value


157 28 9

80.9 14.4 4.6

146 31 18

74.9 15.9 9.2

0.13


172 18 2

89.6 9.4 1.0

165 20 9

85.1 10.3 4.6

0.011


172 12 1

93.0 6.5 0.5

172 14 7

89.1 7.3 3.6

0.067


178 9 1

94.7 4.8 0.5

179 9 5

92.7 4.7 2.6

0.80

A simplistic way to interpret these results is that 17 out of the 40 primary comparisons showed statistical significance, all in favour of nasal diamorphine. So there is at least a suggestion of differences between the formulations. The pattern is fairly, albeit not completely, consistent, with differences seen after 5, 10 and 20 minutes that are lost by the 30 minute time-point – suggesting an earlier onset of action in the nasal diamorphine group (both groups are clearly effective individually, showing large changes from baseline and high proportions of improvement, though without a placebo arm the size of benefit cannot be quantified). Beyond the general picture it’s hard to get a precise feeling for the size of differences between the treatments, as there are discrepancies between the change and the frequency distribution analyses of the same data, and between the different raters and different scales at the same time-points. Also the analysis technique used does not give estimates of difference in average score, or provide confidence intervals, which could help with interpretation by showing which magnitude of difference can be ruled out. Due to the limitations of these results, the study data were reanalysed using ANOVA on mean scores. The analysis sets used for the reanalysis were the same as those used in the original analysis. The VAS pain scoring was planned to be completed by patients ≥ 8 years old only, according to the protocol. However, some children that were <8 years old completed the VAS scoring also. Therefore, the summaries and analyses were performed both for ‘all patients’ and also for ‘patients ≥ 8 years old’ (as planned in the protocol). A copy of the statistical analysis plan generated for the purpose of this re-analysis was provided.


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Results and discussion of re-analysed data The re-analysed data show statistically significant differences (at the 5% level) over time between the treatment groups in favour of nasal diamorphine for:

• Change from baseline in and AUC of Wong Baker Faces pain score for patients’ and parents’ assessments (not evaluated by medical staff).

• Change from baseline in and AUC of VAS pain score for all patients’, patients’ ≥ 8 years old and medical staff assessments. (Parents’ assessments showed similar reductions for both change from baseline in and AUC of VAS between treatment groups).

Thus, the benefit profile for intranasal diamorphine has been appropriately qualified and is acceptable compared to IM morphine. Multiplicity issues: For the re-analysis of the data, use of the summary measure of AUC and the repeated measures analysis of variance reduced the need for multiple comparisons at each of the time points. No further steps were taken to address the multiplicity issues arising due to pain scores being captured on two different pain rating scales (Wong Baker Face and VAS), by multiple assessors (patients, parents and medical staff), and the inclusion of the sub group of patients ≥ 8 years. Pre-specified objectives of the study: This study was designed by doctors prior to the introduction of the UK Clinical Trial Regulations and robust standards. Section 8.1 of the protocol states that the trial was designed to establish whether nasal diamorphine is as efficacious and safe as IM morphine sulphate. Thus it is assumed that the pre-specified objective was to show similarity. However, the results actually show a difference in favour of IN diamorphine by both the original sets of analyses and the re-analysis. Thus, although it is acknowledged that ideally one primary objective/endpoint should have been set e.g. to show a similar reduction in pain score based on the Wong Baker Face scale, together with a definition of what is meant by ‘similar’, the results demonstrate the effectiveness of IN diamorphine compared to IM morphine on pain reduction. Timing of the decision to change the analysis specified in the protocol in relation to the data being unblinded and the analysis being conducted. Due to the length of time since the study was conducted (over 10 years) and that it was conducted prior to the introduction of the UK Clinical Trial Regulations, unfortunately there is no record or recollection of when the decision to change the protocol-specified analysis was made. It is assumed that it was made prior to the data being unblinded and the analysis conducted. However, the reanalysis was conducted in accordance with the protocol-specified analysis and demonstrated that the results from the original methodology are consistent with the results from the analyses used for the report. The potential impact on the results of the children/parents being unblinded and some staff raters also potentially seeing through the blind. It was considered unethical to adopt a “double dummy” design for this study in children due to the need for administration of a placebo injection. However, such a design would also have precluded measurement of differences between groups in


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patients' reactions to treatment and acceptability of that treatment to parents and staff, which were secondary endpoints in the studies. Thus, the best attempt at blinding was made in the circumstances. The study was intended to be single blind with the staff observer being different to the staff member who administered the study medication. In each group, approximately 89% of patients were assessed by a different observer, i.e. for 11% of patients the staff observer was not blind. In the IM morphine group approximately 50% of staff correctly identified what treatment had been administered which is as would be anticipated if the blind has held. In the nasal diamorphine group the majority (approximately 90%) of staff incorrectly guessed the treatment allocation; thus reinforcing the maintenance of the blind. However, as suggested in the MHRA Assessment Report, there was a small percentage of staff raters that were unblinded to treatment. The impact of this on the results together with the fact that the patients (children) and their parents were unblinded is difficult to quantify and a degree of bias was possible. An indication of the impact on the results can be ascertained by review of an objective physiological measure, oxygen saturation, rather than the subjective measure of pain scores. Although not clinically important, both median and mean oxygen saturation (and their change from baseline) was slightly lower in the IN diamorphine group compared to IM morphine group at 5, 10, and 20 minutes after treatment with no (or minimal) difference at baseline or 30 minutes (see Table 57 below and CSR CP9703 Table 4.1). Thus, the oxygen saturation values mirror the greater pain relief as rated by patients, parents and staff at 5, 10 and 20 minutes after treatment but not at baseline or 30 minutes for IN diamorphine compared to IM morphine. If there was a potential tendency for patients in the IN group to rate their pain as less severe because of the greater acceptability to them of this type of treatment, this might account for some of the difference in reported pain between the groups. However, if this was the case, perhaps this should be considered part of the effect of the intervention rather than the result of bias, because any such effect would persist outside the context of the study. Thus, although there is the possibility of some bias in the results of the study in favour of IN diamorphine, the degree of bias is considered to be minimal as demonstrated by the objective measure of oxygen saturation.

Plots and tabulations of the pain score data and an analysis of area under the curve (AUC) were provided. This allows confidence intervals to be generated for the


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difference between treatments in average pain scores, and gives an idea as to the size of the differences. From both the plots and the analysis we can see that on average lower pain scores were seen for intra-nasal diamorphine compared to intra-muscular. The difference was statistically significant for all the analyses, except the parents’ VAS assessment, and even for that comparison the trend favoured intra-nasal. By using AUC rather than individual time-points the multiplicity problem is reduced, and the general consistency across the analyses means there is no need for any adjustment to account for the fact that there are six analyses remaining; the five positive results are generally fairly extreme, the chance of five positive results out of six simply by chance is small, the only negative result still trends in the right direction. Further, there is no requirement that the IN needs to be superior to IM – similar efficacy would be sufficient. These results at the very least present a strong suggestion of superiority and no suggestion of any inferiority. The company concedes that the original protocol was poorly worded and the conduct was not ideal; the objective of the study was not clear and the analysis was changed without clear documentation. However the new analyses are those requested by the assessors so these concerns can be overlooked when considering these new results. Regarding the lack of blinding, there are no signs that it had a large impact on the results, though the possibility of bias can never be completely ruled out. Patients and parents were unblinded while the majority of medical staff were blinded – yet the assessment by medical staff led to one of the largest differences. The oxygen saturation data also provides reassurance. Overall, seems to be sufficient evidence that intra-nasal diamorphine is efficacious and there is no suggestion of any inferiority to intra-muscular administration (see results below). Analysis of AUC Geometric LS mean Ratio IM IN IM/IN 95% CI p-value Wong Baker Face Pain Scores Patient 93.91 84.69 1.11 1.03, 1.19 0.0056 Wong Baker Face Pain Scores Parent 92.93 85.05 1.09 1.03, 1.16 0.0053 VAS Patient 79.16 67.18 1.18 1.05, 1.32 0.0062 VAS (≥ 8 years only) Patient 83.95 73.58 1.14 1.02, 1.28 0.0234 VAS Parent 69.06 62.99 1.10 0.98, 1.22 0.0984 VAS Medical Staff 63.31 54.01 1.17 1.05, 1.31 0.0052


66


67


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Rescue analgesia Rescue medication was needed by 31 patients in total: 16 (8%) in the nasal diamorphine group and 15 (7%) in the IM morphine group (p=0.86).

Safety/tolerability Adverse events were reported in 50 (24.5%) of patients in the IN diamorphine group and in 37 (18.2%) of patients in the IM morphine group. The most frequent event in the IN diamorphine group was irritation in the nose, reported in 27 (13.2%) of patients. In the IM morphine group the most frequent event was irritation at the injection site, reported in 22 (10.8%) of patients. There were statistically significant falls in mean oxygen saturation, from 97.79% at baseline to a minmum of 97.37% at 5 minutes in the IM morphine group (p<0.0000), and from 97.79 at baseline to a minmum of 97.14% at 5 and 10 minutes in the IN diamorphine group (p<0.0000). There was no difference between the groups at any time point. No individual patient recorded an oxygen saturation below 90% at any time point and only 19 patients in the IM morphine group and 15 in the diamorphine group with a baseline oxygen saturation equal to or above 95% recorded a value below 95% at any time point after dosing.


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Adverse Events

There was one serious AE in a 10 year old male patient who was randomised to IM morphine (8mg IM). The patient left hospital with his parents feeling nauseous. He returned to casualty the same day having vomited three times. He was given prochlorperazine 5 mg but vomited again. He was admitted to the ward for the night and was discharged in the morning. The vomiting was moderate in intensity and was regarded as reasonably attributable to study medication. The blind was broken for this patient. 3.4 Supportive studies in Children 3.4.1 Wilson JA et al. – J Accid Emerg Med 1997; 14:70-2 Methods Design This was a pilot study for the main one described above (CJ9703). Children presenting to the A&E department (Bristol Frenchay Hospital) from January to September 1995, between the ages of 3 and 16 years, with a clinical diagnosis of limb fracture were recruited in the prospective, randomised study. Patients with head injuries, nasal obstruction, and injuries requiring immediate IV access were excluded.


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Treatment Children between the ages of 3 and 16 were randomised to receive either IN diamorphine hydrochloride (0.1 mg/kg) or IM morphine sulphate (0.2mg/kg). IND was given in one nostril through a 1 ml syringe with the patient reclining in a position of comfort. IM administration was by conventional technique. Both routes of administration were performed by the nursing staff. Outcome measures: - Analgesic efficacy was measured by a reduction in pain scores as recorded on

VAS and Wong Baker Faces. - Parental acceptability was assessed by grading on a questionnaire (unacceptable,

stressful, acceptable). - AEs were also recorded, including Glasgow Coma Score (GCS). Measurements were made at baseline, 5, 10, 20 and 30 minutes post-dose. Rescue analgesia involved IM morphine sulphate within 30 minutes, if required. Pain scores were measured using Wong Baker Faces (in the children aged between 3 and 8 years old) and VAS in the children aged between 8 and 16 years old. There were six faces ranging from happy to sad, which were numbered from 1 to 6, and the VAS was divided into six equal segments and numbered from 1 to 6. Results A total of 58 children entered the study and 51 (88%) had complete data collection. Data were incomplete because of child non-compliance with pain scoring or inadequate data collection by staff. There were no significant differences between the groups at baseline. To compare the analgesic efficacy, a single summary statistic was calculated for each patient (the median summed decrease in pain score).

No significant differences were seen between the two groups and in each group one patient required rescue analgesia. The episode was recorded as “acceptable” in all parents whose child received IN diamorphine compared with only 55% of parents in the IM morphine group (p<0.0001, Fisher’s exact test). Median decrease in pain scores (with 95% confidence intervals of medians) IN diamorphine IM morphine


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t = 5 min t= 10 min t = 20 min t = 30 min Summed medians

1 (0 to 2) 2 (1 to 3) 3 (1 to 3) 3 (2 to 4) 9*

1 (0 to 1) 2 (1 to 2) 2 (1 to 3) 3 (2 to 3) 8*

* Not significant (P=0.4, Mann-Whitney U) There was no incidence of decreased peripheral oxygen saturation or depression in the level of consciousness of the patient. 3.5 Other data in children 3.5.1 Marzouk et al. – ABSTRACT - Annals Emergency Med 2008; 51, 4:480 Treatment: IND 0.1mg/kg as a fixed volume of drug of 0.2mL saline water (atomised spray in one nostril) or Oramorph 0.4mg/kg, and respective placebo. Primary outcome: time of onset of 50% or greater reduction in pain scores from baseline. Methods: Single blind, double-dummy, randomised controlled trial in the emergency department. Patients: 244 (124 IND, 120 Oramorph) children 4-16 years of age (mean age 9 years), 184 males and 60 females, presenting with traumatic injury not needing IV. Results: Median time to achieve 50% reduction in pain scores was 20 minutes in the IND group compared to 40 minutes for the Oramorph group (CI: 1.1-2.20, p<0.005). There was no incidence of AE in either group. However, the parental questionnaire showed that children who received the active IND preparation reported significant higher nasal irritation (50% vs. 12%, p<0.01). Mean time to reduce pain was expected to be better with the IN administration considering the PKs of the two products. The quality of the study cannot be assessed from the information provided. 3.5.2 Sajjanhar T – 2007, Unpublished personal communication Methods: Randomised control trial involving children aged between 3-16 with suspected fracture and moderate/severe pain who fulfil inclusion and exclusion criteria. Children scored their pain from 1 to 5 on arrival. Patients were either given Oramorph or nasal diamorphine administered by spraying a small volume of the drug up one nostril. Information collected included age, pain scores before drug administration and at 5, 10, 20, and 30 minutes after drug administration, ease of administration by staff and acceptability by child and parent. Results: 50 patients were randomised, but data were available for only 43 patients, 23 in the Oramorph arm and 20 in the nasal diamorphine arm. Both groups were comparable for age, ease of administration, acceptability to the child and the parent, and baseline pain level. Mean pain level started at 4.5 in the first 5-minute interval


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and declined to 2.7 in the last 10-minute interval. The most significant decrease in pain was detected during the first 5 minutes and was statistically significant in favour of diamorphine (1.2 v 0.6) (95% CI 0.04 to 1.3, p=0.03). There was no statistical difference in reduction of pain over the 10-20 minute period (0.48 v 0.29) (95%CI –0.18 to 0.6, p=0.31). Time to relief of pain (time taken to reduce level of pain from score of 5 to 2) was significantly in favour of diamorphine (p=0.02). 3.6 Uncontrolled studies in children Methodology Dose Diagnosis Results Communication Davies F, 2004 Retrospective,

uncontrolled Audit of efficacy and safety of IND in children

Single dose of IND (0.1 mg/kg in 0.2ml water delivered with 1mL syringe into ONE nostril

Pain requiring opiate analgesic

Reduction in pain scores from an average of 7.5 to 3 (n=32). Two children required additional Entonox (1 broken clavicle and 1 laceration) and 2 failed treatment and were recalled for general anaesthesia (both for suturing). No reports of drowsiness, respiratory depression or oxygen desaturation. Side effects were seen in 3 children – dizziness (n = 2) and nausea and vomiting (n = 1) all of which resolved within a few minutes.

Publication Gahir KK et al., 2005

Retrospective, uncontrolled Audit of first 6 months’ use of IND integrated care pathway for paediatric analgesia.

Assume single dose of IND 0.1mg/kg in 0.2ml sterile water with 1ml syringe into ONE nostril

Acute severe pain

British Association for Emergency Medicine (http:// www.emergencymed. org.uk/BAEM/) and the Scottish Intercollegiate Guideline Network (www.sign.ac.uk/guidelines/fulltext/58/evidence.html). The final INDICP incorporated inclusion and exclusion criteria, tasks to be performed, and their sequence and timescales

IND: intranasal diamorphine 3.7 ADULT Studies in other indications 3.7.1 Ward M et al. – Anaesthesia 2002; 57:44-81 Methodology Dose Diagnosi

s Results

Single centre, randomised controlled PCA 48 patients (24 IND / 24 IVD)

IND 1.0mg (~0.011mg/kga) in180μl water [assumed diluent] delivered by nasal spray OR IVD 0.5mg (~0.006mg/kgb) (both bolus doses with 3 minute lockout).

Hip or knee replacement. PCA after leaving recovery room

Significantly higher VAS pain scores in the IN group than those in the IV group both at rest (IN median 35.5 vs. IV median 20; p=0.030) and on movement (IN median 64 vs. IV median 50; p=0.016). But significantly higher incidence of vomiting for patients in the IV group (6) compared with the IN group (0) (p=0.022). At the doses studied, IN diamorphine appears to be less effective than IV diamorphine for PCA.

IND: intranasal diamorphine; IVD: intravascular diamorphine; PCA: patient controlled analgesia

http://www.emergencymed/�


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The dosing was quite low at only 0.01mg/kg. At similar doses IN diamorphine was less effective than IV. 3.7.2 Hallett A et al. - Anaesthesia, 2000; 55:532-29 Methodology Dose Diagnosis Results Publication Single centre,

open label PCA study Uncontrolled

IND 0.5mg (~0.6mg/kg using bodyweight of 70kg) diamorphine nasal spray with a lockout period of 3 minutes. Multiple dose

Non-emergency orthopaedic or gynaecological surgery in recovery for 24 hours

Satisfaction was reported as good or complete by 69% of patients and 69% of nurses. Pain relief was assessed as better than expected by 45% of patients and as better than normal by 50% of nurses. 79% of patients stated that they would be pleased to use patient-controlled IN diamorphine again and 89% of nurses would be happy for their patients to use it again. Sedation was uncommon and mild and there were no episodes of significant respiratory depression. 53% of patients reported no nausea and 74% did not vomit at any stage. There were 7 withdrawals, 4 due to problems with the device and 3 due to therapeutic problems. It was recommended that the nasal spray (different from the present one) is modified.

IND: intranasal diamorphine; PCA: patient controlled analgesia 3.8 Clinical studies in special populations / combined data Not applicable 3.9 Assessors’ overall conclusions on clinical efficacy 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.


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The data show 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) Even though the database to support the efficacy of diamorphine for relief of acute pain in children relates to approximately 432 (42 uncontrolled) subjects receiving diamorphine for the target indication at the proposed dose, study CP9703 (and its pilot study) is the only study where the methodology can be reliably assessed. 4 CLINICAL SAFETY 4.1 Introduction Diamorphine Hydrochloride for Injection is authorised in the UK (22 March 1993 (International Birth Date)) and Malta (1 October 2008). Post-marketing safety reports to cover the period since authorisations to date comprise three Periodic Safety Update Reports (PSURs) covering the periods: 01 February 1997 to 31 May 2002, 1 June 2002 to 31 May 2007 and 1 June 2007 to 31 May 2010 (PSUR1, PSUR2 and PSUR3, respectively). 4.2 STUDY DIA002 – Clinical Study Report General Study Title: An open label, single dose safety study of Diamorphine

Hydrochloride Nasal Spray (0.1 mg/kg) in children 2 - <16 Methodology Study Design Open label, prospective, uncontrolled study.


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Objectives Primary objective: To establish the safety of IN diamorphine in children from the time they receive Ayendi Nasal Spray until their discharge from the emergency department (normally up to 4 hours). Secondary objectives: To obtain information on the potential nasal irritation when diamorphine is delivered intranasally to children.


76

Study Population Inclusion criteria 1. Male or female aged from 2 – <16 years of age. 2. Suffering from suspected clinical fractures or trauma which requires immediate pain relief as part of their routine treatment. 3. To be administered diamorphine hydrochloride for pain relief by the attending physician. 4. Weight in range of 12 - 50 kg. 5. Parent(s) or legal guardian in attendance. 6. Parent(s)/legal guardian must be able and willing to provide written informed consent. Male or female aged from 2 – < 16 years of age, suffering from suspected clinical fractures or trauma and to be administered diamorphine hydrochloride for pain relief by the attending physician. Exclusion criteria 1. Presence of airway/respiratory problems. 2. Evidence or history of epistaxis. 3. Known allergy to opiate medication or any excipients of the nasal spray (benzalkonium chloride and disodium edetate (ethylenediaminetetraacetic acid; EDTA)). 4. Exposure to drugs known to interact with diamorphine in the preceding 7 days. 5. Exposure to opiate analgesia in the preceding 7 days. 6. Head injury or neurological problem. 7. Treatment with monoamine oxidase inhibitors in the previous 14 days. 8. Participation in a clinical study in the previous 30 days. 9. Subject trauma requiring cardiovascular resuscitation. 10. Females who are pregnant, lactating or planning to become pregnant Study Treatments Single dose (0.1mg/kg) safety study of Ayendi Nasal Spray “The IN spray device delivers the drug as a very fine mist into the richly vascularised nasal epithelium which negates the requirement in current practice for turning the child’s head from side to side after administering the diamorphine in drop form.” “The freeze dried powder is provided in a glass bottle along with a tube containing 10ml 0.5% preserved saline solution for reconstitution. Once the diamorphine has been reconstituted a snap-on actuator pump fitted with a paediatric nasal tip is attached and primed and the child receives two-four sprays of diamorphine into alternate nostrils according to their body weight. The nasal spray is designed as a multi-use product with replacement of the paediatric tip and priming between patients. The reconstituted spray remains stable at room temperature (below 25°C) for 14 days, so can remain in the controlled drug cabinet of the emergency department ready for immediate use (following two priming sprays).” In order to ensure that absorption took place through the nasal mucosa, rather than directly into the brain via the cribriform plate, the investigators were provided with additional instructions for administration of the nasal spray: - Ensure that the nasal spray is administered whilst the child is sitting in an upright

position.


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- Ensure that the nasal spray is not administered straight up the nose. Direct the nasal spray at a slight angle to ensure that the spray is directed at the nasal side wall (lateral nasal wall) rather than straight up.

Endpoints Primary endpoint: Safety Profile as measured by:

• AE category according to the current version of MedDRA. Secondary endpoints:

• Nasal irritation by classification and severity • Oxygen saturation • Respiratory rate • Heart rate (supine pulse rate) • Pupil dilation • Glasgow Coma Scores

Randomisation/blinding: not applicable Statistical methods (including pre-specified interim analyses or other looks at the data) Summary statistics for quantitative data were recorded as n, mean, standard deviation, %CV, minimum, median and maximum. For categorical data, frequency tables (showing n and %) were generated. Unless stated otherwise, data were to be summarised overall and by age group (age 2-11 years and age 12-<16 years), as appropriate. All safety evaluations (i.e. all evaluations) were based on the safety analysis population and were to be appropriately summarised. Results 226 unique patients (male and female) were screened, entered the study and were treated with Ayendi Nasal Spray – this was the safety population evaluated. One patient withdrew from the study as they needed surgery; 225 patients completed the study. To ensure the cohort was appropriately represented by age, patients were allocated to the following stratifications:

• Age 2 -11 years: planned 180 to 200 patients; 191 recruited • Age 12-<16 years: planned 45 to 50 patients; 35 recruited

All patients were included in the analysis set, safety population, as this was a safety study.


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Adverse events: - The incidence of TEAEs was 26.5% (95% CI: 20.9%-32.8%) and most events

were unremarkable.


79


80

• The majority (93%) of events were mild in severity. There were no severe or serious events. • The incidence of related AEs (89% of all TEAEs) was anticipated for the test product. All were known effects of the drug or route of administration, with the exception of three events in two patients (eye pruritus (1 child); pallor and feeling hot (1 child)) • The most commonly reported body system for AEs was respiratory, thoracic and mediastinal disorders with 45 patients reporting 53 events. The most common of these events included nasal discomfort (24(10.6%) patients) and sneezing (22 (9.7%) patients). Eleven children reported nervous system disorders (15 events), the most common event being dysgeusia (5 (2.2%) children). Nine children reported gastrointestinal disorders (11 events), the most common being vomiting (7 (3.1%) children). • The incidence of TEAEs related to local (nasal) irritation/tolerability was anticipated, with 20.4% (95% CI: 15.3% – 26.2%) of patients reporting 54 events, all mild except one moderate event and one of ‘unknown’ severity • There was no respiratory depression (in terms of clinically notable changes in vital signs) seen during the study that resulted in reporting as AEs. • There were three AE reports relating to CNS depression (reduced GCS), all were mild. Local tolerability: • There were 54 treatment-emergent AEs relating to nasal irritation reported by 46 patients in the safety population. This was anticipated. • 20.4 % of all patients reported at least one event; 19.9% of the younger children (2-11 years), and 22.9% of the older children (12-<16). • None of these events were serious or led to withdrawal or death of a patient. • All events reported were considered mild except one event (itching) reported as moderate in one patient, and one event (‘nasal irritation’) for which the severity was not recorded (listed as ‘unknown’); and all were considered to be related to treatment. • The most common classification was itching reported by 22 (9.7%) patients; all considered mild except one (moderate). Persistent and troublesome sneezing (mild) was reported by 9 (4%) patients. There were single reports of mild redness, and mild nasal discharge. The remainder of the events were classified as “Other” (19 (8.4%) patients). “Other” included instances where a patient experienced a single sneeze (i.e. sneeze, sneeze x 1, sneezed, sneezed once (all mild, and classified into preferred term “sneezing” in 14 patients)) following administration, or where irritation had not been classified but was entered as “nasal irritation” (four mild and one ‘unknown’ and classified into preferred term “nasal discomfort” in five patients). No patient reported local tenderness or swelling. Vital signs and Glasgow Coma Score (GCS): There were no clinically notable changes in vital sign values recorded during the study. Vital signs remained within the range that would normally be expected for a population of children reporting to emergency departments in pain and stress. No AEs were reported for any vital sign parameter measured during the study. Eight children had reduced GCS (lowest score was 13 out of a possible 15) following treatment. Three of these children had associated AEs recorded. All were mild, and considered to be related to the test product (possibly, probably, definite) and all but


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one was resolved within the study period. Overall (excluding those reported as AEs) any observed GCS changes were minimal and not considered to be clinically significant. The results of study DIA002 suggest that nasal irritation of mild severity will occur at an incidence of approximately 20% with use of Ayendi Nasal Spray. The rates are higher than that observed in the pivotal study CP9703 since they were more rigorously and specifically evaluated in DIA002. This frequency of nasal AEs with the proposed product is not dissimilar to that reported with Beconase Aqueous Nasal Spray, which is authorised for multiple dose use in children. The nature of the nasal irritation has been demonstrated to be tolerated, as indicated by the various acceptability data of IN diamorphine treatment compared to the other routes evaluated. In the pivotal study (CP9703) staff described the treatment as acceptable for 98% of IN diamorphine patients compared with 32% for IM morphine (p<0.001). In the Marzouk study, despite the nasal irritation in the IN diamorphine group, more of this parent group stated that they would be happy to repeat the treatment (73% IN diamorphine versus 49% Oramorph group, p<0.01). On the basis that the product is intended for single dose use, it is considered that the risk: benefit profile of the product with respect to the potential nasal irritation effects is acceptable. Table 61 (extract): Summary of data on nasal products authorised for use in children

Major protocol deviations There were 56 children with major protocol deviations (60 deviations). These children were not excluded from any of the analyses as this was a safety study. - Many of these (36) were due to insufficient safety observations. - Ten children were included in the study despite being ineligible: two without

parental consent; two children were too young (21 and 2 months old); one child was over 50.5 kg of weight; five children had received Oramorph in the ambulance

- Incorrect dosage: 13 children were underdosed. 12 were dosed in a lower weight band, one was dosed with a device that was not primed; one was overdosed with a resultant 0.206 mg/kg without suffering any AE.


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The statistical power of the study, with respect to the primary endpoint of detection of an AE in greater than 2% of patients, required a minimum sample of 150 patients. Thus, since 170 patients completed the study without major deviation and could be considered to be sufficiently evaluable from a safety perspective, this sample size criterion has been fulfilled. This study shows that one single administration of diamorphine IN did not result in a high incidence of AEs. This study highlights the difficulty in administering this product in the emergency department where it can be difficult to assess pain at entry, to take parent’s consent and to collect data. More importantly, there were a few incidences of the wrong dose being given or in association with other opioids. This has been taken into account in the Risk Management Plan. These events also show that this product should only be administered by practitioners who are familiar with the use of opioids in children. 4.3 Patient exposure The total patient exposure to Diamorphine Hydrochloride for Injection for the period 1 February 1997 – 31 May 2010 is 15,849,870 (adults and children by number of ampoules of diamorphine (all strengths) sold). There were no reports or pattern of reports that gave rise to concern in the three PSURs. Diamorphine is considered to be safe when used in accordance with the approved SmPCs. It is estimated that more than 100,000 children have now been treated in the UK with off-label IN diamorphine. The Applicant is not aware of any safety concerns or lack of efficacy raised by this off-label use.


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4.4 Demographics of study population

4.5 Deaths None reported. 4.6 Serious Adverse Events Only three serious AEs were reported across the studies, and all of these were from studies in children: - two patients administered IN diamorphine (both in the PK study conducted with the Applicant with the proposed product and both events due to a significant increased sedative effect (narcotic intoxication) causing prolongation of existing hospitalisation considered to be due to interaction of the diamorphine with concomitant medication (or procedures) used during the course of the general anaesthesia (DIA001)),


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- one patient administered IM morphine in the pivotal study [CP9703]. The safety data show that the risk of respiratory depression following administration of IN diamorphine is no greater than the risk following administration of marketed diamorphine currently available. The SmPC contains suitable information concerning the risk for respiratory depression in the paediatric population. 4.7 Adverse Events 4.7.1 Treatment-Emergent Adverse Event 4.7.1.1 Studies in children In the safety study DIA002, more events were reported in the younger age group (65 events) compared to the older age group (22 events). This was expected as there was a larger number of children in the younger age group. However, the percentage of patients experiencing an AE was slightly higher in the older age group (34.3% of patients reporting compared to 25.1% of younger patients reporting). The reason for this is unknown but could be due to the fact that older children are more likely to verbalise how they are feeling. There was no apparent relationship between incidence of AEs and age. From the clinical studies in children, the most commonly reported related events were nasal (nasal discomfort (irritation/itching/redness/ rhinorrhoea), sneezing, paraesthesia mucosal - in all cases of mild severity where reported (except one moderate event)), gastrointestinal (vomiting/nausea/abdominal pain), dizziness, dysgeusia and pruritus (including eye). There were less frequent reports of laryngitis, hypoxia and somnolence. Other events were reported in only one or two children. The main safety concern regarding the use of nasal diamorphine relates to local (nasal) tolerability. The nasal irritation observed with IN diamorphine is an expected reaction to administration of products to the nasal cavity as demonstrated by 12% of patients who received IN placebo (normal saline) in the Marzouk et al.study (2008A/B). It does not appear to be directly related to the volume administered nasally per se but just to exposure to the product in those sensitive to the drug, excipients or nasal administration in general. The severity of irritation, where reported, has been mild only, except for one moderately severe report. It is not considered to be unacceptable, as indicated by the various acceptability data of IN diamorphine treatment compared to the other routes evaluated. In the pivotal study (CP9703) staff described the treatment as acceptable for 98% of IN diamorphine patients compared with 32% for IM morphine (p<0.001). In the Marzouk study, despite the nasal irritation in the IN diamorphine group, more of this parent group stated that they would be happy to repeat the treatment (73% IN diamorphine versus 49% Oramorph group, p<0.01). The results of the safety study suggest that nasal irritation of mild severity will occur at an incidence of approximately 20% with use of Ayendi Nasal Spray. However, as the study by Marzouk et al. is only available as an abstract its methodology cannot be assessed.


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4.7.1.2 Studies in adults The four studies in adults in the defined safety dataset are all published studies for which limited safety data are available only. The key safety findings from these four studies conducted in adults treated with a variety of doses of IN diamorphine are summarised in Module 2.7.4, Table 2.1.2. There were no unexpected AEs reported. Overall, the studies showed that diamorphine administered at single doses in the range of 0.5mg – 40 mg (~0.007 mg/kg – 0.6mg/kg) by IN (n=72), 6mg (~0.08mg/kg) by IM (n=6) and 0.5mg (~0.006mg/kg (n=24)) or 40mg (~0.6mg/kg (n=4)) by IV administration is safe and well tolerated with a comparable safety profile between the three different routes of administration. 4.7.2 Treatment-related treatment-emergent adverse events Tolerability: Tolerability of the proposed nasal product was specifically evaluated in children in the three studies conducted by the Applicant by monitoring of nasal irritation and, in the pivotal study only, by the child’s reaction to treatment administration (CP9703; DIA001; DIA002). In all three of these studies, the maximum volume administered per nostril was 100μl, which reflects the proposed posology. In the pivotal study (CP9703), the maximum concentration of diamorphine in solution was similar but slightly higher than that proposed (52.6mg/ml vs. 14.4mg/ml and 32.0mg/ml) but the diluent (0.5% preserved saline) was the same. Thus, nasal irritation data from these studies reflect that expected from marketed use. Of the published studies in children and adults, only the single blind, double dummy controlled study comparing IN diamorphine and oral morphine in children specifically reported on nasal irritation (Marzouk et al., 2008A/B). The IN dose of 0.1mg/kg was administered with a nasal atomizer as a fixed volume of 200ml in normal saline into one nostril. The study was a double dummy design and thus included administration of IN placebo (200ml normal saline). Acceptability: Acceptability of IN diamorphine was statistically significantly better than either IM or oral morphine in three of the four controlled studies in children (CP 9703; Wilson et al., 1997; Marzouk et al. 2008A) and comparable to oral morphine in the fourth controlled study (Sajjanhar 2007).


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The following summary table shows the total number of treatment-emergent SAEs and AEs across the clinical development. Summary of all treatment-emergent AEs and serious AEs by MedDRA System Organ Class and preferred term (safety populations) – studies conducted by the applicant

System organ classa Preferred term

COMPARATOR NASAL DIAMORPHINE CP9703 IM Morphine (N=203) Patients (%)

CP9703 Nasal diamorphine (N= 204) Patients (%)

DIA001 Nasal diamorphine (N=56) Patients (%)

DIA002 Nasal diamorphine (N=226) Patients (%)

TOTAL Nasal diamorphine Across Studies (N=486) Patients (%)

Patients with any TEAE 37 (18.2) 50 (24.5) 23 (41.1) 60 (26.5) 133 (27.4) Respiratory, thoracic and mediastinal disorders

Nasal discomfortb 2 (1.0) 27 (13.2) 5 ( 8.9) 24 (10.6) 56 (11.5) Sneezing 0 0 0 22 (9.7) 22 (4.5)

Epistaxis 0 0 5 ( 8.9) 1 (0.4) 6 (1.2) Laryngitis 0 6 (2.9) 0 0 6 (1.2) Hypoxia 1 (0.5) 3 (1.5) 0 0 3 (0.6)

Hiccups 0 0 0 1 (0.4) 1 (0.2) Nasal mucosal disorder 0 0 0 1 (0.4) 1 (0.2) Rhinorrhoea 0 0 0 1 (0.4) 1 (0.2) Nervous system disorders Dizziness 0 6 (2.9) 1 (1.8) 4 (1.8) 11 (2.3) Dysgeusia (bitter taste) 0 3 (1.5) 0 5 (2.2) 8 (1.6) Somnolence 0 0 0 3 ( 1.3) 3 (0.6) Paraesthesia mucosal 1 (0.5) 1 (0.5) 0 2 (0.9) 3 (0.6) Depressed level of consciousness 0 0 0 1 (0.4) 1 (0.2) Nervousness 0 1 (0.5) 0 0 1 (0.2) Headache 1 (0.5) 0 1 (1.8) 0 1 (0.2) Gastrointestinal disorders Vomiting 1 (0.5)c 1 (0.5) 6 (10.7) 7 (3.1) 14 (2.9) Nausea 3 (1.5) 4 (2.0) 3 (5.4) 3 (1.3) 10 (2.1) Abdominal Pain 0 2 (1.0) 0 0 2 (0.4) Haematemesis 0 0 1 (1.8) 0 1 (0.2) Skin and subcutaneous tissue disorders Pruritus 4 (2.0) 6 (2.9) 0 2 (0.9) 8 (1.6)

Irritation at injection site 22 (10.8) 0 0 0 0 Injury, poisoning and procedural complications

Procedural pain 0 0 12 ( 21.4) 0 12 (2.5) Narcotic intoxication 0 0 2 (3.6)d 0 2 (0.4) Eye disorders Eye pruritus 0 0 0 1 (0.4) 1 (0.2) Conjunctivitis 0 1 (0.5) 0 0 1 (0.2) General disorders and administration site conditions

Pyrexia 0 0 0 2 (0.9) 2 (0.4) Feeling hot 0 0 0 1 (0.4) 1 (0.2) Mouth dry 0 1 (0.5) 0 0 1 (0.2)

Leg pain 2 (1.0) 0 0 0 0 Othere 2 (1.0) 0 0 0 0

Vascular disorders Pallor 0 0 0 1 (0.4) 1 (0.2) Musculoskeletal Disorders

Skeletal pain 1 (0.5) 0 0 0 0 Psychiatric disorders

Anxiety 0 0 0 1 (0.4) 1 (0.2)


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a MedDRA dictionary version 13.0 was used for coding AEs. b Irritation /itching/redness/rhinorrhea. c One patient (6029) experienced a serious AE (moderate, repeated vomiting) requiring hospitalization. d Two patients (1001 and 1010) experienced a serious AE ( both severe, narcotic intoxication). e Unhappy with administration of analgesia, O2 saturation probe applied too tightly. Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened after first administration of nasal spray If a patient experienced more than one TEAE, the patient is counted once for each system organ class (SOC) and once for each preferred term (PT). SOCs are ordered by decreasing frequency of the total number of patients with TEAEs, and PTs are ordered within a SOC in decreasing frequency of the total number of patients with each TEAE. N = the number of patients in the population. (%) = Patients/N*100. This table forms the basis of section 4.8 of the SmPC. 4.8 Monitoring in clinical studies conducted by the applicant Table 63-1 provides details of the monitoring of children following administration of IN diamorphine in the three studies conducted by the Applicant. In CP9703 patients were monitored for up to 30 minutes post administration only. In the DIA001 and DIA002 studies patients were to be monitored until discharge from the surgical day centre and emergency department respectively. A minimum discharge time was not specified as sites were expected to discharge patients in accordance with routine practice. 95% and 91% of patients were monitored for over 1 hour in DIA001 and DIA002 respectively. The College of Emergency Medicines’ Clinical Effectiveness Committee’s “Guideline for the Management of Pain in Children (CEM 2010)” states that a child who has had IN diamorphine only requires monitored observation for 20 minutes. Table 63-1 Frequency of Monitoring Observations as per the Applicant Study Protocols

The SmPC advises that patients should be monitored for 30 minutes following administration of IN diamorphine. This is acceptable.


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4.9 Discontinuation due to adverse events No discontinuation due to AE was reported. As diamorphine IN was used once only, discontinuation due to AEs is irrelevant. 4.10 Laboratory findings No data was submitted by the applicant. 4.11 Safety in special populations 4.11.1 Elderly Not applicable 4.11.2 Pregnancy/lactation Details on use in pregnancy and lactation are unchanged from the current SmPC for the approved injectable product. 4.11.3 Developmental effect in children This product is for single use only. No long-term effect is expected in children. 4.12 Drug-specific safety considerations 4.12.1 Overdose, potential for dependence, rebound and abuse Overdose Details on overdose are unchanged from the current SmPC for the approved injectable product. Drug abuse As stated on the approved injectable product SmPC, 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. However, Ayendi Nasal Spray is intended as a single dose product for relief of acute pain in children and it will not be self-administered. Thus, dependence potential is considered to be not significant. Further details on the abuse potential are addressed in the Risk Management Plan. Withdrawal and rebound Not applicable for a single dose product. 4.12.2 Nasal irritation Although nasal irritation was evaluated in the pivotal study, data were not collected in a systematic way. Irritation at the site of administration was assessed by staff at the time of treatment administration. It was then evaluated ad hoc at later timepoints during the study just by asking patients if they had any irritation rather than specifically assessing the site of administration. Details of the particular type of nasal irritation were not documented. Therefore, study DIA002 was designed to collect


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more detailed information on the nasal effects of the product. The nasal cavity was examined at baseline (pre-dose) and then for clinically relevant changes every 30 minutes following diamorphine administration. Any local clinically relevant changes were recorded as AEs and classified by type of irritation (persistent and troublesome sneezing, redness, itching, local tenderness, swelling, nasal discharge and/or other) and severity. Nasal irritation (manifested as nasal discomfort (irritation/itching/redness/ rhinorrhoea), sneezing, paraesthesia mucosal) does occur in some children following IN diamorphine administration but where recorded it has been described as mild in all cases, except one report of moderately severe itching. The nasal irritation does not appear to be directly related to the volume administered nasally per se but just to exposure to the product in those sensitive to the drug, excipients or nasal administration in general.


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In addition, the pivotal study demonstrated that tolerability (assessed by staff evaluation of reaction to treatment administration) was significantly better for the IN diamorphine group compared to IM morphine (P<0.001). Also, acceptability of IN diamorphine was statistically significantly better than either IM or oral morphine in three of the four controlled studies in children (CP 9703; Wilson et al., 1997; Marzouk et al., 2008A) and comparable to oral morphine in the fourth controlled study (Sajjanhar 2007). 4.12.3 Respiratory, CNS and other vital signs – somnolence In general, safety monitoring in the majority of the studies accounted for the known effects of opiates and included parameters for respiratory and CNS depression (e.g. oxygen saturation level, respiratory rate, heart rate, temperature, pupil diameter, GCS and/or other vital signs). 4.13 Safety related to interactions Any potential interactions are stated in the SmPC. 4.14 Post marketing experience Diamorphine is an established drug with recognised effects. From an exposure of 15,849,870 (adults and children by number of ampoules of diamorphine (all strengths) sold) during the period 1 February 1997–31 May 2010 very few AEs were reported to the MA Holder: only six serious, unexpected and one non-serious, unexpected (sleep-wake cycle disturbed) AEs were reported. There were no reports or pattern of reports that gave rise to concern in the three PSURs issued since the original UK authorisations of Diamorphine Hydrochloride for Injection. Diamorphine is considered to be safe when used in accordance with the approved SmPCs. Literature searches were conducted in support of the PSURs which focussed on establishing whether the SmPCs reflected current knowledge. On that basis some modifications for incorporation into the original approved SmPCs were recommended in the course of Marketing Authorisation maintenance. Summary tabulation of serious, unexpected reports for diamorphine reported between February 1997 and 31 May 2010

4.15 Proposals for post marketing surveillance/studies None was proposed.


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4.16 Assessor’s overall conclusions on clinical safety The safety profile of Ayendi Nasal Spray has been well characterised in the clinical studies conducted by the applicant and in the published literature. Suitable safety information is included in product literature and an acceptable risk management plan is in place for these products. These products are, therefore, considered to have an acceptable level of safety. 5 EXPERT REPORTS The clinical overview, dated December 2011, comprises 48 publications up to the year 2011. The clinical overview is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. 6 PharMacovigilance – PSUR – RMP 6.10 Detailed description of the Pharmacovigilance system The Pharmacovigilance system as described by the applicant fulfils the legislative requirements. 6.11 PSUR The PSUR cycle is appropriate. 6.12 RMP A Risk Management Plan (RMP) for Ayendi Nasal Spray has been submitted in accordance with the EU RMP template in support of the proposed indication of relief of acute pain in children. These products should only be used in emergency departments and should be administered only by practitioners experienced in the prescription of opioids in children. SAFETY SPECIFICATION Module SI: Epidemiology of the indication and target population Diamorphine is not currently available as an intra-nasal formulation in the UK. The Applicant has provided bibliographical references from which it appears that there is significant off-label use of intra-nasal diamorphine in emergency departments in paediatric patients. It is estimated that following authorisation of this intra-nasal product, approximately 120,000 children in the UK will be treated with intra-nasal diamorphine annually in the UK. Module SII: Non-clinical part of the safety specification No non-clinical studies were conducted during the development of this intra-nasal diamorphine product.


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Module SIII: Clinical trials exposure A tabulated summary of all studies (both controlled and uncontrolled) conducted with intra-nasal diamorphine was provided. Study Study population Controlled Total Intra-nasal diamorphine CP9703 405 202 Wilson et al. 1997 51 29 Sajjanhar et al. 2007 43 20 Marzouk et al. 2008 244 124 Total controlled 743 375 Uncontrolled Davies 2004 - 42 Gahir et al. 2006 - Not stated All the studies were conducted in the UK and patients were treated with a single dose of 0.1 mg/kg intra-nasal diamorphine for acute pain relief. Patients were children with traumatic injuries (mainly limb fractures) presenting to emergency departments. Module SIV: Populations not studied in clinical trials A satisfactory discussion of populations not studied in clinical trials has been provided. The section includes the effect of exclusion criteria in the clinical trial development plan. The Applicant has adequately discussed the exclusion criteria which remain as contraindications and those that do not. Module SV: Post-authorisation experience The findings of the safety study conducted by the Applicant to investigate events of nasal irritation are presented in this section. Module SVI: Additional EU requirements for the safety specification Potential for harm from overdose The Applicant considers that the potential for overdose with Ayendi Nasal Spray is considerably less compared to IV or IM administration of diamorphine. This is because the nasal spray is to be reconstituted before use with a fixed amount of diluent and is intended for administration as an acute dose. Potential for transmission of infectious agents The Applicant acknowledges the risk of transmission of infectious agents if the nasal tips are not changed between patients. Potential for misuse for illegal purposes Whilst diamorphine has a known potential for misuse, Ayendi before and after re-constitution will be stored as a controlled drug which should minimise any such risks.


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Potential for medication errors During the development phase of Ayendi Nasal Spray, the following potential reasons for medication error were identified:

• Under-dosing due to lack of priming at reconstitution (occurred once) • Under-dosing due to lack of priming between patient use (occurred on a number

of occasions in different departments) • Overdosing due to priming into the patients nose (occurred once) • Overdosing or under-dosing due to patient weight being estimated incorrectly • Overdosing or under-dosing due to healthcare administrator misreading dosing

chart The Applicant considers that instructions for use, provided as a cut-off section for healthcare professionals in the Patient Information Leaflet, should provide adequate information to minimise these errors. The two different strengths of the product are differentiated by labelling colour and text according to the current colour convention used for diamorphine vials. Specific Paediatric Issues The Applicant has been advised by the MHRA that the product development is exempt from the requirement of a Paediatric Investigation Plan as the application is submitted under Article 10 of Directive 2001/83/EC. Module SVII: Identified and potential risks Details of important identified and potential risks The known risk of dependence and tolerance following repeated administration of diamorphine is considered irrelevant by the Applicant, as this intra-nasal formulation is designed for single administration. Other general precautions of use for opioids are presented in this section, e.g. the need for caution or reduced dose in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, severe inflammatory or obstructive bowel disorders, hypotension, shock, convulsive disorders, adrenal insufficiency or debilitated patients. Identified and potential interactions including food-drug and drug-drug interactions Known interactions of diamorphine are presented in this section, including alcohol, anaesthetics, anti-arrhythmics, CNS depressants, and anti-muscarinic agents. Module SVIII: Summary of safety concerns All safety concerns are adequately summarised. PHARMACOVIGILANCE PLAN Routine and additional pharmacovigilance activities No additional pharmacovigilance activities are proposed by the Applicant.


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RISK MINIMISATION MEASURES Additional risk minimisation activities The proposed additional risk minimisation measures are focused on the potential for abuse and misuse of the product. The Applicant acknowledges that the potential for abuse cannot be ruled out but notes that tests with a placebo product have demonstrated that it is very difficult to administer more than four sprays (two to each nostril), after which the product will trickle out of the nostril or down the back of the throat. The proposals by the Applicant are acceptable. The Applicant has also committed to conduct a post-authorisation safety study (PASS; DIA003) be undertaken to evaluate the practical usage of the product. This observational study of children receiving prescribed Ayendi Nasal Spray for severe acute pain in hospital emergency departments will assess patterns of use, particularly in relation to aspects that may have an impact on the safety of the product. Ayendi Nasal Spray will be administered to the patient, in accordance with the SmPC, although all patients who receive Ayendi Nasal Spray will be considered for study entry. Four hundred patients will be recruited from a minimum of twenty sites which will be selected to ensure stratification to include geographical coverage, department size, experience of using diamorphine and combined or separate paediatric emergency unit. 7 PRODUCT LITERATURE All product literature is acceptable and emphasis the fact that the nasal spray is for children only, in the emergency department, for severe acute pain. 8 OVERALL CONCLUSION The grant of Marketing Authorisations is recommended.


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OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Ayendi 720 microgram/actuation Nasal Spray and Ayendi 1600 microgram/actuation Nasal Spray are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. CLINICAL Pharmacokinetics The study showed that the pharmacokinetic parameters for IN diamorphine were similar to those for IM diamorphine. The rate and extent of absorption after IN administration was not significantly different to that seen in currently marketed IM diamorphine products. Efficacy The pivotal efficacy 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 than morphine delivered intramuscularly. Safety The products have been shown to have an acceptable safety profile in the studies conducted for these applications. Suitable safety information is included in product literature and an acceptable risk management plan is in place for these products. PRODUCT LITERATURE The SmPC, PIL and labelling are acceptable. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with diamorphine products is considered to have demonstrated the therapeutic value of the compound and the clinical efficacy study conducted by the applicant confirm that the nasal sprays have an acceptable level of efficacy. The benefit/risk balance is, therefore, considered to be positive.


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PL 29831/0465-0466

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation application on 22 December 2011.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 18 January 2012.

3 Following assessment of the application and consideration of application by the Chemistry, Pharmacy and Standards subcommittee and the Commission on Human Medicines in March 2012 the MHRA requested information relating to the quality dossier on 15 August 2012, the non-clinical dossier on 20 August 2012 and the clinical dossier on 12 September 2012. The application was also considered by PEAG on 27 February 2013 and the Commission on Human Medicines in March 2013.

4 The applicant responded to the MHRA’s requests providing further information on the dossier on 24 May 2013.

5 Following assessment of the application the MHRA requested information relating to the clinical dossier on 26 June 2013.

6 The applicant responded to the MHRA’s request providing further information on the dossier on 16 July 2013.

7 The applications were granted on 18 October 2013.


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SUMMARY OF PRODUCT CHARACTERISTICS In accordance with Directive 2010/84/EU, the SmPCs for products granted Marketing Authorisations at a national level are available on the MHRA website.


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PATIENT INFORMATION LEAFLET

In accordance with Directive 2010/84/EU, the PILs for products granted Marketing Authorisations at a national level are available on the MHRA website.


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LABELLING Ayendi 720 microgram/actuation Nasal Spray Labels:


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Carton:


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Ayendi 1600 microgram/actuation Nasal Spray Labels:


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Carton:


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ukpar table of contents - gov.uk · ukpar . table of contents lay summary ... spray was compared...

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